Gastroenterology and Endoscopy News by McMahon Group

1978 —

35th Anniversary — 2013

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

DDW 2013

Endoscopy Spares Some From PPIs BY TED BOSWORTH ORLANDO, FLA.—Data on two endoscopic procedures for treating gastroesophageal reflux disease (GERD) show that the procedures are capable of eliminating, or greatly reducing, dependence on proton pump inhibitor (PPI) therapy. Findings were presented at the 2013 Digestive Disease Week meeting. see Antireflux Procedures, page 16

For IBD, ‘Decade of Immunomonitoring’ BY DAVID WILD ORLANDO, FLA.—An increasing number of studies indicate that a triad of measurable variables—including serum drug levels, levels of antibodies to certain drugs and mucosal healing—can help clinicians optimize the safety and efficacy of biologic treatments in patients with inflammatory bowel disease (IBD). see Immunomonitoring, page 13

Prevalence of Celiac Disease Not Reflected in Diagnosis Rate BY MONICA J. SMITH NEW YORK K—Despite a reputation for rampant medical testing in the United States, the diagnosis rate for celiac disease is far lower than the disease’s estimated prevalence. “The fact of the matter is that most U.S. patients with celiac disease are undiagnosed,” said Benjamin Lebwohl, MD, MS, who spoke on the topic at the Intestinal Immune-Based Inflammatory Diseases Symposium, held at Columbia University Medical Center, New York City, in March. “We know from multiple seroprevalence studies that 0.7% to 1% of individuals in this country have celiac disease. Yet, from the studies that also ask patients, ‘do you have a diagnosis of celiac disease,’ the majority was not diagnosed.” Dr. Lebwohl, who is assistant professor of clinical medicine and epidemiology at the Celiac Disease Center, Columbia University, New York City, discussed

several aspects surrounding celiac disease that he and his colleagues have been studying that may shed some light on why some diagnoses are missed.

Falling Short on Biopsy Specimens The diagnosis of celiac disease requires an see Diagnosis, page 10

I N S I D E

Patient Satisfaction and Loyalty Key To Maintaining Competitive Practice

EXPERTS’ PICKS The Best of Digestive Disease Week (DDW): Part 3 Experts share their favorite abstracts from the 2013 DDW meeting .............................................................................................. page 20

BY MONICA J. SMITH BOSTON—At this year’s annual GI Roundtable meeting, held in Boston in March, approximately 250 gastroenterologists, gastroenterology nurses and practice managers gathered to explore issues surrounding health care reform and the future of gastroenterology. The meeting’s roster included a bevy of speakers, but a talk that seemed especially

Ronnie Fass, MD

Benjamin Lebwohl, MD, MS

Randy S. Longman, MD, PhD

see Patient Satisfaction, page 30 PRINTER-FRIENDLY VERSION AVAILABLE AT WEBSITE.COM

Endoscopic Eradication Therapy for

CLINICAL REVIEW

Barrett’s Esophagus SHREYAS SALIGRAM MD, MRCPA,B (1, 2) PRASHANTH VENNALAGANTI MDA (1) PRATEEK SHARMA MDA,B (1, 2)

see insert between pages 18 and 19

Department of Veterans Affairs Medical Center Kansas City, Kansas b University of Kansas School of Medicine Kansas City, Kansas

arrett’s esophagus is the precursor lesion to esophageal

Endoscopic Eradicationn Therapy in Barrett’s Esophagus

adenocarcinoma, which if diagnosed at an invasive stage is associated with

a significant morbidity and mortality. Surgery was the mainstay of treatment

for patients with Barrett’s associated high grade dysplasia and adenocarcinoma; however, surgery in itself carries significant morbidity. There has been tremendous progress in the minimally invasive treatment of Barrett’s esophagus in the last decade.

By Shreyas Saligram, MD, MRCP, Prashanth Vennalaganti, MD, and Prateek Sharma, MD

The premise to be aggressive in treating high grade dysplastic Barrett’s esophagus and early stage of adenocarcinoma is to prevent progression to advanced stage of cancer. Most interventional endoscopists are comfortable in treating high grade dysplasia and intra-mucosal esophageal cancer. Recently there has been emerging data in treating early sub-mucosal cancer in Barrett’s esophagus at one end and low grade dysplasia at the other. New techniques in treating Barrett’s esophagus are constantly evolving with renewed interest in arresting the slide of the fastest growing cancer in the western world. The aim of this article is to review the different modes and strategies on endoscopic treatment of Barrett’s esophagus with emphasis on newer techniques.

Introduction Barrett’s esophagus is defined as displacement of squamocolumnar junction by intestinal metaplasia (goblet cells) proximal to gastro esophageal junction.

The overall population prevalence is estimated at 1.6% 1 with an annual incidence of 62 per100,000. 2 In patients with Barrett’s esophagus, the annual incidence of esophageal adenocarcinoma is reported to be between 0.12 and 0.5%. 3-6 Intestinal metaplasia can have a histological transformation from no dysplasia to low grade dysplasia (LGD), high grade dysplasia (HGD) and eventually to esophageal adenocarcinoma. 7Patients with HGD have the highest tendency to progress to esophageal adenocarcinoma. Therefore, endoscopic eradication therapy is increasingly used to treat HGD and early esophageal adenocarcinoma to decrease the progression to invasive disease. The data extraction from national cancer institute’s surveillance, epidemiology, and end results suggested a six fold increase in incidence of esophageal adenocarcinoma in 2001 and is considered as the fastest rising cancer in USA. 8 The aim of this article is to review the current modalities of endoscopic eradication

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • S E P T E M B E R 2 0 1 3

Clean Freak

Effective cleansing in all bowel segments, including the right colon Percent of patients with NO RESIDUAL STOOL by colon segment1* Colon Segment

Cecum Ascending Descending Transverse Sigmoid/Rectum

SUPREP Bowel Prep Kit split-dose regimen (n=63) 91%† 91%† 92% 92% 94%

4-Liter Prep same-day regimen‡ (n=66)§ 67% 69% 84% 82% 81%

*This clinical trial was not included in the product labeling. †P≤0.02 vs 4-Liter Prep. Statistically signiﬁcant difference. ‡ Standard 4-Liter Prep (sulfate-free PEG electrolyte lavage solution). § One patient was excluded who took the preparation but refused colonoscopy. Three patients had one or more segments that could not be evaluated because the procedure was stopped for poor preparation before cecal intubation.

SUPREP Bowel Prep Kit achieved “excellent” bowel cleansing in patients based on investigator grading1,2 • Split-dose regimens of SUPREP Bowel Prep Kit and MoviPrep®|| were equivalent in colon cleansing2 • Signiﬁcantly more patients had “excellent” preps with SUPREP Bowel Prep Kit compared to MoviPrep (63% vs 53%, respectively; P=0.043¶)2 MoviPrep (PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution) is a registered trademark of Salix Pharmaceuticals, Inc. ¶ Statistically signiﬁcant difference. ||

Important Safety Information SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution is an osmotic laxative indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function or electrolytes. Use can cause temporary elevations in uric acid. Uric acid fluctuations in patients with gout may precipitate an acute flare. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to a final volume of 16 ounces and ingestion of additional water as recommended is important to patient tolerance. Please see brief summary of Prescribing Information on adjacent page.

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

The Radiology Report: Help or Hindrance? Frederick L. Greene, MD, FACS Clinical Professor of Surgery UNC School of Medicine Chapel Hill, North Carolina Some of the more seasoned readers of this publication may remember a time when pathology reports resulting from colectomies, gastrectomies, hepatectomies, lobectomies or pneumonectomies,

mastectomies and esophagectomies for malignancies were characterized by several pages of dictation that necessitated careful perusal just to discern the important findings regarding tumor extent, lymph node involvement, margin status, tumor size and other indicators that would reflect the completeness of the surgical resection and the need for possible additional therapy. Not only did these reports present a non-uniform

approach to pathologic assessment, but the elements contained in these reports also would be very disparate when any quality indicators were applied. Several years ago, the American Joint Committee on Cancer, the cancer committee of the College of American Pathologists and the American College of Surgeons’ Commission on Cancer (COC) Accreditation Program spearheaded a unified effort to introduce a

SUPREP Bowel Prep Kit. Because the quality of cleansing matters. • Effective bowel cleansing2,3 in all bowel segments1

• Low volume

• ACG-recommended split-dose regimen

• No sodium phosphate

References: 1. Rex DK, DiPalma JA, Rodriguez g R, McGowan J, Cleveland M. A randomized clinical study comparingg reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage g solution as ppreparation p for colonoscopy. py Gastrointest Endosc. 2010;72:328-336. 2. DiPalma JA, Rodriguez g R, McGowan J, Cleveland MvB. A randomized clinical study evaluatingg the safety and efﬁcacy of a new, reduced-volume, oral sulfate colon-cleansing preparation for colonoscopy. Am J Gastroenteroll. 2009;104:2275-2284. 3. SUPREP Bowel Prep Kit [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2010.

BRIEF SUMMARY: Before pprescribing, g please p see full Prescribing Information and Medication Guide for SUPREP® Bowel Prepp Kit (sodium sulfate, ppotassium sulfate and magnesium g sulfate) Oral Solution. INDICATIONS AND USAGE: An osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. CONTRAINDICATIONS: Use is contraindicated in the followingg conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allergies g to components p of the kit. WARNINGS AND PRECAUTIONS: SUPREP Bowel Prepp Kit is an osmotic laxative indicated for cleansingg of the colon as a ppreparation p for colonoscopy py in adults. Use is contraindicated in the followingg conditions: ggastrointestinal (GI) obstruction, bowel pperforation, toxic colitis and toxic megacolon, g ggastric retention, ileus, known allerggies to components of the kit. Use caution when pprescribingg for patients p with a historyy of seizures, arrhythmias, y impaired p ggagg reflex, regurgitation g g or aspiration p , severe active ulcerative colitis, impaired p renal function or ppatients takingg medications that mayy affect renal function or electrolytes. y Pre-dose and post-colono p scopy ECG’s should be considered in ppatients at increased risk of serious cardiac arrhythmias. y Use can cause temporary p y elevations in uric acid. Uric acid fluctuations in ppatients with ggout mayy pprecipitate p an acute flare. Administration of osmotic laxative products p mayy pproduce mucosal aphthous p ulcerations, and there have been reports of more serious cases of ischemic colitis requiring q g hospitalization. p Patients with impaired p water handlingg who experience p severe vomitingg should be closelyy monitored includingg measurement of electrolytes. y Advise all patients p to hydrate y adequately q y before, during, g and after use. Each bottle must be dilutted with water to a final volume of 16 ounces and ingestion g of additional water as recommended is important p to patient p tolerance. Pregnancy: g y Pregnancy g y Category g y C. Animal reproduction p studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive p capacity. p y Pediatric Use: Safetyy and effectiveness in ppediatric ppatients has not been established. Geriatric Use: Of the 375 ppatients who took SUPREP Bowel Prepp Kit in clinical trials, 94 (25%) were 65 yyears of age g or older, while 25 (7%) were 75 yyears of age g or older. No overall differences in safety or effectiveness of SUPREP Bowel Prep Kit administered as a split-dose p (2-day) y regimen g were observed between geriatric g patients p and yyounger g patients. p DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of SUPREP mayy not be absorbed completely. p y ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal ppain, nausea, vomitingg and headache. Oral Administration: Split-Dose p (Two-Day) y Regimen: g Earlyy in the eveningg pprior to the colonoscopy: ppy Pour the contents of one bottle of SUPREP Bowel Prepp Kit into the mixingg container provided. Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Consume onlyy a light g breakfast or have onlyy clear liquids q on the dayy before colonoscopy. py Dayy of Colonoscopy py (10 to 12 hours after the eveningg dose): Pour the contents of the second SUPREP Bowel Prepp Kit into the mixingg container provided. p Fill the container with water to the 16 ounce fill line, and drink the entire amount. Drink two additional containers filled to the 16 ounce line with water over the next hour. Complete all SUPREP Bowel Prep Kit and required water at least one hour prior to colonoscopy.y Consume only clear liquids until after the colonoscopy. STORAGE: Store at 20°-25°C (68°-77°F). Excursions permitted between 15°-30°C (59°-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.suprepkit.com ©2012 Braintree Laboratories, Inc.

SU-13280T

January, 2012

synoptic and an element-specific strategy for pathology reports that reflected findings after operative resection in adult patients with cancer. This standardized approach to pathology reporting has been disseminated and is now required as a quality benchmark for the approximately 30% of hospitals in the United States that are accredited by the COC. Using the success realized in the approach to pathology reports, the time has come to develop a similar strategy for imaging reports, especially relating to the patient with cancer. Current reports by our radiology colleagues reflect a wide spectrum of helpfulness and inclusivity of pertinent features that are essential for diagnosis, multidisciplinary discussions and eventual surgical treatment planning. The need for a unified methodology and synoptic approach to these reports is especially desirable in the era of neoadjuvant treatment for cancers of the rectum, pancreas, esophagus, breast, liver, and head and neck—sites where accurate assessment and complete reporting are critical to eventual surgical management. A recent report (Al-Sukhni E et al. Ann Surg Oncoll 2013,20:1148-1155) indicated that only approximately 40% of magnetic resonance imaging (MRI) reports contain complete information regarding nodal assessments, circumferential resection margin information and the clinical T category of the primary rectal tumor—elements that are critical in the management of patients with rectal cancer. The realization of a synoptic format for imaging reports (MRI, computed tomography, positron emission tomography, ultrasound, etc.) obviously requires a national and international strategy, and the engagement of surgical, oncologic and radiologic organizations and accrediting bodies (American College of Radiology, COC). Those of you who manage patients with solid malignancies also can accomplish a great deal toward this goal on the local level through ongoing dialogues with radiology colleagues when reviewing imaging in the radiology suite, at multidisciplinary treatment planning sessions and traditional tumor conferences. Continue to stress the importance of including all the elements needed and the benefit of reporting these in a synoptic fashion just as our pathologists are currently doing. Additionally, we also can begin a critical review of imaging reports by our hospital cancer committees to assess the completeness and readability of these missives at our own institutions. We need to begin a concentrated effort to assure that oncologic imaging is meaningful and that the reports generated from these studies are complete, readable and relevant for us and for our patients with cancer. ■

OPINION

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2013

Computer-Assisted Health Care Delivery Re: â&#x20AC;&#x153;Sedasys Approved; Who Will Use It?â&#x20AC;? by Monica J. Smith. Gastroenterology & Endoscopy News July 2013;64:1,16,18-19.

gastroendonews.com

The Independent Monthly Newspaper for Gastroenterologists

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DDW 2013

New Colonoscope Offers Sweeping, 330-Degree Views of the Colon

Simeprevir Shines In Hep C Trial

Fuse Generates â&#x20AC;&#x2DC;Hugeâ&#x20AC;&#x2122; Interest at DDW Meeting BY DAVID WILD ORLANDO, FLA.â&#x20AC;&#x201D;Of patients who relapsed following treatment with peginterferon (PEG-IFN)based therapy for chronic genotype 1 (GT1) hepatitis C virus (HCV) infection, 80% experienced rapid and sustained virologic response with triple therapy including PEG-IFN-2a, ribavirin (RBV) see Simeprevir, page 20

Sedasys Approved; Who Will Use It?

BY AUDREY ANDREWS

BY MONICA J. SMITH On May 3, the FDA granted premarket approval for a computer-assisted sedation delivery system that allows administration of propofol (Diprivan, AstraZeneca) without an anesthesiologist for patients who are not considered to need one. Some are heralding the new see Sedasys, page 16

ORLANDO, FLA.â&#x20AC;&#x201D;A new colonoscope that provides three simultaneous full-spectrum images of the colon detected significantly more adenomasâ&#x20AC;&#x201D;and missed significantly fewerâ&#x20AC;&#x201D;in findings presented at the 2013 Digestive Disease Week (DDW) meeting. Ian M. Gralnek, MD, MSHS, associate professor of medicine/gastroenterology at the Rappaport Family Faculty of Medicine Technion-Israel

Institute of Technology in Haifa, Israel, presented data on the Fuse Full Spectrum Endoscopy (Fuse) system in a study that rigorously compared the new technology with traditional, forward-viewing (TFV) colonoscopy in a tandem endoscopy study design. â&#x20AC;&#x153;Compared with TFV colonoscopy, Fuse found significantly more adenomas, had a significantly lower adenoma miss rate and impacted colonoscopy surveillance recommendations,â&#x20AC;? Dr. Gralnek said. â&#x20AC;&#x153;Our results are very compelling. We believe see Fuse, page 14

I N S I D E

Doctors Tested in Boston Bombings The morning of April 15, 2013 started as a typical Marathon Monday for Tim Lepore, MD. At 68 years old, Nantucketâ&#x20AC;&#x2122;s only surgeon laced up his trainers and made his way to the starting line of his 45th consecutive Boston Marathon. By mid-morning, long after the elite runnersâ&#x20AC;&#x2122; dust had settled, Dr. Lepore joined the second

Manoop S. Bhutani, MD

Klaus Mergener, MD, PhD, MBA

Prateek Sharma, MD

see Boston, page 42 Supported by

5)& 4$*&/$& #&)*/% 104*5*7& 1"5*&/5 065$0.&4

Colonoscopy Quality Improvement: Quality Indicators and Benchmarks Douglas K. Rex, MD, FACP, FACG Director of Endoscopy Indiana University Hospital Professor Division of Gastroenterology and Hepatology Department of Medicine Indiana University School of Medicine Indianapolis, Indiana

Introduction Increasing efforts to reform health care and contain medical expenditures have accelerated the push to define, capture, and enforce quality measures for delivered care. This trend is evident particularly for procedural and preventative measures that can have a marked effect on patient outcomes and health care costs, such as the use of colonoscopy for screening and surveillance for colorectal cancer (CRC). Although the use of colonoscopy as a CRC screening tool has reduced patient mortality, variability in endoscopistsâ&#x20AC;&#x2122; performance, which has been demonstrated for adenoma detection rates (ADRs), assessment of bowel preparation, complication rates, use of appropriate screening and surveillance intervals, and effective polyp resection, suggest that objective measures are needed to evaluate performance and improve quality. This review discusses the current and emerging landscape regarding quality indicators and benchmarks for colonoscopy.

Colonoscopy Quality Improvement: Quality Indicators and Benchmarks see page 8

Quality Measurement for Colonoscopy-Based Screening And Surveillance Colonoscopy is the dominant screening UFTU GPS $3$ JO UIF 6OJUFE 4UBUFT 6OMJLF CBTJD testing used to screen for other diseases (eg, blood pressure measurements and lipid profile reviews as preventative steps in cardiovascular disease; glucose testing for diabetes mellitus), colonoscopy is highly operatordependent: The quality of this procedure is dependent on the skill and training of the gastrointestinal (GI) endoscopist. Other factors such as adequacy of bowel preparation have a significant effect on the success and cost-effectiveness of colonoscopy programs. Efforts to increase the quality of colonoscopy have been in effect for more than a decade.4 5IF 64 .VMUJ 4PDJFUZ 5BTL 5 'PSDF PO Colorectal Cancer and a combined task force of the American Society for Gastrointestinal Endoscopy and the American College of Gastroenterology have published recommendations for measuring quality in the technical performance of colonoscopy.4,5 These publications are comprehensive in their scope, covering multiple aspects of pre-procedural evaluation and patient selection, intraprocedural technical performance, and postprocedural monitoring of complications.

However, resources for measuring quality may be limited, thereby creating a need to identify priority quality indicators that should be measured in all clinical programs (Table).6-9 Ideal quality indicators are easy and thus feasible to measure; possess clinical relevance (are related to important outcomes); and illustrate substantial variation in performance among endoscopists. Several measures within colonoscopy-based CRC screening/surveillance satisfy these criteria.

Cecal Intubation Rate Current recommendations are that endoscopists should be able to achieve cecal JOUVCBUJPO JO BU MFBTU PG BMM DPMPOPTDPQJFT BOE PG TDSFFOJOH DPMPOPTDPQJFT 4,5 Cecal intubation is defined as passage of the colonoscope tip fully into the cecal caput, with visualization of the mucosa between the appendiceal orifice and the ileocecal valve. Photodocumentation of the appendiceal orifice and ileocecal valve is expected. Low cecal intubation has been associated with an increased risk for interval cancer in the proximal colon.

Adenoma Detection Rate "%3 JT UIF GSBDUJPO PG QBUJFOUT ZFBST of age and older undergoing initial screening colonoscopy who have one or more conventional adenomas detected.4,5 ADR is the most important colonoscopy quality marker as it relates directly to the principle goal of colonoscopy: detection and resection of precancerous lesions and thereby protection against CRC. ADRs below the recPNNFOEFE UISFTIPME PG GPS B NJYFE gender patient population predicted a GPME IJHIFS SJTL GPS EFWFMPQJOH BO JOUFSval cancer after colonoscopy. Guidelines SFDPNNFOE UIBU UIF "%3 CF BU MFBTU JO NFO BOE JO XPNFO 4,5 and there is considerable variability in the ADR among FOEPTDPQJTUT 'JHVSF A number of efforts to improve ADR in poor performers have been unsuccessful, but recently some effective strategies have been identified.

Education Effective methods for improving ADRs have involved some element of education, typically focused on lesion recognition and improved examination technique. Endoscopists should understand the full range of appearances of precancerous lesions in the colon and be able to recognize flat and depressed conventional adenomas as well as serrated lesions in the proximal colon. Sessile serrated polyps (a term synonymous with sessile serrated adenoma) are invariably sessile or flat, have a pale color, and often have a â&#x20AC;&#x153;mucus capâ&#x20AC;? on the surface and/ or adherent debris that often clusters at the MFTJPO FEHF 5IF .BZP $MJOJD +BDLTPOWJMMF T &26*1 &OEPTDPQJD 2VBMJUZ *NQSPWFNFOU 1SPKFDU USJBM SBOEPNJ[FE PG UIF JOTUJtutionâ&#x20AC;&#x2122;s faculty to an educational intervention that focused on lesion recognition and specific colonoscopic techniques, such as examining carefully behind folds, to improve ADRs; educational intervention resulted in an JNQSPWFNFOU JO UIF "%3 GSPN UP Withdrawal Technique Barclay et al found that ADRs were well stratified according to whether endoscopists had an average withdrawal time in normal colonoscopies greater than or less than 6 minutes. Endoscopists whose withdrawal times were greater than 6 minutes detected more than twice as many patients with adeOPNBT UIBU XFSF DN PS MBSHFS JO TJ[F *O B subsequent study, the group evaluated the effect of an educational program combined with enforced 8-minute withdrawal times. 5IF UJNFS TPVOEFE FWFSZ NJOVUFT EVSJOH withdrawal, and served as a reminder that the FOEPTDPQJTU TIPVME TQFOE BU MFBTU NJOVUFT examining each quarter of the colon length. This intervention produced across-the-board JNQSPWFNFOUT JO "%3T 'JHVSF 6 Bowel Preparation Bowel preparation quality also affects ADR. Split-dose and same-day bowel preparations are the most important development in bowel preparation efficacy in the

Appropriate Use of Screening/ Surveillance Intervals

Table. High-Yield Quality Indicators of Colonoscopy-Based Screening and Surveillance for CRC and Suggested Interventions To Improve Performance Quality Indicator

Suggested Interventions To Improve Performance

ADR

Comprehensive education and training Timer-enforced withdrawal â&#x2030;Ľ8 min Split-dose or same-day bowel prep Recognition of right-sided sessile serrated adenomas

Assurance of appropriate Distribution of a wallet-size card with a summary of post-polypectomy guidelines to all endoscopists Placement of guideline charts near computers used for typing endoscopy reports, and distribution screening/surveillance Reinforcement of the guidelines in a monthly continuous quality improvement meeting intervals ADR, adenoma detection rate; CRC, colorectal cancer Adapted from references 6-9. 6 9.

1.2

QBTU EFDBEFT *O B SFUSPTQFDUJWF TUVEZ PG NPSF UIBO DPMPOPTDPQJFT VTF PG split-dose bowel preparations resulted in a marked improvement in bowel preparation quality and an increase in ADRs from UP P Another study suggested that, for patients who are scheduled for afternoon colonoscopy, early morning/ same-day bowel preparation resulted in a better quality examination compared with previous-day or split-dose preparations. Split- and same-day dosing of bowel preparations have their greatest benefit in the proximal colon. Colonoscopy is consistently more effective in preventing distal compared with proximal colon cancer, an effect that may result partly from the tendency of bowel preparation quality to be worse in the cecum and right colon when preparations are given entirely the day or evening before colonoscopy. Additional potential causes of worse protection against proximal cancer include the rightward distribution of lesions that are endoscopically more subtle (including flat and depressed conventional adenomas and serrated lesions), and the more rapid movement through the polyp-cancer sequence in tumors that are microsatellite unstable or hypermethylated. Both of these molecular features are more common in tumors arising in the proximal colon.

Another determinant of the overall utility of colonoscopy for CRC prevention is the interval between examinations. Although detailed evidence-based guidelines have been published with recommended intervals for screening/surveillance examinations based on age, risk factors, and observations during colonoscopy, there is considerable variability in guideline adherence in clinical practice. All current recommendations are UIBU CFHJOOJOH BU BHF DPMPOPTDPQZ TIPVME CF QFSGPSNFE GPS TDSFFOJOH FWFSZ ZFBST in average-risk persons. The recommended interval is 5 years for certain high-risk family histories (CRC in multiple first-degree

Adenoma Per Subject (mean)

â&#x20AC;&#x201D;â&#x20AC;&#x153;nsmurâ&#x20AC;? â&#x20AC;&#x153; Via website July 11, 2013

EXPERTSâ&#x20AC;&#x2122; PICKS The Best of Digestive Disease Week (DDW): Part 1 Experts share their favorite abstracts from the 2013 DDW meeting ................................................................................................ page 6

BY BRIGID DUFFY

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Quality Reporting and Oversight Currently, there are no mandatory reporting/tracking systems in place for quality measures for colonoscopy and CRC detecUJPO TVSWFJMMBODF JO UIF 6OJUFE 4UBUFT )PXever, the landscape for regulatory and reimbursement continues to evolve, shifting from quantity to quality of health care delivery with motivators of either pay-for-qualityâ&#x20AC;&#x201C; performance or reimbursement penalties for failure to meet certain threshold metrics. Based on the quality markers discussed previously, tracking and reporting systems for colonoscopy quality indictors may include some combination of measuring adequacy of bowel preparation, ADRs, cecal intubation rates, and appropriate use of screening/surveillance intervals. Data that currently are being reported on a voluntary basis to the GI Quality Improvement Consortium (GIQuIC) and the American Gastroenterological Association (AGA) Digestive Health Outcomes RegistryÂŽ may help establish the most appropriate benchmarks for high-quality colonoscopy. Even if these reporting and tracking systems remain purely voluntary for the nearterm, groups that participate could realize TVCTUBOUJBM CFOFGJUT 'PS FYBNQMF RVBMJUZ metrics relative to targets or other practices could be used by groups to identify system errors and to identify practitioners within their groups who would benefit from additional training and education to improve overall group performance and patient outDPNFT 'VSUIFSNPSF HSPVQT UIBU QBSUJDJQBUF in these quality reporting systems will be well positioned in the likely event that quality measures will be used for accreditation/ credentialing purposes, marketing purposes, and reimbursement determinations. Participation in colonoscopy quality improvement has been made much easier

0.4

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Figure 1. "EFOPNB EFUFDUJPO SBUF BNPOH JOEJWJEVBM endoscopists. 3FQSJOUFE XJUI QFSNJTTJPO GSPN -FF 3) 5BOH 5 34 .VUIVTBNZ 73 FU BM 2VBMJUZ PG DPMPOPTDPQZ XJUIESBXBM technique and variability in adenoma detection rates (with videos). Gastrointest Endosc

OPTFE XJUI $3$ BU BHF ZFBST However, there is clear evidence of systematic use of ZFBS JOUFSWBMT GPS TDSFFOJOH JO UIF .FEJDBSF population, despite evidence that the yield of repeat screening in 5 years is remarkably low in average-risk persons who have initial negative examinations, and recent evidence that the protective effect of a negative screening colonoscopy performed by a gasUSPFOUFSPMPHJTU FYDFFET ZFBST Several studies suggest that some gastroenterologists repeat colonoscopy for polyp surveillance either more or less frequently than guidelines recommend, which results in increased costs of care and risk for complications or increased risk for cancer, respectively. This over- or underuse of colonoscopy stems from a variety of potential causes, including unfamiliarity or disagreement with guidelines; systematic problems with health care management systems and patient tracking; suboptimal reimbursement arrangements (eg, either absence of reimbursement or financial incentives for overuse of colonoscopy); or noncompliance by patients or referring physicians. In one survey of endoscopists who reported familiarity with society guidelines regarding intervals for screening/surveillance, incorrect answers to common scenarios regardJOH BQQSPQSJBUF JOUFSWBMT XFSF HJWFO JO UP PG IZQPUIFUJDBM DBTFT In a study describing actual utilization of surveillance colonosDPQZ PG QBUJFOUT SFDFJWFE TVSWFJMMBODF PO UJNF UPP FBSMZ NFEJBO EJGGFSFODF ZFBST UPP FBSMZ BOE UPP MBUF NFEJBO EJGGFSFODF ZFBS UPP MBUF Sanaka et al investigated the utility of several interventions to improve adherence to recommended surveillance intervals: Distribution of a wallet-size card with a summary of post-polypectomy guidelines to all endoscopists; placement of guideline charts near computers used for typing endoscopy reports; and distribution and reinforcement of the guidelines in a monthly continuous quality improvement meeting.

Figure 2. Detection of adenomas before and after an intervention involving education and a timer designed to enforce colonoscopy withdrawal time of 8 minutes or more. 3FQSJOUFE XJUI QFSNJTTJPO GSPN #BSDMBZ 3- 7JDBSJ ++ (SFFOMBX 3- &GGFDU PG B UJNF EFQFOEFOU DPMPOPTDPQJD withdrawal protocol on adenoma detection during screening colonoscopy. Clin Gastroenterol Hepatol.

by the development of national registries such as GIQuIC and the AGA RegistryÂŽ that allow electronic submission of procedural data and which provide electronic feedback on group and individual performance with benchmarking.

Conclusion Variable performance in colonoscopy has now been demonstrated for adenoma detection, cancer prevention, cecal intubation, polyp resection effectiveness, and use of screening and surveillance intervals. Achievement of high levels of adequate bowel preparation reduces costs by reducing the need for early repeat procedures. Interest in colonoscopy quality continues to grow. Active participation in colonoscopy quality improvement programs will improve patient outcomes and position endoscopists for expected changes in health care assessment and reimbursement.

References -FWJO # -JFCFSNBO %" .D'BSMBOE # FU BM "NFSJDBO Cancer Society Colorectal Cancer Advisory Group; 64 .VMUJ 4PDJFUZ 5BTL 5 'PSDF "NFSJDBO $PMMFHF PG Radiology Colon Cancer Committee. Screening and surveillance for the early detection of colorectal canDFS BOE BEFOPNBUPVT QPMZQT B KPJOU HVJEFMJOF GSPN UIF "NFSJDBO $BODFS 4PDJFUZ UIF 64 .VMUJ 4PDJFUZ 5BTL 5 'PSDF PO $PMPSFDUBM $BODFS BOE UIF American College of Radiology. Gastroenterology. Rex DK, Cutler CS, Lemmel GT, et al. Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies. Gastroenterology -FF 3) 5BOH 5 34 .VUIVTBNZ 73 FU BM 2VBMJUZ PG colonoscopy withdrawal technique and variability in adenoma detection rates (with videos). Gastrointest Endosc 4. 3FY %, #POE +) 8JOBXFS 4 FU BM 6 4 .VMUJ 4PDJFUZ 5BTL 5 'PSDF PO $PMPSFDUBM $BODFS 2VBMJUZ JO UIF technical performance of colonoscopy and the continuous quality improvement process for colonosDPQZ SFDPNNFOEBUJPOT PG UIF 6 4 .VMUJ 4PDJFUZ 5 'PSDF PO $PMPSFDUBM $BODFS Am J Gastroenterol. 5BTL 5. 3FY %, 1FUSJOJ +- #BSPO 5) FU BM "4(& "$( Taskforce on Quality in Endoscopy. Quality indicators for colonoscopy. Am J Gastroenterol. 6. #BSDMBZ 3- 7JDBSJ ++ (SFFOMBX 3- &GGFDU PG B UJNF dependent colonoscopic withdrawal protocol on adenoma detection during screening colonoscopy. Clin Gastroenterol Hepatol

Longcroft-Wheaton G, Bhandari P. Same-day bowel cleansing regimen is superior to a split-dose regiNFO PWFS EBZT GPS BGUFSOPPO DPMPOPTDPQZ SFTVMUT from a large prospective series. J Clin Gastroenterol. 8. 3FY %, "IOFO %+ #BSPO +" FU BM 4FSSBUFE MFTJPOT of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol. 9. 4BOBLB .3 4VQFS %. 'FMENBO &4 FU BM *NQSPWing compliance with postpolypectomy surveillance guidelines: an interventional study using a continuous quality improvement initiative. Gastrointest Endosc #BYUFS // 4VUSBEIBS 3 'PSCFT 44 FU BM "OBMZTJT PG administrative data finds endoscopist quality measures associated with postcolonoscopy colorectal cancer. Gastroenterology ,BNJOTLJ .' 3FHVMB + ,SBT[FXTLB & FU BM 2VBMJUZ indicators for colonoscopy and the risk of interval cancer. N Engl J Med $PF 4( $SPPL +& L %JFIM // 8BMMBDF .# "O FOEPscopic quality improvement program improves detection of colorectal adenomas. Am J Gastroenterol #BSDMBZ 3- 7JDBSJ ++ %PVHIUZ "4 FU BM $PMPOPscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med. (VSVEV 43 3BNJSF[ '$ )BSSJTPO .& FU BM *ODSFBTFE adenoma detection rate with system-wide implementation of a split-dose preparation for colonoscopy. Gastrointest Endosc F (PPEXJO +4 4JOHI " 3FEEZ / FU BM 0WFSVTF PG TDSFFOJOH DPMPOPTDPQZ JO UIF .FEJDBSF QPQVMBUJPO Arch Intern Med *NQFSJBMF 5' (MPXJOTLJ &" -JO $PPQFS $ FU BM 'JWF ZFBS SJTL PG DPMPSFDUBM OFPQMBTJB BGUFS OFHative screening colonoscopy. N Engl J Med. #SFOOFS ) $IBOH $MBVEF + 4FJMFS $. )PGGNFJTUFS . -POH UFSN SJTL PG DPMPSFDUBM DBODFS BGUFS OFHBUJWF colonoscopy. J Clin Oncol 4IBI 56 7PJMT $* .D/FJM 3 FU BM 6OEFSTUBOEing gastroenterologist adherence to polyp surveillance guidelines. Am J Gastroenterol. 4DISFVEFST & 4JOU /JDPMBBT + EF +POHF 7 7 FU BM The appropriateness of surveillance colonoscopy intervals after polypectomy. Can J Gastroenterol.

Disclosures Dr. Rex reported that he is an advisory board member for American BioOptics, Check-Cap, Epigenomics AG, Exact Sciences, and Given Imaging; has received grant/research funding from Braintree, Given Imaging, and Olympus; and has received speaking fees from Boston Scientific, #SBJOUSFF 'FSSJOH BOE 0MZNQVT

In this race for the professional rock bottom, â&#x20AC;&#x153;forward-thinkingâ&#x20AC;? gastroenterologists will get mid-level [providers] to perform endoscopy because there are â&#x20AC;&#x153;widely quoted,â&#x20AC;? proof-of-concept studies from the United Kingdom and Mayo. Gastroenterologists will soon have a lot of time to do MOC [maintenance of certification], and PIMs [Practice Improvement Modules] of the ABIM [American Board of Internal Medicine] to ensure they are still privileged to practice in their hospitals. Call this value-based purchasing?! When will they come up with an administrator robot?

Adenoma Detection Rate

The administrators of hospitals will most certainly use this [Sedasys system] to replace CRNAs [certified registered nurse anesthetists], whose time is now spentâ&#x20AC;&#x201D;wastedâ&#x20AC;&#x201D;in endosuites. They will aptly call these machines â&#x20AC;&#x153;anesthesia providers.â&#x20AC;? The CRNAs will in turn be replacing anesthesiologists and [will be] supervising Sedasys robots, perhaps 20 to 30 robots to one CRNA. The ASA [American Society of Anesthesiologists], in its characteristic manner, may encourage administrators of community hospitals to completely eliminate anesthesiologists in states like California where they are not even needed to supervise CRNAs. Medicare will most certainly come up with something called R-RVU [robot-relative value units]â&#x20AC;&#x201D;an infinitesimally small value for Sedasys, as it is just a machine administering a cheap drug called propofol!

("4530&/5&30-0(: &/%04$01: /&84 t +6-: 9

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Study Suggests Gastric Bypass Causes Glucose Spikes, Crashes BY MONICA J. SMITH BALTIMORE—Despite its reputation as the gold standard for weight loss, gastric bypass surgery may result in a post-meal glucose spike followed by a blood sugar crash that causes between-meal hunger, according to recent findings. The

research examined the effects of different bariatric procedures on post-meal glucose reactions. Mitchell S. Roslin, MD, Lenox Hill Hospital, New York City, and his colleagues first became interested in glucose tolerance testing after noticing that many of their patients who regained weight after gastric bypass surgery complained

of inter-meal hunger, especially following meals rich in simple carbohydrates. “Consistent with that is the fact that there are new conditions—nesidioblastosis, noninsulinoma pancreatogenous hypoglycemia syndrome, hyperinsulinemia and hypoglycemia—[that are] becoming more common after gastric bypass,” Dr. Roslin said. “These are entities surgeons rarely

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‘The gastric bypass patients have the highest one-hour sugar [levels] and the lowest two-hour sugar [levels], and I think this begins to explain why we have inter-meal hunger with gastric bypass.’

encountered previous to this [era in bariatric surgery].” The research was presented at the 2013 meeting of the Society of American Gastrointestinal and Endoscopic Surgeons. The study was sponsored by Covidien. Dr. Roslin and his team decided to compare glucose metabolism among patients who had undergone gastric bypass, sleeve gastrectomy or duodenal switch (DS), in which a common channel of at least 125 cm was preserved. “This type of model gives us the ability to compare two operations that preserve the pyloric valve, as well as two operations that have an intestinal bypass component,” he said. In the prospective, nonrandomized study, 13 patients received gastric bypass, 12 received sleeve gastrectomy and 13 underwent DS. All completed an oral glucose tolerance test (GTT) at baseline and at six, nine and 12 months. The nine-month GTT comprised a solid mixed-meal muffin. The only significant, preoperative difference among the patients was greater body mass index in

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

From the Literature

Metabolic Therapy or Bariatric Surgery: What’s in a Name? There were no deaths in either group and perioperative complications occurred in approximately 2% of patients in each group. Billing for a surgical procedure as a metaThe study showed that the term “bariatric surbolic therapy rather than a weight loss surgery gery” significantly influenced the selection of surattracted patients who were markedly different gical candidates, the investigators said. Among from typical bariatric surgery candidates, a new traditional bariatric surgery patients, young study has shown. women were overrepresented and diabetes was For the first time, men and women were almost less prevalent than expected for a severely obese equally represented in the metabolic surgery poppopulation, said Dr. Rubino. ulation, and the patients in this group were older “That’s a result, perhaps, of the fact that the than those in most bariatric studies and had a name and focus on weight loss results is more higher prevalence of diabetes. attractive to relatively healthy young females than These patients more accurately represent older men.” America’s severely obese population than those Based on their findings, Dr. Rubino and his colin most studies of bariatric surgery, the investigaleagues are proposing the creation of a new surgitors said. The study was published in Annals of cal specialty called “GI metabolic surgery”—a GI Surgeryy (Rubino F et al. 2013 Jan 10 [Epub ahead operation with the primary intent to treat diabetes of print]). and metabolic disease. The term “bariatric sur“This has huge ramifications that will change gery” would be reserved for patients who require several aspects of perioperative and postsurgisurgery to address physical complications of cal care, therefore defining an excess weight but have no metentirely new field of practice,” abolic disease, said Dr. Rubino. said lead author Francesco ‘This has huge ramifications that will change several aspects of Stacy Brethauer, MD, a barRubino, MD, a bariatric sur- perioperative and postsurgical care, therefore defining an entirely iatric surgeon and researcher geon at the Catholic University at Cleveland Clinic in Ohio, said new field of practice.’ of Rome, Italy. many programs have adopted —Francesco Rubino, MD both terms: bariatric and metaIn 2007, Dr. Rubino moved to New York’s Weill Cornell Medibolic surgery. cal College where he started a “Over time, some programs Gastrointestinal (GI) Metabolic may remove ‘bariatric’ from Surgery Program and Diabetes their title. We have to remember Surgery Center. The metabolic that many obese patients don’t surgery program operated sephave diabetes or metabolic arately from the hospital’s welldisease and are pursuing the established bariatric surgery surgery for weight loss. Using department. The two departboth terms is the most inclusive ments offered the same proceapproach and will attract both dures as the bariatric surgery types of patients,” he said. department and used identical Dr. Brethauer added that bareligibility criteria for patients but iatric and metabolic surgeons had very different stated goals. need to do more to emphasize Instead of focusing primarily the metabolic effects of the on weight loss, the metabolic operations. surgery program emphasized Currently, less than 2% of treatment of diabetes and eligible patients in the United other metabolic disorders. The States have access to bariatric program was not coded as and metabolic surgery. ■ BY CHRISTINA FRANGOU

the DS group. There were no significant differences in their glucose homeostasis parameters, fasting glucose or insulin. At 12 months, the DS patients lost significantly more weight than the other two groups, although those patients also experienced good weight loss. All of the operations reduced fasting blood glucose levels as well. But after GTT, the gastric bypass group had much higher levels of one-hour glucose than the DS group, and the sleeve gastrectomy group had intermediate levels. The gastric bypass group also had higher one-hour insulin levels, higher even than their preoperative level, whereas

a provider of bariatric surgery in the electronic referral system of the institution. To investigate the outcomes of the new program, researchers studied 100 consecutive patients who underwent surgery in the bariatric surgery department and the GI metabolic surgery program. Patients treated in the metabolic program were older by four years (45.8±13.4 vs. 41.8±11.7; P<0.05), had a lower body mass index (42.4±7.1 vs. 48.6±9.5 kg/m2; P<0.01) and were more likely to have diabetes (62% vs. 35%; P<0.01), hypertension (68% vs. 52%; P<0.05), dyslipidemia (48% vs. 31%; P<0.05) and cardiovascular disease (14% vs. 5%; P<0.05). Diabetes was more severe among metabolic surgery patients, measured by higher glycated hemoglobin levels and a greater percentage of insulin use. Men accounted for 42% of the metabolic surgery population compared with 26% of the bariatric cohort (P<0.05).

insulin was suppressed in the DS group. “When you have high insulin, glucose falls, and we know that hypoglycemia causes hunger,” Dr. Roslin said. “Looking at the one- to two-hour glucose ratio, the gastric bypass patients have the highest one-hour sugar [levels] and the lowest two-hour sugar [levels], and I think this begins to explain why we have inter-meal hunger with gastric bypass.” All of the operations resulted in significant weight loss and other positive outcomes, but compared with gastric bypass patients, DS patients had a much smaller rise in one-hour glucose and insulin levels.

“The sleeve behaves intermediately to the bypass and DS, meaning that preserving the pylorus may be part of the explanation, but not the whole story,” Dr. Roslin said. “Obviously, controlled trials between gastric bypass and DS are needed to determine the real long-term significance, but I think we should all be cautious before we label gastric bypass the gold standard operation,” he said. Kevin M. Reavis, MD, of the Division of Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic, Portland, said that improved assays are

allowing for a more rapid and better understanding of the true complexity of the physiologic changes that contribute to the results seen with each of the bariatric procedures. “This study highlights aspects of glucose metabolism that have previously been underappreciated,” Dr. Reavis said. “Although it is a relatively small study, it illustrates that with gastric bypass, sleeve gastrectomy and duodenal switch, there are substantial metabolic changes we are just beginning to understand and must investigate on a larger scale in order to optimize clinical outcomes.” ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Group Identifies Predictors of Successful Weight Loss With Duodenal-Jejunal Bypass Liner Purely Endoscopic Procedure Provides Impressive Weight Loss Dr. Munoz concluded that placement of a DJBL can result in significant weight loss in both patients with and without type 2 diabetes, and that patients with higher BALTIMORE—In obese patients who receive a duodebaseline levels of HbA1c could benefit from early internal-jejunal bypass liner (DJBL), glycemic control may vention to optimize the weight loss effect of this device. be a more significant preDr. Munoz also said that dictor of successful weight the baseline levels of HbA1c loss than the presence or in the group of patients with absence of type 2 diabetes, type 2 diabetes averaged In contrast with previous studies, the presence of type 2 diabetes did not according to recently pre6.7%, which indicated good affect the weight loss effect of the duodenal-jejunal bypass liner. sented research. glycemic control, and HbA1c A DJBL is a highly flexlevels in the patients without ible, nutrient-impermetype 2 diabetes averaged 6%. able, 60-cm sleeve placed A larger trial could yield difendoscopically that covers ferent results. the entire duodenum and “The differences in basethe first portion of the line HbA1c between diabetic jejunum. and nondiabetic patients are “After one year of treatnot great, and I suspect that ment, patients with a this relationship may disapDJBL lose an average of pear in a prospective trial 47% of their excess weight. with more patients,” said Jon However, as with bariatGould, MD, chief, Division ric surgery, weight loss is of Surgery, Alonzo P. Walker variable with this device,” Chair in Surgery and associate said Rodrigo Munoz, MD, professor of surgery, MediPhD, Departamento de cal College of Wisconsin in Cirugia Digestiva, Escuela Milwaukee. de Medicina, Pontificia, “The demographics of the Universidad Catolica de study group suggest these Chile, in Santiago, Chile. patients would otherwise have “The aim of this study been candidates for bariatwas to identify clinical preric surgery. The mean weight dictors of weight loss in this loss seems pretty good for an group of patients treated entirely endoscopic procedure with this device for one using an implantable device, year,” he said. so I think it is notable that The study was prethe weight loss was so good,” sented at the 2013 annual Dr. Gould said. “I would be ‘The mean weight loss seems pretty good for an entirely meeting of the Society of interested to know how many endoscopic procedure using an implantable device, of the diabetics were no longer American Gastrointestinal so I think it is notable that the weight loss was so good.’ and Endoscopic Surgeons. diabetic after a year.” Seeking a correlation Dr. Munoz and his team are —Jon Gould, MD between baseline varicurrently analyzing several gutables and weight loss, Dr. derived peptides and imporMunoz and his colleagues tant metabolites involved in collected data every month for one year on 61 patients inversely associated with weight loss at one year: insulin body weight and glucose regulation from blood samples treated with a DJBL. The collected variables included resistance determined by HOMA [homeostatic model obtained in a fasting condition and after a standard demographic information, baseline comorbidities, and assessment], fasting glycemia and Hb [hemoglobin] meal test of DJBL recipients. The samples will be taken anthropometric and biochemical characteristics. A1c,” Dr. Munoz said. “But after we controlled for all monthly for a year. The majority of the patients were women, with an these three variables, only HbA1c was inversely and “This new set of data will help us to have a betaverage age of 35 years and average body mass index of independently associated with the weight loss effect of ter understanding of how this device impacts a 43 kg/m2. Twenty-one of the patients (34%) had type 2 this device.” In contrast with previous studies, the pres- patient’s physiology, and how these changes cordiabetes. At one year, the average percentage of excess ence of type 2 diabetes did not affect the weight loss relate with weight loss and metabolic outcomes,” body weight lost was 47%, with some patients at either effect of the DJBL. Dr. Munoz said. ■ BY MONICA J. SMITH

extreme, having lost little of their excess weight or almost all of it: Coincidentally, nine patients (14.7%) lost more weight than the average, and nine lost less than the average. “Our univariate analysis indicated three variables

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Diagnosis continued from page 1

endoscopy and a biopsy—gross appearance of duodenal mucosa is not enough. “We know that villous atrophy can be patchy,” Dr. Lebwohl said. Guidelines from the American Gastroenterological Association specify that at least four biopsies should be obtained when celiac disease is suspected (AGA Institute. Gastroenterologyy 2006;131:1977-1980); however, adherence to these guidelines is variable. Analyzing a U.S. pathology database, Dr. Lebwohl and his colleagues found that of more than 132,000 patients who underwent duodenal biopsy between 2006 and 2009, only 35% had four or more biopsies submitted (Lebwohl B et al. Gastrointest Endoscc 2011;74:103-109). “The most common number was two, probably because you can take two specimens with one pass of the biopsy forceps,” Dr. Lebwohl said. “If the practitioner is not aware or doesn’t believe that taking more specimens increases your diagnostic yield, he or she might stop at two.” Adherence to the guidelines varied by clinical indication, but was never higher than 50%, and even when the indication was explicitly celiac disease, fewer than 40% of patients had four or more specimens submitted. “According to this data set, if fewer than four specimens were submitted, the prevalence of celiac disease was 0.7%; if four or more specimens were submitted, this increased to 1.8%,” Dr. Lebwohl said. “It’s a 1% absolute increase, but one could also interpret that as a doubling in diagnostic yield when the guidelines are [followed].”

Variable Adherence to Guidelines After completing their analysis, Dr. Lebwohl and his colleagues found there was wide variability among practitioners: a small cohort of gastroenterologists who nearly always adhered to the guidelines, and a larger

cohort who seldom or never did. This led the researchers to investigate the association between practice milieu and guideline adherence. “Physicians don’t practice in isolation; they practice in endoscopy suites in different regions throughout the United States. We wanted to know whether the physician’s procedure volume, the number of physicians per endoscopy suite and the regional gastroenterologist density affected adherence,” he said. They found that busier practitioners were less likely to adhere to the guidelines: For every additional 100 procedures per endoscopist, the odds of the endoscopist submitting four to six biopsy specimens decreased by 8%. Conversely, for every additional endoscopist per suite, the odds rose by 8%. The density of endoscopists within a given zip code, however, had no influence one way or the other. “Having other gastroenterologists nearby was important, but only if they’re down the hall,” Dr. Lebwohl said, suggesting colleagues may help keep each other informed and up to date on guidelines and practice trends.

‘According to this data set, if fewer than four specimens were submitted, the prevalence of celiac disease was 0.7%; if four or more specimens were submitted, this increased to 1.8%.’ —Benjamin Lebwohl, MD, MS

Missed Opportunities for Biopsy Examining the Clinical Outcomes Research Initiative database for patients who underwent endoscopy for the indications of diarrhea, iron deficiency, anemia and weight loss—all of which are manifestations of celiac disease that warrant consideration of a duodenal biopsy—Dr. Lebwohl and his colleagues found the majority of patients were not being biopsied at all (Lebwohl B et al. Gastrointest Endosc 2012;76:779-785). “Of 13,000 procedures, only 43% had a duodenal biopsy when undergoing endoscopy for these indications,” Dr. Lebwohl said. “These rates are increasing, but the 50% mark was only passed in 2009.”

Wondering if patients were really being missed, Dr. Lebwohl and his colleagues analyzed electronic medical records of 17 patients, all of whom had undergone endoscopy at their center before the endoscopy that diagnosed celiac disease. “The most common number of biopsies performed on those patients during the nondiagnostic endoscopy was zero, and the number of patients who had four or more specimens was very low,” Dr. Lebwohl said.

Universal Celiac Screening Put to the Test BY BRIGID DUFFY As a disease that is difficult to pin down and potentially life-threatening if left undetected, celiac disease has well earned its reputation as “the silent killer.” Recent studies estimate that as many as 70% of patients who have celiac disease are unaware of it—a frightening statistic considering that individuals who ignore symptoms or those who are asymptomatic can suffer from poor intestinal absorption of nutrients, bone demineralization, osteoporosis, and hip and vertebrae fractures, among other complications. A consensus among some in the gastroenterology community is that undiagnosed celiac disease is draining patients’ health and wallets, and it is therefore paramount that more measures be taken to detect the disease as early as possible. Given this background, K.T. Park,

MD, from the Division of Gastroen- model of celiac disease screen- checkup, and those who had a terology, Hepatology, and Nutrition, ing strategies using male or female positive result for markers of celiac Stanford University in Palo Alto, cohorts of 1,000 patients who were disease would receive a standard Calif., and his colleagues endoscopic workup per the rectested the cost-effectiveommended guidelines. ness of a universal serologic The researchers found that screening program for celiac ‘Those who have a false-positive the average lifetime costs for disease to prevent nontrau- would ultimately get an endoscopy and universal serologic screening matic hip and vertebral frac(USS) and symptomatic at-risk general anesthesia, and that was added screening (SAS) were $8,532 tures, a health risk that was determined to be the most cost and added risk to those who would and $8,472, respectively, yieldquantifiable in nature. The not have needed it otherwise.’ ing average quality-adjusted results of their study were life-year gains of 25.511 and —K.T. Park, MD 25.515, respectively. In short, recently published in Clinical Gastroenterology and USS was associated with higher Hepatology (Park KT et al. average lifetime costs and lower 2013;11:645-653), and became the 12 years old when screening began. quality of life for both sexes comsubject of a Twitter chat hosted by Serum samples were screened for pared with SAS, which is the current the American Gastroenterological immunoglobulin (Ig)A, compared standard of care. Association (AGA) in June. with tissue transglutaminase and “It was clear that patients who total IgA, with confirmation by are asymptomatic would definitely Model of Universal Serologic mucosal biopsy. The rationale was benefit from knowing that they have Screening that 12-year-olds would already celiac,” Dr. Park said in an interview. To test the cost-effectiveness of be undergoing blood tests to be “But those who have a false-positive universal screening, Dr. Park and his screened for anemia and dyslip- would ultimately get an endoscopy team developed a lifetime Markov idemia at their general pediatric and general anesthesia, and that

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

The Pathologist’s Interpretation

He noted that it is somewhat controversial to suggest that all patients who undergo endoscopy should have a routine duodenal biopsy, and that the cost-effectiveness of doing so in patients with gastroesophageal reflux disease had not been established. “Still, the fact that many patients with celiac disease had already undergone endoscopy suggests to me that patients probably are slipping through the cracks,” Dr. Lebwohl said.

was added cost and added risk to those who would not have needed it otherwise. The question became: Are we really willing to [take] patients who are otherwise healthy and subject them to an invasive procedure in light of catching this subgroup of patients who are asymptomatic?” Although the analysis was comparable in terms of results, the scales tipped in favor of SAS.

Sparks Fly During AGA Twitter Chat Although the Stanford study did not present a radical approach to screening for celiac disease, the AGA’s Twitter chat sparked some mild outrage among some participants who were frustrated with the dearth in early diagnoses. As public awareness of missed celiac diagnoses heightens, many patients tend to reject any kind of health care provider–initiated model of screening and take matters into

Although the endoscopist performs the biopsy, the pathologist also contributes to the diagnosis of celiac disease, leading to another factor in the underdiagnosis of the disease. “Even if the endoscopist takes an appropriate number of biopsies, the diagnosis could still be missed,” Dr. Lebwohl said. Dr. Lebwohl described a study that compared biopsy interpretation of Columbia pathologists experienced in celiac disease histopathology with those rendered by pathologists practicing in other settings. “When we compared our pathologists’ interpretations of the same biopsy slides with those reviewed at university hospitals, there was good correlation,” Dr. Lebwohl said (Arguelles-Grande C et al. J Clin Pathol 2012;65:242-247). But when the Columbia pathologists’ interpretation was compared with those provided by pathologists at community hospitals and at commercial laboratories, the correlation declined to moderate. “So there appears to be inter–pathology laboratory variability with regard to histopathology interpretation,” said Dr. Lebwohl. There are multiple explanations for this variability, said Govind Bhagat, MBBS, professor of clinical pathology and cell biology in medicine at Columbia University, and senior author of the pathology comparison study. “There are issues with sample preparation. For the most part, in the United States, biopsies are not oriented in the endoscopy suite or prior to processing in the laboratory. When there is no orientation, assessment of villous atrophy or crypt hyperplasia becomes challenging.” This can lead to both underdiagnosis and overdiagnosis of celiac disease, he said. Addressing the problem of sample orientation may be a bit tricky because it adds to cost, and it’s not clear

their own hands by requesting a serologic screening. When it was noted during the chat that the margin of cost savings was a mere $60 per patient with the SAS model, one chatter remarked: “I don’t care all that much about cost-effectiveness when it comes to my health, thank you.” But Dr. Park, who hosted the chat, emphasized to his audience that it is not the $60 that should be the focus of the conversation. “It’s about the quality of life,” he said. Although a routine endoscopy is generally benign, there are some potential adverse risks for the 5% of the population who have a falsepositive test result. “There are always risks for bleeding, the possibility of perforation, mucosal injury, and just the compromised quality of life emotionally when given a false diagnosis,” Dr. Park said. “This is a case of

whose responsibility it is—the gastroenterologist’s or the pathologist’s. “Is it cost-effective? Should it be done? That’s out for debate,” Dr. Bhagat said. “But orientation of the samples will benefit histopathology review. Also, being aware of and using ancillary tests, like immunohistochemical stains to evaluate any increase in enteropathy lymphocytes, which might not be obvious on review of light microscopy features, would help bolster the diagnosis of celiac disease.” To a large degree, however, inter-laboratory variability may stem from simple lack of awareness. “One reason may be that the pathologist is not familiar with the spectrum of histopathologic alterations associated with celiac disease, or is not thinking about celiac disease, as it is still not a very common diagnosis outside of specialized or tertiary care referral centers,” Dr. Bhagat said. “A high proportion of reports from referring institutions lacked data regarding the degree of villous atrophy and many didn’t even mention the presence—or lack—of an increase in intraepithelial lymphocytes. “But there is also a lack of information from the clinicians, who perhaps themselves aren’t aware, or who haven’t provided information to rule out celiac disease as a reason for the patient’s symptoms, alerting the pathologist that that’s what they should be evaluating for,” Dr. Bhagat said. Correcting the discrepancy in celiac disease diagnoses among different types of pathology laboratories, and raising the rate of diagnoses overall, will probably require some degree of education of all parties involved, Dr. Bhagat said. “Awareness is multifaceted. Patient awareness also will drive physician awareness. Pathologists and clinicians who attend seminars or symposia about celiac disease will realize this is something we need to check off or think about.” ■

complete dominance, in which one particular strategy costs less and yields better quality of life.”

Improving Screening Strategies If there was any consensus among the Twitter chat participants, it was that defining celiac screening guidelines is a critical area of focus not only for gastroenterologists but also for the medical community at large. Joseph A. Murray, MD, professor of medicine, Mayo Clinic, Rochester, Minn., who has done extensive research on celiac disease and who coauthored the American College of Gastroenterology clinical guidelines on celiac disease, published in May (RubioTapia A et al. Am J Gastroenterol 2013;108:656-676), echoed similar sentiments about improving screening strategies. Although he concurred that there is not enough evidence to recommend USS from

a health policy standpoint, the category of people who are tested must be broadened, he said, and knowing who to test starts with primary care physicians. “There is very little debate,” Dr. Murray said. “If you have bad diarrhea, weight loss, iron deficiency, anemia, a family history of celiac disease, type 1 diabetes or premature osteoporosis, you should be tested. If a test isn’t performed, it is because the health care provider doesn’t know to test.” Although most gastroenterologists are already in tune with the signs and symptoms that accompany celiac disease, it is crucial for other health care providers to become part of the conversation on celiac disease as new paradigms for diagnosis are worked out. “Will this make life simpler for us?” Dr. Murray asked, rhetorically. “Probably not. But it’s going to take more of an awareness.”

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

New FDA Rule Defines ‘Gluten-Free’ on Product Labeling The FDA has published a new regulation defining the term “glutenfree” for voluntary food labeling. The agency said the initiative will provide a standard definition to help approximately 3 million Americans who have celiac disease. “Adherence to a gluten-free diet is the key to treating celiac disease, which can be very disruptive to everyday life,” said FDA Commissioner Margaret A. Hamburg,

MD. “The FDA’s new ‘gluten-free’ definition will help people with this condition make food choices with confidence and allow them to better manage their health.” Foods that carry the term “glutenfree” on labels must now meet all of the requirements of the FDA’s new definition, including a gluten content of less than 20 ppm. The rule also requires foods with the claims “no gluten,” “free of gluten” and “without

gluten” to meet that new threshold. However, the agency stressed that the new rule is not a mandate. “Gluten-free is a voluntary claim that manufacturers may elect to use on the labeling of their foods, provided that those foods meet all final rule requirements for a gluten-free food,” the FDA stated on its website. Although food manufacturers will have a year after the rule is published to ensure that their product labeling

meets the new gluten-free standard, “we encourage the food industry to [comply] with the new definition as soon as possible,” said Michael R. Taylor, the FDA’s deputy commissioner for foods and veterinary medicine.

‘The FDA’s new “gluten-free” definition will help people with [celiac disease] make food choices with confidence and allow them to better manage their health.’ —Margaret A. Hamburg, MD, FDA Commissioner

IRA M. JACOBSON, MD Vincent Astor Distinguished Professor of Medicine Chief, Division of Gastroenterology and Hepatology Medical Director, Center for the Study of Hepatitis C NewYork-Presbyterian Hospital/Weill Cornell Medical College New York, New York

ecent research has demonstrated the eagerly awaited proof of concept that hepatitis C virus (HCV) infection can be cured without interferon. Trials involving directacting antiviral agents of several classes, as well as drugs with other mechanisms of action, either with or without interferon and ribavirin are proceeding at a remarkable pace. These exciting developments mandate the education of all physicians who treat patients with HCV infection in the proper use of the new agents, including management of side effects. Individualization of treatment decisions, both in treatment-naive and treatment-experienced patients, remains of paramount importance. The latest data will be summarized in this comprehensive review, scheduled for publication in 2014.

The FDA further noted that manufacturers share the bulk of the responsibility for ensuring “their product labels are truthful and not misleading.” Still, the agency said it “may use the full range” of its routine postmarket monitoring activities “to enforce the final rule on gluten-free labeling.” Such activities may include periodic inspections of manufacturing facilities and gluten analysis of food samples, especially in cases where consumer and industry complaints are reported to the FDA. The term “gluten” refers to proteins that occur naturally in wheat, rye, barley and cross-bred hybrids of these grains. In people with celiac disease, foods that contain gluten can trigger the production of antibodies that attack and damage the lining of the small intestine. This damage limits the ability of individuals with celiac disease to absorb nutrients and puts them at risk for other very serious health problems, including nutritional deficiencies, osteoporosis, growth retardation, infertility, miscarriages, short stature and intestinal cancers, the agency noted. The FDA issued the new regulation under the Food Allergen Labeling and Consumer Protection Act, which directed the agency to set guidelines for the use of the term “gluten-free” to help people with celiac disease maintain a gluten-free diet. ■ —Based on a press release from the FDA

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Immunomonitoring continued from page 1

“We now have the tools to make dosing decisions based on empirical findings,” said Ellen Scherl, MD, director of the Jill Roberts Center for Inflammatory Bowel Disease and associate professor in the Division of Gastroenterology and Hepatology at Weill Cornell Medical College/ NewYork Presbyterian Hospital in New York City. This is the “decade of immunomonitoring” in IBD, she said.

Mucosal Healing Mucosal healing is becoming an increasingly important treatment target and is arguably at the head of the triad, she said during the 2013 Digestive Disease Week (DDW) meeting. “Although not all patients with clinical remission have mucosal healing, it is predictive of clinical remission and also may lower the risk for colorectal cancer and surgery,” Dr. Scherl said.

‘This is an important study that demonstrates that even if patients discontinue use of an antiTNF due to reactions or loss of response, they can safely be restarted on the same drug.’ —Ellen Scherl, MD

The American College of Gastroenterology has noted the importance of mucosal healing in its recent guidelines on management of patients with Crohn’s disease (CD) and ulcerative colitis (UC). The guidelines highlight the possible effects of mucosal healing on the natural history of both diseases, as well as cancer risk (Lichtenstein GR et al. Am J Gastroenteroll 2009;104:465-483; Kornbluth A et al. Am J Gastroenteroll 2010;105:510-523).

Clinicians can measure serum anti–tumor necrosis factor (TNF) antibody levels, as well as levels of antibodies to these drugs to noninvasively track mucosal healing, Dr. Scherl explained. She also referred to a subanalysis of ACT 1 and 2 data presented at last year’s DDW, which linked levels of serum infliximab (IFX) and antibodies to IFX (ATIs) with clinical response, durable remission and mucosal healing (Reinisch W et al. DDW 2012; abstract 566). Specifically, there was a 55% remission rate in patients who had IFX serum trough

levels greater than 2.4 mcg/mL compared with a 25% remission rate in the overall study population; patients with IFX trough levels of more than 5 mcg/mL had the highest remission rates. There were “similar trends” in the relationship between immunoassay findings and clinical response, and mucosal healing, the researchers said.

Loss of Response Dr. Scherl said that in patients who lose response to treatment, immunoassays can be used to identify the reason for loss

of response and to guide clinicians to the appropriate treatment decision (Afif W et al. Am J Gastroenteroll 2010;105:11331139). These researchers studied patients who lost response to IFX and found that 86% of those who had low IFX trough levels regained response by undergoing a dose increase, whereas 33% of patients regained response by switching to another antiTNF. Among patients with ATIs, increasing the dose restored response in 17% of patients, whereas 92% regained response by switching to another anti-TNF agent. see Immunomonitoring, page 19

COLORECTAL CANCER:

The “Right” Perspective

Adenocarcinoma Detection and Prevalence in the Proximal Colon

Diagnoses of colorectal cancer (CRC) in the proximal (right) colon are recognized to be of increasing importance 1-3 • In a review of 9 population-based cancer registries of patients with CRC (N=243,861)1: — There was a relative increase of 18% in the proportion of right colon CRC cases from 1978 to 1998, while diagnoses in the left (distal) colon decreased1 • Right colon CRC is more common in the elderly,1,4,5 which is a growing percentage of the population6

Adenomas present special challenges in the right colon • “Endoscopically subtle” lesions* (Figure 17) are harder to detect and more common in the right colon8 • Cancers developing from serrated lesions are usually in the proximal region8 — Serrated adenocarcinoma represents up to 17.5% of most proximal CRCs (vs ≈7.5% of all CRCs)9 • Split-dose bowel preparations that improve cleansing may improve adenoma detection in the right colon8 — Ingestion of the second dose close to the time of colonoscopy clears mucus/chyme that tends to stick to the cecum/right colon8

Figure 1. Types of colorectal lesions* that are more difficult to detect7,8

*These include nonpolypoid (ﬂat, depressed) lesions and serrated lesions.8 Photographs shown to the left are from the cecum and were taken during a colonoscopy in a patient who had used a split-dose bowel preparation.7

Flat lesion

Serrated lesion

Importance of thorough adenoma detection during colonoscopy Adenoma detection rates (ADRs) ≥20% are signiﬁcantly associated with lower risk of interval colorectal cancer (Figure 2)10 Figure 2. Interval Colorectal Cancers Reported in a Colonoscopy-based Screening Program10*

Number of interval cancers†

35 33.6

30 25

*Results encompass the ﬁndings of 186 endoscopists in 45,026 patients. Each endoscopist had performed at least 30 screening examinations within the study period (October 2000– December 2004).

25.5 22.1

†Number of interval cancers/ 100,000 person-years of follow-up. A person-year represents one person at risk of development of CRC during a 1-year period.

15 10

‡ Proportion

2.4

5 0

<11%

11%-14.9% 15%-19.9% Adenoma detection rates‡

of subjects in whom at least one polyp was identiﬁed.

≥20%

Tracking ADR as a quality measure in colonoscopy will soon be required by law 11 Table. ACS/MSTF§ Colorectal Cancer Surveillance Guidelines12

Screening colonoscopy: adenoma ﬁndings

1-2 <1 cm tubular adenomas with low-grade dysplasia

3-10 adenomas; adenomas ≥1 cm; adenoma with villous features; high-grade dysplasia

>10 adenomas

Sessile adenomas removed piecemeal

Recommended timing of follow-up

5-10 years

3 years

<3 years; consider possibility of familial syndrome

2-6 months to verify complete removal

ACS, American Cancer Society; MSTF, Multi-Society Task Force on Colorectal Cancer.

References: 1. Rabeneck L, Davila JA, El-Serag HB. Is there a true “shift” to the right colon in the incidence of colorectal cancer? Am J Gastroenterol. 2003;98:14001409. 2. Kee F, Wilson RH, Gilliland R, et al. Changing site distribution of colorectal cancer. BMJ. 1992;305:158. 3. Cucino C, Buchner AM, Sonnenberg A. Continued rightward shift of colorectal cancer. Dis Colon Rectum. 2002;45:1035-1040. 4. Benedix F, Kube R, Meyer F, et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53:57-64. 5. Strul H, Kariv R, Leshno M, et al. The prevalence rate and anatomic location of colorectal adenoma and cancer detected by colonoscopy in average-risk individuals aged 40-80 years. Am J Gastroenterol. 2006;101:255-262. 6. US Census Bureau. Unprecedented global aging examined in new Census Bureau report commissioned by the National Institute on Aging. http://www.census.gov/newsroom/releases/archives/aging_population/cb09-108.html. Published July 20, 2009. Accessed November 14, 2012. 7. Data on ﬁle. Braintree, MA; Braintree Laboratories, Inc.; 2012. 8. Lasisi F, Rex DK. Improving protection against proximal colon cancer by colonoscopy. Expert Rev Gastroenterol Hepatol. 2011;5:745-754. 9. Mäkinen MJ. Colorectal serrated adenocarcinoma. Histopathology. 2007;50:131-150. 10. Kaminski MF, Regula J, Kraszewska E, et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med. 2010;362:1795-1803. 11. GIQulC colonoscopy quality registry surpasses 100,000 cases: milestone underscores value of clinical benchmarking tool for gastroenterology practices [press release]. Bethesda, MD: American Society for Gastrointestinal Endoscopy. October 11, 2012. 12. Kaiser Family Foundation, American Cancer Society, National Colorectal Cancer Roundtable. Coverage of colonoscopies under the Affordable Care Act’s prevention beneﬁt. http://www.kff.org/healthreform/upload/8351.pdf. Published September 2012. Accessed November 12, 2012.

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May, 2013

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DDW 2013

Antireflux Procedures continued from page 1

One of the procedures, EsophyX2, a transoral fundoplication technique, has outcome data available for six months post-procedure. The other procedure, Stretta, a radiofrequency technique that augments the integrity of the lower esophageal sphincter (LES), has been in clinical use long enough to generate outcome data at 10 years.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

‘Stretta demonstrates a significant sustained improvement measured in quality of life, patient satisfaction, and reduced need for PPIs. Overall, 64% of patients either eliminated or reduced pre-Stretta PPI use.’ —Mark Noar, MD

EsophyX2 In a randomized, multicenter study for EsophyX2, the primary end point of complete elimination of GERD symptoms was achieved in 62% of patients compared with 5% of those who were placed on a maximal dose of PPIs. Of those treated with EsophyX2, 90% were completely off PPIs at six months. The key eligibility criteria for participation in the EsophyX2 trial were persistent, troublesome, daily GERD symptoms and a regimen of PPI therapy for at least six months. Exclusion criteria included a hiatal hernia greater than 2 cm in axial length; esophagitis of grade C or higher; or obesity. Patients were randomized in a 2:1 ratio to undergo EsophyX2 or to increase to a full PPI dosage. The EsophyX2 procedure involves creating a circumferential valve at the gastroesophageal junction. Physicians do require training but the procedure is not considered technically challenging. In this study, EsophyX2 was performed by both surgeons and gastroenterologists, and the average length of the procedure was 38 minutes. All procedures were completed without significant adverse events (AEs), such as blood transfusion or hospital readmission. Of the 196 patients screened for the study, 63 were randomized and the outcomes of 60 were available for analysis after three patients were lost to follow-up, according to lead investigator, Karim S. Trad, MD, clinical professor of surgery, George Washington University Medical Faculty Associates, Washington, D.C. When evaluated with 48-hour pH monitoring, pH was normalized in 54% of patients who underwent the procedure and were off all PPI treatments versus 52% in the control group on maximum of doses PPIs. Healing of esophagitis was achieved in 90% of those patients treated with transoral fundoplication compared with 38% of those who remained on PPIs (P=0.004). According to patient questionnaires, 72% of patients in the EsophyX2 group were satisfied with the procedure compared with 5% of patients in the PPI group. EsophyX2 also was significantly favored on specific quality-of-life measures. According to Dr. Trad, this procedure “avoids the undesirable post-fundoplication AEs such as bloating, flatulence, or dysphagia.” Dr. Trad did acknowledge that 10% of patients in that group were back on PPIs at the last follow-up, but he noted, “They were now responding better to therapy, so [surgery] still seems to be a useful adjunct in this group.” Although much longer follow-up studies are needed to verify a sustained benefit of EsophyX2, Dr. Trad said that up to two years of follow-up from an earlier series of patients does exist and has not shown any significant deterioration in benefit.

function of the LES. Almost all of these have subsequently been abandoned, but Stretta, which received FDA approval in 2000, is still available. By one count, 32 studies have been conducted to evaluate Stretta, and the procedure also is included in the guideline recommendations of the Society of American Gastrointestinal and Endoscopic Surgeons for the treatment of GERD. In the most recent study, patient satisfaction scores showed no substantial diminution at intervals of one, two, three, four and 10 years in the data presented by Dr. Noar. Based on the long-term benefit of Stretta in a patient population with inadequate GERD control despite twice-daily PPI use, Dr. Noar called this “mature endoscopic procedure … safe, clinically effective and economically effective.”

Linx Reflux Management System Explored

Dr. Trad also said that a study using a sham procedure is now under way that “will not burn any bridges,” so that other procedures, including conventional fundoplication, can be performed in the event of an inadequate response.

Stretta An open-label, prospective study of 217 patients provided long-term outcome data on the Stretta procedure. A single endoscopist performed all of the procedures, the first of which was performed in August 2000. A subgroup of patients was followed for more than 10 years. “Stretta demonstrates a significant sustained improvement measured in quality of life, patient satisfaction and reduced need for PPIs,” said Mark Noar, MD, Heartburn and Reflux Center, Endoscopic Microsurgery Associates, Towson, Md. “Overall, 64% of patients either eliminated or reduced pre-Stretta PPI use.” Stretta emerged at a time when a variety of endoscopic procedures were proposed to increase the barrier

Asked to comment about these procedures, Joel Richter, MD, director of the Division of Digestive Diseases and Nutrition, University of South Florida, Tampa, was cautious about both studies. With regard to the EsophyX2 device, Dr. Richter said that normalization of acid occurred only in about 50% of patients, whereas in other procedures—notably the Linx Reflux Management System—normalization has been achieved in almost 70% of patients. With 10% of EsophyX2 patients back on PPIs at six months, he also suggested that long-term follow-up will be crucial to confirm that this rate remains low. Regarding the Stretta results, Dr. Richter said that the study was a single-center experience from a private practice, and that Stretta remains poorly supported by evidence. “There are lots of abstracts, but few peer-reviewed articles.” Dr. Richter added it was worth noting that few Stretta procedures are performed in academic centers of excellence. Asked for a surgeon’s perspective, Reginald Bell, MD, founder of SurgOne Foregut Institute, Englewood, Colo., and principal investigator of a study with up to two years of follow-up data for EsophyX, said previous studies have typically recruited patients who have responded positively to PPIs and then randomized them to continued PPIs or surgery. He noted that poor response to PPIs often predicts poor response to surgery. In contrast, this study recruited poor responders to PPIs, which Dr. Bell said typically represent the largest pool of candidates for surgery. The high response rate “is a very important finding because we can recommend this therapy to patients with documented GERD, even if their response to PPI therapy is poor,” he said. He added that the most recent data on the Linx Reflux Management System (Ganz RA et al. N Engl J Medd 2013;368:719-727) showed normalization of acid in 58% of patients at year 1, which is similar to that achieved with the EsophyX system. ■ Dr. Trad is a consultant for EndoGastric Solutions. Dr. Noar is a consultant for Mederi Therapeutics Inc. Dr. Bell has received a research grant from EndoGastric Solutions. Dr. Richter reported no conflicts of interest.

HAVING A CONVERSATION ABOUT IBS IS NEVER EASY. Ah, IBS. Hearing one symptom per visit is a victory. Last week, abdominal pain. This week, bloating. Next, gas and diarrhea? Despite Rome III Criteria1, there is not an easy way to diagnose her. Dietary management with VSL#3 provides significantly greater improvements in discomfort, bloating and gas2. Recommend VSL#3, a potent probiotic medical food for the dietary management of IBS to your patients. VSL#3 is a medical food and must be used under medical supervision. For further information visit www.vsl3.com 1

“Rome Foundation // Home.” Rome Foundation // Home. N.p., n.d. Web. 19 Mar. 2013. <http://www.romecriteria.org/>. 2 Kim HJ et al. Aliment Pharmacol Ther 17:895-904 (2003).

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NOW 510(k) CLEARED IN THE U.S. References 1. P/N V-0234-02 (A), Report, Channel Design Veriﬁcation Testing. On ﬁle at Covidien, GI Solutions. 2. Barrx™ Channel RFA Endoscopic Catheter Instructions For Use (IFU). COVIDIEN, COVIDIEN with logo, Covidien logo and positive results for life are U.S. and internationally registered trademarks of Covidien AG. Other brands are trademarks of a Covidien company. ©2013 Covidien. 8.13 US130064

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Immunomonitoring continued from page 13

Data presented at this year’s DDW demonstrate the efficacy of another strategy for restoring response to IFX, Dr. Scherl said. She pointed to a study by Baert et al, in which 29 patients who discontinued IFX due to loss of response or adverse reactions took a “drug holiday” for an average of 15 months (range, six to 125 months; DDW 2013; abstract 492). Following the treatment hiatus, the investigators found 62% of patients were able to safely restart treatment and experienced a clinical response after 14 weeks of treatment, whereas 45% and 41.3% were able to maintain clinical response after one year and after a median of four years of follow-up, respectively. Notably, those who had IFX serum trough concentrations greater than 2 mcg/mL and undetectable ATIs soon after restarting treatment were significantly more likely to experience clinical response, the researchers found. Concomitant immunomodulator use also was predictive of response. “This is an important study that demonstrates that even if patients discontinue use of an anti-TNF due to reactions or loss of response, they can safely be restarted on the same drug,” Dr. Scherl said.

Homogeneous Mobility Shift Assay Other findings presented at this year’s DDW showed that a novel, homogeneous mobility shift assay (HMSA) can accurately detect drug antibody levels during IFX infusions, eliminating the need to wait until an infusion is complete (Eser A et al. DDW 2013; abstract 1164). “Traditional solid-phase assays (ELISA [enzyme-linked immunosorbent assay] and ECLIA [electrochemiluminescence immunoassay]) experience interference in detecting both IFX and antibodies to IFX during or early after infusion,” Dr. Scherl noted. Eser et al compared trough and midinfusion readings measured with HMSA and ELISA and found that measurements obtained with HMSA matched well with trough levels, whereas ELISA readings did not. Similar to the aforementioned Baert study, these findings also demonstrated the potential benefits of concurrent immunomodulator use when administering IFX, Dr. Scherl said. “ATIs were detected at lower rates in patients receiving concomitant azathioprine therapy, although this difference was not statistically significant,” she noted.

Adalimumab and Antibodies Although the usefulness of IFX-related immunoassays has been studied quite extensively, Dr. Scherl said that data presented at the 2013 DDW meeting helped

to fill a gap in knowledge about the correlation between serum levels of adalimumab (ADA), antibodies to ADA and treatment outcomes in IBD. Velayos et al (DDW 2013; abstract 490) documented levels of serum ADA and antibodies to ADA in 118 patients with UC and CD using an ADA-specific HMSA and looked for associations with concentrations of the inflammatory biomarker, C-reactive protein (CRP). The researchers reported that 90% of patients had levels of serum ADA greater than 1 mcg/mL (median, 9.11 mcg/mL), and

22% had antibodies to ADA, using a lower-end cutoff of 1.7 mcg/mL. The presence of antibodies was associated with serum levels of ADA of less than 5 mcg/ mL, and levels of antibodies to ADA of greater than 1.7 mcg/mL were correlated with higher levels of CRP, they found. “The prevalence of antibodies to adalimumab found in this study is comparable to what we see with infliximab,” Dr. Scherl said. Serum ADA levels greater than 5 mcg/ mL, as well as an absence of antibodies to ADA, were associated with improved

clinical response and remission, Dr. Scherl noted. “I would have liked to see a correlation with mucosal healing and drug levels,” she said. “With existing immunomonitors and drug and antibody-todrug assays, it is possible to optimize the dose, decrease antibody formation and decrease the drug attenuation rate in the nearly half of initial responders who lose response within a year.” ■ Dr. Scherl has consulted for and has received grant and research funding from Prometheus Laboratories.

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Experts’ Picks:

The Best of Digestive Disease Week 2013: Part 3 COMPILED AND WRITTEN BY DAVID WILD

Gastroenterology & Endoscopy Newss asked three experts to select their favorite abstracts from this year’s Digestive Disease Week meeting. Following are their picks and comments on their selected abstracts.

Ronnie Fass, MD Director, Division of Gastroenterology and Hepatology Head of the Esophageal and Swallowing Center MetroHealth Medical Center Cleveland, Ohio

Nortriptyline for Idiopathic Gastroparesis: A Multicenter, Randomized, DoubleMasked, Placebo-Controlled Trial (NORIG) (Parkman HP et al)

Researchers randomized 130 patients with idiopathic gastroparesis to receive either nortriptyline, a tricyclic antidepressant, or placebo, for 15 weeks. Nortriptyline was started at 10 mg daily and titrated up to 25, 50 and 75 mg every three weeks. Study participants had delayed gastric emptying and Gastroparesis Cardinal Symptom Index (GCSI) scores higher than 21. Investigators compared specific and overall symptom relief, defining the latter as a decrease of 50% or greater in scores on the GCSI relative to baseline and on two consecutive visits. They found that 23% and 21% of drug and placebo recipients, respectively, experienced overall symptom relief. Patients in the nortriptyline group had significantly greater improvements in measures of nausea and abdominal pain at three weeks, although that difference subsequently diminished. Compared with placebo recipients, patients in the nortriptyline group experienced significantly greater improvements in appetite and body mass index (BMI), and also had greater improvement in their ability to finish a meal. The greatest symptomatic improvement in nortriptyline patients occurred among those with impaired meal consumption. Nineteen nortriptyline recipients discontinued treatment, including 10 patients with adverse events (AEs). Six placebo recipients terminated treatment, including three patients with AEs. Dr. Fass: Tricyclic antidepressants are used often in the clinical treatment of patients with gastroparesis. It is assumed that through their neuromodulatory effect they can relieve symptoms of nausea, vomiting and epigastric discomfort, all important symptoms in patients with moderate to severe gastroparesis. However, to date, there are no data to support their use in clinical practice. This study from the Gastroparesis Consortium, a well-respected project funded by the National Institutes of Health, examined nortriptyline and found it no better

than placebo for the treatment of gastroparesis. However, nortriptyline improved patients’ appetite and satiety, and increased BMI. Therefore, this type of treatment may be appropriate for patients with such severe gastroparesis that they are losing weight because of limited oral intake. Another important finding from this study is that a significant number of patients in the nortriptyline group developed side effects and dropped out of the trial. It could be that by pushing patients to a dose of 75 mg, as the researchers did here, more side effects were encountered. Possibly, the same benefits of nortriptyline could be achieved with a lower dose.

‘Although this was a very small study, most of the patients experienced a marked improvement in HRQoL scores over a one-year period after band ligation, and most were able to discontinue PPI use.’ —Ronnie Fass, MD

A Prospective, Randomized Study on the Effect of Band Ligation With or Without Mucosectomy As a Treatment for GERD: Pilot Study, 12 Month Experience (Kessler WR et al)

51.

Investigators randomized 10 patients with gastroesophageal reflux disease (GERD) and a clinical response to treatment with a proton pump inhibitor (PPI), but abnormal esophageal pH, to undergo targeted band ligation with or without mucosectomy. They measured GERD Health-Related Quality of Life (HRQoL) scores, as well as pH levels. At the time of abstract presentation, seven patients had completed 12-month follow-up. The investigators reported no complications during the procedure. Three patients reported de novo dysphagia following the procedure, one of whom was successfully treated with esophageal dilation. Mean HRQoL scores normalized in 60% and 71% of patients at six and 12 months, respectively, and there were no significant differences in HRQoL scores between the mucosectomy and non-mucosectomy groups. The percentage of time with total pH less than 4.0 in the mucosectomy group dropped from 8.3% at baseline to 4.7% at 12 months compared with 8.4% at baseline and 7% at 12 months in the non-mucosectomy group.

Six months after the procedure, all patients remained free of daily PPI use; one patient restarted PPI treatment at 12 months post-procedure. Dr. Fass: Although this was a very small study, most of the patients experienced a marked improvement in HRQoL scores over a one-year period after band ligation, and most were able to discontinue PPI use. Regarding safety, dysphagia was reported d in i three h patients i and d treated d with i h one round d off esophageal dilation in one patient. One concern is that although the mean intraesophageal acid exposure time decreased relative to baseline with band ligation, it still remained abnormal. Questions include what will happen over time if esophageal acid exposure persists, and will patients eventually return to the levels of acid exposure they had before intervention. The procedure needs to be studied in a larger number of patients over a longer period of time in order to demonstrate the durability and safety of this technique. Predictors of Response in Patients With Chronic Cough Referred for GERD Evaluation (Kavitt RT et al) Investigators enrolled 140 patients with chronic cough lasting more than eight weeks to undergo esophageal impedance monitoring and esophagogastroduodenoscopy (EGD) during a trial of twice-daily treatment with a PPI. Subsequently, some patients underwent twicedaily PPI treatment for four months, whereas another group underwent surgical fundoplication. Wireless 48-hour pH monitoring was conducted one week after the end of PPI therapy or surgery. At baseline, 20% of patients had esophagitis (mostly grade A or B), and 36% had a hiatal hernia, including 63% with a segment less than 3 cm in length. Thirtyeight percent of patients had abnormal results of impedance monitoring during initial PPI testing. The researchers found that 80% of study participants had abnormal pH exposure one week after discontinuation of PPI therapy, including 20% who had moderate to severe GERD. Nearly half of PPI recipients and 72% of surgical fundoplication patients experienced a greater than 50% improvement in chronic cough symptoms one week after PPI discontinuation or surgery. Statistical analyses showed that esophageal pH less than 4.0 for more than 12% of the time, concomitant

234.

see Best of DDW, page 24

ASGE Endoscopic Learning Library

Six New DVDs for 2013!

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Colonoscopy Technique: Basic and Advanced 2nd Edition (DV055) This updated instructional video covers informed consent, selecting the type of colonoscope, understanding tip deflection, anatomic landmarks in the colon, colonoscopic insertion technique, intubation of the terminal ileum, the impact of sedation on technique, maintaining safety during colonoscope insertion, withdrawal technique, and finally, the very difficult colonoscopy. This title is also available in Spanish. 1.75 AMA PRA Category 1 Credits™

Colonoscopic Polypectomy 2nd Edition (DV056) This DVD provides updated content on identifying indications and techniques for polypectomy, and ccovers a variety of key topics, including high-risk polypectomy and the use of ancillary techniques. You will learn to recognize the principal complications of polypectomy, identify visual cues to polyp Yo histology, st and formulate recommendations for follow-up of colorectal polyps after polypectomy. 4.00 00 AMA PRA Category 1 Credits™

Endoscopic Management of Early Stage Cancers of the Esophagus and Stomach (DV057) This program ro offers a comprehensive, evidenced-based review of the current endoscopic techniques qu for endoscopic resection of malignant and premalignant lesions of the esophagus and stomach. h Beneﬁt from detailed demonstrations of EMR/ESD in the esophagus and stomach that are shown in n HD, and categorized by speciﬁc location (cardia, body, antrum, prepyloric area). This DVD focuses o on delivering practical information for beginner as well as advanced endoscopists. 1.25 AMA M PRA Category 1 Credits™ 2013 Audiovisual Award Honorable Mention

Anorectal Bleeding (DV058) While a sspectrum of anorectal causes for bleeding exist, patients and physicians often tend to believe tthat this area is restricted to the evaluation and management of hemorrhoids. This DVD focusess on the etiology, evaluation and management of anorectal bleeding, and provides the necessary sa knowledge to manage common anal ﬁssures, recognize and manage diversion colitis, and m manage radiation proctopathy. 1.25 5A AMA PRA Category 1 Credits™

Ofﬁce-Based, Non-Endoscopic Treatments for Hemorrhoids (DV059) Th DVD covers the non-surgical care of hemorrhoids and ﬁssures, an area many gastroenterologists This have previously tended to shy away from. This educational program will improve your diagnostic skills regarding the anorectum, as well as help you recognize and discuss the anatomy of the anorectum and pathophysiology of hemorrhoids. 0.75 AMA PRA Category 1 Credits™ 2013 Audiovisual Award Winner

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Learn the endoscopic technique of cyanoacrylate glue injection of varices based on current guidelines. This DVD describes and discusses the readily available cyanoacrylate, the details of the glue and endoscope preparation, the pearls of successful injection and the methods to avoid complications. Participants of this program will be able to perform successful injection of cyanoacrylate and design proper application process to avoid complications. 0.50 AMA PRA Category 1 Credits™ Continuing Medical Education – ASGE is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. ASGE designates these enduring materials for the stated maximum number of AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. For more information about claiming AMA PRA Category 1 Credit™ for activities in the Endoscopic Learning Library, visit www.asge.org.

Superior GPIERWMRK IJ½ GEG]*

*Demonstrated non-inferiority with both split-dose and day-before regimens, evaluated in randomized trials using the validated Aronchick scale. Superior cleansing efficacy of split-dose regimen demonstrated vs day-before regimen comparator (84% vs 74%, respectively, achieving “excellent or good” visualization). The comparator was 2L PEG with electrolytes (PEG+E) plus 2x 5 mg bisacodyl tablets, dosed as labeled. The primary efficacy endpoint was the proportion of patients with successful colon cleansing defined as bowel preparations with >90% of the mucosa seen and mostly liquid stool, assessed by blinded colonoscopists. P<0.002 [Prepopik: n=256/304; comparator: n=221/297].1-3

INDICATION AND IMPORTANT SAFETY INFORMATION Prepopik ® for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. • Prepopik is contraindicated in the following conditions: patients with severely reduced renal function, gastrointestinal obstruction or ileus, bowel perforation, toxic colitis or toxic megacolon, gastric retention, or in patients with a known allergy to any of the ingredients in Prepopik. Patients should be advised on the importance of adequate hydration, and post-colonoscopy lab tests should be considered if a patient develops significant vomiting or signs of dehydration after taking Prepopik • Patients with electrolyte abnormalities should have them corrected before treatment. Use caution when prescribing for patients who are at risk for seizures, or arrhythmias, including those patients with a history of prolonged QT, recent myocardial infarction, unstable angina, congestive heart failure, or cardiomyopathy. Caution should also be used in patients with impaired gag reflex, regurgitation or aspiration, severe active ulcerative colitis, impaired renal function or patients taking medications that may affect renal function, electrolyte imbalance and/or water retention • Oral medication administered within one hour of the start of administration of Prepopik solution may be flushed from the GI tract and the medication may not be absorbed. Prior or concomitant use of antibiotics with Prepopik may reduce its efficacy. Tetracycline and fluoroquinolone antibiotics, iron, digoxin, chlorpromazine and penicillamine, should be taken at least 2 hours before and not less than 6 hours after administration of Prepopik to avoid chelation with magnesium. Osmotic laxatives may produce colonic mucosal aphthous ulcerations and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Concurrent use of additional stimulant laxatives with Prepopik may increase this risk • Prepopik should not be used if gastrointestinal obstruction or perforation is suspected. Prepopik is not for direct ingestion. Each packet must be dissolved in 5 ounces of cold water and administered at separate times, in addition to additional clear fluids, according to the dosing regimen. In randomized, multicenter, controlled clinical trials, nausea, headache, and vomiting were the most common treatment-emergent adverse reactions (>1%) following Prepopik administration Please see brief summary of Prescribing Information following this advertisement.

…with the lowest volume of active prep solution

Prepopik helps patients arrive ready with: SUPERIOR CLEANSING with ACG-recommended split-dose regimen*†1 84% of Prepopik bowel preparations were graded as “excellent” or “good” vs 74% with the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets), assessed using the validated Aronchick scale*1,2

90% of Prepopik patients had successful cleansing in the ascending colon vs 79% with the comparator, assessed using the validated Ottawa scale†1

EXCELLENT TOLERABILITY reported by patients in pivotal trials1,3 89% of patients found Prepopik easy to take vs 29% of those taking the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets); P<0.00011

99% of patients taking Prepopik completed their regimen vs 91% of those taking the comparator (2L PEG+E plus 2x 5 mg bisacodyl tablets)1

FLEXIBLE DOSING using either a split-dose or day-before regimen 4 A DUAL MECHANISM that stimulates peristalsis and produces osmotic water retention 4 †

The Ottawa bowel preparation scale assesses bowel cleanliness by section, based on numeric scores of 0-4. A score of 0 denotes “excellent” cleansing with ascending numbers denoting “good,” “fair,” “poor,” and “inadequate.” Additional numeric value is assigned based on the amount of ﬂuid present (small, moderate, or large). [Prepopik: n=272/304; comparator: n=234/297].1,2 References: 1. Rex DK, Katz PO, Bertiger G, et al. Split-dose administration of a dual-action, low-volume bowel cleanser for colonoscopy: the SEE CLEAR I study [published online ahead of print]. Gastrointest Endosc. 2013. http://dx.doi.org/10.1016/j.gie.2013.02.024. 2. Data on ﬁle. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA. 3. Katz PO, Rex DK, Epstein M, et al. A dual-action, low-volume bowel cleanser administered the day before colonoscopy: results from the SEE CLEAR II study. Am J Gastroenterol. 2013;108:401-409. 4. Prepopik® Prescribing Information, July 2012. Ferring Pharmaceuticals Inc. Parsippany, NJ 07054, USA.

Visit prepopik.com/tools to access a variety of helpful patient tools!

DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2013

Best of DDW continued from page 20

presence of heartburn, regurgitation and hiatal hernia greater than 4 cm were independent predictors of treatment response. Baseline impedance parameters and symptom index scores on or off initial PPI therapy did not predict treatment response. Dr. Fass: This is the first study to examine a large number of patients with chronic cough in order to determine

â&#x20AC;&#x2DC;The introduction of impedance as a diagnostic tool in this patient population may not help in predicting response to treatment.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Ronnie Fass, MD

which clinical parameters predict response to medical and surgical treatment. Some of the study findings are known. For

Aspiration Patients with impaired gag reĂ&#x20AC;ex and patients prone to regurgitation or aspiration should Ee oEserYed during the administration of PREPOPIK. Use with caution in these patients. Not for Direct Ingestion Each packet must Ee dissolYed in ounces of cold water and administered at separate times according to the dosing regimen. The following is a brief summary only; see full Prescribing Ingestion of additional water is important to patient tolerance. Direct Information for complete product information. ingestion of the undissolYed powder may increase the risk of nausea, Yomiting, dehydration, and electrolyte disturEances. INDICATIONS AND USAGE PREPOPIKâ&#x201E;˘ (sodium picosulfate, magnesium oxide and anhydrous ADVERSE REACTIONS citric acid) for oral solution is indicated for cleansing of the colon as a preparation for colonoscopy in adults. Clinical Trials Experience %ecause clinical trials are conducted under widely Yarying conditions, CONTRAINDICATIONS adYerse reaction rates oEserYed in the clinical trials of a drug cannot PREPOPIK is contraindicated in the following conditions: Ee directly compared to rates in clinical trials of another drug and may Â&#x2021; Patients with seYerely reduced renal function (creatinine clearance not reĂ&#x20AC;ect the rates oEserYed in practice. less than 30 mL/minute) which may result in accumulation of In randomized, multicenter, controlled clinical trials, nausea, headache, magnesium and Yomiting were the most common adYerse reactions (! ) Â&#x2021; *astrointestinal oEstruction or ileus following PREPOPIK administration. 7he patients were not Elinded to Â&#x2021; %owel perforation the study drug. 6ince aEdominal Eloating, distension, pain/cramping, Â&#x2021;7 7oxic colitis or toxic megacolon and watery diarrhea are known to occur in response to colon cleansing Â&#x2021; *astric retention preparations, these effects were documented as adYerse eYents in Â&#x2021; $n allergy to any of the ingredients in PREPOPIK the clinical trials only if they reTuired medical interYention (such as a change in study drug or led to study discontinuation, therapeutic or WARNINGS AND PRECAUTIONS diagnostic procedures, met the criteria for a serious adYerse eYent), Serious Fluid and Serum Chemistry Abnormalities or showed clinically signiÂżcant worsening during the study that was $dYise patients to hydrate adeTuately Eefore, during, and after the not in the frame of the usual clinical course, as determined Ey the use of PREPOPIK. 8se caution in patients with congestiYe heart inYestigator. failure when replacing Ă&#x20AC;uids. If a patient deYelops signiÂżcant Yomiting PREPOPIK was compared for colon cleansing effectiYeness with or signs of dehydration including signs of orthostatic hypotension a preparation containing two liters ( L) of polyethylene glycol plus after taking PREPOPIK, consider performing post-colonoscopy electrolytes solution (PE* E) and two -mg Eisacodyl taElets, all laE tests (electrolytes, creatinine, and %81) and treat accordingly. administered the day Eefore the procedure. 7a 7 Ele displays the most $pproximately 0 of patients in Eoth arms (PREPOPIK, L of PE* common adYerse reactions in 6tudy and 6tudy for the PREPOPIK E plus two x -mg Eisacodyl taElets) of clinical trials of PREPOPIK 6plit-Dose and Day-%efore dosing regimens, respectiYely, each as had orthostatic changes (changes in Elood pressure and/or heart rate) compared to the comparator preparation. on the day of colonoscopy. In clinical trials orthostatic changes were documented out to seYen days post colonoscopy. Table 1: Treatment-Emergent Adverse Reactions observed in at )luid and electrolyte disturEances can lead to serious adYerse eYents Least (>1%) of Patients using the Split-Dose Regimen and Dayincluding cardiac arrhythmias or seizures and renal impairment. Fluid Before Regimen** and electrolyte aEnormalities should Ee corrected Eefore treatment with PREPOPIK. In addition, use caution when prescriEing PREPOPIK Adverse Study 1: Split-Dose Regimen Study 2: Day-Before Regimen for patients who haYe conditions or who are using medications that Reaction increase the risk for Ă&#x20AC;uid and electrolyte disturEances or that may PREPOPIK 2L PEG+E* PREPOPIK 2L PEG+E* increase the risk of adYerse eYents of seizure, arrhythmia, and renal with 2 x (N=305) with 2 x 5-mg (N=296) impairment. n (% = n/N) 5-mg n (% = n/N) bisacodyl Seizures 7here haYe Eeen reports of generalized tonic-clonic seizures with the use of Eowel preparation products in patients with no prior history of seizures. 7he seizure cases were associated with electrolyte aEnormalities (e.g., hyponatremia, hypokalemia, hypocalcemia, and hypomagnesemia) and low serum osmolality. 7he neurologic aEnormalities resolYed with correction of Ă&#x20AC;uid and electrolyte aEnormalities. 8se caution when prescriEing PREPOPIK for patients with a history of seizures and in patients at risk of seizure, such as patients taking medications that lower the seizure threshold (e.g., tricyclic antidepressants), patients withdrawing from alcohol or Eenzodiazepines, patients with known or suspected hyponatremia. Use in Patients with Renal Impairment $s in other magnesium containing Eowel preparations, use caution when prescriEing PREPOPIK for patients with impaired renal function or patients taking concomitant medications that may affect renal function (such as diuretics, angiotensin conYerting enzyme inhiEitors, angiotensin receptor Elockers, or non-steroidal anti-inĂ&#x20AC;ammatory drugs). 7hese patients may Ee at increased risk for renal inMury. $dYise these patients of the importance of adeTuate hydration Eefore during and after the use of PREPOPIK. &onsider performing Easeline and post-colonoscopy laEoratory tests (electrolytes, creatinine, and %81) in these patients. In patients with seYerely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur.

tablets (N=298) n (% = n/N)

bisacodyl tablets (N=302) n (% = n/N) 1ausea 8 (2.6) 11 (3.7) 9 (3.0) 13 (4.3) Headache 5 (1.6) 5 (1.7) 8 (2.7) 5 (1.7) Vomiting 3 (1.0) 10 (3.4) 4 (1.4) 6 (2.0) L PE* E two liters polyethylene glycol plus electrolytes solution. aEdominal Eloating, distension, pain/cramping, and watery diarrhea not reTuiring an interYention were not collected

arrhythmias, and prolonged 47 in the setting of Ă&#x20AC;uid and electrolyte aEnormalities. 7his includes patients receiYing drugs which may Ee associated with hypokalemia (such as diuretics or corticosteroids, or drugs where hypokalemia is a particular risk, such as cardiac glycosides) or hyponatremia. Use caution when PREPOPIK is used in patients on nonsteroidal anti-inĂ&#x20AC;ammatory drugs (16$ID6) or drugs known to induce $ntidiuretic Hormone 6ecretion (6I$DH), such as tricyclic antidepressants, selectiYe serotonin re-uptake inhiEitors, antipsychotic drugs and carEamazepine, as these drugs may increase the risk of water retention and/or electrolyte imEalance. &onsider additional patient eYaluations as appropriate.

DRUG INTERACTIONS

Dr. Fass reported no relevant conflicts of interest.

Potential for Altered Drug Absorption Oral medication administered within one hour of the start of administration of PREPOPIK solution may Ee Ă&#x20AC;ushed from the *I tract and the medication may not Ee aEsorEed. 7etracycline and Ă&#x20AC;uoroTuinolone antiEiotics, iron, digoxin, 7 chlorpromazine and penicillamine, should Ee taken at least hours Eefore and not less than hours after administration of PREPOPIK to aYoid chelation with magnesium. Antibiotics Prior or concomitant use of antiEiotics with PREPOPIK may reduce efÂż f cacy of PREPOPIK as conYersion of sodium picosulfate to its actiYe metaEolite %HP0 is mediated Ey colonic Eacteria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy &ategory % Reproduction studies with PREPOPIK haYe Eeen performed in pregnant rats at oral doses up to 000 mg/kg/day (aEout . times the recommended human dose Eased on the Eody surface area), and did not reYeal any eYidence of impaired fertility or harm to the fetus due to PREPOPIK. 7he reproduction study in raEEits was not adeTuate, as treatment-related mortalities were oEserYed at all doses. $ pre and postnatal deYelopment study in rats showed no eYidence of any adYerse effect on pre and postnatal deYelopment at oral doses up to 000 mg/kg twice daily (aEout . times the recommended human dose Eased on the Eody surface area). 7here are, howeYer, no adeTuate and well-controlled studies in pregnant women. %ecause animal reproduction studies are not always predictiYe of human response, PREPOPIK should Ee used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. %ecause many drugs are excreted in human milk, caution should Ee exercised when PREPOPIK is administered to a nursing woman. Pediatric Use 7he safety and effectiYeness of PREPOPIK in pediatric patients has not Eeen estaElished.

Geriatric Use In controlled clinical trials of PREPOPIK, of 0 ( ) patients were years of age or older. 7he oYerall incidence of treatmentemergent adYerse eYents was similar among patients Â&#x2022; years of age ( 3 ) and patients < years of age ( ). $mong all patients Â&#x2022; years of age, the proportion of patients with successful colon cleansing Electrolyte abnormalities was greater in the PREPOPIK group ( . ) than in the comparator In general, PREPOPIK was associated with numerically higher rates group ( 0. ). of aEnormal electrolyte shifts on the day of colonoscopy compared to the preparation containing L of PE* E plus two x -mg Eisacodyl Renal InsufĂ&#x20AC; f ciency taElets. 7hese shifts were transient in nature and numerically similar Patients with impaired renal function or patients taking concomitant Eetween treatment arms at the Day 30 Yisit. medications that may affect renal function (such as diuretics, angiotensin conYerting enzyme inhiEitors, angiotensin receptor Postmarketing Experience Elockers, or non-steroidal anti-inĂ&#x20AC;ammatory drugs) may Ee at 7he following foreign spontaneous reports haYe Eeen identiÂżed during increased risk for further renal inMury. $dYise these patients of the use of formulations similar to PREPOPIK. %ecause these eYents are importance of adeTuate hydration Eefore during and after the use reported Yoluntarily from a population of uncertain size, it is not always of PREPOPIK. &onsider performing Easeline and post-colonoscopy possiEle to reliaEly estimate their freTuency or estaElish a causal laEoratory tests (electrolytes, creatinine, and %U1) in these patients. relationship to drug exposure. In patients with seYerely reduced renal function (creatinine clearance < 30 mL/min), accumulation of magnesium in plasma may occur. 7he Allergic reactions signs and symptoms of hypermagnesemia may include, Eut are not &ases of hypersensitiYity reactions including rash, urticaria, and limited to, diminished or aEsent deep tendon reĂ&#x20AC;exes, somnolence, purpura haYe Eeen reported. hypocalcemia, hypotension, Eradycardia, muscle, respiratory paralysis, complete heart Elock, and cardiac arrest. Electrolyte abnormalities 7here haYe Eeen reports of hypokalemia, hyponatremia and OVERDOSAGE hypermagnesemia with the use of PREPOPIK for colon preparation 7he patient who has taken an oYerdose should Ee monitored carefully, prior to colonoscopy. and treated symptomatically for complications.

Cardiac Arrhythmias 7here haYe Eeen rare reports of serious arrhythmias associated with the use of ionic osmotic laxatiYe products for Eowel preparation. 8se caution when prescriEing PREPOPIK for patients at increased risk of arrhythmias (e.g., patients with a history of prolonged 47, 7 uncontrolled arrhythmias, recent myocardial infarction, unstaEle angina, congestiYe heart failure, or cardiomyopathy). Pre-dose and post-colonoscopy Gastrointestinal E&*s should Ee considered in patients at increased risk of serious $Edominal pain, diarrhea, fecal incontinence, and proctalgia haYe Eeen reported with the use of PREPOPIK for colon preparation cardiac arrhythmias. prior to colonoscopy. 7here haYe Eeen isolated reports of reYersiEle Colonic Mucosal Ulceration, Ischemic Colitis and Ulcerative Colitis aphthoid ileal ulcers. Ischemic colitis has Eeen reported with the use Osmotic laxatiYes may produce colonic mucosal aphthous ulcerations of PREPOPIK for colon preparation prior to colonoscopy. HoweYer, a and there haYe Eeen reports of more serious cases of ischemic colitis causal relationship Eetween these ischemic colitis cases and the use reTuiring hospitalization. &oncurrent use of additional stimulant of PREPOPIK has not Eeen estaElished. laxatiYes with PREPOPIK may increase this risk. 7he potential for mucosal ulcerations should Ee considered when interpreting Neurologic colonoscopy Âżndings in patients with known or suspected inĂ&#x20AC;ammatory 7here haYe Eeen reports of generalized tonic-clonic seizures associated with and without hyponatremia in epileptic patients. Eowel disease. Use in Patients with SigniĂ&#x20AC;cant Gastrointestinal Disease If gastrointestinal oEstruction or perforation is suspected, perform appropriate diagnostic studies to rule out these conditions Eefore administering PREPOPIK. 8se with caution in patients with seYere actiYe ulceratiYe colitis.

example, erosive esophagitis and hiatal hernia are relatively uncommon in this patient population.

Importantly, when researchers looked at predictors of treatment response, impedance results, per se, were not predictive of response to therapy compared with what the authors called traditional parameters, such as extent of esophageal acid exposure, symptom severity and presence of esophageal inflammation. This study confirms that what weâ&#x20AC;&#x2122;ve been doing for a long timeâ&#x20AC;&#x201D;using the aforementioned parametersâ&#x20AC;&#x201D;is probably the right thing to do, and that the introduction of impedance as a diagnostic tool in this patient population may not help in predicting response to treatment; however, impedance might be useful in determining the likelihood of response to other types of treatment apart from antireflux medications in patients with chronic cough who do not respond to medical treatment or surgery. â&#x2013;

0anufactured Ey: Ferring Pharmaceuticals (China) Co., Ltd. 1o. HuiLing Lu (Ferring Road) 1ational Health 7 7echnology Park =hongshan City, *uangdong ProYince, CHI1$ 0anufactured for: Ferring Pharmaceuticals Inc. Parsippany, 1.-. 0 0

www.ferringusa.com - -FERRI1* Drugs That May Increase Risks of Fluid and Electrolyte Abnormalities Â&#x2039; 0 Ferring Pharmaceuticals Inc. Use caution when prescriEing PREPOPIK for patients with conditions $ll rights reserYed. Printed in U6$. or who are using medications that increase the risk for Ă&#x20AC;uid and PREPB%R60B00 B0 electrolyte disturEances or may increase the risk of seizure,

Benjamin Lebwohl, MD, MS Assistant Professor of Medicine and Epidemiology Columbia University Medical Center New York, New York

Serum I-Fabp Is a Useful Tool for Evaluation of Gluten Challenge in Adults With Celiac Disease (Adriaanse M et al)

70.

This study included 20 adults with celiac disease in clinical remission, defined as an absence of symptoms, tissue transglutaminase (tTG) less than 10 U/mL and strict adherence to a gluten-free diet for at least 12 months. Participants underwent a gluten challenge with 3 or 7.5 g of gluten per day for 14 days. Researchers documented symptoms, serum levels of intestinal fatty acidâ&#x20AC;&#x201C;binding protein (I-FABP) and immunoglobulin A (IgA) antibodies to tTG and deamidated gliadin peptide (DGP) both before and during the 28-day study period. Researchers also collected duodenal biopsies two weeks before and three and 14 days after gluten challenge, documenting villous height-to-crypt depth ratio (Vh:Cd) and intraepithelial lymphocyte (IEL) counts. Serum I-FABP levels were significantly elevated two weeks after gluten challenge and decreased after gluten was discontinued. Levels of I-FABP and IEL counts at baseline and at two weeks were

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

significantly correlated, as well as change in I-FABP levels and IEL counts during the two-week gluten challenge. IgA anti-tTG and IgA anti-DGP antibodies increased slightly during the gluten challenge but were markedly increased 14 days after gluten challenge. There were no significant correlations between I-FABP and IgA anti-tTG and IgA anti-DGP antibody levels, Vh:Cd ratio or symptoms at any time during the study. Also, there were no differences in I-FABP levels between the two doses of the gluten challenge. There was a trend toward lower I-FABP levels in patients who had adhered to a gluten-free diet for a longer time before gluten challenge.

‘Although the diagnosis of celiac disease in adults requires a small intestinal biopsy, there may be an eventual role for I-FABP to aid in the diagnosis of celiac disease and to serve as a marker for recent gluten exposure among patients with known celiac disease.’ —Benjamin Lebwohl, MD, MS

no difference in mortality rates among women with IgA anti-tTG

antibodies. Nineteen percent of deaths in the IgA anti-tTG group were due to

respiratory disease compared with 6% of deaths in the general NHANES population (adjusted HR, 5.11; 95% CI, 2.769.46). There were no other differences in causes of death. Dr. Lebwohl: Prior analyses of mortality risk in patients with undiagnosed celiac disease using stored serum samples have yielded conflicting results. In this analysis of the NHANES database, the investigators found that most patients with a positive tTG test did not have a positive see Best of DDW, page 26

Dr. Lebwohl: This study expands on our knowledge of a potentially promising biomarker that has been investigated in inflammatory bowel disease (IBD), and more recently, celiac disease. A common clinical conundrum is the patient who presents for evaluation after already starting a self-prescribed glutenfree diet. Celiac disease status can be difficult to determine in this scenario, and a gluten challenge may be indicated. Conventional serologies (tTG and DGP) may be slow to rise during the period of a gluten challenge, as was the case in this study. The rise and fall of I-FABP appears to have a closer temporal relationship with gluten ingestion. Although the diagnosis of celiac disease in adults requires a small intestinal biopsy, there may be an eventual role for I-FABP to aid in the diagnosis of celiac disease and to serve as a marker for recent gluten exposure among patients with known celiac disease. Increased Mortality Among Men Aged 50 Years Old or Older With Elevated IgA Anti-Tissue Transglutaminase Antibodies: NHANES III 1988-1992 Follow-up Study (Rubio-Tapia A et al)

Sa1251.

Investigators examined data from 3,185 women and 2,847 men registered in the National Health and Nutrition Examination Survey (NHANES) III database (1988-1992) who were at least 50 years of age. They analyzed stored serum samples for IgA anti-tTG, and if these were present, for IgA endomysial antibodies (EMA). They also documented mortality rates, which were available through Dec. 31, 2006, and conducted statistical analyses controlling for the effects of age, sex, smoking status and race. The researchers identified 85 participants with IgA anti-tTG antibodies and seven with IgA anti-EMA antibodies. There was an increased risk for death among IgA anti-tTG–positive men (adjusted hazard ratio [HR], 1.69; 95% confidence interval [CI], 1.26-2.29), but

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DDW 2013

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Best of DDW continued from page 25

EMA test, the latter of which is more specific for the presence of celiac disease. Nonetheless, tTG positivity was associated with an increased risk for death, particularly from respiratory disease. Because most of these tTG-positive patients had negative EMA results, this group likely consisted of many patients who did not have celiac disease. The implications are that a positive tTG result, even in the absence of celiac disease, may indicate significant morbidity.

Sa1275.

Decreased Risk of Celiac Disease in Patients With Helicobacter pylori Infection; Analysis of a National Histology Database (Lebwohl B et al)

Randy S. Longman, MD, PhD Assistant Attending Physician NewYork-Presbyterian Hospital Assistant Professor of Medicine Weill Cornell Medical College New York, New York

Chronic Immune-Mediated Colitis Is Associated With a Significantly Altered Luminal Microbial Metatranscriptome (Hansen JJ et al)

261.

This was a cross-sectional study of 136,179 patients without previously diagnosed celiac disease who had Researchers colonized two groups of germ-free, wildundergone EGD with gastric and duodenal biopsies type (WT) mice or interleukin (IL)-10 -/- knockout between January 2008 and June 2012. Researchers (KO 129 SvEv) mice with bacterial isolates representing compared the prevalence of histologically proven each major phylum of the intestinal microbiome over Helicobacter pylori in patients with celiac disease 10 weeks. The eight bacterial isolates were commensal (defined as villous atrophy and predominantly humanwith a Marsh score of 3) and derived. The investigators those with normal duodeconducted histologic exami‘Although the eradication nal histology. Patients were nations of colon specimens to of H. pylori has beneficial a mean 51 years of age, and document the extent of inteseffects with regard to peptic 66% were women. The investinal inflammation as well as tigators conducted analyses secretion of IL-12/23p40. ulcer disease and gastric controlling for age, sex and They also characterized fecal cancer, this database socioeconomic status. bacterial composition at five Two percent (2,689) of parweeks and cecal microbial analysis found a strong ticipants met the criteria for metatranscriptomes after 10 inverse correlation between celiac disease. Among those weeks. with celiac disease, 4.4% had They found that KO 129 H. pylori and celiac disease, H. pylori compared with 8.8% SvEv mice had more severe implying a possible protective of those without celiac disease histologic inflammation as effect of H. pylori against this (P<0.0001). Multivariate analwell as increased secretion yses confirmed that H. pylori of IL-12/23p40 compared autoimmune condition.’ was associated with a 52% with WT mice at five and 10 —Benjamin Lebwohl, MD, MS reduction in the likelihood weeks. However, the comof having celiac disease (odds position of fecal bacteria was ratio [OR], 0.48; 95% CI, similar in WT and KO mice, 0.40-0.58). Individuals with H. with Bacteroides thetaiotaomipylori also had an increased risk for intraepithecron, B. vulgatus and Ruminococcus gnavus dominating in lial lymphocytosis with normal villi (OR, 1.72; 9 5 % both groups. Notably, in both groups Escherichia faecalis comprised 4% of cecal microbial composition at 10 CI, 1.59-1.86). weeks but represented 51.7% of differentially expressed Dr. Lebwohl: There has been a marked rise in the microbial genes. Also, at 10 weeks, the researchers found prevalence of celiac disease over the past 50 years, significant differences in intestinal microbial metatranwhich has been demonstrated to represent a true scriptomes between the two groups. increase, and cannot be attributed merely to increased detection. During the same time period, rates of gas- Dr. Longman: Numerous studies have revealed tric H. pylori colonization have dropped precipitously. changes in the luminal microbes of patients with IBD. Although the eradication of H. pylori has beneficial The expansion of certain species, including adherent and effects with regard to peptic ulcer disease and gas- invasive E. coli (Baumgart M et al. ISME J 2007;1:403tric cancer, this database analysis found a strong 418), may promote inflammation, whereas the coninverse correlation between H. pylori and celiac dis- traction of other species, including Faecalibacterium ease, implying a possible protective effect of H. pylori prausnitzii, may correlate with increased rates of postagainst this autoimmune condition. The mechanism operative recurrence (Sokol H et al. Proc Natl Acad Sci for such a proposed link is not clear. H. pylorii may USA 2008;105:16731-16736). The majority of current affect the digestion of gluten due to modulation of studies in the area of the microbiome and IBD focus gastric pH. This organism may also serve to promote on identifying which bacteria are present by analyzing immune tolerance based on recruitment of regulatory DNA; however, they do not examine what the bacteria T lymphocytes to the gastric mucosa. ■ are doing, through analysis of RNA. In this study, Hansen et al assessed the metatranscripDr. Lebwohl reported no relevant conflicts of interest. tome, or the bacterial genes that are actively expressed.

Surprisingly, they found that the E. faecaliss transcriptome contained more than 50% of the differentially regulated genes despite representing only 4% of the total intestinal bacterial population. These results will drive a new standard in human microbiome analysis, encouraging others to define the functional elements of the metatranscriptome in patients with IBD, with potential applications in therapeutic microbiome manipulation. Iron Supplemented Diet Protects Against Chronic Immune Mediated Colitis in IL-10 Deficient Mice (Ellermann M et al) Researchers inoculated two cohorts of IL-10 -/- germfree mice with feces from a conventionally housed mouse and placed the inoculated mice on either an iron-deficient, iron-sufficient or iron-supplemented diet for four weeks. The mice were assessed for clinical disease severity, histologic inflammation and IL-12 p40 secretion. The investigators also identified microbial populations using bacterial 16S ribosomal RNA sequencing and bacteria-specific quantitative polymerase chain reaction analysis of stool and cecal mucosal samples. The researchers found that mice that received iron supplementation had significantly less severe colitis than mice receiving an iron-sufficient diet and also had lower serum and colonic IL-12 p40 levels. Mice with an irondeficient diet had slightly less severe colitis. Although the researchers noted that “compositional changes of the enteric bacteria did not explain the findings,” mice receiving iron supplements had a decreased total mucosal bacteria load and a 2.3-fold higher proportion of mucosa-associated F. prausnitzii compared with those on an iron-sufficient diet.

317.

‘Diet, obesity and inflammation correlate with profound changes in the intestinal microbiome, and both organic and inorganic compounds in the diet may shape the diversity and function of the microbiota.’ —Randy S. Longman, MD, PhD

Dr. Longman: Diet, obesity and inflammation correlate with profound changes in the intestinal microbiome, and both organic and inorganic compounds in the diet may shape the diversity and function of the microbiota. For example, one recent report suggests that red meat, which contains L-carnitine, can be metabolized by intestinal bacteria to the byproduct trimethylamine N-oxide, which subsequently promotes atherosclerosis N (Koeth RA et al. Nat Med 2013;19:576-585). Oral iron supplementation often is replaced by parenteral supplementation in patients with active IBD, given the superior efficacy and theoretical risk for inflammation associated with oxygen radicals produced by the Fenton reaction. However, the effect of oral iron supplementation on microbial species and immune cell polarization is not known.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

This study by Ellermann et al uses an elegant study (CDI). Investigators conducted genetic analyses to design to assess the effect of oral iron supplementa- identify possible correlations between 163 gene loci and tion in mouse the risk for developing models of colitis CDI among patients ‘This study by Ellermann et al uses an with human comwith UC. Individuals mensals. Although were a median 27 years elegant study design to assess the their results revealed of age at the time of effect of oral iron supplementation in no change in total fecal diagnosis. mouse models of colitis with human bacteria, they showed a Univariate statistidecrease in total mucocal analyses revealed commensals.’ sal associated microbial that six genetic loci —Randy S. Longman, MD, PhD burden and an increase were associated with in the anti-inflammaan increased risk for tory species F. prausnitCDI, and two loci zii with oral iron supplementation. This study supports were linked to a reduced risk for CDI. Individuals a surprising and potentially beneficial role for oral iron with a single high-risk locus had a 20% increased risk that needs to be evaluated in human cohorts. for CDI. Having more than one high-risk locus was linked to earlier CDI. The strongest correlations were Genetic Risk Factors for with the rs864745 (CREB5) locum (OR, 10.9; 95% Clostridium difficile Infection in CI, 1.5-81.7) and rs6667605 (TNFRSF14; OR, 6; 95% Ulcerative Colitis (Ananthakrishnan AN et al) CI, 1.4-25.8). This study comprised 319 patients with ulcerative coliUnivariate analyses showed that patients with CDI tis (UC) treated at a single tertiary care center. Of the were younger (mean age, 35 vs. 45 years; P=0.0002), patients, 29 had developed Clostridium difficile infection more likely to have pancolitis (69% vs. 51%; P=0.06)

835.

and less likely to have received anti–tumor necrosis factor therapy (24% vs. 42%; P=0.06). However, none of these variables were significantly correlated with CDI risk in multivariate analyses controlling for genetic risk factors. Dr. Longman: The epidemic of CDI over the past decade has been particularly burdensome in patients with IBD. Although colonic inflammation results in a contraction in microbial diversity and decreased colonization resistance, genetic factors that might enable CDI to take hold in patients with IBD have not been explored. Using a database compiled at Massachusetts General Hospital, Ananthakrishnan et al identified 29 cases of CDI in a cohort of 319 cases of UC. Notably, the presence of at least one high-risk allele was associated with a 20% increased risk for CDI. Although this was a small study, the data suggest that host genetics may influence susceptibility to CDI. Larger cohort analyses may identify subgroups of patients that could benefit from prophylaxis. ■ Dr. Longman reported no relevant conflicts of interest.

confronted with regulatory action in one location, the operators may move to another state and begin again. Indeed, laws and regulations can be their friends. Children’s Cancer Recovery Foundation was able to list some of its fundraising as a charitable program on its taxes, by having the solicitors deliver messages on cancer prevention and survival when they call to ask for donations.

BY GEORGE OCHOA

What are the worst cancer charities in the United States? The Tampa Bay Times and the Center for Investigative Reporting (CIR) answered this question by compiling a list of America’s worst charities—including organizations purporting to help children, police, firefighters and the fight against cancer. What makes these Table. The 10 Worst Cancer 50 charities so bad is that they spend the bulk of To Solicitors Over 10 Years the donations they receive—collectively, 69.3%—on paid solicitors, 27.2% on operating the charity and a mere 3.5% on direct cash aid (see Table).

What makes these charities so bad is that they spend a mere 3.5% of the donations they receive on direct cash aid. Ten of the 50 worst charities—or 20%—have cancer (or, in one case, leukemia) in their titles. Others claim to be addressing cancer under a more general heading, such as the Optimal Medical Foundation and the National Caregiving Foundation. The most popular theme among charities that are explicitly cancer-related is breast cancer—four have titles containing those words. Children’s cancer is the supposed target of another three, with the remaining three featuring positive words such as America, hope and national. Despite some efforts, regulators have achieved little to stop the perpetrators behind these charities, according to the Tampa Bay Times and CIR. When

Charities, Ranked By Total Paid

Ranka Charity

Total Raised By Solicitors

Total Paid To Solicitors

Percentage Paid on Direct Cash Aid

Cancer Fund of America

$98 million

$80.4 million

0.9

American Breast Cancer Foundation

$80.8 million

$59.8 million

5.3

Breast Cancer Relief Foundation

$63.9 million

$44.8 million

2.2

Children’s Cancer Fund of America

$37.5 million

$29.2 million

5.3

Children’s Cancer Recovery Foundation

$34.7 million

$27.6 million

0.6

National Cancer Coalition

$41.5 million

$14 million

1.0

Woman To Woman Breast Cancer Foundation

$14.5 million

$13.7 million

0.4

Children’s Leukemia Research Association

$9.8 million

$6.8 million

11.1

United Breast Cancer Foundation

$11.6 million

$6.6 million

6.3

Hope Cancer Fund

$1.9 million

$1.6 million

0.5

Rank among the top 50 worst charities of any kind Source: Tampa Bay Times and Center for Investigative Reporting

Crack the Case Wide Open For a patient living with carcinoid syndrome, a proper diagnosis is the ﬁrst step to appropriate disease management. Conﬁrm your suspicions and make the diagnosis. To learn more, visit www.carcinoidfacts.com.

Printed in USA

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CAR-1065521

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Patient Satisfaction continued from page 1

resonant with attendees was one given by M. Bridget Duffy, MD, founder of ExperiaHealth and chief medical officer for Vocera Communications on creating a competitive practice through enhancing the patient’s experience. Dr. Duffy discussed tactics and provided concrete examples of changes that gastroenterology practices could implement quickly to make their patients happy and build loyalty. Although some

physicians may view patient satisfaction as the softer side of medicine, she noted, in an era when reimbursement will be increasingly linked with measures of quality, it matters. “There is a lot of data that show the link between patient satisfaction with their experience and the quality of outcomes in an organization, in terms of both quality and safety, and financial metrics. They are intimately linked,” Dr. Duffy said. During her tenure as chief experience officer of the Cleveland Clinic, when the

institution enlisted her help in improving the patient experience, Dr. Duffy examined data on the clinic’s 15,000 annual complaints. “The No. 1 complaint was communication: [The patient] wasn’t listened to, wasn’t treated with respect, wasn’t treated with compassion,” she said. “When you ask patients … to define what quality means, it doesn’t mean a great physician, high-tech equipment or a state-of-the-art facility. They equate quality with how you communicate with them—and with compassion.”

‘There is a lot of data that show the link between patient satisfaction with their experience and the quality of outcomes in an organization, in terms of both quality and safety, and financial metrics. They are intimately linked.’ —M. Bridget Duffy, MD

Ingenuity Delivered!

Dr. Duffy presented a compelling argument for designing a practice around the patient experience that would create loyalty, and ultimately drive volume and financial livelihood. “What I see across the nation is a shotgun approach. People don’t know where to start,” she said. “If you’re going to address central-line infections, you get your whole organization aligned around the problem and the solutions to solve it and you closely track the data. But with patient satisfaction, people are trying all kinds of things; it’s not clear what metrics matter, and it’s exhausting your organizations.” Dr. Duffy suggested ideas that could be adopted by medical organizations that would have a positive influence on the patient’s total experience, including before they arrive, during their visit and after they leave. Several strategies resonated with gastroenterologists and practice managers, either as ideas they already had implemented in their practices, as new approaches to consider or as suggestions they hoped to bring on board in the near future.

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The patient experience begins before they walk through the door: often with a phone call, where kindness, informed assurance, and at the very least, a human

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

‘When you ask patients … to define what quality means, it doesn’t mean a great physician, high-tech equipment or a state-of-the-art facility. They equate quality with how you communicate with them —and with compassion.’ —M. Bridget Duffy, MD

voice will distinguish a patient-centered practice from an assembly line. “Humanize the process,” Dr. Duffy said. “It takes only one person at your clinic to destroy your great clinical outcomes.” Chal Nunn, MD, CEO of Gastroenterology Associates of Central Virginia in Lynchburg, who has worked with his front office staff to stress the importance of the patient experience, encourages his employees to practice the mnemonic AIDET: • Acknowledge the patient and his or her family; • Introducee yourself; • Duration—explain what will happen throughout the visit, who they will see, and when and what to expect; • Explain things carefully to the patient; and • “Thank you”—don’t ” forget to say it. “Patients don’t usually hear ‘thank you’ when they first show up, but they need to be thanked for coming to our practice,” Dr. Nunn said. “This is an example of what Dr. Duffy was talking about.”

‘Informed Hope’ One concept that Dr. Duffy suggested is what she called “informed hope.” Informed consent must be obtained before a procedure, but it serves to prepare the patient for what could go wrong. Conversely, informed hope serves to prepare a patient for what could go right, an

important consideration, for example, as they prepare to undergo sedation. “If I tell you ‘there’s a chance of perforation, bleeding and aspiration and please sign on the dotted line; now we’ll sedate you and talk to you when you wake up,’ it creates a lot of fear,” said Klaus Mergener, MD, director of GI Hospitalist Services, Digestive Health Specialists, Tacoma, Wash., and co-director of the GI Roundtable conference. “But we could emphasize some of the positive aspects that will likely result from this endoscopic intervention.” Dr. Mergener gave some examples of

how to communicate in a positive way with patients. For example, for diagnostic clarity, one could say, “this procedure will help us understand what’s making you sick so that we can create a treatment plan together.” Or for resolution of symptoms: “Once we remove the bile stone obstructing your duct, your belly pain will be gone.’” Or for cancer prevention: “If we find a polyp, we’ll remove it before it becomes a problem.” “I like the idea of ending the preprocedure discussion with a positive

message,” Dr. Mergener said. “Some people might view that as a minor issue, but I don’t think it is for many patients.” Dr. Nunn softens the preprocedure conversation by asking patients an open, unscripted question: “ ‘What kind of work do you do? Tell me something about your kids.’ I may be on a tight schedule, but I know I can give them 30 seconds to talk about their work, or about someone we know in common,” Dr. Nunn said. “That totally changes the dynamic.” see Patient Satisfaction, page 32

Patient Satisfaction continued from page 31

Frederick C. Saunders, MD, of Lancaster Gastroenterology Procedure Center, Lancaster, Pa., attended medical school at Loma Linda University School of Medicine in California, where patientâ&#x20AC;&#x201C;physician interactions were strongly emphasized, including the spiritual nature of that relationship and the importance of respecting that aspect of a patientâ&#x20AC;&#x2122;s needs. Dr. Saunders stressed the importance of cushioning observations of potential risk with a generous statement about outcomes when communicating with the patient. â&#x20AC;&#x153;Look them in the eye and tell them, â&#x20AC;&#x2DC;Iâ&#x20AC;&#x2122;m going to do the best job for you that I can,â&#x20AC;&#x2122; and introduce them to everyone in the room so they know the people taking care of them are committed to doing well,â&#x20AC;? he said.

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2013

patient. But I explained that the whole point of this is to take care of the patient we diagnosed, and that weâ&#x20AC;&#x2122;ll get better as we learn from it,â&#x20AC;? he said. â&#x20AC;&#x153;But we need to start somewhere.â&#x20AC;?

Biopsy Tracker One of the most anxiety-provoking experiences patients may endure is the time spent waiting to hear about biopsy results. Taking a cue from a national pizza chain, Dr. Duffy presented the idea of a biopsy tracker: People who place an online order with Dominoâ&#x20AC;&#x2122;s Pizza can

follow a â&#x20AC;&#x153;pizza trackerâ&#x20AC;? to watch the progression of their order from the time they place it until it is sent out on delivery. â&#x20AC;&#x153;I donâ&#x20AC;&#x2122;t understand why â&#x20AC;Ś we take a biopsy on a Tuesday, and our patients go into the weekend having no idea who is going to call them, or when,â&#x20AC;? Dr. Duffy said. Can we work with pathologists to figure out a way to inform patients what stage their biopsy is at so they can make sure they have the support they need when that phone call comes, she asked. â&#x20AC;&#x153;I think itâ&#x20AC;&#x2122;s a neat idea,â&#x20AC;? Dr. Mergener said, noting that his mother recently

Patient Navigators The concept of a health care navigator has become quite popular in health care conversations, and examples of navigator programs can be found in specialties such as breast cancer care and cardiology, where patients are closely followed as they transition from diagnosis to surgery and to outpatient care. â&#x20AC;&#x153;I think there is a tremendous opportunity for you all to create a gastroenterology navigator,â&#x20AC;? Dr. Duffy said, describing as an example the breast cancer navigator assigned to a woman the first time she has an abnormal mammogram. â&#x20AC;&#x153;There is a peace of mind that goes with having a human being guiding you to the next mammogram or fine needle biopsy. I think this will be a funded, reimbursable role in the future; one that goes beyond the case manager or social worker.â&#x20AC;? Dr. Nunn identified this concept as one that he could implement more or less immediately. â&#x20AC;&#x153;Often we see patients, diagnose their cancer on screening and schedule them to see a surgeon, but then we leave them hanging,â&#x20AC;? he said. â&#x20AC;&#x153;Theyâ&#x20AC;&#x2122;re shocked and they have a lot of questions, but they donâ&#x20AC;&#x2122;t hear from anyone until they see the surgeon.â&#x20AC;? Dr. Nunn turned to a local cancer center for advice on how to establish a colon cancer navigator. Now his patients with colon cancer are given procedure notes so that they know what is going on, and within a day or two they are contacted by a navigator who guides them through the entire cancer treatment program, from seeing the surgeon, to chemotherapy, to radiation. Initially Dr. Nunn met with a bit of resistance from some of his colleagues. â&#x20AC;&#x153;I had to talk my partners into it. Some said they didnâ&#x20AC;&#x2122;t want to give up their

In Active, Mild to Moderate Ulcerative Colitis (UC)1

INDICATIONS AND USAGE UCERISâ&#x201E;˘ is a glucocorticosteroid indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. DOSAGE AND ADMINISTRATION The recommended dosage of UCERIS is one 9-mg tablet to be taken once daily in the morning with or without food for up to 8 weeks.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS UCERIS is contraindicated in patients with known hypersensitivity to budesonide or any of the ingredients of UCERIS. WARNINGS AND PRECAUTIONS t )ZQFSDPSUJDJTN BOE BESFOBM TVQQSFTTJPO 4JODF 6$&3*4 JT B glucocorticosteroid, general warnings concerning glucocorticoids should be followed. t 5SBOTGFSSJOH QBUJFOUT GSPN TZTUFNJD DPSUJDPTUFSPJET Risk of impaired adrenal function when transferring from oral steroids with high systemic effects. Taper patients slowly from systemic corticosteroids if transferring to UCERIS. t *NNVOPTVQQSFTTJPO 1PUFOUJBM XPSTFOJOH PG JOGFDUJPOT FH existing tuberculosis, fungal, bacterial, viral, or parasitic

infection; or ocular herpes simplex). Use with caution in patients with these infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. t *ODSFBTFE TZTUFNJD HMVDPDPSUJDPJE TVTDFQUJCJMJUZ 3FEVDFE MJWFS function affects the elimination of glucocorticosteroids. t 0UIFS HMVDPDPSUJDPJE FGGFDUT $BVUJPO TIPVME CF UBLFO JO QBUJFOUT with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Most common adverse reactions (incidence â&#x2030;Ľ2%) are headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. DRUG INTERACTIONS Avoid Cytochrome P450 3A4 inhibitors (eg, ketoconazole, grapefruit juice). May cause increased systemic corticosteroid effects. USE IN SPECIFIC POPULATIONS )FQBUJD JNQBJSNFOU .POJUPS QBUJFOUT GPS TJHOT BOE PS TZNQUPNT of hypercorticism.

The Important Safety Information does not include all of the information needed to use UCERIS safely and effectively. Please see Brief Summary of Prescribing Information on the following page and Full Prescribing Information at www.UCERIS.com.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

‘Patients don’t usually hear “thank you” when they first show up, but they need to be thanked for coming to our practice.’ —Chal Nunn, MD

spent an agonizing week and weekend waiting for a biopsy result. “[Patients] sit at home and worry whether it will show cancer or not, and when the phone call will come. Some sort of mechanism, be it high-tech or low-tech, that would allow patients to track the whereabouts of their tissue is a good idea. An important concept,” said Dr. Mergener. Even without specific technology, gastroenterologists can address patient anxiety with transparency and reassurance. “What we do is pretty reproducible,” Dr. Nunn said. “I know when [biopsy tissue]

will get there, and I often know after the biopsy what it’s going to reveal. If I find a tumor and biopsy it, I’ll tell the patient I suspect cancer and we’ll find out about the biopsies in two or three days and I’ll call you with the results when that happens. If we explain how the process works and lay out when they’re going to hear from us, we can manage their expectations.”

Staff Experience One of Dr. Duffy’s suggestions focused on setting up a practice where every employee feels that their work is

UCERIS™:

A POWERFUL, LOCALLY ACTING STEROID1-3 t

MMX® technology targets delivery of budesonide throughout the full length of the colon1,2

3 times more patients taking UCERIS achieved combined clinical remission and mucosal healing compared with placebo3*

A SAFETY PROFILE THAT OFFERS CONFIDENCE1 t The rates of overall expected glucocorticoid-related side effects were similar for UCERIS

and placebo at 8 weeks—10.2% vs 10.5%, respectively1*

www.UCERIS.com CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: ≥4 and ≤10 at entry). The primary endpoint was induction of combined clinical remission and mucosal healing (defined as a UCDAI score of ≤1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a ≥1-point reduction in the endoscopic index [EI] score) after 8 weeks of treatment.1 *In a pooled analysis of 2 Phase III clinical trials.1,3 References: 1. UCERIS Prescribing Information. Santarus, Inc. January 2013. 2. Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61:31-38. 3. Data on file. Santarus, Inc. UCERIS is a trademark of Santarus, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd.

important and integral to the success of the practice. “If you create an optimal employee experience, you automatically have a great patient experience,” she said. “Creating a culture of engaged and loyal employees who act like owners improves patient satisfaction and the bottom line.” Dr. Saunders learned in a very tangible way what can happen when all employees are encouraged. Three years ago, he engaged in a quality initiative to see how his practice measured up against centers see Patient Satisfaction, page 34

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2013

Patient Satisfaction continued from page 33

of excellence in terms of adenoma detection rate (ADR). Six months later, the initial findings were encouraging. â&#x20AC;&#x153;We had a 6% sessile serrated adenoma (SSA) detection rate compared with 4% to 5%, and a 34% total ADR, [compared with 27%],â&#x20AC;? he said. But he thought they could do better, and having been dissatisfied for a long while by employee chatter in the endoscopy suite, he forbade nonessential conversation, BRIEF SUMMARY Please see package insert for Full Prescribing Information available at www.uceris.com UCERIS (budesonide) extended release tablets, for oral use Rx Only INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections. Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: t )ZQFSDPSUJDJTN BOE "ESFOBM 4VQQSFTTJPO t 4ZNQUPNT PG TUFSPJE XJUIESBXBM JO UIPTF QBUJFOUT USBOTGFSSJOH from Systemic Glucocorticosteroid Therapy t *NNVOPTVQQSFTTJPO t * ODSFBTFE 4ZTUFNJD (MVDPDPSUJDPTUFSPJE 4VTDFQUJCJMJUZ t 0UIFS (MVDPDPSUJDPTUFSPJE &GGFDUT Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo. They ranged in age from 18-77 years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1. Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2)

Headache Nausea Decreased Blood Cortisol Upper Abdominal Pain Fatigue Flatulence Abdominal Distension Acne Urinary Tract Infection Arthralgia Constipation

UCERIS 9 mg (N = 255) n (%) 29 (11.4) 13 (5.1)

UCERIS 6 mg (N = 254) n (%) 37 (14.6) 12 (4.7)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3)

11 (4.3)

6 (2.4)

1 (0.4)

10 (3.9)

8 (3.1)

5 (1.9)

8 (3.1) 6 (2.4) 6 (2.4) 6 (2.4) 5 (2.0) 5 (2.0) 5 (2.0)

5 (2.0) 8 (3.1) 4 (1.6) 2 (0.8) 1 (0.4) 5 (2.0) 1 (0.4)

5 (1.9) 5 (1.9) 2 (0.8) 5 (1.9) 1 (0.4) 4 (1.6) 2 (0.8)

especially during the withdrawal phase of the procedure. â&#x20AC;&#x153;That didnâ&#x20AC;&#x2122;t work. It was a negative approach and led to low morale,â&#x20AC;? he said. â&#x20AC;&#x153;But I also noticed that some of our technicians enjoyed finding polypsâ&#x20AC;&#x201D; sometimes before we didâ&#x20AC;&#x201D;and telling us.â&#x20AC;? So he decided to see if encouraging that interest could have a positive effect. For six months, Dr. Saunders and his colleagues educated all staff in how to identify polyps and encouraged them to speak up if they saw something the doctor had missed. 0G 6$&3*4 NH QBUJFOUT B UPUBM PG EJTDPOUJOVFE USFBUNFOU EVF to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies. Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2)

0WFSBMM Mood changes Sleep changes Insomnia Acne Moon face Fluid retention Hirsutism Striae rubrae Flushing

UCERIS 9 mg (N = 255) n (%) 26 (10.2) 9 (3.5) 7 (2.7) 6 (2.4) 6 (2.4) 3 (1.2) 2 (0.8) 1 (0.4) 0 0

UCERIS 6 mg (N = 254) n (%) 19 (7.5) 10 (3.9) 10 (3.9) 6 (2.4) 2 (0.8) 3 (1.2) 3 (1.2) 0 0 1 (0.4)

Placebo (N = 258) n (%) 27 (10.5) 11 (4.3) 12 (4.7) 8 (3.1) 5 (1.9) 4 (1.6) 3 (1.2) 0 2 (0.8) 3 (1.2)

No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating UCERIS 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1), but had not achieved remission. Among patients who took UCERIS 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took UCERIS 9 mg for 8 weeks in Study 1. In Study 4, the safety of long-term treatment with UCERIS 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to UCERIS 6 mg or placebo once daily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and UCERIS 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the UCERIS 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects were similar in patients with up to 12 months of therapy with UCERIS 6 mg and placebo. (Table 3) Table 3. Summary of Glucocorticoid Related Effects Over 12-month Treatment (Study 4)

0WFSBMM Insomnia Mood changes Moon face Sleep changes Acne Hirsutism Flushing Fluid retention

UCERIS 6 mg (N = 62) n (%) 9 (14.5) 4 (6.5) 4 (6.5) 3 (4.8) 3 (4.8) 3 (4.8) 3 (4.8) 1 (1.6) 1 (1.6)

Placebo (N = 61) n (%) 7 (11.5) 4 (6.6) 2 (3.3) 3 (4.9) 3 (4.9) 0 0 1 (1.6) 1 (1.6)

Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is pH dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids). USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects:: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable

â&#x20AC;&#x2DC;If you have ever been a patient or had a loved one as a patient, you understand where health care is broken. It is time for us as physicians to step up and lead the effort to improve it.â&#x20AC;&#x2122; â&#x20AC;&#x201D;M. Bridget Duffy, MD

to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/L, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately 0.007 and 0.014 mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/L in four infants and <0.04 nmol/L in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 Îźg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/L which is up to 10 times higher than the 1-2 nmol/L for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they SFTQPOE EJGGFSFOUMZ GSPN ZPVOHFS TVCKFDUT 0UIFS SFQPSUFE DMJOJDBM experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. If glucocorticosteroids are used at excessive doses for prolonged periods, systemic glucocorticosteroid effects such as hypercorticism and adrenal suppression may occur. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage may be reduced temporarily. Single oral budesonide doses of 200 and 400 mg/kg were lethal in female and male mice, respectively. The signs of acute toxicity were decreased motor activity, piloerection and generalized edema. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity Carcinogenicity studies with budesonide were conducted in rats and mice. In a two-year study in SpragueDawley rats, budesonide caused a statistically significant increase in the incidence of gliomas in male rats at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In addition, there were increased incidences of primary hepatocellular tumors in male rats at 25 mcg/kg (approximately 0.023 times the maximum recommended human dose on a body surface area basis) and above. No tumorigenicity was seen in female rats at oral doses up to 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). In an additional two-year study in male Sprague-Dawley rats, budesonide caused no gliomas at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). However, it caused a statistically significant increase in the incidence of hepatocellular tumors at an oral dose of 50 mcg/kg (approximately 0.05 times the maximum recommended human dose on a body surface area basis). The concurrent reference glucocorticosteroids (prednisolone and triamcinolone acetonide) showed similar findings. In a 91-week study in mice, budesonide caused no treatment-related carcinogenicity at oral doses up to 200 mcg/kg (approximately 0.1 times the maximum recommended human dose on a body surface area basis). Mutagenesiss Budesonide was not genotoxic in the Ames test, the mouse lymphoma cell forward gene mutation (TK+/â&#x20AC;&#x201C;) test, the human lymphocyte chromosome aberration test, the Drosophila melanogasterr sex-linked recessive lethality test, the rat hepatocycte UDS test and the mouse micronucleus test. Impairment of Fertilityy In rats, budesonide had no effect on fertility at subcutaneous doses up to 80 mcg/kg (approximately 0.07 times the maximum recommended human dose on a body surface area basis). However, it caused a decrease in prenatal viability and viability in pups at birth and during lactation, along with a decrease in maternal body-weight gain, at subcutaneous doses of 20 mcg/kg (approximately 0.02 times the maximum recommended human dose on a body surface area basis) and above. No such effects were noted at 5 mcg/kg (approximately 0.005 times the maximum recommended human dose on a body surface area basis).

UCERISâ&#x201E;˘ is a trademark of Santarus, Inc. U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293,273. ÂŠ 2013 Santarus, Inc.

1-UCE13033 V1

â&#x20AC;&#x153;Most technicians arenâ&#x20AC;&#x2122;t accustomed to telling their doctor that he or she missed something, so we wanted to deal with the fear that kept them from speaking up, and to reward them when they did,â&#x20AC;? he said. Six months later, the clinicâ&#x20AC;&#x2122;s ADR increased to 42%, and the SSA detection rate increased to 7%. They continued the study for another six months, with astonishing results. â&#x20AC;&#x153;We were so astounded, we had every physician involved pull their charts and audit the researcherâ&#x20AC;&#x2122;s work because we were afraid sheâ&#x20AC;&#x2122;d made a mistake,â&#x20AC;? he said. His center was now reporting an ADR of 52% and an SSA detection rate of 14%. After the audit, Dr. Saunders said they found a few mistakes; once the mistakes were rectified, the ADR â&#x20AC;&#x153;turned out to be even higher than we thought,â&#x20AC;? he said.

Final Thoughts In closing, Dr. Duffy described the necessity of addressing the fragmented, disjointed nature of health care today. â&#x20AC;&#x153;If you have ever been a patient or had a loved one as a patient, you understand where health care is broken. It is time for us as physicians to step up and lead the effort to improve it,â&#x20AC;? she said. She urged listeners to disrupt the status quo and lead innovations in health care that optimize the patient and staff experience. â&#x20AC;&#x153;These are not often costly or complex innovations, but ones that can readily be implemented with resources that already exist in your organizations,â&#x20AC;? Dr. Duffy said. She also stressed the importance of putting science behind those innovations to demonstrate the business case for focusing on the quality of the patient experience. â&#x20AC;&#x153;Therein lies the opportunity for you, as an organization, to lead innovation in the human experience of care, create new standards of care for gastroenterology, and measure the results to show that patient experience matters,â&#x20AC;? Dr. Duffy said. â&#x2013;

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Real-Time Clinical Data Make A Difference in Pharmacy Dynamic Monitoring Boosts Clinical Outcomes, Prevents Adverse Events, Saves Money BY AL HELLER The number of hospitals adopting electronic health records has more than tripled since 2009—a “revolution” in medical informatics that already has yielded major benefits in clinical pharmacy operations, according to David Bates, MD, MSc, medical director of clinical and quality analysis-information systems at Partners HealthCare, in Wellesley, Mass. “Pharmacists have an opportunity to see a wide array of data about patients that wasn’t previously possible,” Dr. Bates said in a recent interview. “With pharmacists caring for 80 to 120 patients at a time, depending on the hospital, having a synopsis on each makes it a lot easier to do what needs to be done.”

Given an average cost per preventable ADE of $4,685 (1997 value), the annual cost of the 37 events would be $173,345. By contrast, the cost to implement and maintain the technology was $124,600 in year 1 and $81,900 in subsequent years, according to the study results. Dr. Bates, who also serves as chief quality officer for Brigham and

Women’s Hospital, in Boston, said the hospital has developed a system with less frills than the one used in the Drug Safety study that currently saves the facility an estimated $950,000 per year. He also expects the hospital to implement Hospira’s TheraDoc technology later in 2013 to detect hospital-acquired infections.

‘On the order of 90% of the time, when a pharmacist makes an action-oriented therapeutic suggestion based on dynamic monitoring, the provider team makes a change.’ —David Bates, MD, MSc

Part of the synopsis Dr. Bates wants clinical pharmacists to be able to see in real time includes patient lab values, pharmaceutical orders and patient demographic data that, if acted on quickly, could help prevent adverse drug events (ADEs). ADEs can be quite costly to hospitals and patients, according to Dr. Bates, a long-time advocate of real-time dynamic monitoring as a tool for reducing the incidence and effect of medication mishaps. His latest research on the topic demonstrated the value of a targeted ADE monitoring system in a 140-bed community teaching hospital (Seger AC et al. Drug Saff 2007;30:817824). Over the six-month study period, 3,547 alerts were issued. A review of just the high-level alerts found two preventable ADEs—one led to a hypoglycemic episode in a patient with diabetes, and another led to hyperkalemia. Based on the results, the researchers projected that there would be 37 ADEs the hospital could detect early by fully implementing the dynamic-monitoring technology used in the study (VigiLanz).

motility monitoring

“Every institution should do something in dynamic monitoring,” Dr. Bates urged. “There’s no doubt that automated real-time surveillance makes clinical pharmacists much more efficient at intervening in situations where it is likely to have a benefit.” Such an approach has the added benefit of resulting in “more see Real-Time Monitoring, page 36

GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2013

John Russillo, RPh, clinical pharmacy manager at John Muir Medical Centers, in Concord and Walnut Creek, Calif., uses VigiLanz Dynamic Monitoring Suite software to help prevent adverse drug events, detect health careâ&#x20AC;&#x201C;associated infections and improve medication safety and patient outcomes.

Real-Time Monitoring continued from page 35

cohesive work patternsâ&#x20AC;? between pharmacists and other health care providers, he noted. When a hospital first adopts the technology, itâ&#x20AC;&#x2122;s understandable that â&#x20AC;&#x153;some physicians resist listening to pharmacists. But as they realize pharmacists are armed with critical data and insights, physicians find it easier to accept suggestions,â&#x20AC;? Dr. Bates said. â&#x20AC;&#x153;Weâ&#x20AC;&#x2122;ve tracked this. On the order of 90% of the time,

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when a pharmacist makes an actionoriented therapeutic suggestion based on dynamic monitoring, the provider team makes a change. Thatâ&#x20AC;&#x2122;s a high level of respect for pharmacists and also the underlying system.â&#x20AC;? Indeed, at both campuses of John Muir Medical Centers, in Concord and Walnut Creek, Calif., which have a combined 600 beds, clinical pharmacy manager John Russillo, RPh, uses the VigiLanz Dynamic Monitoring Suite to help prevent ADEs, detect health careâ&#x20AC;&#x201C;associated infections, improve medication safety and patient outcomesâ&#x20AC;&#x201D;and, he emphasized, raise the clinical competency of the entire staff of 75 pharmacists. The rules-guided software package merges hospital-based drug therapy, laboratory findings, surgery, radiology, documentation and other clinical data for clinicians to quickly identify potential pharmacotherapy interventions where needed. Contrasting with an estimated 85% of U.S. hospitals that still lack clinical decision support in electronic health records, Mr. Russillo was glad to blaze the trail with VigiLanz as its first client eight years ago. â&#x20AC;&#x153;I saw weâ&#x20AC;&#x2122;d be able to write exception-based rules to our own protocols and practice,â&#x20AC;? he said. For example: Whatâ&#x20AC;&#x2122;s the patientâ&#x20AC;&#x2122;s latest lab value? Which new drug is ordered? Did the patient have prophylaxis? Did the patient just come out of surgery? These customized rules, he explained, trigger â&#x20AC;&#x153;intelligent,â&#x20AC;? clinically significant alerts, and thus Muirâ&#x20AC;&#x2122;s pharmacists feel confident these are actionable items. â&#x20AC;&#x153;I call it noise reductionâ&#x20AC;&#x201D;itâ&#x20AC;&#x2122;s huge for avoiding alert fatigue and building pharmacist acceptance,â&#x20AC;? Mr. Russillo said. He noted that Muir runs close to 1,000 rules, and VigiLanz issues 30 to 50 alerts per 100 patients each day. Pharmacists canâ&#x20AC;&#x2122;t ignore any alerts because the system issues them to the various hospital units where they work, he added. A critical alert reaches a pharmacist on his or her iPad or iPhone while they are making rounds with physicians, where decisions to change medication therapy can be made promptly. In case of questions about an alert, the software describes the rule that triggered it, gives guidance for action needed, and shows links to further references such as a page on the FDA websiteâ&#x20AC;&#x201D;for instance, one describing a black box warning. Pharmacist responses to alerts are

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

also tracked, which ensures accountability with electronic audit trails. Mr. Russillo underscored the importance of this feature because clinical pharmacist interventions reduce the occurrence of avoidable ADEs, improve patient outcomes, and contribute to John Muir scoring higher on the 13 Medicare clinical measures. This, in turn, could help Muir potentially be eligible to recover some or all of the Centers for Medicare & Medicaid Services’ 1% basepayment withholding in 2013-2016 or 2% in 2017, which is part of the agency’s Value-Based Purchasing Program. Muir initially used VigiLanz to help achieve safe and appropriate medication dosing, Mr. Russillo recalled. As trust in it built, he said, John Muir began to use the software to help achieve best practices in medication safety; deliver consistent care quality via the application of evidence-based rules and the knowledge gained by pharmacists; and improve drug utilization and core-measure compliance with Joint Commission standards for treating specific conditions, such as acute myocardial infarction, pneumonia and thromboembolism. For example, John Muir has reduced its anticoagulation-related ADEs by more than 50% over a year’s time. This occurred during the hospital’s second year of use, and the automated technology continues to sustain the lower rate. In absolute numbers, avoidable anticoagulation ADEs have fallen from 30 to less than 10 ADEs per year, which by itself translates into a savings of $230,000 annually, Mr. Russillo said. He estimated the technology saves the hospital overall greater than five times its annual cost each year, while costing less than a full-time equivalent pharmacist to operate. Savings occur largely in pharmacists’ time—by making them more efficient, avoiding about two hours of manual screening time per pharmacist per day, and identifying more opportunities to improve medication oversight and utilization. Moreover, John Muir uses VigiLanz as an antimicrobial stewardship program aid that allows it to efficiently, voluntarily report the hospital’s infection rates

Questions, comments, suggestions? Contact the Editor 212.957.5300 x277 cgordon@mcmahonmed.com

and antibiotic utilization to the Centers for Disease Control and Prevention’s National Healthcare Safety Network. Mr. Russillo said by being one of only about 50 U.S. hospitals to report both outcomes, John Muir could more effectively analyze its use of antibiotics, identify where it could improve and benchmark its performance against others. ■ Mr. Russillo has consulted for VigiLanz. Dr. Bates has consulted for VigiLanz and also has received research support from the company.

Real-time patient information such as the data shown above can be accessed via dynamic monitoring technology.

NEW

In bowel preparation

The NEW Combination Makes the Difference Introducing Suclear Provides the ﬂexibility and convenience of two dosing regimens (same-day, split-dose), with success* achieved in 90% of patients1,2 Significantly more “excellent” preps* with Suclear vs HalfLytely (47.7% vs 35.6%, respectively; P=0.01†) in same-day dosing comparison1 – Prep time was 33% less with Suclear compared to HalfLytely (3.7 hours vs 5.5 hours, respectively; P<0.001†)1 Equivalent rates of excellent cleansing* between Suclear and MoviPrep®‡ (51.9% vs 51.4%, respectively) in split-dose comparison1 Cecum reached in almost all patients using Suclear (split-dosing: 100%; same-day dosing: 99%)1 * *Based on investigator grading. † Statistically signiﬁcant difference. ‡ MoviPrep [PEG-3350, sodium sulfate, sodium chloride, potassium chloride, sodium ascorbate and ascorbic acid for oral solution] is a trademark of the Norgine group of companies.

IMPORTANT SAFETY INFORMATION Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution) is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reﬂex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended (sodium sulfate, potassium sulfate, and magnesium sulfate ﬁnal volume.

NEW

Please see brief summary of Full Prescribing Information on adjacent page.

oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

AMA Blasts Pharmacists’ ‘Intrusion Into Medical Practice’ BY BRUCE AND JOAN BUCKLEY A bluntly worded American Medical Association (AMA) resolution that was intended to curb a barrage of retail pharmacy phone calls to physicians requesting additional information about pain medication prescriptions has triggered a backlash from pharmacists, some of whom objected to the resolution’s sharp tone as a departure from the mostly

collegial relationships that exist between the two professions. “It’s a step backward,” said David Craig, PharmD, BCPS, a clinical pharmacy specialist at the H. Lee Moffitt Cancer Center and Research Institute, in Tampa, Fla. “I work collaboratively with many physicians who do not agree with this resolution at all. In fact, they welcome any pharmacist’s input, advice and recommendations.” The policy passed by the AMA

House of Delegates in June was written in response to what the resolution described as “pharmacy intrusion into medical practice.” It stated that the AMA “deem[s] inappropriate inquiries from pharmacies to verify the medical rationale behind prescriptions, diagnoses and treatment plans to be an interference with the practice of medicine and unwarranted.” It also threatened that if the issue were not resolved, the AMA would “advocate for legislative

NEW (sodium sulfate, potassium sulfate, and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution)

Introducing Suclear The NEW combination for dosing flexibility High success rates in same-day and split-dose regimens1,2 Cecum reached in nearly 100% of patients1 Significantly less prep time compared to HalfLytely1 References: 1. Data on ﬁﬁle. Braintree Laboratories, Inc., Braintree, MA. 2. Suclear [package insert]. Braintree, MA: Braintree Laboratories, Inc; 2013.

BRIEF SUMMARY: Before prescribing, please see Full Prescribing Information and Medication Guide for Suclear™ (sodium sulfate, potassium sulfate and magnesium sulfate oral solution; and PEG-3350, sodium chloride, sodium bicarbonate and potassium chloride for oral solution). INDICATIONS AND USAGE: A combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. CONTRAINDICATIONS: Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to components of the kit. WARNINGS AND PRECAUTIONS: Suclear is a combination of osmotic laxatives indicated for cleansing of the colon as a preparation for colonoscopy in adults. Use is contraindicated in the following conditions: gastrointestinal (GI) obstruction, bowel perforation, toxic colitis and toxic megacolon, gastric retention, ileus, known allergies to Suclear. Use caution when prescribing for patients with a history of seizures, arrhythmias, impaired gag reflex, regurgitation or aspiration, impaired renal function or patients taking medications that may affect renal function or electrolytes. Patients with severe active ulcerative colitis may be at increased risk of exacerbation of their disease. Pre-dose and post-colonoscopy ECG’s should be considered in patients at increased risk of serious cardiac arrhythmias. Administration of osmotic laxative products may produce mucosal aphthous ulcerations, and there have been reports of more serious cases of ischemic colitis requiring hospitalization. Patients with impaired water handling who experience severe vomiting should be closely monitored including measurement of electrolytes. Advise all patients to hydrate adequately before, during, and after use. Each bottle must be diluted with water to the recommended final volume. Pregnancy: Pregnancy Category C. Animal reproduction studies have not been conducted. It is not known whether this product can cause fetal harm or can affect reproductive capacity. Pediatric Use: Safety and effectiveness in pediatric patients has not been established. Geriatric Use: Of the 362 patients who took Suclear in clinical trials, 90 (25%) were 65 years of age or older, while 29 (8%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between geriatric patients and younger subjects. DRUG INTERACTIONS: Oral medication administered within one hour of the start of administration of each Suclear dose may not be absorbed completely.y Concurrent use of stimulant laxatives and Suclear may increase the risk of mucosal ulcerations or ischemic colitis. ADVERSE REACTIONS: Most common adverse reactions (>2%) are overall discomfort, abdominal distention, abdominal pain, nausea, vomiting and headache. Oral Administration: Consume only clear liquids (no solid food or milk) and avoid alcohol on the day before colonoscopy until after completion of the colonoscopy. Split-Dose (2-Day) Regimen (Preferred Method): Dose 1 – Evening before the colonoscopy (10 to 12 hours prior to Dose 2): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Refill the container and drink another 16 oz. of water over the next 2 hours, and another before going to bed. Dose 2 – Next morning on the day of colonoscopy (start at least 3 ½ hours prior to colonoscopy): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Complete drinking the solution at least 2 hours before the colonoscopy. Consume only clear liquids until 2 hours prior to colonoscopy. Day-Before (1-Day) Regimen (Alternative Method): On the evening before the colonoscopy: Dose 1 (begin at least 3 ½ hours prior to bedtime): Dilute the 6 oz. oral solution by pouring the entire contents of the bottle into the 16 oz. mixing container and then filling the container with cool water to the fill line and mix. Drink the entire solution in the container. It is best to complete drinking the solution within 20 minutes. Drink another 16 oz. of water over the next 2 hours. Dose 2 (approximately 2 hours after starting Dose 1): Dissolve the powder of Dose 2 by adding water to the fill line on the jug. Shake jug until powder is dissolved. The solution can be used with or without the addition of a flavor pack. Using the 16 oz. container provided, drink all the solution in the jug at a rate of one 16 oz. container every 20 minutes. Refill the container and drink another 16 oz. of water before going to bed. Consume only clear liquids until 2 hours prior to colonoscopy. STORAGE: Store at 20-25°C (68-77°F). Excursions permitted between 15-30°C (59-86°F). Rx only. Distributed by Braintree Laboratories, Inc. Braintree, MA 02185 For additional information, please call 1-800-874-6756 or visit www.braintreelabs.com ©2013 Braintree Laboratories, Inc.

SU-14168

March, 2013

and regulatory solutions to prohibit pharmacies and pharmacists from denying medically necessary and legitimate therapeutic treatments to patients.” Scott Strassels, PharmD, PhD, a pain management specialist who spent more than seven years as an assistant professor and a researcher at the University of Texas at Austin College of Pharmacy, called the policy a “dangerous precedent to shut off important phone calls or important contact with prescribers.” He added, “Nobody wants to spend time on the phone that they don’t really need to, but there are times when a pharmacist and prescriber need to be on the same page with regard to safety issues, and that includes the potential for drug interactions as well as the effect of a given drug for a particular person.” B. Joseph Guglielmo, PharmD, dean and chair of clinical pharmacy at the University of California, San Francisco School of Pharmacy, added that the future of patient care “has to be one in which medical information about patients is made available to all relevant health care providers, so that ... the safest and most effective medication use will take place.” He noted that what has “limited pharmacists from maximizing their input in the community pharmacy setting has been the lack of such information.”

Policy on Prescription Drug Abuse At the heart of the issue is the federal government’s stepped-up efforts to block diversion of controlled medications and contain the growing nationwide prescription drug abuse epidemic. In response to tightened Drug Enforcement Administration (DEA) scrutiny, many drugstore chains have beefed up their controls over narcotic drug dispensing by their pharmacies. The result has been more pharmacy phone calls and faxes to prescribers requesting the validation of information to ensure that the pain-killing drugs were not being abused or falling into the wrong hands. Richard Pieters, MD, a radiation oncologist at the University of Massachusetts Medical Center and president-elect of the Massachusetts Medical Society, who wrote the original draft for the AMA resolution, told Gastroenterology & Endoscopy Newss that a major reason for the AMA’s action was the Walgreens Company’s policy of requiring its pharmacists to “demand” information before filling narcotic prescriptions, including diagnoses, International Classification of Diseases Ninth Revision codes, patient treatment plans and previously tried medications. “This is beyond the scope of practice for the pharmacist,” Dr. Pieters said. “It’s not appropriate to be asking that kind of

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

question. It’s an intrusion into the practice of medicine. “Pharmacy phone calls for allergies, drug interactions, strengths are totally appropriate,” he said. “And we understand that there is a [prescription drug abuse] scourge and that drug overdoses are a major problem. But this is not how you fix it. This is the drugstore chains trying to look like good citizens on the backs of the medical community.” Walgreens did not reply to a request for comment, but a spokesman for the National Association of Chain Drug Stores told American Medical Newss that pharmacies have had to respond to new levels of DEA scrutiny over the purported overdispensing of controlled substances. In June, Walgreens agreed to pay $80 million to settle DEA and Department of Justice charges that it failed to exercise sufficient controls over the dispensing of narcotic medications at some of its pharmacies, according to a Walgreens press release. As part of the settlement, the company also agreed to surrender its DEA registrations at six Florida pharmacies until May 2014 and at its Jupiter distribution center until September 2014. Walgreens also instituted an education program for its pharmacy team members to provide them “with the tools, training and support they need to ensure the appropriate dispensing of controlled substances and to improve collaboration across the industry.” Kermit Crawford, president of the Pharmacy, Health and Wellness division of Walgreens, said in a statement, “We are fully committed to doing our part to prevent drug abuse. We also will continue to advocate for solutions that involve all parties—including leaders in the community, physicians, pharmacies, distributors and regulators—to play a role in finding practical solutions that combat the abuse of controlled substances and ensure patient access to critical medications.” As part of its controversial resolution, the AMA also stated that it was willing to work with stakeholders to develop “appropriate policy for pharmacists to work with physicians in order to reduce the incidence of drug diversion and inappropriate dispensing.”

Physicians’ Perspective William Hopkins, MD, an anesthesiologist and pain specialist in Campbell, Calif., has experienced first hand the frustrations of dealing with pharmacists who have recently accelerated their demands for detailed clinical information for chronic pain patients—an experience that he says has led him to support the AMA resolution. Most commonly, he noted, it is the “big-box” chain pharmacies that will send a fax or call him requesting diagnostic details on these patients,

especially when opioids are involved. “They’ll also ask whether I have plans for transitioning the patient off opioids and onto alternative agents,” he said. “There simply is not enough time in my day to give them a detailed response on the responsible steps I have taken to ensure these patients’ regimens are appropriate, whether it’s counseling and education, consultations with their primary care physicians or other involved specialists.” The “arrogance of ignorance” that underpins these requests by some pharmacists “is frankly astounding,”

Dr. Hopkins saiid. “They presume that I didn’t already takke these appropriate actions—that som mehow I am prescribiing controlled substances indiscriminately. They make assumptions without assessing the patien nt and with hout knowing my level of evalu uaattiion u and decision makin ng.” By seeking to t block his see AMA Resolution, solution, page 40

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AMA Resolution continued from page 39

prescribing decisions, “these big-box pharmacists are rendering medical determinations without a good-faith assessment of the patient,” Dr. Hopkins said. “If I were to do that, I would be censured by the medical board. Franz Kafka couldn’t have envisioned a more absurd scenario.” This is not to say, he stressed, that there aren’t physicians who misprescribe or patients who abuse medications.

1978

—

“This is a huge problem,” he said. “But questioning the clinical decisions of responsible physicians ... isn’t the solution.” Dr. Hopkins noted, “I am not antipharmacy. I hold community and hospital pharmacists in high regard. They provide a superb service by providing alerts on potential drug interactions, incorrectly written prescriptions, suspicious prescription-filling, etc. I want calls and faxes about those issues.” However, Dr. Hopkins pointed out, “What I don’tt need are demands for detailed clinical information from a

pharmacist who, far removed from the clinic, is making a medical decision at variance to my own, and in so doing, causing patient distress and wasting my time. This promotes friction and distrust. This latest trend seems driven by fear of current media and pressure, not by clinical competence or compassion.” Indeed, Dr. Pieters acknowledged that, outside of the experiences that led to the AMA resolution, his own working relationships with pharmacists are excellent. “Pharmacists are very valuable members of the team. In addition to being a

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ACG 2012

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Experts’ Picks

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MDs and DOs Plan Unified Accreditation System For Graduate Medical Education ............... page 5

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radiation oncologist, I’m board-certified in hospice and palliative medicine, and pharmacists are fantastic resources in terms of suggesting alternative drugs,” Dr. Pieters said.

Pharmacy Groups Chime In Pharmacy groups had various reactions to the AMA policy declaration. The National Community Pharmacists Association (NCPA) opposed it, calling it “shortsighted” and “simplistic” in its approach to the prescription drug abuse epidemic. “We support a collective approach to controlling abuse and diversion that involves everyone: patient, pharmacist, pharmacy benefit manager, wholesaler, manufacturer and prescriber,” the NCPA said. It also noted that “additional education of prescribers” was needed to combat prescription drug abuse, an apparent reference to the AMA’s failure to mention the role that inappropriate prescribing has played in such abuse. At the American Pharmacists Association, Thomas E. Menighan, BSPharm, MBA, executive vice president and CEO, said although pharmacists were “disappointed in the passage of a resolution that discourages a team-based approach to health care, the policy provides an opening to find solutions for controlled substance verification.” He said it was “not pharmacy’s intent to delay patients from receiving these needed medications or to unnecessarily interrupt prescribers,” and added that the situation underscored “the need for pharmacy, medicine and regulators to collaborate on solutions that address the root cause of ... abuse problems in this country.” Kasey Thompson, PharmD, vice president of Policy, Planning and Communications for the American Society of Health-System Pharmacists (ASHP), said, “The bottom line is that there is a major prescription drug abuse epidemic in this country, and we need to find more ways to work together as a health care community to solve it.” He added that “ASHP and our other pharmacy organizations have a really good working relationship with the AMA, and I’m quite confident that we’ll find productive ways to collaborate in an interdisciplinary fashion on this issue. That’s what we’re focused on.” As for the resolution itself, Dr. Thompson said he thought it did not “really reflect the state of collaboration that exists today. If you talk with a vast majority of ASHP’s 42,000 members, you’ll hear story after story about how they work in an interdisciplinary team in the care of patients. It’s the health care delivery system of the 21st century; there’s more collaboration, not less, going on.” ■ —Additional reporting by David Bronstein

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

MediSafe Project Raises Medication Adherence Rates BY GEORGE OCHOA In the first eight weeks since its launch, the mobile app MediSafe Project achieved a reported medication adherence rate of 81% among its users. That figure is 31% higher than the World Health Organization’s estimated average medication adherence rate of 50%, according to a press release from the company, MediSafe Project, based in Haifa, Israel. For example, for MediSafe Project users who recorded their use of statins, the adherence rate was 84%, which is 34% higher than in the general population.

and when a user misses a dose, sends alerts to selected family members, friends and caregivers. Users have visited the app a total of 95,000 times per month and recorded taking more than 100,000 medication doses as directed. According to the MediSafe Project website (www.medisafeproject. com), low-tech alternatives to the app will become available to people without smartphones in 2013, via an

“

automated phone system. Patients will be able to use touchtone to record medication doses, and caregivers will be able to receive alerts about missed doses via automated calls. The MediSafe Project was inspired by the accidental and potentially fatal insulin double dose of the diabetic father of brothers and cofounders Omri and Rotem Shor. The co-founders, according to the press release, regard MediSafe Project as

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“Medication adherence is a persistent and elusive problem, interrupting patients’ well-being, costing health providers and insurers billions annually, and causing preventable deaths,” MediSafe Project CEO Omri “Bob” Shor said in a statement. “MediSafe Project’s involvement of patients’ loved ones and caretakers is proving itself a breakthrough in reducing the harm that comes from medication nonadherence.” Launched in November 2012 and available as a free download in both Android and iOS versions, the MediSafe Project is the first cloudsynced mobile app helping families prevent emergencies caused by over- or under-dosing medications, according to the press release. MediSafe Project reminds users when it is time to take a medication,

a way to lower hospitalization and mortality rates, promote sustainable behavior changes that prolong health, and reduce long-term health care costs. The developers added that the MediSafe Project also provides aggregated patient behavior data, physician trends and other market aspects to help pharmaceutical companies better understand how their medications are used. ■

With Standards that are nationally recognized and annually reviewed, AAAHC has accredited more than 5,500 health care facilities. Because our surveys are collaborative by nature and not just a checklist, we strive to match each of our surveyor’s credentials and experience to your specialty.

For more information, Contact us: 847-853-6060 By email: info@aaahc.org Log on: www.aaahc.org/TRO

Improving Health Care Quality through Accreditation

”

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

FDA Takes Action Against Illegal Online Pharmacies During the last two weeks of June, the FDA took action against more than 9,600 websites that illegally sell potentially dangerous, unapproved prescription medicines to consumers. Working with international regulatory and law enforcement agencies, the FDA seized offending websites and more than $41 million worth of illegal medicines worldwide. “Illegal online pharmacies put

American consumers’ health at risk by selling potentially dangerous products,” said John Roth, director of the FDA’s Office of Criminal Investigations, in a statement. “This is an ongoing battle in the United States and abroad, and the FDA will continue its criminal law enforcement and regulatory efforts.” The FDA’s action occurred as part of the sixth annual International Internet Week of Action, a global

cooperative effort to combat the online sale and distribution of potentially counterfeit and illegal medical products. The international operation, called Operation Pangea, took place from June 18 to June 25. During this year’s effort, Operation Pangea VI, the FDA’s Office of Criminal Investigations worked in coordination with the U.S. Attorney’s Office for the District of Colorado to seize and shut down 1,677 illegal pharmacy websites.

Optimizing the Prevention and Management of Postsurgical Adhesions To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MN125” Release date: December 1, 2012

Chair

Jon Gould, MD Chief, Division of General Surgery Alonzo P. Walker Chair in Surgery Associate Professor of Surgery Medical College of Wisconsin Senior Medical Director of Clinical Affairs Froedtert Hospital Milwaukee, Wisconsin

Faculty

Michael J. Rosen, MD Associate Professor of Surgery Division Chief, General Surgery University Hospitals Case Medical Center Cleveland, Ohio

Statement of Need Adhesions are the most common complication of abdominopelvic surgery, developing postoperatively in 50% to 100% of all such interventions. They can lead to serious medical complications, substantial morbidity, high monetary costs, large surgical workloads, dangerous and difficult reoperations, and an increasing number of medicolegal claims. An official definition of the Sponsored by

Expiration date: December 1, 2013 condition has not been established, and an unequivocally effective prevention method has not been identified. A standardized classification for adhesion assessment and scoring also is lacking, as are guidelines for diagnosis and management. To close these gaps, clinician education is necessary.

Goal The goal of this educational activity is to provide surgeons with up-to-date, clinically useful information concerning the prevention and management of postoperative adhesions.

Learning Objectives 1 Review the pathophysiology and complications of postoperative adhesion formation. 2 Summarize current strategies used to prevent postoperative adhesion formation. 3 Describe the various types of barrier materials used to prevent postoperative adhesion formation.

Intended Audience The intended audience for this educational activity includes general surgeons, vascular surgeons, colon and rectal surgeons, critical care surgeons, surgical oncologists, trauma surgeons, and thoracic surgeons. Supported by an Educational Grant from

Estimated Time for Completion: 60 minutes Course Format Monograph (print and online)

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical College of Wisconsin and Applied Clinical Education. The Medical College of Wisconsin is accredited by the ACCME to provide continuing medical education for physicians.

Designation of Credit Statement The Medical College of Wisconsin designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should only claim credit commensurate with the extent of their participation in the activity.

Method of Participation There are no fees for participating in or receiving credit for this activity. To receive CME credit, participants should read the preamble and the monograph and complete the post-test and evaluation. A score of at least 70% is required to complete this activity successfully. Distributed via

According the FDA, many of the websites they encountered appeared to be operating as a part of an organized criminal network. The sites falsely purported tto b be “C “Canadian di pharmacies,” h i ” and d displayed fake licenses and certifications to convince U.S. consumers to purchase drugs that they advertised as “brand name” and “FDA-approved.” These websites also used the names of major U.S. pharmacy retailers to trick consumers into believing that an affiliation existed with these retailers. Some examples of the phony websites, which now have been seized and display a message from the FDA’s Office of Criminal Investigations Cybercrime Investigations Unit, include: • www.canadianhealthandcaremall. com • www.walgreens-store.com • www.c-v-s-pharmacy.com As part of its investigation, the FDA targeted websites that were selling unapproved and potentially dangerous prescription medicines that could pose significant risks to public health. The drugs seized by the agency were not from Canada, and were neither brand name nor FDA-approved. Prescription products purchased from the websites also bypassed existing safety controls required by the FDA, including the requirement of a valid prescription from a licensed health care provider.

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

F D A U P D AT E & P R O D U C T N E W S

medications also have potentially dangerous drug–drug interactions and serious adverse effects. Clozapine: FDA-approved, brand-name Clozaril (clozapine) is used to treat severe schizophrenia and is associated with potentially fatal agranulocytosis, a sseverely low (and dangerous) wh hite blood cell count that can

predispose patients to serious, lifethreatening infections. To minimize potential risks, consumers who are prescribed Clozaril must be enrolled in a registry that ensures regular blood count monitoring. In addition to potential health risks, these online pharmacies pose non–health-related risks to consumers such as credit card fraud, identity theft and computer viruses. The FDA encourages consumers

to report suspected criminal activity to the Office of Criminal Investigations at www.fda.gov/OCI. The FDA also sponsors “FDA BeSafeRx— Know Your Online Pharmacy,” a national campaign to educate consumers about the dangers of buying medicine from fake online pharmacies and to help people safely buy medicine online. Information is available at www.fda.gov/BeSafeRx. —Based on a press release from the FDA

Think of Enterography as a GPS for Crohn’s disease. Some of the medicines sold illegally by the websites included: Avandaryl (glimepiride and rosiglitazone): This medicine is used to treat type 2 diabetes and to minimize potential t ti l associated i t d risks, i k includi l d ing edema caused by fluid retention or heart failure. Avandaryl must be prescribed by a certified health care provider and dispensed by a certified pharmacy with a medication guide explaining the potential risks. “Generic Celebrex”: FDAapproved, brand-name Celebrex (celecoxib) is a nonsteroidal antiinflammatory drug used to treat the signs and symptoms of osteoarthritis and rheumatoid arthritis and to manage acute pain in adults. “Generic Celebrex,” sold online, is not an FDA-approved product. To minimize the potential associated risks including gastrointestinal bleeding, heart attack or stroke, Celebrex must be dispensed with a medication guide explaining potential risks. “Levitra Super Force” and “Viagra Super Force”: Levitra (vardenafil) and Viagra (sildenafil) are FDAapproved medicines used to treat erectile dysfunction. Levitra Super Force and Viagra Super Force are not FDA-approved products and claim to contain dapoxetine, the safety or efficacy of which has not been determined by the FDA. People with certain heart conditions should not take medicines containing vardenafil or sildenafil, and these

Image shows not only thickening of the bowel wall, but also the increased attenuation of the mucosa compatible with active Crohn’s disease.*

Enterography gives you a highly effective diagnostic tool for evaluating and managing treatment of small bowel disorders like Crohn’s disease.1 By producing abdominal images that provide clear visualization of the small bowel wall and lumen,2 enterography shows the degree, extent and location of Crohn’s disease3 and is quickly becoming a first-line exam in leading IBD Centers for the evaluation of small bowel disorders.2 For more information about the benefits of enterography for small bowel diagnostics, please contact Bracco Professional Services at 1-800-257-5181, option 1. * Representational image, individual results may vary. Image courtesy of Alec Megibow, MD, NYU REFERENCES: 1. Bruining DH, Siddiki HA, Fletcher JG, et al. Benefit of computed tomography enterography in Crohn’s disease: Effects on patient management and physician level of confidence. Inflamm Bowel Dis. 2012;18(2):219-225. 2. Fletcher JG. CT enterography technique: theme and variations. Abdom Imaging. 2009;34(3):283-288. 3. MDCT and 3D imaging of the small bowel and mesentery. Mahmoud M. Al-Hawary, MD, Ravi K. Kaza, MD, and Joel F. Platt, MD, University of Michigan Health System, Ann Arbor, MI. Applied Radiology. 2011 Nov;40(11). ©2012 Bracco Diagnostics Inc. All Rights Reserved.

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Specialty Compounding Recalls All Sterile-Use Products BY GEORGE OCHOA On Aug. 9, Specialty Compounding, LLC, announced a voluntary nationwide recall of all lots of unexpired medications for sterile use, according to press releases from the company and the FDA. The recall applies to all such products dispensed since May 9, 2013. The recall is based on reports,

received by the FDA, of 15 patients from two hospitals in Texas who had an infusion of calcium gluconate 2 g in sodium chloride 0.9% for injection, prepared by Specialty Compounding. Afterward, the patients developed bacterial bloodstream infections caused by Rhodococcus equi. Cultures from an intact sample of calcium gluconate compounded by the company showed bacterial growth consistent with Rhodococcus

species. The Texas hospitals affected were Corpus Christi Medical Center Doctors Regional and Corpus Christi Medical Center Bay Area. “The FDA believes that use of these products would create an unacceptable risk for patients,” Janet Woodcock, MD, director of FDA’s Center for Drug Evaluation and Research, said in a statement. “Giving a patient a contaminated injectable drug could result in a life-threatening infection.”

“Because of the potential association between the hospital-based infections and sterile compounded medications produced by Specialty Compounding, we are voluntarily recalling all sterile products out of an abundance of caution,” Ray Solano, RPh, pharmacist in charge at Specialty Compounding, which is a subsidiary of People’s Pharmacy Inc., commented in a statement. “We deeply regret the impact this recall has on our patients and the hospitals that we serve, but patient safety must always be our first concern.”

New York Society for Gastrointestinal Endoscopy

37th Annual New York Course Challenges and Controversies in Endoscopy GI Nurses: Building for Tomorrow December 19 – 20, 2013 New York Marriott Marquis Hotel 1535 Broadway, New York, NY 10036 Program Topics

Program Features

Fecal Transplantation for C. difﬁcile

Endoscopic Video Forum

Imaging and Endoscopy

4th Annual Scientiﬁc Poster Session

Stricture and Stenosis

Live Telecast from Lenox Hill Hospital

(Registration Limited--Separate Registration Required)

The Impact of Healthcare Reform on Endoscopy

Artiﬁcial and Animal Tissue Model Demonstrations

Exploring Complexities of Capsule Endoscopy: A Course for Advanced Users

Polyps “R” Us Management of GERD

Live Broadcast from the New ASGE IT&T Center

Esophageal Technological Innovation: Optimizing the Old and Implementing the New

Non-dysplastic Barrett’s Esophagus

Lunch Programs and Exhibits

Advances in Medical and Surgical Approaches to Inﬂammatory Bowel Disease

Pancreatic Cysts Preventing a Bad Day in the Endo Unit POEM and Full Thickness Resection Techniques Pancreaticobiliary Disorders Small Bowel Enteroscopy

Visit www.NYSGE.org and click on “The Course” All registration and hotel reservations are online

Foreign Body Removal C5: The View Forward Through the First 10 Years IBD and Endoscopy

Don’t miss the Early Bird registration and hotel discounts!

Accreditation Physicians: This activity approved for 14.25 AMA PRA Category 1 Credits™ Nurses: A minimum of 16 contact hours is anticipated Jointly sponsored by Albert Einstein College of Medicine and New York Society for Gastrointestinal Endoscopy Intended Audience: Practicing gastroenterologists, gastrointestinal endoscopists and surgeons, GI fellows, and GI nurses and associates

Advanced Hands-On Workshops and Satellite Symposia

Advancements in Hepatitis Therapies ERCP for Everyday Problems: Hands-On Workshop with the Masters Advanced Endoscopic Resection and Closure: ESD/POEM Endoscopic Suturing Live Demonstration and Hands-On Ex-Vivo Models Practical EUS: Hands-On and Case Discussions Advanced Colon Diagnostics and Therapeutics: Improving Skills in Complex Procedures

Recalled products were sent directly to patients nationwide except North Carolina. Additionally, recalled products were distributed to hospitals and physicians’ offices in Texas. “Facilities, health care providers and patients who have received the products since May 9, 2013, should immediately discontinue use, quarantine the products and return the products to Specialty Compounding,” stated the FDA press release. For assistance related to the recall, users should contact Specialty Compounding in Cedar Park, Texas, at (512) 219-0724, Monday through Friday between 10 a.m. and 5 p.m. CDT, according to the company press release. Adverse reactions associated with Specialty Compounding products may be reported to the FDA’s MedWatch Adverse Event Reporting program at www.fda.gov/Safety/ MedWatch. ■

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

F D A U P D AT E & P R O D U C T N E W S

FDA Issues Warning About Sterile Products From NuVision Compounding Pharmacy BY GEORGE OCHOA The FDA continued to advise health care providers not to use sterile products from NuVision Pharmacy of Dallas, because the sterility of the products is not assured, according to an Aug. 16 FDA news release. This alert followed an April recall by NuVision of methylcobalamin injection and lyophilized injection products due to a lack of sterility assurance,

lots of all sterile products produced at NuVision that are within expiry,” and warned, “if a drug product marketed as sterile contains microbial contamination, patients could be at risk for serious infections, which may be life-threatening.” NuVision responded by refusing the requested recall, according to the Aug. 16 news release. On NuVision’s website, the company stated that it is not recalling

all sterile injectables, and that all its sterile injectables are tested for sterility by a third-party laboratory before dispensing. The website also reported that NuVision is a compounding pharmacy, not a manufacturer. “We are in compliance with USP [Chapter] <795> and [Chapter] <797> which are the standards of law for compounding pharmacy. The FDA has been inspecting

compounding pharmacies based on a different set of standards for manufacturers called FDA 210 and 211. … The current state laws do not require compounding pharmacies to follow the standards for manufacturing.” The FDA advises health care professionals to check their medical supplies for NuVision sterile products, quarantine any such products, and not administer them to patients. ■

WE’RE

ORM

FOR PATIENTS WITH CROHN’S DISEASE After Crohn’s surgery, it is common for the disease to return within a few months despite anti-inﬂammatory medicine. At UPMC, our multidisciplinary team developed a new post-op treatment approach that has reduced the recurrence of

and a May 18 FDA announcement of expanded concerns about a lack of sterility assurance of all NuVision’s sterile drug products. “The FDA received adverse event reports of fever, flu-like symptoms and soreness at the injection site associated with the methylcobalamin injection product” that was recalled, said the Aug. 16 news release. According to the news release, NuVision has repeatedly declined FDA requests to recall its sterile products, and the FDA lacks the authority to require such a recall. Most recently, on July 26, the FDA issued a letter to NuVision outlining poor sterile production practices observed during an FDA inspection of NuVision’s Dallas facility. The letter, from Melinda K. Plaisier, the acting associate commissioner for regulatory affairs at the FDA, requested an immediate “recall of all

Crohn’s disease by nearly two thirds. And now many other hospitals are adopting this novel approach. Because when you make patients feel better, it’s normal to want them to stay that way. Learn more at UPMCPhysicianResources.com/Crohns.

UPMC is afﬁliated with the University of Pittsburgh School of Medicine.

F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

New Tools Available To Assist With AAAHC Accreditation Process The Accreditation Association for Ambulatory Health Care (AAAHC) has reached an agreement with two companies—Basha LLC, a software company, and PowerDMS, a document management solution company—to license the AAAHC standards for use in their software tools. The two companies offer software to ambulatory

surgery centers (ASCs) to assist them in better organizing and managing their accreditation process. Basha LLC’s software system, ASCpro, and PowerDMS’s cloudbased application provide a more efficient process for ASCs to ensure compliance, store data and use AAAHC standards. The new

tools allow ASC administrators to electronically store appropriate policies, procedures and maintenance records adjacent to relevant standards, making the whole process easier and more transparent; search for specific standards by keyword; and monitor their ASC’s position in meeting regulatory compliance requirements,

including AAAHC standards and federal and state rules. “We’re pleased to have reached an agreement with ASCpro C [Basha LLC] and PowerDMS in order to assist organizations as they prepare for an accreditation survey,” said John Burke, PhD, president and CEO of AAAHC. “These two systems offer organizations seeking their first accreditation, or preparing to reaccredit, a new tool to help simplify the process.”

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H E PAT O L O G Y IN F O C U S

Guidance Equivocal On HCV Screening Of Baby Boomers

Despite Above Average Income, Gastros Report Job Dissatisfaction BY VICTORIA STERN

BOSTON—Recent evidence suggests that nonalcoholic fatty liver disease (NAFLD) is emerging as a significant public health problem. One study revealed an “alarming” rate of HCC related to NAFLD, even among

Gastroenterologists are the fourth most highly compensated physicians compared with doctors in 24 other medical specialties, according to an online survey conducted by Medscape in February 2013. Average annual income for gastroenterologists was up 13% in 2012 compared with 2011, coming in at $342,000. The three specialties that beat out gastroenterology in average yearly compensation were orthopedists at $405,000, cardiologists at $357,000 and radiologists at $349,000 (see Figure 1, page 28). But despite robust earnings, less than half (48%) of the gastroenterologists surveyed said they felt fairly compensated, the same percentage as that of physicians of all specialties who said they felt fairly compensated. The findings were based on responses collected in a third-party online survey of 21,878 U.S. physicians, 2% of whom were gastroenterologists. Most gastroenterologists who responded were men (84%) and board certified (96%), and 62% were aged 45 years or older.

see NAFLD, page 14

see Income, page 28

BY CHRISTINA FRANGOU Hepatologists have added their voices to the debate over screening for hepatitis C virus (HCV) infection and are urging the U.S. Preventive Services Task Force (USPSTF) to upgrade its current recommendation see HCV Screening, page 18

NAFLD Threatening Public Health BY KATE O’ROURKE

I N S I D E

Cost Sharing for Polyp Removal During Colonoscopy Waived for Some Patients

H E PAT O L O G Y

I N

FOCUS

Investigational Device Prolongs Survival of Livers For Transplantation .................................................page 8

BY MONICA J. SMITH

tor

Ma Vis it y DD 19-2 us W bo 1, 20 oth 13 15 31

Effect of Preexisting Cardiovascular Disease On Outcomes After Liver Transplantation May Be Underestimated..........................................page 9

Patients with private insurance will no longer be responsible for any cost sharing in the event that a polyp is removed during a screening colonoscopy, according to a recent clarification, issued by the federal government, on preventive screening benefits under the Affordable Care Act (ACA). “This is very good news,” said Durado Brooks, MD, MPH, direcof Prostate and Colorectal Cancers at the American Cancer Society in

Retreatment of Hepatitis C With Interferon Alone May Increase Mortality ..........................................«>}iÊ£È Statins Linked to Reduction in Mortality From Liver Cancer .................................................«>}iÊÓ{

see Cost Sharing, page 32 PRINTER FRIENDLY VERSION AT GASTROENDONEWS.COM

CLINICAL REVIEW see insert between pages 20 and 21

Ulcerative Colitis: Treatment Strategies By Ellen J. Scherl, MD, Arun Swaminath, MD, Brian Bosworth, MD, and Vinita Jacob, MD

PRODUCT ANNOUNCEMENT

Ulcerative Co olitis: Optimizing Mesalamine Strategies ELLEN J. SCHERL, MD Director, Jill Roberts Center for Inflammatory Bowel Diseasea Jill Roberts Center for Inflammatory Bowel Disease Director of Researchb Jill Roberts Associate Professor of Inflammatory Bowel Diseaseb Associate Professor of Clinical Medicineb Adjunct Associate Professor of Medicinec

ARUN SWAMINATH, MD Assistant Attending Physiciana Assistant Professor of Clinical Medicinec

BRIAN BOSWORTH, MD

see page 63 for product information

he greatest challenge for ch clinicians who

treat pattients with inflamma atory bowel disease (IBD) is to move from symptomoriented (step--up) strategies toward preventio on-orie ented (early intervention) strategies aimed at tight inflammation control and alteration of the natural history of IBD. This review focuses on a personalized approach to the treatment of IBD using 5-aminosalicylic acid (5-ASA) agents.

Assistant Attending Physiciana Assistant Professor of Medicineb Anne and Ken Estabrook Clinical Scholar in Gastroenterologyb

VINITA JACOB, MD Assistant Attending Physiciana Assistant Professor of Medicineb

DANA J. LUKIN, MD, PHD Gastroenterology Fellowc a

NewYork-Presbyterian Hospital/ Weill Cornell Medical Center New York, New York b Weill Cornell Medical College New York, New York c Columbia University College of Physicians and Surgeons New York, New York

Challenging the Traditional IBD Diagnosis Traditionally, IBD has been divided into 2 distinct entities: ulcerative colitis (UC) and Crohn’s disease (CD). A nuanced view presents IBD as an immunoinflammatory spectrum of chronic and recurring diseases of the intestines defined by individual molecular signatures. This newly gained perspective holds the promise of moving treatment in a more proactive, personalized direction, toward targeting molecules and risk assessment, rather than treating symptoms of the disease. One of the major questions facing clinicians is whether IBD is a single entity or a spectrum of multiple disorders. This distinction becomes particularly difficult to make when attempting to

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS •

2013

FibroScan® Cleared by the FDA For Sale in the United States

AAAHC serves as an advocate for the provision of highquality health care through the development of nationally recognized standards and survey and accreditation programs. AAAHC accreditation is recognized as a symbol of quality by third-party payors, medical organizations, liability insurance companies, state and federal agencies, and the public, the organization said. For more information, visit www.aaahc.org. —Based on a press release from the AAAHC

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

F D A U P D AT E & P R O D U C T N E W S

FDA Approves New Test for Faster Confirmation of Medical Device Sterilization The FDA recently granted permission for marketing of the Verify Cronos Self Contained Biological Indicator (SCBI), a new test that can help speed the determination of the effectiveness of steam sterilization of reusable medical devices. According to the test’s manufacturer, Steris Corporation, the Verify Cronos SCBI is the first biological indicator test that gives test results in two hours. “This is a novel and innovative use of recombinant DNA technology in biological indicator tests,” said Christy Foreman, director of the Office of Device Evaluation in the FDA’s Center for Devices and Radiological Health. “By providing faster confirmation of sterilization, this innovation may help health care facilities provide their medical staff with a faster turnaround of their sterilized reusable devices.” The test is used in reprocessing—a multistep process to clean and disinfect or sterilize reusable medical devices, such as endoscopes. For steam sterilization, medical devices are loaded into a chamber that is sealed and filled with steam. Specific conditions, such as temperature, exposure time and chamber pressure, must be maintained throughout the process to kill microorganisms that may be present on the reusable medical devices. Like other biological indicator tests, the Verify Cronos SCBI consists of a vial containing dried spores from the heatresistant bacteria Geobacillus stearothermophilus. Before the sterilization cycle begins, the reprocessing technician places the vial inside the sterilization chamber, along with the devices to be sterilized. After the sterilization cycle is complete, the spores are incubated in “recovery medium,” a liquid that provides an ideal environment for the growth of any surviving bacteria, and monitored for spore growth. The Verify Cronos SCBI test uses a genetically engineered strain of G. stearothermophilus that produces an enzyme that fluoresces in reaction with the recovery medium if test microorganisms are present after the sterilization

process. Genetically engineered G. stearothermophilus that survive a sterilization cycle will start growing and producing the enzyme within two hours, providing results to the reprocessing technicians much sooner than the 24 hours normally needed with a natural bacterial strain. Growth of bacteria indicates that sterilization has failed.

To support its FDA petition, Steris conducted a number of tests to ensure the performance of the Verify Cronos SCBI. This included subjecting more than 300 Verify Cronos SCBIs to a partial sterilization cycle and then comparing results after two hours and at seven days of incubation. The results showed that samples that fluoresced at

Get recognized for promoting Quality and Safety in your endoscopy unit

two hours also exhibited growth at seven days. The FDA reviewed the data for Verify Cronos SCBI through the “de novo classification” premarket review regulatory pathway for low- to moderate-risk medical devices that are not substantially equivalent to an already legally marketed device. —Based on a press release from the FDA

ASGE Endoscopy Unit Recognition Program committed to the highest standards of quality and safety. It is the only national program recognizing quality and safety in the practice of endoscopy. recognitio among healthcare professionals, public and private > Gain recognition regulatoryy bodies, and patients as a unit dedicated to quality care > Prepare to meet the changing expectation of public and private regulatory bodies > Promote improvement and create uniformity in your practice > Access marketing tools to promote your recognition Program eligibility criteria includes completion of the ASGE Quality Course, “Improving Quality and Safety in your Endoscopy Unit,” by a representative of your unit within one year of program application. ASGE offers mu ultiple courses throughout the year. The upcoming cou urses are as follows: No ovember 15, 2013 – Downers Grove (Chicago), IL Feb bruary 21, 2014 – Washington, DC 9LJLP] ÄJH[L VM 9LJVNUP[PVU [V WYV\KS` KPZWSH` PU `V\Y LUKVZJVW` \UP[»Z VMÄJL Ä

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GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

Exalenz Bioscience Announces Global Launch of New Breath Test To Detect H. Pylori On July 15, Exalenz Bioscience announced the global launch of BreathID Hp, a next-generation device in the company’s BreathID product line. BreathID Hp facilitates a “test-and-treat” protocol for Helicobacter pylorii by offering a technologically advanced, fast, highly accurate, specific and noninvasive test, according to Exalenz. Designed for in-office and urgent care facility use, BreathID is a compact system that can fit on a small table or countertop. The new device is compatible with electronic medical record systems and is not regulated by the Clinical Laboratory Improvement Act, thus allowing any properly trained health care professional to operate it simply by following the directions displayed on screen. The test is easy to perform, according to Exalenz, and takes approximately 10 to 15 minutes to complete and deliver results, allowing a physician to prescribe treatment immediately, if necessary. The system also can be used to determine if H. pylori has been eradicated. BreathID facilitates “a test-and-treat” protocol, a strategy recommended by the

Designed for in-office and urgent care facility use, BreathID is a compact system that can be operated by any properly trained health care professional simply by following directions displayed on screen. Photo courtesy of Exalenz Bioscience

American College of Gastroenterology. According to the company, the test can significantly reduce overall health care costs and repeat patient visits: The cost of the test is

reimbursable by Medicare, Medicaid and the majority of payors. Exalenz also announced that it has formed a direct sales and clinical support organization in the

United States to better address customer needs. “Our new strategy is to provide physicians with the best technology and complementary service to assist them in caring for their patients and help them to test and treat in the most cost-effective, efficient manner possible,” said Ted Foltyn, vice president of worldwide marketing and business development at Exalenz. “Our new sales and clinical support teams are available to work directly with physicians in terms of system education, training, utilization and proper integration. According to the University of Arizona College of Public Health, in the United States, H. pylori prevalence is higher among Hispanics, African Americans and the elderly. H. pylori prevalence is approximately 60% among Hispanics, 54% among African Americans and 20% among whites. Infection rates are similar for men and women. In the United States, the estimated prevalence of H. pylori is 20% for people younger than 30 years, and 50% for those older than 60 years. —Based on a press release from Exalenz Bioscience

US Endoscopy Announces Release of New Brush for Standard Cytology On July 16, US Endoscopy announced the full market release of the Infinity cytology device, which is designed to collect substantial, quality samples from the upper and lower gastrointestinal tract. The bristle design of the Infinity cytology device mimics that of the Infinity ERCP sampling device that was launched by the company in 2011. The unique configuration helps endoscopists

collect quality samples during cytology procedures. The brush has a combination of stiffer bristles to help create a defect in the tissue, and softer bristles to capture abraded material, allowing for retrieval of an abundant cellular sample. Spaces between the bristles help pack cells together. “Our customers have achieved great results with the Infinity ERCP sampling device, so much so that they have requested a similar version

The brush has a combination of stiffer bristles to help create a defect in the tissue, and softer bristles to capture abraded material. Photo courtesy of US Endoscopy

for standard cytology,” said Tony Siracusa, vice president and general manager of US Endoscopy. “Using the same technology as the original device, we have created a premium solution to address this need, giving our customers confidence that they are getting the best sample a brush can provide.” For more information, visit www.usendoscopy. com. —Based on a press release from US Endoscopy

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GASTROENTEROLOGY & ENDOSCOPY NEWS â&#x20AC;˘ SEPTEMBER 2013

FDA Approves Genotyping Test for Patients With Hepatitis C Virus Infection The FDA has approved a test that identifies the genotype of hepatitis C virus (HCV) in infected patients. Manufactured by Abbott Molecular Inc., the Abbott RealTime HCV Genotype II test can differentiate between genotypes 1, 1a, 1b, 2, 3, 4 and 5 using a sample of blood plasma or serum. Knowledge of HCV genotype can aid physicians in determining the appropriate approach to treatment:

Because different HCV genotypes respond differently to different drugs, knowing the HCV genotype can result in better patient outcomes. â&#x20AC;&#x153;Along with other clinical factors, the particular type of HCV is an important consideration in aiding health care professionals in determining if and when to initiate treatment, and the appropriate level of treatment,â&#x20AC;? said Alberto Gutierrez,

The Abbott RealTime HCV Genotype II from Abbott Molecular Inc.

PhD, director of the Office of In Vitro Diagnostics and Radiological Health in the FDAâ&#x20AC;&#x2122;s Center for Devices and Radiological Health. The Abbott RealTime HCV Genotype II test is approved for individuals with documented chronic HCV infection. It is not approved for use as a diagnostic test or as a screening test for the presence of HCV genetic material in blood, blood products or tissue donors. It has not been evaluated in infants, pediatric patients or patients with compromised immune systems, such as individuals with HIV infection. The FDA based its approval of the Abbott RealTime HCV Genotype II in part on an assessment of the testâ&#x20AC;&#x2122;s accuracy in differentiating specific HCV viral genotypes compared with a validated gene-sequencing method. The FDA also reviewed data from investigators demonstrating the relationship between HCV genotype and effectiveness of drug therapy. According to the Centers for Disease Control and Prevention, HCV infection is the most common chronic blood-borne infection in the United States, with about 3.2 million people who are chronically infected. Chronic HCV infection is the leading indication for liver transplants in the United States. â&#x20AC;&#x201D;Based on a press release from the FDA

Photo courtesy of Abbott Molecular Inc.

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F D A U P D AT E & P R O D U C T N E W S

GASTROENTEROLOGY & ENDOSCOPY NEWS • SEPTEMBER 2013

FDA Limits Use of Nizoral Antifungal Tablets Due to Risks for Liver Injury In July, the FDA announced several actions to limit the use of Nizoral (ketoconazole, McNeil Consumer Healthcare) oral tablets, warning that the drug may be associated with severe liver injury, harmful drug–drug interactions and adrenal gland problems. Nizoral oral tablets should not be a first-line treatment for any fungal infection, the FDA stated in a July 26 press release. Topical formulations of Nizoral—including creams, shampoos, foams and gels applied to the skin—have not been associated with liver damage, adrenal problems or drug interactions, and are not affected by the FDA warning.

oral Nizoral and should monitor levels of alanine aminotransferase serum during treatment. Additionally, Nizoral oral tablets may cause adrenal insufficiency by decreasing the body’s production of corticosteroids, and physicians should monitor adrenal function in patients with adrenal insufficiency, borderline adrenal function and those under prolonged periods of

stress (e.g., major surgery or intensive care). Nizoral also may interact with other drugs and may cause serious and potentially life-threatening outcomes, such as heart rhythm problems. The FDA has approved a new patient medication guide that contains information on the potential risks associated with Nizoral oral tablets and that must be dispensed

BRIEF SUMMARY Please consult package insert for full prescribing information. INDICATIONS AND USAGE APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. DOSAGE AND ADMINISTRATION The recommended dose for maintenance of remission of ulcerative colitis in adult patients is 1.5 g (four APRISO capsules) orally once daily in the morning. APRISO may be taken without regard to meals. APRISO should not be co-administered with antacids. An evaluation of renal function is recommended before initiating therapy with APRISO. CONTRAINDICATIONS APRISO is contraindicated in patients with hypersensitivity to salicylates or aminosalicylates or to any of the components of APRISO capsules. WARNINGS AND PRECAUTIONS Renal Impairment Renal impairment, including minimal change nephropathy, acute and chronic interstitial nephritis, and, rarely, renal failure, has been reported in patients given products such as APRISO that contain mesalamine or are converted to mesalamine. It is recommended that patients have an evaluation of renal function prior to initiation of APRISO therapy and periodically while on therapy. Exercise caution when using APRISO in patients with known renal dysfunction or a history of renal disease.

Based on the new FDA recommendation, Nizoral oral tablets may be used only for the treatment of certain life-threatening fungal infections known as “endemic mycoses”—including blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis and paracoccidioidomycosis—in patients who have failed or are intolerant to other antifungal medications. Nizoral oral tablets are not indicated for the treatment of fungal infections of the skin or nails. New labeling for Nizoral oral tablets states that the drug can cause liver injury that may potentially result in liver transplantation or death. A boxed warning includes a strong recommendation against the use of Nizoral tablets in patients with liver disease. For patients who do take oral Nizoral, the FDA has issued new recommendations for assessing and monitoring liver toxicity: Physicians should assess liver status before starting

In animal studies, the kidney was the principal organ for toxicity. Mesalamine-Induced Acute Intolerance Syndrome Mesalamine has been associated with an acute intolerance syndrome that may be difficult to distinguish from a flare of inflammatory bowel disease. Although the exact frequency of occurrence has not been determined, it has occurred in 3% of patients in controlled clinical trials of mesalamine or sulfasalazine. Symptoms include cramping, acute abdominal pain and bloody diarrhea, sometimes fever, headache, and rash. If acute intolerance syndrome is suspected, promptly discontinue treatment with APRISO. Hypersensitivity Some patients who have experienced a hypersensitivity reaction to sulfasalazine may have a similar reaction to APRISO capsules or to other compounds that contain or are converted to mesalamine. Hepatic Impairment There have been reports of hepatic failure in patients with pre-existing liver disease who have been administered mesalamine. Caution should be exercised when administering APRISO to patients with liver disease. ADVERSE REACTIONS APRISO was studied in two placebo-controlled trials (n=367 treated with APRISO) and in one open-label, long-term study (n=190 additional patients). The population consisted of patients with ulcerative colitis; the mean age was 47 years, 54% were female, and 93% were white. Patients received doses of APRISO administered orally once per day for six months in the placebo-controlled trials and for up to 24 months in the open-label study. In the two placebo-controlled trials, 59% of APRISO-treated patients experienced an adverse reaction compared with 64% of placebo patients. Most adverse reactions with APRISO were mild or moderate in severity. Severe adverse reactions occurred in 6% of APRISO-treated patients and 5% of placebo-treated patients. Discontinuations due to adverse reactions occurred in 11% of APRISO-treated patients and 17% of placebo-treated patients; the most common adverse reaction resulting in study discontinuation was recurrence of ulcerative colitis (APRISO 6%, placebo 14%). The most common treatment-related adverse events occurring in at least 3% of adult patients taking 1.5 g/day of APRISO and at a rate greater than placebo were headache (11% vs 8% for placebo), diarrhea (8% vs 7% for placebo), upper abdominal pain (5% vs 3% for placebo), nausea (4% vs 3% for placebo), nasopharyngitis (4% vs 3% for placebo), influenza and influenza-like illness (4% vs 4% for placebo), and sinusitis (3% vs 3% for placebo).

with every prescription of the drug. Health care professionals and patients are encouraged to report adverse events or side effects related to Nizoral oral tablets to the FDA’s MedWatch Safety Information and Adverse Event Reporting Program at www.fda.gov/MedWatch/report.htm. —Based on a press release from the FDA

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies with mesalamine have been performed in rats at oral doses up to 320 mg/kg/day (about 1.7 times the recommended human dose based on a body surface area comparison) and rabbits at doses up to 495 mg/ kg/day (about 5.4 times the recommended human dose based on a body surface area comparison) and have revealed no evidence of impaired fertility or harm to the fetus due to mesalamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Mesalamine is known to cross the placental barrier. Nursing Mothers Low concentrations of mesalamine and higher concentrations of its N-acetyl metabolite have been detected in human breast milk. The clinical significance of this has not been determined and there is limited experience of nursing women using mesalamine. Caution should be exercised when APRISO is administered to a nursing woman. Pediatric Use Safety and effectiveness of APRISO capsules in pediatric patients have not been established. Geriatric Use Clinical studies of APRISO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy in elderly patients should be considered when prescribing APRISO. Reports from uncontrolled clinical studies and postmarketing reporting systems suggested a higher incidence of blood dyscrasias, i.e., neutropenia, pancytopenia, in patients who were 65 years or older who were taking mesalamine-containing products such as APRISO. Caution should be taken to closely monitor blood cell counts during mesalamine therapy. Mesalamine is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken when prescribing this drug therapy. (see WARNING AND PRECAUTIONS) Phenylketonuria Patients with phenylketonuria should be aware that APRISO contains aspartame, equivalent to 0.56 mg of phenylalanine. CLINICAL STUDIES Two similar, randomized, double-blind, placebo-controlled, multi-center studies were conducted in a total of 562 adult patients in remission from ulcerative colitis. Ulcerative colitis disease activity was assessed using a modified Sutherland Disease Activity Index1 (DAI), which is a sum of four subscores based on stool frequency, rectal bleeding, mucosal appearance on endoscopy, and physician’s rating of disease activity. Patients were randomized 2:1 to receive either APRISO 1.5 g or placebo once daily in the morning for six months. In both studies, the proportion of patients who remained relapse-free at six months was greater for APRISO than for placebo. In study 1 (N=305), 68% of subjects taking APRISO were relapse-free at 6 months EOT vs 51% with placebo (P<0.001). In study 2 (N=257), 71% of subjects in the APRISO group were relapse-free at 6 months EOT vs 59% for placebo (P=0.046). HOW SUPPLIED APRISO is available as light blue opaque hard gelatin capsules containing 0.375 g mesalamine and with the letters “G” and “M” on either side of a black band imprinted on the capsule. NDC 65649-103-02 NDC 65649-103-01

Bottles of 120 capsules Bottles of 4 capsules

STORAGE AND HANDLING Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). See USP Controlled Room Temperature. Reference: 1. Sutherland LR, Martin F, Greer S, Robinson M, Greenberger N, Saibil F, et al. 5-Aminosalicylic acid enema in the treatment of distal ulcerative colitis, proctosigmoiditis, and proctitis. Gastroenterology. 1987;92:1894-1898.

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

GM 08/22-1

MANUFACTURED FOR:

Maintain UC remission with a low average co-pay

APRISO SAVINGS PROGRAM HER MISSION:

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* CO-PAY ON YOUR

FIRST PRESCRIPTION OF APRISO

*Maximum beneﬁt of $110 off the ﬁrst use.

BIN: 610020

PAY NO MORE THAN FOR ALL FUTURE APRISO PRESCRIPTIONS

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*Maximum beneﬁt of $100 off each subsequent use.

ID: XXXXXXXXXXX

Card is valid for one use per month. Offer expires 12/31/2013.

APRISO is a locally acting aminosalicylate indicated for the maintenance of remission of ulcerative colitis in patients 18 years and older. The use of APRISO for treating ulcerative colitis beyond 6 months has not been evaluated in controlled clinical trials. The most common adverse reactions (incidence ≥3% and >placebo) with APRISO in clinical trials were headache, diarrhea, upper abdominal pain, nausea, nasopharyngitis, inﬂuenza and inﬂuenza-like illness, and sinusitis1 *Average co-pay (all payers), Wolters Kluwer Health, August 2012. †Fingertip Formulary®, November 2012. ‡VA Healthcare System, October 2012.

Please see Brief Summary of complete Prescribing Information. Please see complete Prescribing Information available at AprisoRx.com. APRISO® and INTELLICOR® are registered trademarks of Salix Pharmaceuticals, Inc. ©2013 Salix Pharmaceuticals, Inc. All rights reserved. GM 12/95

See reverse side of APRISO Card for eligibility criteria. For help processing this card, call 1-855-740-3034.

Transition to APRISO, an affordable, once-daily ulcerative colitis (UC) therapy for your adult patients Average co-pay of less than $35 (all tiers)* Extensive formulary coverage with ~90% covered lives† #1-prescribed 5-ASA in the VA Health Care System‡

For more information, visit AprisoRx.com.

PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

Endoscopic Eradication Therapy for

Barrett’s Esophagus SHREYAS SALIGRAM, MD, MRCPa,b PRASHANTH VENNALAGANTI, MDa PRATEEK SHARMA, MDa,b a

Department of Veterans Affairs Medical Center Kansas City, Kansas b University of Kansas School of Medicine Kansas City, Kansas

Disclosures—Dr. Sharma has received grant support from Barrx Medical, Cook Medical, NinePoint Medical, and Olympus, Inc. Drs. Saligram and Vennalaganti reported no conflicts of interest.

arrett’s esophagus esoph (BE) is the precursor lesion to stage esophageal adenocarcinoma, which if diagnosed at an invasive stage,

is associated with significant morbidity and mortality. Surgery has been

the mainstay of treatment for patients with BE-associated high-grade dysplasia (HGD) and adenocarcinoma; however, surgery in itself carries significant morb morbidity. The past decade has seen tremendous pro progress in the minimally invasive treatment of BE. The premise behind aggressive tr treatment for patients with BEas associated HGD and early-stage es esophageal adenocarcinoma is to prev prevent progression to advancedstage cancer. Most interventional endosco endoscopists are comfortable treating HGD and in intramucosal esophageal cancer. R l d Recently, data h have emerged on the treatment of early submucosal cancer in BE at one end of the spectrum, and low-grade dysplasia (LGD) at the other. New techniques for the treatment of BE are constantly evolving, with renewed interest in arresting the rise of the fastest growing cancer in the Western world. The aim of this review is to examine the different modes and strategies of the endoscopic treatment of BE, with an emphasis on newer techniques.

Introduction BE is defined as displacement of squamocolumnar junction by intestinal metaplasia (goblet cells) proximal to the gastroesophageal junction. The overall population prevalence of BE is estimated at 1.6%,1 with an

er annual incidence of 62 cases per e 100,000.2 In patients with BE, the annual incidence of esophageal adenocarcinoma is reported to be between 0.12% and 0.5%.3-6 Intestinal metaplasia can have m a histologic transformation from nd no dysplasia to LGD, to HGD, and careventually, esophageal adenocarave the cinoma.7 Patients with HGD have h l adenod highest tendency to progress to esophageal carcinoma. Therefore, endoscopic eradication therapy increasingly is used to treat HGD and early esophageal adenocarcinoma to decrease the risk for progression to invasive disease. Data from the National Cancer Institute’s Surveillance, Epidemiology and End Results suggests a 6-fold increase in the incidence of esophageal adenocarcinoma in 2001, and esophageal cancer is considered as the fastest rising cancer in the United States.8 The aim of this review is to examine the current modalities of endoscopic eradication therapy used in the treatment of HGD and superficial esophageal adenocarcinoma.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS • S E P T E M B E R 2 0 1 3

Progression of Barrettâ&#x20AC;&#x2122;s Esophagus to Cancer BE has the potential to progress to esophageal adenocarcinoma by genetic alteration of intestinal metaplasia, where there is unregulated cell growth due to the inactivation of tumor suppressor genes and the activation of oncogenes. This causes morphological changes in the lining of the epithelium of the esophagus called dysplasia.9,10 The aim of ablation/eradication therapy is to destroy this abnormal lining of the esophagus and reinstate neosquamous epithelium. Before reviewing the various endoscopic therapies for BE, it is important to understand the risk for dysplasia and cancer associated with BE. Intestinal metaplasia, or nondysplastic BE, is the early stage of the disease and has the lowest incidence of transformation to dysplasia or esophageal adenocarcinoma. A retrospective study of 1,204 patients diagnosed with nondysplastic BE at index endoscopy and followed for a mean of 5.52 years found 98.6% and 97.1% of patients were cancer free at 5 and 10 years, respectively, based on a survival analysis.11 The incidence of esophageal adenocarcinoma was 0.27% per year, HGD was 0.48% per year, and LGD was 3.6% per year. Similar findings were reported in a large, population-based study from Denmark, where the risk for cancer in patients with nondysplastic BE was less than 0.2% per year.6 Thus, based on contemporary literature, the reported rate of progression to cancer or dysplasia in nondysplastic BE is very low. LGD is associated with a low number of dysplastic cells and is the initial stage of dysplasia. Several studies have shown varying results for the progression of LGD to HGD or cancer. A multicenter study of 210 patients with LGD followed for an average of 6.2 years reported a low incidence of esophageal adenocarcinoma (0.44% per year) and HGD (1.6% per year).12 In the same study, the combined incidence of HGD/esophageal adenocarcinoma was 1.83% per year, with a mean time to progression to esophageal adenocarcinoma of 4.41 years. A survival analysis revealed that 97.4% of patients were cancer free at 5 years. The study showed that 2.6% of patients developed cancer at the end of 5 years, and, overall, patients with LGD had a low risk for progression to cancer. However, other studies have shown a higher incidenceâ&#x20AC;&#x201D;up to 13.6% per yearâ&#x20AC;&#x201D;of progression to HGD/esophageal adenocarcinoma among patients with LGD.13-15 These inconsistencies in findings are suspected to be due to sampling errors and significant interobserver variability among pathologists.12-16 The natural history of LGD thus appears to be highly variable. HGD is associated with a higher number of dysplastic cells and is the advanced stage of dysplasia. Timely treatment at this stage can prevent progression to cancer. A 2008 meta-analysis revealed a high incidence of esophageal adenocarcinoma (6% per year) among patients with HGD who had not undergone ablation therapy or surgery.17 Of 236 patients who met inclusion criteria for the study, 69 had developed esophageal adenocarcinoma within 1.5 to 7 years

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

of follow-up. Furthermore, a landmark multicenter trial of 63 patients with HGD randomized to receive radiofrequency ablation (RFA) or a sham procedure showed that a significant proportion of patients in the sham group progressed to esophageal adenocarcinoma at 12 months, although 19% had spontaneous regression of dysplasia.18 These studies show beyond a doubt that HGD, if left untreated, is associated with a significant risk for progression to cancer.

Endoscopic Eradication Therapy Esophagectomy is effective in treating early-stage esophageal adenocarcinoma but is a radical therapy and carries significant morbidity (30%-40%) and mortality (1%-4%).19-24 Therefore, it is used for patients with a high risk for or presence of lymph node metastasis. A systematic review of 1,350 patients who underwent esophagectomy for intramucosal (T1a) esophageal adenocarcinoma showed that only 26 patients (1.4%) had lymph node metastasis, suggesting a low rate of advanced disease in T1a cancers.25 Additionally, a retrospective review including 70 patients with T1a esophageal adenocarcinoma and 56 patients with submucosal (T1b) esophageal adenocarcinoma revealed lymph node metastasis in 1.3% and 22% of patients, respectively.26 Lymphovascular invasion, tumor size of 2 cm of greater, and poor differentiation were associated with an increased risk for lymph node metastasis in this study. Another retrospective study of T1b lesions found that superficial and deep submucosal invasion were associated with substantial rates of metastatic lymphadenopathy (12.9% and 20.4%, respectively).27 Based on these studies, it can be concluded that the risk for lymph node metastasis in early esophageal adenocarcinoma is low and that endoscopic eradication therapy can be attempted in the vast majority of patients with T1a lesions; however, endoscopic eradication therapy usually is precluded in T1b esophageal adenocarcinoma because of the higher risk for lymph node metastasis. In order to obtain accurate staging of visible lesions and cancer, endoscopic mucosal resection (EMR) is performed to assess the depth of invastion. In patients with known cancer, the accuracy of TNM staging is higher when endoscopic ultrasound is combined with EMR.28 After accurate staging and resection of early esophageal adenocarcinoma, it is important to ensure that the rest of the BE is eradicated completely in order to prevent recurrence of cancer. A retrospective study of 349 patients who were treated with ablation therapy for BE revealed occurrence of metachronous lesions in 21.5% patients at a median of 15 months of followup.29 Notably, metachronous lesions were not found in patients who had undergone complete eradication of intestinal metaplasia. The current practice for endoscopic eradication of BE is resection of visible lesions with EMR, ablation of residual BE to prevent occurrence of metachronous lesions or recurrent neoplasm, and follow-up surveillance. Multimodal endoscopic eradication therapy with EMR and

residual BE after the use of EMR and/or RFA for the treatment of focal lesions. EMR or endoscopic submucosal dissection (ESD) is used, depending on the depth of the tissue that is being removed.

Table. Endoscopic Eradication Therapy for Barrett’s Esophagus Thermal ablation therapy

Multipolar electrocoagulation

ENDOSCOPIC MUCOSAL RESECTION

Argon plasma coagulation Laser therapy

Nonthermal ablation therapy

Photodynamic therapy Radiofrequency ablation Cryotherapy

Endoscopic resection

Endoscopic mucosal resection Endoscopic submucosal dissection

RFA is commonly performed. Visible or flat lesions are described by the Paris classification, and endoscopic inspection for visible or flat lesions is currently performed with white-light endoscopy.30 Advanced imaging techniques, including chromoendoscopy, virtual chromoendoscopy, and optical frequency domain imaging or confocal laser endomicroscopy, are available but underused. A recent meta-analysis showed that detection of HGD or cancer increased by 34% when advanced imaging techniques were used.31 This suggests that advanced imaging techniques used for initial endoscopic inspection lead to higher detection rates of HGD and cancer. Based on the available evidence, the American Gastroenterological Association issued guidelines for endoscopic surveillance and eradication therapy of BE.32 Endoscopic surveillance should be performed every 3 to 5 years for nondysplastic BE, every 6 to 12 months for LGD, and every 3 months for HGD if endoscopic eradication therapy is not performed. The treatment of early-stage dysplastic lesions—LGD—has been attempted; however, variability in the diagnosis and natural history of LGD is challenging. The publication of results of large, randomized controlled trials being conducted in Europe are awaited. All patients with dysplasia should have the diagnosis confirmed by at least 2 experienced gastrointestinal pathologists. The aim of endoscopic eradication therapy should be to eradicate BE completely once dysplasia has been eradicated to prevent residual intestinal metaplasia from progressing to recurrent or metachronus neoplasm. Different modalities of endoscopic eradication therapy are listed in the Table. Some older therapies—including thermal therapies (eg, multipolar electrocoagulation, argon plasma coagulation [APC], YAG laser) and nonthermal therapies (eg, photodynamic therapy)—are rarely used as first-line treatments since the advent of RFA.33 APC is used for eradication of

Focal and radical (wide-area) resections are the 2 types of EMR that can be performed.34 Focal EMR is used to excise visible polypoid flat or nodular lesions of esophageal mucosa suspected to harbor cancer. Focal EMR serves as a diagnostic tool for T-staging and as a therapeutic tool for excising neoplastic lesions. Two commonly used techniques are the multiband ligator and the cap-assisted device.35 The multiband ligator uses suction to draw lesions into a cap, and a rubber band is applied to create a pseudopolypoid lesion, which is then snared using electrocoagulation; subsequently, the specimen is retrieved.36 The cap-assisted technique uses saline or diluted epinephrine (1:100,000) to lift the suspected lesion.37 After raising the suspected lesion, the snare is looped to the rim of the transparent cap attached to the endoscope tip; then, the raised lesion is then sucked into the cap, creating a pseudopolyp, which is then snared by electrocoagulation before the specimen is retrieved. Radical EMR is used to remove larger areas of BE, where side-by-side resections are done to achieve complete eradication of neoplastic and metaplastic tissue. EMR is repeated every 2 to 3 months until all visible BE has been removed. This technique is frequently used in patients with noncircumferential BE of a maximal length of 4 to 5 cm. Short-Term Results There are a few studies that have used EMR as the sole treatment for eradication of all BE tissue. The majority of the studies have used multimodal endoscopic eradication, that is, initial focal EMR, followed by ablation therapy to evaluate the efficacy of EMR in treating HGD and early esophageal adenocarcinoma. A retrospective study of 49 patients (67%, HGD; 33%, T1a adenocarcinoma) who underwent radical EMR with a mean follow-up of 22.9 months showed complete eradication of intestinal metaplasia in 97% of patients.38 There was no recurrence of dysplasia or cancer in the 32 patients who completed the eradication protocol; however, nearly one-third of the patients developed symptomatic stenosis, which was successfully dilated. In another study, researchers randomized patients to receive radical EMR (n=25) or multimodal endoscopic therapy (focal EMR with ablation; n=22).39 During a mean follow-up of 24 months, complete eradication of intestinal metaplasia was achieved in 92% of patients in the radical EMR group and 96% of patients in the combined modality group. Similar rates of complete eradication of dysplasia/cancer were obtained (100% for radical EMR; 96% for combined modality). Based on these studies and several others,40,41 radical EMR appears to have good short-term efficacy for the treatment of HGD and early esophageal adenocarcinoma.

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Figure 1. Barrett’s esophagus with visible lesion pre– and post–endoscopic mucosal resection.

Long-Term Results There are now robust data regarding the longterm efficacy of EMR in treating patients with HGD and early esophageal adenocarcinoma. A prospective study of 100 patients with T1a esophageal adenocarcinoma who underwent EMR with a mean follow-up of 36.7 months revealed complete eradication of dysplasia/cancer in 99% of patients; 11% of patients had metachronous lesions that were retreated successfully with EMR.42 Another retrospective study of 132 patients with T1a esophageal adenocarcinoma and a mean follow-up of 43 months revealed that 75 patients who underwent EMR alone achieved complete eradication of dysplasia/cancer at a rate of 96% with a rate of recurrence of 11%, all successfully treated with a repeat EMR.43 Based on the above studies, eradication of BE by widespread EMR has excellent short-term efficacy, with rates of 92% to 99%; however, long-term studies with follow-up of up to 5 years revealed an issue with recurrence of metachronous lesions in 10% to 15% of patients. Complications Adverse events (AEs) associated with EMR are generally low. Dysphagia, strictures requiring dilation,39,44-48 bleeding (immediate and delayed, >48 hours),38,48-51 chest pain, and perforation (1%-5%) are some of the reported complications.52 Resection of more than 50% of esophageal circumference is associated with higher rates of strictures.45 Radical EMR is associated with more complications than focal EMR, also with high rate of strictures.38,39,52-57

ENDOSCOPIC SUBMUCOSAL DISSECTION ESD is a technique used for en bloc resection of larger lesions. The technique was pioneered in Japan, mainly for the treatment of early gastric lesions. A coagulation

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tip is used to mark around the lesion. Diluted epinephrine with 10% glycerol (multiple other agents, such as hyaluronidate, mannitol, and indigo carmine also may be used) is injected into the submucosa to separate the lesion from the muscle layer. Initially, a needle knife is used to resect the mucosa; subsequently, a hook knife is used to resect submucosal fibers and vessels. The resected lesions are retained for histopathology. The advantage of this procedure over EMR is that larger lesions (approximately 7 cm) can be resected en bloc, and more accurate information about the depth of the lesion can be obtained.58,59 Short-Term Results A single study was published evaluating the outcome of ESD. Twenty-nine patients known to have large T1a cancers in the setting of BE with a median diameter of 2 cm underwent ESD and were followed for a mean period of 17 months. R0 resection was achieved in 38.5% of these patients. Complete eradication of intestinal metaplasia and neoplasia was achieved in 53.6% and 96.4% of patients, respectively. The rate of complete eradication of intestinal metaplasia increased to 80% when additional treatment with RFA was performed.60 Long-Term Results Because it is a relatively new technique, there have not been many studies on the long-term efficacy of ESD. In a study of 25 patients with T1a or T1b adenocarcinoma who underwent ESD with a mean followup of 30.6 months, en bloc resection was achieved in 100% of patients but R0 resection was attained in only 72%.59 The mean size of the resected lesions was 1.6 cm. Patients who achieved R0 resection had no recurrence of neoplasia. Complications Published reports suggest that complications of ESD are minimal when performed by expert hands. Some

Figure 2. Barrett’s esophagus pre– and post–radiofrequency ablation.

complications that may occur include delayed bleeding, incomplete (tumor curative) R0 resection, strictures, and sudden cardiac death.59,60

RADIOFREQUENCY ABLATION RFA is the most commonly used and the best-studied endoscopic ablative therapy currently available. Ablation with RFA can be delivered using either a circumferential or focal device. The circumferential ablation device has a 3-cm cylindrical balloon with circular electrodes that deliver the preset energy for ablation in a circumferential fashion. The focal ablation device is placed over the tip of the endoscope to ablate smaller areas of tissue. Short-Term Results There have been several published studies evaluating the short-term efficacy of RFA, which appears to be excellent. One was a retrospective multicenter study including 335 patients (HGD, 72%; T1a esophageal adenocarcinoma, 24%; LGD, 4%) from 19 centers in the United Kingdom treated with either focal EMR and RFA (49%), or RFA alone (51% patients).61 After a mean of 2.5 treatments and 12 months of follow-up, complete eradication of intestinal metaplasia and dysplasia was achieved in 62% and 81% of patients, respectively. Invasive cancer developed in 3% of patients, and the cumulative risk for cancer progression over 5 years was 8%. Another retrospective study of 54 patients with T1a adenocarcinoma who underwent focal EMR (100%) combined with ablation (81%) with a mean follow-up of 23 months demonstrated complete eradication of dysplasia/cancer in 96% of patients and complete eradication of intestinal metaplasia in 59%.48 Additionally, a recent Cochrane review including 1,074 patients from 16 studies for a 12-month follow-up period found overall rates of complete eradication of

intestinal metaplasia and dysplasia of 82% and 94%, respectively.33 Thus, based on the available evidence, the short-term efficacy of RFA for complete eradication of intestinal metaplasia is 62% to 82%, and complete eradication of dysplasia is 81% to 94%. Recurrence of cancer in a minor set of patients (3%) was seen at the end of 12 months. Long-Term Results Several recent studies have now focused on the long-term efficacy of RFA after initial successful eradication of BE. In a multicenter study of 448 patients (HGD, 60%; LGD, 15%; nondysplastic BE, 14%; T1a esophageal adenocarcinoma, 11%) who underwent RFA or combined EMR and RFA (55%) revealed that complete eradication of intestinal metaplasia was achieved in 26%, 56%, and 71% of patients at 1, 2, and 3 years, respectively.62 Kaplan-Meier analysis showed that the incidence of recurrent intestinal metaplasia at 1 and 2 years was 20% and 33%, respectively. Younger patients and those with short-segment BE responded much better to RFA. A single-center, longterm retrospective study of 72 patients with BE (HGD, 49%; T1a esophageal adenocarcinoma, 22%; LGD, 17%) who underwent RFA alone showed that after a mean of 2.3 treatments and 9.5 months of followup, complete eradication of intestinal metaplasia and dysplasia was achieved in 79% and 89% of patients, respectively.63 Superficial adenocarcinoma was persistent in 5% of patients, and they underwent esophagectomy. Thirty-four patients who achieved complete eradication of intestinal metaplasia were followed for 3 years, and no further recurrences were observed. The overall rate of complete eradication of intestinal metaplasia was 73%. Thus, based on these studies, RFA appears to have an excellent short-term efficacy (complete eradication

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Figure 3. Barrett’s esophagus pre- and post-cryotherapy.

of intestinal metaplasia, 71%-93%; complete eradication of dysplasia, 98%-100%). However, during longterm follow-up, 15% to 30% of patients can have recurrence of intestinal metaplasia within 2 to 3 years of complete eradication, thereby requiring ongoing surveillance. Complications RFA is generally well tolerated with minimal complications. Bleeding, mucosal tears, dysrhythmias, chest pain, buried metaplasia (a systematic review showed that of 1,004 patients who underwent RFA, only 0.9% had buried metaplasia64), recurrent esophageal adenocarcinoma, and HGD61,65-69 are some of the reported complications.

CRYOTHERAPY Cryotherapy is a relatively new technique that uses extremely low temperatures to target BE tissue for ablation. This technique takes advantage of the fact that cellular apoptosis occurs between temperatures of –76°C and –158°C.70 Rapid-freezing and slow-thawing repetitive cycles cause changes at the cellular and molecular levels that lead to tissue destruction through immediate and delayed processes. The formation of extracellular and intracellular ice disrupts cell membranes and causes tissue ischemia.70-72 Two types of cryotherapy devices are available: a device from CSA Medical, Inc., with a modified cryodecompression tube that uses liquid nitrogen delivered at –196°C, and another from GI Supply, with a suction catheter that attaches to the tip of the endoscope and uses high-pressure carbon dioxide gas to cause cooling at –78°C. The depth of the tissue injury depends on the duration of the freezing time. The technical advantages of cryotherapy over other ablative therapies are that it is easy to cover large areas of mucosa, causing tissue destruction without precise close contact; therefore, it is particularly

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useful in patients with tortuous esophageal anatomy and also at the area of the gastroesophageal junction. However, robust data on short- and long-term results are lacking with this technique. Short-Term Results A retrospective study of 60 patients followed for a mean period of 10.5 months showed that after a mean of 3.4 treatments of liquid nitrogen cryotherapy, complete eradication of dysplasia was achieved in 87% of patients, and complete eradication of intestinal metaplasia was achieve in 57%.73 In another small study, 30 patients with BE (HGD, 25; T1a adenocarcinoma, 5) underwent liquid nitrogen cryotherapy and were followed for a mean period of 12 months.74 For 90% of these patients, pathology was downgraded within a mean of 5 sessions. Reported rates of complete eradication of intestinal metaplasia and dysplasia/cancer were 3.3% and 60%, respectively. Additionally, a study of 23 patients treated with 6 treatments of carbon dioxide cryotherapy and followed for a mean period of 11.5 months reported complete eradication of intestinal metaplasia and dysplasia in 95.6% of patients; many of these patients had failed prior ablative measures like RFA, photodynamic therapy, and EMR.75 Long-Term Results A single retrospective study of 32 patients with HGD has evaluated the long-term efficacy of cryotherapy.76 Patients underwent a mean of 4 treatments and were followed for a mean 37 months. In this study, complete eradication of HGD was achieved in 96% of patients, and complete eradication of intestinal metaplasia was achieved in 81%. Complications AEs reported with cryotherapy are generally self-limiting. Chest pain and dysphagia are the predominant complications; strictures are minimal and perforation rare. Odynophagia and sore throat are among other known AEs of cryotherapy.73,74,77

high-grade dysplasia: a meta-analysis. Gastrointest Endosc. 2008;67(3):394-398.

Summary Current evidence suggests that multimodal endoscopic eradication therapy with focal EMR and RFA is the best therapy for treatment of BE with HGD and T1a esophageal adenocarcinoma; this is the preferred option over surgery. Radical EMR is associated with more complications than focal EMR. ESD is technically challenging with low R0 resection rates, making it a less attractive treatment option; this procedure is still in an incipient stage. Cryotherapy appears promising because of low cost and ease of the procedure, but more evidence regarding its long-term efficacy is required. Continued surveillance after complete eradication of intestinal metaplasia is achieved is recommended because of the risk for recurrence of intestinal metaplasia, buried metaplasia, and subsequent development of neoplasia.67,78

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Yoshinaga S, Gotoda T, Kusano C, et al. Clinical impact of endoscopic submucosal dissection for superficial adenocarcinoma located at the esophagogastric junction. Gastrointest Endosc. 2008;67(2):202-209. 60. Neuhaus H, Terheggen G, Rutz EM, et al. Endoscopic submucosal dissection plus radiofrequency ablation of neoplastic Barrett’s esophagus. Endoscopy. 2012;44(12):1105-1113. 61. Haidry RJ, Dunn JM, Butt MA, et al. Radiofrequency ablation and endoscopic mucosal resection for dysplastic Barrett’s esophagus and early esophageal adenocarcinoma: outcomes of the UK national halo RFA registry. Gastroenterology. 2013;145(1):87-95. 62. Gupta M, Iyer PG, Lutzke L, et al. Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett’s esophagus: results from a us multicenter consortium. Gastroenterology. 2013;145:79-86. 63. Dulai PS, Pohl H, Levenick JM, et al. Radiofrequency ablation for long- and ultralong-segment Barrett’s esophagus: a comparative long-term follow-up study. Gastrointest Endosc. 2013;77(4):534-541. 64. Gray NA, Odze RD, Spechler SJ. Buried metaplasia after endoscopic ablation of Barrett’s esophagus: a systematic review. Am J Gastroenterol. 2011;106(11):1899-1908. 65. Titi M, Overhiser A, Ulusarac O, et al. Development of subsquamous high-grade dysplasia and adenocarcinoma after successful radiofrequency ablation of Barrett’s esophagus. Gastroenterology. 2012;143(3):564-566. 66. Phoa KN, Pouw RE, van Vilsteren FG, et al. Remission of Barrett’s esophagus with early neoplasia 5 years after radiofrequency ablation with endoscopic resection: a Netherlands cohort study. Gastroenterology. 2013;145(1):96-104. 67. Orman ES, Kim HP, Bulsiewicz WJ, et al. Intestinal metaplasia recurs infrequently in patients successfully treated for Barrett’s esophagus with radiofrequency ablation. Am J Gastroenterol. 2013;108(2):187-195. 68. Kim MP, Brown KN, Schwartz MR, et al. Advanced esophageal cancer in patients who underwent radiofrequency ablation for Barrett esophagus with high-grade dysplasia. Innovations (Phila). 2013;8(1):17-22. 69. Shaheen NJ, Overholt BF, Sampliner RE, et al. Durability of radiofrequency ablation in Barrett’s esophagus with dysplasia. Gastroenterology. 2011;141(2):460-468. 70. Gage AA, Baust J. Mechanisms of tissue injury in cryosurgery. Cryobiology. 1998;37(3):171-186. 71. Baust JG, Gage AA. The molecular basis of cryosurgery. BJU Int. 2005;95(9):1187-1191. 72. Greenwald BD, Dumot JA. Cryotherapy for Barrett’s esophagus and esophageal cancer. Curr Opin Gastroenterol. 2011;27(4):363-367. 73. Shaheen NJ, Greenwald BD, Peery AF, et al. Safety and efficacy of endoscopic spray cryotherapy for Barrett’s esophagus with high-grade dysplasia. Gastrointest Endosc. 2010;71(4):680-685. 74. Dumot JA, Vargo JJ 2nd, Falk GW, et al. An open-label, prospective trial of cryospray ablation for Barrett’s esophagus high-grade dysplasia and early esophageal cancer in high-risk patients. Gastrointest Endosc. 2009;70(4):635-644. 75. Canto MI, Gorospe EC, Shin EJ, et al. Carbon Dioxide (CO2) Cryotherapy is a safe and effective treatment of Barrett’s esophagus (BE) with HGD/intramucosal carcinoma. Gastrointest Endosc. 2009;69:AB341. 76. Gosain S, Mercer K, Twaddell WS, et al. Liquid nitrogen spray cryotherapy in Barrett’s esophagus with high-grade dysplasia: long-term results. Gastrointest Endosc. 2013;78(2):260-265. 77. Greenwald BD, Dumot JA, Horwhat JD, et al. Safety, tolerability, and efficacy of endoscopic low-pressure liquid nitrogen spray cryotherapy in the esophagus. Dis Esophagus. 2010;23(1):13-19. 78. Gorospe EC, Sun G, Wang KK. Endpoints for radiofrequency ablation in Barrett’s dysplasia. Am J Gastroenterol. 2013;108(2):197-199. DISCLAIMER—This review is designed to be a summary of information and represents the opinions of the author. Although detailed, the review is not exhaustive. Readers are strongly urged to consult any relevant primary literature, the complete prescribing information available in the package insert of each drug, and the appropriate clinical protocols. No liability will be assumed for the use of this review, and the absence of typographical errors is not guaranteed. Copyright © 2013, McMahon Publishing, 545 West 45th Street, 8th Floor, New York, NY 10036. Printed in the USA. All rights reserved, including right of reproduction, in whole or in part, in any form.

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SEPTEMBER 2013

REPORT Management of Opioid-Induced Constipation in Patients With Advanced Illness of pain related to tumor enlargeoderate to severe pain is a ment, metastasis or, as another common clinical problem Faculty example, neuropathic pain in the among patients with advanced illsetting of diabetes mellitus. Other ness, particularly in the palliative Darren Brenner, MD times, the pain may be iatrogenic care setting. Although cancer pain Assistant Professor of Gastroenterology in etiology, such as complicahas historically received the most and Hepatology tions related to radiation therapy attention, patients with AIDS, Northwestern University Feinberg for the treatment of cancers, or advanced congestive heart failure, School of Medicine neuropathy induced by antiretroand advanced lung disease also Chicago, Illinois viral or chemotherapeutic agents. commonly experience pain.1 Unfortunately, the prevalence of “When we look at patients with Joseph Pergolizzi, MD pain is quite high in the palliative advanced illness, pain is one of Adjunct Associate Professor of care setting.” the most prevalent symptoms Pharmacology In fact, a meta-analysis of that patients report,” said Joseph Temple University School of Medicine studies published during the Pergolizzi, MD, adjunct associate Philadelphia, Pennsylvania past 40 years found that 64% professor of pharmacology, Temof patients with advanced-stage ple University School of Medicine cancer reported significant pain in Philadelphia, Pennsylvania. in their daily lives.2 Another review, which included patients “This pain can arise due to the illness itself, such as in cases

Indication ®

RELISTOR is indicated for the treatment of opioidinduced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.

Contraindications RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstructions. Please see Important Safety Information throughout and brief summary of Prescribing Information on page 12.

Supported by

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with advanced illnesses such as cancer, AIDS, heart disease, chronic obstructive pulmonary disease (COPD), and renal disease reported that the prevalence of pain across 28 studies ranged between 34% and 96%.3 Moreover, the prevalence of pain among patients receiving hospice care may be as high as 90%.4 “The severity of pain has an important influence in the choice of treatment strategy,” Dr. Pergolizzi explained. “When patients report moderate to severe pain, that’s where we really rely on the opioids. In fact, escalating doses of opioids are oftentimes the only effective option for pain control in advanced disease.” This notion is endorsed by guidelines from several major societies in the United States, such as the American College of Physicians and the National Comprehensive Cancer Network, which recommend that opioids should be used for the treatment of moderate to severe pain in patients with advanced illness.5,6 Opioids, however, are associated with numerous adverse events (AEs), including nausea, sedation, pruritus, and respiratory depression.5,7 Perhaps the most common opioid AEs are those affecting the gastrointestinal (GI) tract, including opioidinduced constipation (OIC).8-10 The following report provides an overview of OIC, including a review of its epidemiology, risk factors, and how its pathophysiology and management differ from that of primary constipation, as well as a review of data for recently approved options for the management of this condition.

Pathophysiology of OIC Darren Brenner, MD, assistant professor of gastroenterology and hepatology, Northwestern University Feinberg School of Medicine in Chicago, Illinois, noted that, “in terms of pathophysiology, OIC is quite distinct from other forms of constipation.” For example, physiologic constipation results from extrinsic, non–disease-related factors that affect bowel function, such as decreased physical activity and inadequate dietary fiber and fluid intake. These factors may cause decreased bowel motility and increased transit time, which allows more time for fluid resorption in the intestinal lumen, leading to hard and dry stools.9 In other cases, constipation may result from pathologic conditions in the setting of underlying GI, nervous system, or metabolic disorders that interfere with GI motility or fluid absorption/secretion.9,11

“In contrast, OIC is mediated by the effect of opioids on opioid receptors that are located throughout the GI tract and the enteric nervous system,” said Dr. Brenner. The 3 major opioid receptors in the enteric nervous system are the μ-, γ-, and κ-subtypes.12 The μ-receptors are widely distributed in the GI tract submucosa as well as the ileal mucosa, where they influence ion transport changes.12 The primary mediator involved in the development of OIC is the μ-opioid receptor; inhibition of excitatory and inhibitory neurotransmitters occurs when opioid agonists bind to this receptor, causing multiple effects that contribute to OIC.7,13,14 These include inhibition of gastric emptying, reduction of mucosal secretions, and a decrease in peristalsis throughout the GI tract, thereby delaying transit.14,15 Furthermore, opioids stimulate non-propulsive motility, intestinal segmentation and tone, and increased pyloric and ileocecal sphincter tone. Opioids also result in increased absorption of fluids, mainly by delayed transit—increasing contact time for absorption—and by stimulating mucosal sensory receptors that activate a reflex arc that facilitates further fluid absorption.14 All of these pathophysiologic processes conspire to result in hard, dense stools and decreased motility, resulting in significant constipation14 that may be refractory to traditional strategies used to alleviate constipation.15 “Patients with advanced illness also may have autonomic dysfunction leading to GI motility disorders. For example, HIV affects local humoral immunity and causes motility disturbances via its influence on autonomic nerves,” said Dr. Pergolizzi. “Using opioids for any treatment [in patients with advanced illness] is going to be detrimental to the GI tract given the plethora of μ-opioid receptors located across the entire intestinal lining,” said Dr. Brenner. “However, treatment guidelines still rely on opioids for the treatment of moderate to severe pain, and I don’t see that changing any time soon. So the best thing we can do is develop strategies to overcome adverse GI events related to their use.” Nonselective opioid-receptor antagonists such as naloxone and naltrexone target the μ-, γ-, and κ-opioid receptors, which led to interest in their use for opioid therapy.15 However, both agents can cross the blood–brain barrier and antagonize receptors that mediate the analgesic effect of opioids.12,16

Important Safety Information RELISTOR ® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been

reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR

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“The last thing that we want to do in the palliative care setting is to reduce the analgesic effects of our opioids, because our primary goal is to reduce pain in these patients,” said Dr. Pergolizzi.

Epidemiology and Consequences of OIC OIC is an anticipated side effect of opioid therapy. Its overall relevance to the clinical community continues to increase, mainly because of the rising therapeutic use of opioids.17 For example, OIC rates in patients receiving cancer treatment and opioids can range from 69% to 90%,18,19 and studies of patients with advanced cancer who are receiving hospice care report rates as high as 87%.20 Additionally, among individuals with advanced illnesses other than cancer who are receiving opioid therapy, the prevalence of opioid-induced GI AEs approaches 90%.21 “In the palliative care patient with advanced disease, we are more aggressive in the use of opioids to reduce pain with the goal of comfort,” said Dr. Pergolizzi. “Although we try to balance the role of analgesic-related side effects, oftentimes, relief of pain is more important for these patients. As such, we typically use higher dose of opioids, which results in more adverse effects.” Risk factors for OIC include advanced age, opioid type/ strength, and advanced illness (eg, cancer, AIDS, or cardiovascular disease).18,20,21 Furthermore, the risk for OIC increases with relative immobility, dehydration, and altered nutritional intake, all of which are common in patients with advanced illnesses, particularly in the palliative care setting.21 Although patients may slowly acquire a tolerance to opioid-related side effects such as nausea or sedation, OIC may continue unabated throughout treatment.21 Dr. Pergolizzi said that there are several notable consequences of OIC. “First, OIC can result in other GI symptoms, including nausea and vomiting and a decreased ability to take in oral medications and nutrients. Second, if patients have no remedy to relieve the symptoms and complications of OIC as an outpatient, they really have no other option than to come to the emergency department to be evaluated. In some cases, the symptomatology and consequences of OIC are sufficiently severe to warrant hospitalization for more aggressive

interventions,” he said. “When you consider the patient with advanced illness, especially those in the palliative care setting, they would really rather not be hospitalized provided they have some option to adequately relieve OIC at home.” The consequences of OIC are diverse and significant. Clinical manifestations include abdominal pain, distension, and nausea and vomiting.9 When left untreated, OIC may lead to inadequate absorption of oral medications, fecal impaction, hemorrhoids, bowel obstruction, and intestinal perforation.9 “There is a vicious circle that exists between opioid use for the relief of pain and the subsequent pain and discomfort that can result from the development of secondary constipation,” said Dr. Pergolizzi. “Specifically, patients are given opioids to relieve the primary pain related to their advanced illness but end up developing OIC, which can, itself, be a painful condition. [When laxative agents provide insufficient relief,] patients are then faced with the choice of either refraining from further opioid therapy to relieve OIC, in which case the pain from their primary condition is not adequately treated, or taking larger doses of opioids and potentially worsening the pain associated with OIC.”

Treatment of OIC in Advanced Illness Physiologic constipation is typically managed through a combination of behavioral strategies and the use of agents designed to increase stool bulk, improve intestinal motility, and/ or aid the passage of stools through softening agents.9 Supportive strategies include increased hydration and improved patient mobilization—which can be difficult for patients with advanced illness—along with addressing the etiologic triggers of constipation.9 Laxatives are the first-line therapeutic option for OIC, and the various classes of laxative agents used to relieve physiologic mechanisms of constipation are summarized in Table 1.22,23 However, data from clinical trials suggest that conventional laxatives (eg, over-the-counter laxatives, polyethylene glycol, lactulose, magnesium citrate) may not offer adequate symptom relief for some patients.15,21 As reviewed in the section on the pathophysiology of different types of constipation, OIC in advanced illness is unique from other forms of constipation. “When we look at laxatives

Important Safety Information (continued) and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Use of RELISTOR has not been studied in patients with peritoneal catheters. Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients.

The most common adverse reactions reported with RELISTOR compared with placebo in clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%). Please see Important Safety Information throughout and brief summary of Prescribing Information on page 12.

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Table 1. Conventional Laxative Options for Opioid-Induced Constipation in Advanced Illness Type

Attributes

Examples

Side Effects/Complications

Bulk laxatives

Dietary fiber; causes water retention in the colon and increases stool bulk

Psyllium husk, methylcellulose

Increased gas; risk for bowel obstruction in patients with strictures

Osmotic laxatives

Salt content retains fluid retention and increased intestinal secretions

Sorbitol, lactulose, polyethylene glycol, magnesium citrate

Electrolyte imbalances; increased gas, nausea, and dehydration

Stool softeners

Decrease surface tension to lubricate and soften fecal matter

Dioctyl sodium, calcium sulfosuccinate

Require adequate fluid intake, useless in patients with compromised bowel motility

Stimulants

Increase colonic motility and electrolyte transport; stimulate fluid secretion

Senna, cascara, bisacodyl

Electrolyte imbalances; abdominal pain, nausea, and colonic dysmotility

From references 22 and 23.

and stool softeners, we see dramatic variability in terms of the response to such agents across our patient populations. A lot of that has to do with the specific mechanisms of constipation, particularly in patients with OIC,” said Dr. Pergolizzi. Another strategy that has been recommended to relieve AEs while maintaining analgesia is that of opioid rotation.5,24 This tactic is predicated on the fact that patients react differently to various types of opioids, which implies both incomplete crosstolerance and distinct variations in their pharmacodynamics and opioid-receptor binding affinities.24,25 However, this strategy has shown only moderate benefits in the reduction of OIC

and other related AEs. Narabayashi and colleagues investigated the safety of an opioid rotation in cancer patients and found that side effects commonly recurred after switching from one agent to another.26 There also are therapeutic equivalence concerns when switching from one opioid to another. Current recommendations are based on studies conducted within different patient populations that analyzed dose equivalency, not pain management.24,25 The relative ineffectiveness of traditional strategies for OIC has prompted research and development of targeted therapies, as some patients require additional therapeutic options.

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Blood-Brain Barrier Opioid

RELISTOR

Mu-opioid μ-opioid receptor receptor

Figure 1. Relistor inhibits opioids from m binding with μ-receptors in tissues such as the gastrointes gastrointestinal tract.

“Until recently, the only agents available were ere those being used to treat the more typical types of constipation—bulknstipation—bulking agents, osmotic and stimulant laxatives,” said Dr. Brenner. “Now we’re moving into an era where we’re developing [second-line] agents that focus on the precise pathophysiologic mechanisms of OIC to provide specific and effective antidotes.”

Peripheral Opioid-Receptor Antagonists The limitations of nonselective opioid antagonists have prompted the development of agents that do not cross the blood–brain barrier. These agents ideally would avoid the

of opioidanalgesic-dampening and opioid-withdrawal effects ef receptor antagonists while maintaining therapeutic efficacy for therape the alleviation of OIC.15 N-methylation of naltrexone results in a charged derivative, methylnaltrexone (Relistor, Salix Pharmaceuticals), which has restricted ability to cross the blood–brain barrier in humans because of its polarity and low lipid solubility.27 Relistor antagonizes μ-opioid receptors, which reverses opioid-induced delays on GI motility in a dose-dependent manner.27 Figure 1 shows Relistor blocking opioids from binding to μ-receptors within the GI tract.

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Placebo

RELISTOR 0.15 mg/kg

62%

58% a

Patients, %

RELISTOR 0.30 mg/kg 48% a

50 40 30 20

16% 14%

10 0 (n=52)

(n=47)

(n=55)

Study 1

(n=71)

(n=62)

Study 2

Figure 2. Laxation response rates within 4 hours of the first dose during clinical trials of Relistor in patients with advanced illness. a

P<0.0001 vs placebo

From reference 27.

The efficacy and safety of Relistor for OIC in patients with advanced illness were investigated in 2 clinical trials (Figure 2).27 Slatkin and colleagues conducted a randomized double-blind, placebo-controlled trial that compared a single subcutaneous injection of Relistor (0.15 mg/kg or 0.30 mg/kg) with placebo for OIC.21 The study included 154 patients with advanced illness such as cancer or other end-stage conditions (eg, cardiovascular disease, HIV/AIDS) who were receiving palliative care.21 Participants had received opioid therapy for at least 3 days before study randomization and had not experienced a bowel movement within 48 hours of the first dose.21

Within 4 hours of treatment, laxation response rates for Relistor doses of 0.15 mg/kg (n=47) and 0.30 mg/kg (n=55) were 61.7% and 58.2%, respectively, compared with 14% for placebo (P<0.0001). In fact, roughly half of the Relistor responders defecated within 30 minutes of receiving the agent.21 Within 24 hours, laxation rates remained steady for 0.15 mg/kg Relistor (68.1%) and 0.30 mg/kg Relistor (63.6%) compared with placebo (26.9%).21 The investigators reported comparable efficacy between both doses of Relistor, but patients in the 0.30 mg/kg treatment arm had higher rates of abdominal pain (38.2% vs 27.7%).21

Important Safety Information RELISTOR ÂŽ (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been

reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvieâ&#x20AC;&#x2122;s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR

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Table 2. Common Adverse Reactions Associated With Relistor During Clinical Trials in Patients With Advanced Illness RELISTOR a (n=165)

Placebo (n=123)

Pts (%)

Abdominal pain

47 (28.5)

12 (9.8)

Flatulence

22 (13.3)

7 (5.7)

Nausea

19 (11.5)

6 (4.9)

Dizziness

12 (7.3)

3 (2.4)

Diarrhea

9 (5.5)

3 (2.4)

Hyperhidrosis

11 (6.7)

8 (6.5)

Adverse Reaction

Includes doses of 0.075, 0.15, and 0.30 mg/kg

From reference 27.

Other common AEs related to Relistor during this trial in the 0.15 mg/kg and 0.30 mg/kg treatment arms were flatulence (12.8% and 14.5%), nausea (4.3% and 14.5%), and dizziness (4.3% and 9.1%).21 In a similar study by Thomas and colleagues, 133 patients who had received opioids for at least 2 weeks and developed OIC that was refractory to the use of laxatives were randomly assigned to receive subcutaneous Relistor (0.15 mg/kg; n=63) or placebo (n=71) every other day for 2 weeks.28 Participants were recruited from palliative care settings and had advanced illness such as cancer, cardiovascular disease, COPD, emphysema,

Alzheimerâ&#x20AC;&#x2122;s disease, or dementia.28 The proportion of patients who experienced laxation within 4 hours was significantly higher in the Relistor group than in the placebo group (48% vs 15%, respectively; P<0.0001).28 Additionally, the median time to laxation after the first dose was significantly shorter in the Relistor group than in the placebo group (6.3 vs 48 hours, respectively; P<0.002).28 The most common AEs related to Relistor during this trial were abdominal pain (17%), flatulence (13%), nausea (11%), increased body temperature (8%), and dizziness (8%).28 The study by Thomas and colleagues also included an open-label extension in which patients received Relistor as

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needed each day for 3 months. A total of 89 patients entered this phase of the trial (47 from the Relistor group, 42 from the placebo group).28 By the end of the 3-month extension, patients from the placebo group improved their rescuefree response rates from 11% to 52%; patients from the initial Relistor group improved their response rates from 45% to 57%.28 Median time to laxation for all patients was less than 45 minutes.28 The most common AEs during this phase were abdominal pain (30%), progression of malignant neoplasm (24%), nausea (21%), and vomiting (20%). Serious AEs related to Relistor were muscle spasms (1 patient) and exacerbated pain (1 patient); 32 deaths occurred, with all attributed to underlying disease.28 In both the Slatkin and Thomas studies, participants were permitted to continue their previously initiated laxative therapy, just not within 4 hours of study treatments. Figure 2 provides laxation rates from the 2 clinical trials of Relistor within 4 hours of the first dose.27 “In the 2 pivotal trials, the clinical benefit associated with the fact that methylnaltrexone does not cross the blood–brain barrier was confirmed by observations showing there was no analgesic-stealing effect,” said Dr. Pergolizzi. Indeed, in both trials there was no change in pain scores or evidence of central-opioid withdrawal in response to Relistor.21,28 Abdominal pain and flatulence were the most common AEs attributed to Relistor during the 2 clinical trials (Table 2).27 A post hoc analysis of abdominal pain rates during these studies found that it consisted primarily of abdominal cramping and did not affect patients’ overall evaluation of pain.29 These AEs were mostly mild to moderate in severity and did not affect patients’ global evaluation of pain. The incidence of abdominal pain in Relistor-treated patients was highest following the first dose and it decreased with subsequent doses.29 Of note, rare postmarketing cases of GI perforation have been reported in association with Relistor, particularly in patients with abnormal structural integrity in the walls of the GI tract, such as those with cancer, peptic ulcer, or Ogilvie’s syndrome. As a result, the prescribing information includes a warning that Relistor should be used with caution in patients with a known or suspected GI tract lesions.27 On the basis of these trials, in 2008 the FDA approved the use of Relistor for the treatment of OIC in patients with

advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. 27 Relistor is administered as a subcutaneous injection, and a typical schedule is 1 dose every other day as needed, but not to exceed more than 1 dose in a 24-hour period.27 Use of Relistor beyond 4 months has not been studied. The recommended dose of Relistor is 8 mg for patients who weigh between 38 and 61 kg; 12 mg for patients who weigh between 62 and 114 kg; and 0.15 mg/kg for patients who fall outside of these weight ranges.27 Only patients who require an 8- or 12-mg dose should be prescribed prefilled syringes. No dose adjustment is required in patients with mild or moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30 mL/min), dose reductions of Relistor by one half are recommended.27 If severe or persistent diarrhea occurs during treatment, patients should discontinue therapy with Relistor and consult their physician. If patients develop severe, persistent, and/or worsening abdominal symptoms, they should discontinue therapy with Relistor and promptly notify their physician. Use of Relistor has not been studied in patients with peritoneal catheters. Dr. Pergolizzi views subcutaneous Relistor administration as one of several unique advantages. “The fact that we can administer this agent via the subcutaneous route in patients undergoing palliative care is important, as many of these patients are unable to take in medications by mouth due to nausea, dysphagia, or decreased levels of consciousness. OIC itself can also cause significant nausea and may preclude oral medication intake for some patients,” he said.

Treatment Algorithm for Opioid-Induced Constipation in Advanced Illness With the approval of Relistor for the treatment of OIC in patients with advanced illness who are receiving palliative care when laxative therapy has not been sufficient, Drs. Brenner and Pergolizzi discussed the current landscape and clinical management of OIC in patients with advanced illness, including a potential treatment algorithm (Figure 3). “According to the FDA-approved labeling, methylnaltrexone is indicated for the second-line treatment of OIC. Therefore, the first step for patients with OIC will still be a trial of

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OIC in a patient with advanced illness undergoing palliative care

ª Trial of oral first-line laxative agent

ª Nonresponse or insufficient response

ª Relistor Trial Subcutaneous injection every other day, as needed, but no more frequently than 1 dose in a 24-h period Approved doses: • 8 mg for patients weighing 38-61 kg • 12 mg for patients weighing 62-114 kg • 0.15 mg/kg for patients whose weight falls outside of these ranges

the traditional laxative therapies. For patients who fail to have a response to the traditional agents, you would proceed to methylnaltrexone. The mechanism of action for methylnaltrexone is well-suited for the treatment of OIC, so if the patient describes a clinical history in which they had regular bowel movements then developed constipation after initiation of opioid therapy, I would use methylnaltrexone,” said Dr. Pergolizzi. “Methylnaltrexone is indicated to be used when other laxatives have failed. But if a patient has a clear history of OIC [and hasn’t responded to first-line therapies], I wouldn’t spend a great deal of time switching from one laxative to another before prescribing methylnaltrexone,” said Dr. Brenner. According to Dr. Pergolizzi, determining the success of laxative therapy is, thankfully, not all that difficult. “When prescribing medications for the treatment of OIC, you have an easy, objective end point to follow: Has the patient had symptomatic relief in terms of a bowel movement or not? Methylnaltrexone offers a predictable and rapid response in the majority of patients with OIC,” he said.

Conclusion OIC is a highly prevalent side effect of opioid therapy. The pathophysiology of OIC is unique from that of physiologic constipation or constipation due to primary GI, neurologic, or metabolic conditions. Conventional therapies may be ineffective in restoring normal bowel function in patients with OIC. Relistor is an effective second-line therapy and initial prescription option for the treatment of OIC in patients with advanced illness who are receiving palliative care.

Nonresponse or insufficient response

ª Rescue therapy (ie, enemas, manual disimpaction)

Figure 3. Faculty-proposed treatment algorithm for OIC in advanced illness. OIC, opioid-induced constipation

Important Safety Information about RELISTOR RELISTOR ® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Rare cases of gastrointestinal (GI) perforation have been reported in advanced illness patients with conditions that may

REPORT

be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (ie, cancer, peptic ulcer, Ogilvie’s syndrome). Perforations have involved varying regions of the GI tract (eg, stomach, duodenum, colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Use of RELISTOR has not been studied in patients with peritoneal catheters.

Use of RELISTOR beyond four months has not been studied. Safety and efficacy of RELISTOR have not been established in pediatric patients. The most common adverse reactions reported with RELISTOR compared with placebo in clinical trials were abdominal pain (28.5%), flatulence (13.3%), nausea (11.5%), dizziness (7.3%), diarrhea (5.5%), and hyperhidrosis (6.7%).

References

Glare P, Walsh D, Sheehan D. The adverse effects of morphine: a prospective survey of common symptoms during repeated dosing for chronic cancer pain. Am J Hosp Palliat Med. 2006;23(3):229-235.

Mancini I, Bruera E. Constipation in advanced cancer patients. Support Care Cancer. 1998;6(4):356-364.

van den Beuken-van Everdingen MH, de Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol. 2007;18(9):1437-1449.

Solano JP, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disorder, and renal disease. J Pain Symptom Manage. 2006;31(1):58-69.

Fine PG, Portenoy RK. Opioid therapy in advanced medical illness. In: William Roberts, Colleen Sauber, eds. A Clinical Guide to Opioid Analgesia. New York, NY: McGraw-Hill; 2004:115-120.

Kutner JS, Kassner CT, Nowels DE. Symptom prevalence at the end of life: hospice providers’ perceptions. J Pain Symptom Manage. 2001;21(6):473-480. Swarm R, Abernethy AP, Anghelescu DL, et al; NCCN Adult Cancer Pain. Adult cancer pain. J Natl Compr Canc Netw. 2010;8(9):1046-1086. Qaseem A, Snow V, Shekelle P, et al; Clinical Assessment Subcommittee of the American College of Physicians. Evidence-based interventions to improve the palliative care of pain, dyspnea, and depression at the end of life: a clinical practice guidelines from the American College of Physicians. Ann Intern Med. 2008;148(2):141-146. Bader S, Jaroslawski K, Blum HE, Becker G. Opioid-induced constipation in advanced illness: safety and efficacy of methylnaltrexone bromide. Clin Med Insights Oncol. 2011;5:201-211.

Please see brief summary of Prescribing Information on page 12.

10. Clemens KE, Klaschik EK. Managing opioid-induced constipation in advanced illness: focus on methylnaltrexone bromide. Ther Clin Risk Manage. 2010;6:77-82. 11. Wingate D, Hongo M, Kellow J, et al. Disorders of gastrointestinal motility: towards a new classification. J Gastroenterol Hepatol. 2002;(17 suppl):S1-S14. 12. Camilleri M. Opioid-induced constipation: challenges and therapeutic opportunities. Am J Gastroenterol. 2011;106(5): 835-842. 13. Kurz A, Sessler DI. Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. Drugs. 2003;63(7):649-671. 14. De Schepper HU, Cremonini F, Park MI, Camilleri M. Opioids and the gut: pharmacology and current clinical experience. Neurogastroenterol Motil. 2004;16(4):383-394. 15. Thomas JR, Cooney GA, Slatkin NE. Palliative care and pain: new strategies for managing opioid bowel dysfunction. J Palliat Med. 2008;(11 suppl 1):S1-S19. 16. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone prevents morphine-induced delay in oral-cecal transit time without affecting analgesia: a double-blind randomized placebo-controlled trial. Clin Pharmacol Ther. 1996;59(4): 469-475.

REPORT

17. Manchikanti L, Singh A. Therapeutic opioids: a ten-year perspective on the complexities and complications of the escalating use, abuse, and non-medical use of opioids. Pain Physician. 2008;11(2 suppl):S63-S88.

24. Mercandante S, Casuccio A, Fulfaro F, et al. Switching from morphine to methadone to improve analgesia and tolerability in cancer patients: a prospective study. J Clin Oncol. 2001;19(11):2898-2904.

18. Rosti G, Gatti A, Costantini A, et al. Opioid-related bowel dysfunction: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol Sci. 2010;14(12):1045-1050.

25. Vissers KP, Besse K, Hans G, et al. Opioid rotation in the management of chronic pain: where is the evidence? Pain Pract. 2010;10(2):85-93.

19. Quigley C. The role of opioids in cancer pain. BMJ. 2005; 331(7520):825-829. 20. Sykes NP. The relationship between opioid use and laxative use in terminally ill cancer patients. Palliat Med. 1998;12(5):375-382. 21. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid-induced constipation in advanced illness patients. J Support Oncol. 2009;7(1):39-46. 22. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 suppl): S105-S120. 23. Schaefer DC, Cheskin LJ. Constipation in the elderly. Am Fam Physician. 1998;58(4):907-914.

26. Narabayashi M, Saijo Y, Takenoshita S, et al; Advisory Committee for Oxycodone Study. Opioid rotation from oral morphine to oral oxycodone in cancer patients with intolerable adverse effects: an open-label trial. Jpn J Clin Oncol. 2008;38(4):296-304. 27. Relistor (methylnaltrexone bromide) subcutaneous injection [prescribing information]. Philadelphia, PA: Wyeth Pharmaceuticals, Inc; 2012. 28. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid-induced constipation in advanced illness. N Engl J Med. 2008;358(22):2332-2343. 29. Slatkin NE, Lynn R, Su C, et al. Characterization of abdominal pain during methylnaltrexone treatment of opioid-induced constipation in advanced illness: a post hoc analysis of two clinical trials. J Pain Symptom Manage. 2011;42(5):754-760.

Disclosures: Dr. Brenner reported that he has served as a consultant for Perrigo and has served as a consultant for and on the speakers’ bureau of Salix Pharmaceuticals. Dr. Pergolizzi reported that he has served as a consultant for, on the speakers’ bureau of, and received honorarium from Endo Pharmaceuticals, Johnson & Johnson, Purdue Pharma, and Salix Pharmaceuticals. He has also served as a consultant for and received honorarium from Kirax Corporation.

Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. REL 13/22

SR1317

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Salix, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.

Adverse Reactions from all Doses in DoubleBlind, Placebo-Controlled Clinical Studies of RELISTOR*

The following is a brief summary only; see full Prescribing Information for complete product information. INDICATIONS AND USAGE RELISTOR is indicated for the treatment of opioidinduced constipation in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied. CONTRAINDICATIONS RELISTOR is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction. WARNINGS AND PRECAUTIONS Severe or Persistent Diarrhea If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician. Intestinal Perforation Rare cases of gastrointestinal (GI) perforation have been reported in advanced illness patients with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the GI tract (i.e., cancer, peptic ulcer, Ogilvieâ&#x20AC;&#x2122;s syndrome). Perforations have involved varying regions of the GI tract (e.g., stomach, duodenum, or colon). Use RELISTOR with caution in patients with known or suspected lesions of the GI tract. Advise patients to discontinue therapy with RELISTOR and promptly notify their physician if they develop severe, persistent, and/or worsening abdominal symptoms. Peritoneal Catheters The use of RELISTOR has not been studied in patients with peritoneal catheters. ADVERSE REACTIONS Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in clinical practice. The safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in patients with advanced illness receiving palliative care: Study 1 included a single dose, double blind, placebo-controlled period, whereas Study 2 included a 14-day multiple dose, double-blind, placebo-controlled period. The most common adverse reactions (>5%) in patients receiving RELISTOR are shown in the table above.

Adverse Reaction

RELISTOR N = 165

Placebo N = 123

Abdominal Pain

47 (28.5%)

12 (9.8%)

Flatulence

22 (13.3%)

7 (5.7%)

Nausea

19 (11.5%)

6 (4.9%)

Dizziness

12 (7.3%)

3 (2.4%)

Diarrhea

9 (5.5%)

3 (2.4%)

Hyperhidrosis

11 (6.7%)

8 (6.5%)

* Doses: 0.075, 0.15, and 0.30 mg/kg/dose The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1.2%) and placebo (2.4%). Postmarketing Experience In addition to adverse events reported from clinical trials, the following adverse events have been identified during post-approval use of RELISTOR. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to either their seriousness, frequency of reporting or causal connection to RELISTOR, or a combination of these factors. Gastrointestinal Cramping, perforation, vomiting General Disorders and Administrative Site Disorders Diaphoresis, flushing, malaise, pain DRUG INTERACTIONS Drugs Metabolized by Cytochrome P450 Isozymes

In in vitro drug metabolism studies methylnaltrexone bromide did not significantly inhibit the activity of cytochrome P450 (CYP) isozymes CYP1A2, CYP2A6, CYP2C9, CYP2C19 or CYP3A4, while it is a weak inhibitor of CYP2D6. In a clinical drug interaction study in healthy adult male subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone bromide did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate. Drugs Renally Excreted The potential for drug interactions between methylnaltrexone bromide and drugs that are actively secreted by the kidney has not been investigated in humans. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B Reproduction studies have been performed in pregnant rats at intravenous doses up to about 14 times the recommended maximum human subcutaneous dose of 0.3 mg/kg based on the body

surface area and in pregnant rabbits at intravenous doses up to about 17 times the recommended maximum human subcutaneous dose based on the body surface area and have revealed no evidence of impaired fertility or harm to the fetus due to methylnaltrexone bromide. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, methylnaltrexone bromide should be used during pregnancy only if clearly needed. Labor and Delivery Effects of RELISTOR on mother, fetus, duration of labor, and delivery are unknown. There were no effects on the mother, labor, delivery, or on offspring survival and growth in rats following subcutaneous injection of methylnaltrexone bromide at dosages up to 25 mg/kg/day. Nursing Mothers Results from an animal study using [3H]-labeled methylnaltrexone bromide indicate that methylnaltrexone bromide is excreted via the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when RELISTOR is administered to a nursing woman. Pediatric Use Safety and efficacy have not been established in pediatric patients. Geriatric Use In the phase 2 and 3 double-blind studies, a total of 77 (24%) patients aged 65-74 years (54 methylnaltrexone bromide, 23 placebo) and a total of 100 (31.2%) patients aged 75 years or older (61 methylnaltrexone bromide, 39 placebo) were enrolled. There was no difference in the efficacy or safety profile of these elderly patients when compared to younger patients. Therefore, no dose adjustment is recommended based on age. Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault). No studies were performed in patients with end-stage renal impairment requiring dialysis. Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of methylnaltrexone bromide has not been studied.

www.salix.com 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1 800-508-0024 ÂŠ2012 Salix Pharmaceuticals, Inc. All rights reserved. Printed in USA. REL REL 13/22 13/02