Comparison of Treatment Response in Idiopathic and Connective Tissue Disease-associated Pulmonary Arterial Hypertension

Abstract

Rationale: Studies suggest that patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) have a poorer treatment response to therapies for PAH compared with patients with idiopathic PAH (IPAH), but individual randomized controlled trials (RCTs) have been underpowered to examine differences within these subgroups.

Objectives: To compare the effect of therapy for PAH in CTD-PAH versus IPAH.

Methods: We obtained individual participant data from phase III placebo-controlled RCTs of therapies for PAH submitted to the U.S. Food and Drug Administration for drug approval. A treatment-by-diagnosis interaction term evaluated differences in treatment response between CTD-PAH and IPAH. Outcomes included change in 6-minute-walk distance (∆6MWD) from baseline to 12 weeks, clinical worsening, and all-cause mortality.

Measurements and main results: The study sample included 827 participants with CTD-PAH and 1,935 with IPAH from 11 RCTs. Patients with CTD-PAH had less improvement in 6MWD when assigned to active treatment versus placebo compared with patients with IPAH (difference in treatment effect on ∆6MWD in CTD-PAH vs. IPAH, -17.3 m; 90% confidence interval, -31.3 to -3.3; P for interaction = 0.043). Treatment was less effective in reducing the occurrence of clinical worsening in CTD-PAH versus IPAH (P for interaction = 0.012), but there was no difference in the placebo-adjusted effect of treatment on mortality (P for interaction = 0.65).

Conclusions: Treatment for PAH was less effective in CTD-PAH compared with IPAH in terms of increasing 6MWD and preventing clinical worsening. The heterogeneity of treatment response supports the need for identifying therapies that are more effective for CTD-PAH.

Keywords: clinical trial; meta-analysis; pulmonary hypertension.

Figure 1.

Cumulative change in 6-minute-walk distance (∆6MWD) stratified by treatment and diagnosis. Reverse cumulative distribution curves of ∆6MWD among patients with (1) IPAH assigned to active treatment (blue line), (2) CTD-PAH assigned to active treatment (red line), (3) IPAH assigned to placebo (green line), and (4) CTD-PAH assigned to placebo (yellow line). Extreme values (∆6MWD < −250 and ∆6MWD >250) are not depicted. P for treatment-by-diagnosis interaction = 0.043. Adjusted for age, sex, race, body mass index, study, baseline 6MWD, World Health Organization functional class, baseline right atrial pressure, mean pulmonary artery pressure, cardiac index, serum creatinine, and hemoglobin. CTD-PAH = connective tissue disease–associated pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension.

Figure 2.

Adjusted odds ratios (95% confidence interval) of clinical worsening in treatment versus placebo groups stratified by diagnosis. Adjusted for age, sex, race, body mass index, study, baseline 6-minute-walk distance, World Health Organization functional class, baseline right atrial pressure, mean pulmonary artery pressure, cardiac index, serum creatinine, and hemoglobin. P values represent P for interaction of treatment group and diagnosis. CTD-PAH = connective tissue disease–associated pulmonary arterial hypertension; IPAH = idiopathic pulmonary arterial hypertension; SSc-PAH = systemic sclerosis–associated pulmonary arterial hypertension.