Background/Purpose: Whether the risk of treatment-related adverse events (AEs) in patients with pulmonary arterial hypertension (PAH) differs based on diagnosis, either connective tissue disease (CTD-PAH) or idiopathic (IPAH), is unknown.

Methods: This study compared the occurrence of AEs and serious AEs (SAEs) among patients with CTD-PAH vs IPAH enrolled in clinical trials of new therapies for PAH. A pooled analysis was conducted using de-identified, patient-level data from 11 randomized double-blind placebo-controlled trials of therapies for PAH submitted to the US Food and Drug Administration. These trials ranged from 3-4 months in duration. Therapies studied included endothelin receptor antagonists (ERA), phosphodiesterase-5 inhibitors (PDE-5i), and prostacyclin analogues.

Results: The study sample included 2,581 participants: 562 with CTD-PAH, including 28% with diffuse systemic sclerosis, 26% with limited systemic sclerosis, 13% with systemic lupus erythematosus, and 11% with mixed connective tissue disease, and 1,426 patients had IPAH. Patients with CTD-PAH were older, more likely to be female, and had a shorter 6-minute walk distance at baseline (Table). Patients with CTD-PAH had a higher rate of AEs (13.6 [95% CI, 9.4 – 17.9] additional events per 100 patient-years, p< 0.001) and had a greater risk of having at least 1 SAE (OR 1.55 [95% CI 1.18 – 2.03], p = 0.002) compared to patients with IPAH, after adjustment for age, race, and sex, and treatment assignment (drug or placebo). A sub-analysis of AE types showed that patients with CTD-PAH were more likely to have an infection compared to patients with IPAH (OR 1.46 [1.06 – 2.01], p = 0.020). In ERA trials, diagnosis modified the relationship between treatment and the occurrence of at least 1 AE (p for interaction = 0.026, OR in CTD-PAH 0.55 [95% CI 0.25-1.22], OR in IPAH 1.54 [95% CI 0.92-2.59]). In PDE-5i trials, diagnosis modified the relationship between treatment and rate of AE (p for interaction = 0.005, IRR in CTD-PAH 0.76 [95% CI 0.69-0.87], IRR of IPAH 0.96 [95% CI 0.88-1.04]).  

Conclusion: Patients with CTD-PAH are at a higher risk of experiencing AEs and SAEs in clinical trials of therapy for PAH compared to patients with IPAH, independent of age and other potential confounders. Patients with CTD-PAH may have had less drug-associated AEs.  Understanding the difference in risks of AEs for this specific population may inform the design of future trials and bring greater awareness to patients and clinicians on the safety of therapy for PAH.

Table: Characteristics of Study Participants

Data are presented as mean ± standard deviation unless otherwise indicated otherwise.