FormalPara Key Summary Points

Why carry out this study?

Although connective tissue disorders (CTDs) are commonly associated with pulmonary arterial hypertension (PAH) and tend to be associated with poorer outcomes among patients with PAH, there is limited real-world evidence on treatment patterns among patients with CTD-related PAH.

A better understanding of real-world treatment patterns among patients with CTD-related PAH is needed to identify potential gaps and areas for improvement in the management of CTD-related PAH.

Therefore, the present study aimed to describe treatment patterns among patients with CTD-related PAH and PAH from other etiologies in a real-world setting in the US stratified by treatment class and strategy.

What was learned from the study?

Treatment patterns were generally similar among patients with CTD-related PAH and PAH from other etiologies, although the use of combination therapy, including triple therapy, was more frequent among those with CTD-related PAH; treatment persistence was similar across cohorts and remained low for the first three treatment regimens, with fewer than one in two patients persistent at 12 months.

Our findings suggest that both patients with CTD-related PAH and PAH from other etiologies may potentially benefit from broader access to all available PAH treatment classes as early as possible, including combination therapy to target the nitric oxide, endothelin, and prostacyclin pathways.

Furthermore, a better understanding of the factors driving low persistence rates with PAH therapies could enable clinicians to devise more effective strategies aimed at improving this outcome among patients, thereby maximizing the benefits of treatment.

Introduction

Pulmonary arterial hypertension (PAH) is a rare, severe, and progressive subtype of pulmonary hypertension (World Health Organization Group 1) [1,2,3], which may lead to reduced cardiac output, right heart failure, and ultimately death [1, 2]. In the US, the prevalence of PAH is estimated at 12.4 cases per million adult inhabitants [1, 2]. In terms of etiology, PAH may be idiopathic (46.2%; i.e., with no identifiable cause) or associated with an identifiable factor (50.7%) [4]. Among patients whose PAH is associated with an identifiable factor, these factors may include a primary condition (84.0%; e.g., congenital heart disease, portal hypertension, HIV), drug/toxin exposure (10.5%), or other factors (5.5%; e.g., genetic factors) [4, 5].

Connective tissue disorders (CTDs) are the most frequent conditions associated with PAH, accounting for 11–28% of all PAH cases [6]. Among patients with CTD-related PAH (CTD + PAH), the most common cause, which accounts for approximately three in four cases in the US, is systemic sclerosis (SSc), an autoimmune disease that causes scar tissue to form in the skin, internal organs, and small blood vessels [5, 7]. In addition, PAH may arise as a complication of other CTDs such as systemic lupus erythematosus, dermatomyositis/polymyositis, rheumatoid arthritis, Sjögren’s syndrome (Sicca), and mixed CTD, which displays features commonly seen in three different CTDs (i.e., systemic lupus erythematosus, scleroderma, and polymyositis) [8]. CTD + PAH is typically associated with poor clinical outcomes, including worse overall survival than idiopathic PAH (iPAH) [9,10,11,12,13]. Based on the REVEAL registry data, patients with CTD + PAH were found to have a twice greater risk of 1-year fatality relative to those with iPAH (14% vs. 7%, p < 0.001), while those with SSc showed the poorest survival outcomes compared to patients with other CTDs [9]. Compared to iPAH, other studies have shown that patients with SSc-PAH had a more than twice greater risk of death at 1 year (12% vs. 5%, p = 0.002) and more than three times greater risk of death at 3-years (51% vs. 16%, p = 0.002), respectively [11]. Moreover, patients with CTD + PAH may be prone to more severe PAH, as evidenced by higher-risk disease markers (including lower 6min walk distance [6MWD] and higher NT-proB-type natriuretic peptide [BNP] level) compared to patients with iPAH [9, 14, 15].

Randomized controlled trials have demonstrated that the use of modern PAH therapies, including combination therapies with phosphodiesterase type 5 inhibitors (PDE5is), endothelin receptor antagonists (ERAs), and prostacyclin pathway agents (PPAs), improves clinical outcomes in PAH and CTD + PAH [16,17,18,19,20,21,22]. Based on this evidence, the use of early combination therapy is recommended for the treatment of PAH regardless of etiology per the American Heart Association (AHA) in 2023 [23] and the CHEST guidelines in 2019 [24], as well as the 2022 guidelines of the European Society of Cardiology (ESC) and European Respiratory Society (ERS) [25]. For instance, in their 2023 update, the AHA recommends initial combination therapy with a PDE5i and an ERA for non-vasoreactive patients without evidence of high-risk disease (e.g., chest pain, syncope, World Health Organization functional class IV, etc.) and initial triple therapy with a PDE5i, ERA, and injectable PPA for those with evidence of high-risk disease [23]. In the absence of cardiopulmonary comorbidities, the 2022 ESC/ERS guidelines recommend initial oral double combination therapy with a PDE5i or ERA for treatment-naïve patients who are low or intermediate risk (for patients who present at intermediate-low risk of death while receiving a PDE5i and ERA, switching from a PDE5i to a soluble guanylate cyclase stimulator [sGC; i.e., riociguat] may also be considered) and initial triple therapy including an injectable PPA for those who are at high-risk) [25]. Among patients with cardiopulmonary comorbidities (i.e., diabetes, systemic hypertension, coronary artery disease, and low lung diffusion capacity for carbon monoxide), the 2022 ESC/ERS guidelines recommend initial monotherapy with a PDE5i or ERA, while the addition of another PAH medication among intermediate-to-high risk patients may be considered on an individual basis [25]. When considering different PAH etiologies, the AHA and CHEST guidelines do not provide specific recommendations [23, 24], while the 2022 ESC/ERS guidelines recommend that patients with CTD + PAH follow a similar treatment algorithm to that of PAH overall [25]. However, given their worse prognosis compared to other PAH etiologies [9, 15, 26], prompt access to the appropriate treatment may be especially critical among patients with CTD + PAH [7].

Regarding treatment patterns in PAH, evidence suggests that monotherapy with PDE5i remains the most commonly used strategy [27, 28] despite meta-analyses reporting that combination therapy significantly reduces the risk of progression by approximately 35% [19, 20]. In contrast to PAH, there is currently limited information on treatment patterns among patients with CTD-related PAH [15]. A paucity of studies have investigated treatment patterns among CTD + PAH patients within the context of prospective, observational studies of specific PAH agents (e.g., selexipag, macitentan) [15, 26, 29]. However, further data regarding the use of all available PAH-specific therapies among the general CTD + PAH population is warranted. Such evidence could help identify potential areas for improvement in the management of CTD-related PAH.

Therefore, the present study aimed to describe real-world treatment patterns in terms of PAH agents (i.e., generic molecules used for the treatment of PAH), treatment classes, and strategy (monotherapy and combination therapy) among patients with CTD-related PAH and PAH from other etiologies in the US.

Methods

Data Source

The Optum’s de-identified Clinformatics® Data Mart (CDM) Database was used to identify adult patients diagnosed with CTD + PAH and PAH from other etiologies between October 1, 2015, and September 30, 2021. Optum’s CDM database is geographically diverse and represents all 50 states (as well as the District of Columbia and Puerto Rico). It includes adjudicated health insurance claims for commercial and Medicare Advantage enrollees within a large national managed care company affiliated with Optum, as previously described [30]. Using the Expert Determination method and in accordance with the Health Insurance Portability and Accountability Act (HIPAA) of 1996, the CDM database was statistically de-identified and managed according to Optum’s customer data use agreements; therefore, no review by an institutional review board was required per Title 45 of CFR, Part 46.101(b)(4) (https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/#46.101). The present study was performed in accordance with the Helsinki Declaration of 1964, and its later amendments.

Study Design

A retrospective cohort study design was used to describe and compare treatment patterns in CTD + PAH and PAH overall (Fig. 1). The index date was defined as the date of the first documented prescription fill for a PAH-related treatment. To increase the likelihood of capturing treatment initiation as of the treatment index date, patients were required to be continuously enrolled in their healthcare plan for ≥ 6 months prior to their index date (i.e., baseline period). Treatment patterns were assessed from the index date until the end of the follow-up, which is the earliest of the end of data availability, end of continuous healthcare plan enrollment, or death, whichever came first. No minimal duration of follow-up was required to limit survival bias.

Fig. 1
figure 1

Study design. CTD connective tissue disorder, CTEPH chronic thromboembolic pulmonary hypertension, PAH pulmonary arterial hypertension

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Study Population

Adult patients diagnosed with PAH (International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10-CM]: I27.0x, I27.20, I27.21, I27.89) and newly initiated on a PAH-related treatment (i.e., sildenafil citrate [excluding dosage corresponding to Viagra], tadalafil [excluding dosage corresponding to Cialis], ambrisentan, bosentan, macitentan, riociguat, treprostinil, selexipag, iloprost, epoprostenol) were eligible for inclusion in the study if they had at least 6 months of continuous eligibility enrollment in their healthcare plan prior to the index date and no medical claims with a recorded diagnosis for chronic thromboembolic pulmonary hypertension (ICD-10-CM: I27.24) at any time. Patients were further classified in the mutually exclusive CTD + PAH and PAH cohorts based on the presence of CTD diagnosis (ICD-10-CM: M32, M33, M34, M35.0, M35.1, M35.5, M35.9, M36.8) as described in Fig. 2.

Fig. 2
figure 2

Sample selection. CTD connective tissue disorder, ICD-10-CM International Classification of Diseases, 10th Revision, Clinical Modification, PAH pulmonary arterial hypertension. (1) Sildenafil citrate (excluding Viagra), tadalafil (excluding Cialis), ambrisentan, bosentan, macitentan, riociguat, treprostinil, selexipag, iloprost, epoprostenol

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Measures, Outcomes, and Statistical Analyses

Patients’ demographic and clinical characteristics were measured during the 6-month baseline period. Treatment patterns (e.g., sequence of agents received, combination therapy) were assessed separately for each cohort and descriptively summarized. A treatment regimen was defined as all PAH agents (i.e., generic molecules used for the treatment of PAH) observed within 60 days of the first PAH-related agent observed. A treatment change was defined as a treatment discontinuation (i.e., ≥ 90-day gap without any agents from the treatment regimen), drop (i.e., discontinuation of ≥ 1 agent in a regimen while other agents were continued), switch (i.e., initiation of a new agent while other agents in the treatment regimen were discontinued), or augmentation/add-on (i.e., initiation of a new agent while ≥ 1 agent of the treatment regimen was continued). A patient could also remain on the same treatment regimen until the end of the follow-up. PAH-related regimens (i.e., regimens that included ≥ 1 PAH agent) were defined as follows: first treatment regimen was the treatment regimen initiated on the index date, second treatment regimen was defined as the first treatment regimen observed following the first treatment change, and third treatment regimen was defined as the treatment regimen following the second treatment change.

Descriptive statistics were used to assess baseline characteristics and treatment patterns at follow-up among CTD + PAH and PAH cohorts. Kaplan-Meier (KM) analyses of time to combination therapy (time from the index date to initiation of the first treatment regimen with ≥ 2 agents) and treatment persistence (time from treatment initiation to treatment change or the end of the patient follow-up if there was no treatment change [censor date] for the first 3 treatment regimens) were performed. Patients who did not experience the event were censored as of the end of their follow-up.

Results

After applying the eligibility criteria, the CTD + PAH cohort comprised 728 eligible patients and the PAH cohort included 4023 patients (Fig. 2).

Patient Characteristics

Patients in the CTD + PAH and PAH cohorts were observed for an average of 18.8 and 19.6 months following their index date, respectively (Table 1). Patients in the CTD + PAH cohort tended to be younger than in the PAH cohort (64.2 and 69.1 years old, respectively) and were female in a larger proportion (85.7% vs. 60.8%, respectively). Among patients in the CTD + PAH cohort, 57.3% had systemic sclerosis and 24.7% had systemic lupus erythematosus.

Table 1 Patient characteristics
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Treatment Patterns

For both cohorts, the most common first treatment regimens observed were sildenafil (CTD+PAH: 38.7%; PAH: 51.5%), tadalafil (10.0%; 9.4%), and macitentan (8.1%; 5.4%) in monotherapy. Sildenafil, tadalafil, and macitentan were also the most frequent agents included in any of the first three treatment regimens (Fig. 3a). Combination therapy was more frequent in the CTD+PAH cohort than in the PAH cohort (any regimen: 40.9% vs. 27.2%; first treatment regimen: 26.9% vs. 18.5%; second: 52.8% vs. 42.0%; third: 55.2% vs. 48.5%); patients with CTD+PAH were also more likely to have triple therapy when having combination therapy (Fig. 3b). KM analysis showed that patients in the CTD+PAH cohort were more likely to be initiated on combination therapy at any time post-index (Fig. 4). At 12 months post-index, 44.8% of patients in the CTD+PAH cohort had been initiated on a combination therapy compared to 30.2% in the PAH cohort. Most patients had cardiologist (83.0% in the PAH+CTD and 81.7% in the PAH cohort, respectively), pulmonologist (71.0% and 61.8%), and/or rheumatologist (59.1% and 5.2%) visits during the baseline period, but time to combination therapy was similar regardless of the type of specialist visits (data not shown). Treatment persistence was similar across cohorts and first three treatment regimens, with 12-month persistence rates of 43.2% and 46.5% in the CTD+PAH and PAH cohorts respectively for the first observed treatment regimen, 49.7% and 44.9% for the second regimen, and 42.6% and 45.9% for the third regimen (Fig. 5). For both cohorts, treatment discontinuation was the most frequent type of treatment change for the first and second treatment regimen, while treatment augmentation (add-on) was the most frequent change for the third treatment regimen for the CTD+PAH cohort (Fig. 6). Among those who discontinued their first treatment regimen, many reinitiated the same treatment after more than 90 days (CTD + PAH: 29.2%; PAH: 22.4%), and the vast majority of those patients restarted a tadalafil or sildenafil monotherapy (CTD + PAH: 86.5%; PAH: 90.1%).

Fig. 3
figure 3

Treatment regimens in the CTD + PAH and PAH cohorts. CTD connective tissue disorder, ERA endothelin receptor antagonist, PAH pulmonary arterial hypertension, PDE5i phosphodiesterase type 5 inhibitor, PPA prostacyclin pathway agent, sGC soluble guanylate cyclase stimulator. (1) All agents received are listed regardless of whether they were used as monotherapy or combination therapy

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Fig. 4
figure 4

Kaplan-Meier analysis of time to first combination treatment regimen in the CTD + PAH and PAH cohorts. CI confidence interval, CTD connective tissue disorder, PAH pulmonary arterial hypertension

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Fig. 5
figure 5

Kaplan-Meier analysis of treatment persistence in the CTD + PAH and PAH cohorts. CTD connective tissue disorder, PAH pulmonary arterial hypertension

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Fig. 6
figure 6

Type of treatment change at the end of the first, second, and third treatment regimens in the CTD + PAH and PAH cohorts. CTD connective tissue disorder, PAH pulmonary arterial hypertension

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Discussion

In this real-world study in a US patient population, treatment patterns were generally similar between the CTD + PAH and PAH cohorts. However, the use of combination therapy, including triple therapy, was more frequent among patients in the CTD + PAH cohort. Overall, less than half of patients used combination therapy. This underscores an unmet need for improved access to the full spectrum of available PAH treatment classes as early as possible, including recommended treatment strategies such as combination therapy. Our findings further underscore the low persistence to treatment in real-world clinical practice. Indeed, for the first three treatment regimens, fewer than one in two patients were persistent to their treatment 12 months after initiation.

Given the scarcity of real-world data on treatment patterns among patients with CTD + PAH, the present study findings help to fill an important gap in the literature. In a manner consistent with our findings, a few prior real-world studies have shown that combination therapy remains an underutilized strategy in routine clinical practice.[14, 15, 29, 31] Specifically, in analyses of the combined datasets from the ongoing OPsumit® USers (OPUS) prospective US drug registry study (since 04/2014) and the OPsumit® Historical USers cohort (OrPHeUS) retrospective US chart review study (10/2013–03/2017) [29, 31], a large proportion of patients with PAH and with CTD + PAH initiated on macitentan received monotherapy at initiation, and in most cases, this treatment strategy did not change during the follow-up period. Among patients with PAH overall (including 44.7% with iPAH and 24.6% with CTD–PAH) in the OPUS/OrPHeUS dataset (data cutoff 02/2020; N = 4540) [31], 31–44% were receiving monotherapy at the time of macitentan initiation across the US regions, and 52–60% of them were still receiving monotherapy at 2 years post-macitentan initiation. Among patients with CTD + PAH in the OPUS/OrPHeUS dataset (data cutoff 08/2019; N = 1130) [29], 38.3% were receiving monotherapy at the time of macitentan initiation, and 72.9% were still receiving monotherapy at 6 months post-macitentan initiation.

While combination therapy may be underutilized, prior real-world evidence also suggests that it may be more common among patients with CTD + PAH than in those with PAH, which is aligned with the present study findings. For instance, an analysis of the Uptravi® (SelexiPag): tHe usErs dRug rEgistry (SPHERE) study of patients initiated on selexipag in the US (data cutoff of 20/12/2019; N = 500) [15] found that double combination therapy was more common in the CTD + PAH cohort (64.9%) [15] than the overall PAH cohort (55.0%) prior to selexipag initiation [32]. Another study analyzed data from the Post-authorization safety study (PASS): observational cohort study of PAH patients newly treated with either Uptravi (selexipag) or any other PAH-specific therapy, in clinical practice (EXPOSURE; EUPAS19085) study of adult patients with CTD + PAH and iPAH initiated on selexipag in Europe and Canada (09/2017–11/2020; N = 382) [14]. The results indicate that selexipag was mainly taken as part of triple combination therapy for all patients at the time of initiation. However, triple therapy was slightly more frequent in CTD + PAH vs. iPAH patients (81.0% vs. 74.0%).

In agreement with the present study, treatment persistence was found to be generally low in prior real-world studies regardless of PAH etiology. In the analysis of data from the EXPOSURE study with up to 21 months of follow-up [14], a sizable proportion of patients in CTD + PAH and iPAH cohorts discontinued treatment with selexipag (37% and 28%, respectively) with an average time to discontinuation of 5.5 and 7.6 months. Likewise, the analysis of the SPHERE registry study with up to 18 months of follow-up observed high selexipag discontinuation rates among CTD + PAH and iPAH cohorts (46.3% and 44.9%, respectively) with an average time to discontinuation of 16.4 and 16.9 months [15]. Prior evidence suggests that tolerability issues are a common reason for failed escalation attempts and discontinuation of treatment among patients with PAH [14, 15, 28]. Our findings and these prior ones highlight the need to better understand the low persistence rates with PAH therapies in routine clinical practice.

Prior real-world studies further suggest that patients with CTD+PAH may have more severe disease at treatment initiation and subsequently experience worse clinical outcomes than PAH overall. In the EXPOSURE study [14], patients with CTD+PAH had greater functional impairment (i.e., lower 6MWD) at selexipag initiation. This may have contributed to worse clinical outcomes, including a shorter time to all-cause death over 21 months of follow-up than iPAH [14]. In the SPHERE registry study [15], the median 18-month survival rate was numerically lower in the CTD+PAH cohort (71.0% [95% CI 53.7%, 82.8%]) than in the iPAH cohort (84.4% [95% CI 71.6%, 91.8%]). Taken together, these prior findings and those of the present study highlight an opportunity for earlier initiation of combination therapy, especially among patients with CTD + PAH.

Our study findings have several important implications for clinical practice. Although early combination therapy is now considered a standard of care for patients with PAH [23,24,25, 33, 34], the present findings suggest that routine clinical practice may lag behind treatment guidelines. In our study, monotherapy was found to be dominant in the first treatment regimen, despite recommendations for upfront combination therapy among treatment-naïve patients who are non-vasoreactive or high-risk per the 2016 AHA guidelines and 2015 ESC/ERS guidelines that were in effect during the study period [34, 35]. Since the time that our study was conducted, the role for combination therapy in the treatment of PAH has been further expanded. While the 2016 AHA guidance considered monotherapy as a viable alternative to combination therapy for the initial treatment of non-vasoreactive patients at low or intermediate risk [35], the AHA now recommends combination therapy only as an initial treatment for non-vasoreactive patients across all risk levels [23]. Furthermore, the 2022 ESC/ERS guidelines have updated their recommendations for treatment-naïve patients without cardiopulmonary comorbidities to initial oral double combination therapy with a PDE5i or ERA for those who are low or intermediate risk and initial triple therapy with an injectable PPA for those who are high-risk [25]. Moreover, approximately half of patients in our study were not treated with combination therapy in the second and third treatment regimen even though the AHA and the 2015 and 2022 ESC/ERS guidelines recommend treatment escalation following failure on initial therapy (i.e., patients who fail to achieve low-risk status while on therapy) [23, 25, 34, 35].

The underutilization of combination therapy in routine clinical practice may reflect several concerns. First, the costs of treatment, including out-of-pocket costs for patients, may act as a deterrent [36, 37]. However, increased pharmacy costs among patients treated with combination therapy are likely to be at least partly offset by a reduction in healthcare resource utilization and costs, which could alleviate these economic concerns [36, 38,39,40]. Second, combination therapy regimens could lead to additive side effects and reduced tolerability compared with monotherapy, although various strategies have been found to successfully reduce these additive effects (e.g., staggered treatment initiation, careful up-titration, and regular monitoring) in clinical practice [41]. Finally, evidence suggests that patients with cardiopulmonary comorbidities respond less well to PAH medication and are more likely to discontinue this medication due to efficacy failure or lack of tolerability, which could be another factor limiting the use of combination therapy in routine clinical practice [25].

Prior evidence suggests that there may be greater clinical benefits to combination therapy in patients initiated earlier compared to those initiated later [42, 43]. Thus, providing patients with prompt access to all available PAH treatment classes is key to improving long-term outcomes and potentially mitigating any downstream costs associated with disease progression [36, 44]. Early screening and detection among patients at higher risk of developing PAH may help to expedite treatment with combination therapy. Indeed, in their 2023 update, the AHA recommends that clinicians consider the possibility of a PH diagnosis among patients with unexplained dyspnea or tricuspid regurgitant jet velocity > 2.8 cm/s on echocardiography (including screening patients for sleep-disordered breathing and assessing exertional hypoxemia) [23]. The 2022 ESC/ERS guidelines recommend screening of asymptomatic individuals with SSc and early detection of symptomatic individuals with non-SSc CTD (as lower prevalence rates do not support asymptomatic screening) [25]. Moreover, the American College of Rheumatology recommends that patients with SSc, mixed CTD, or other CTDs with scleroderma features undergo screening for PAH [45]. For patients with SSc and scleroderma-spectrum disorders, initial screening evaluation should involve pulmonary function testing (PFT; including DLCO), TTE, and NT-Pro BNP, while TTE and PFT should be performed on an annual basis [45].

Interestingly, our study found that combination therapy, including triple therapy, was more common among patients in the CTD + PAH cohort. On the one hand, this appears to diverge from the 2015 ESC/ERS guidelines in effect at the time of our study and the later 2022 guidelines, which expressly recommend the same treatment algorithm for CTD + PAH and iPAH [25, 34, 46]. On the other hand, the AHA, and CHEST, and ESC/ERS guidelines recommend treatment based on patient disease severity [23,24,25, 34, 35]. Thus, increased use of combination therapy among CTD+PAH patients in the present study might reflect the use of differing treatment strategies across PAH etiologies due to the potentially greater risk of progressive disease and mortality in CTD+PAH compared to iPAH [9, 14, 15] and/or reflect higher risk at treatment initiation due to other factors besides CTD (e.g., lower 6MWD, higher NT-proBNP levels, etc.).

Limitations

Patients may have been misclassified in a given cohort because of inaccuracies in health insurance claims data, including regarding diagnosis codes and treatment received (e.g., if they had a rule-out diagnosis or had information recorded incorrectly). For instance, it is possible that some patients might have been incorrectly diagnosed with PAH and treated with a PAH-related medication when in fact they might have had Group 2 PH. However, we note that the likelihood of misclassification may have been lower in the CTD+PAH cohort given that CTD is a strong risk factor for PAH [5,6,7]. Furthermore, the demographic distribution of patients in the CTD+PAH cohort differs from that of Group 2 PH. For instance, patients with CTD+PAH in our study were younger on average relative to those with Group 2 PH in a prior study (e.g., 64 years vs. 72 years) with a higher proportion of females (e.g., 85.7% vs. 54.1%) [47]. Treatment patterns were observed based on prescription fills from pharmacy claims; however, this does not imply that the medication was actually taken. Furthermore, this study only captured medications for which an insurance claim was submitted. As such, it did not capture medications received through patient support programs without a record in an insurance claim. The study results might not be generalizable to patients without health insurance or those with insurance plans other than commercial ones. Observed differences in treatment patterns might be partly explained by differences in patient characteristics between cohorts, including unobserved variables such as disease severity and hemodynamics. Finally, the reasons behind treatment patterns cannot be obtained from the pharmacy and medical claims; further studies are warranted to assess the rationale for treatment choice and treatment changes in real-world practice.

Conclusion

In this study, real-world treatment patterns were described among patients with CTD + PAH and PAH from other etiologies. Although combination therapy is a cornerstone of PAH treatment per current guidelines [23,24,25, 34, 35], our findings suggest that it remains underutilized among both patients with CTD + PAH and with PAH in routine clinical practice. Nonetheless, combination therapy was more common in the CTD + PAH cohort, which appears consistent with evidence of the greater medical complexity and/or increased risk of mortality in this population [7, 9, 26]. Overall, our findings suggest that both CTD + PAH and PAH patients may potentially benefit from broader access to all available PAH treatment classes as early as possible, including combination therapy to target the nitric oxide, endothelin, and prostacyclin pathways [23,24,25, 35, 36, 44]. Our findings also highlight the low persistence rates with PAH therapies, despite the life-threatening nature of this condition. A better understanding of the factors driving treatment discontinuation and/or changes could enable clinicians to devise more effective strategies aimed at improving these metrics of treatment success.