Background/Purpose: Recent studies have shown that therapies for pulmonary arterial hypertension (PAH) improve exercise capacity, but subgroup analyses suggest that these therapies may be less effective in patients with connective tissue disease (CTD-PAH). The aim of this study was to compare the effect of treatment on the change in six minute walk distance (D6MWD) and clinical events in CTD-PAH vs idiopathic PAH (IPAH).

Methods: A pooled analysis was performed on patient-level data from 12 Phase III randomized placebo-controlled trials of advanced therapies for PAH that were submitted to the FDA for approval.  Outcomes for this analysis included D6MWD from baseline to 12 weeks, the occurrence of clinical worsening (defined as first occurrence of death, hospitalization for PAH, addition of other PAH medications, lung transplant, atrial septostomy, or worsening exercise capacity and/or functional class), and all-cause mortality.  Missing 6MWD at 12 weeks was multiply imputed.  A robust generalized estimating equation within a linear or logistic regression model was utilized using an exchangeable correlation structure and clustering on study trial.  Effect modification of treatment assignment (drug vs placebo) by diagnosis (CTD-PAH vs IPAH) was assessed.  All regression models were adjusted for age, sex, race, drug class, baseline 6MWD, functional class, and baseline hemodynamics (right atrial pressure, pulmonary vascular resistance, and cardiac index).

Results: The study sample included 2,736 participants: 824 had CTD-PAH and 1,912 had IPAH.  Patients with CTD-PAH were significantly older, more often female, and had a lower baseline 6MWD compared to patients with IPAH (Table 1).  There was a significant interaction between treatment assignment and diagnosis in terms of the D6MWD, such that the treatment-related improvement in D6MWD was significantly less in CTD-PAH than in IPAH (difference-in-difference -11.3 meters, [95% CI -20.0, -2.6], p for interaction = 0.011).  There was also greater treatment-associated reduction in clinical worsening and mortality in IPAH than in CTD-PAH (Table 2).

Conclusion: In clinical trials, treatment for PAH was less effective in CTD-PAH compared to IPAH in terms of increasing 6MWD, preventing clinical worsening, and possibly reducing the risk of death.  The differential treatment response in CTD-PAH and IPAH supports the need for stratified analysis in future trials and suggests that a different pathophysiological process may exist in the two phenotypes of disease.