Baseline Sex Differences in Pulmonary Arterial Hypertension Randomized Clinical Trials
Corey E. Ventetuolo, Jude Moutchia, Grayson L. Baird, Dina Appleby, Robyn L. McClelland, Jasleen Minhas, Jeff Min, John H. Holmes, Ryan J. Urbanowicz, Nadine Al‐Naamani, Steven M. Kawut
Abstract
Abstract Rationale Sex-based differences in pulmonary arterial hypertension (PAH) are known, but the contribution to disease measures is understudied. Objectives We examined whether sex was associated with baseline 6-minute-walk distance (6MWD), hemodynamics, and functional class. Methods We conducted a secondary analysis of participant-level data from randomized clinical trials of investigational PAH therapies conducted between 1998 and 2014 and provided by the U.S. Food and Drug Administration. Outcomes were modeled as a function of an interaction between sex and age or sex and body mass index (BMI), respectively, with generalized mixed modeling. Results We included a total of 6,633 participants from 18 randomized clinical trials. A total of 5,197 (78%) were female, with a mean age of 49.1 years and a mean BMI of 27.0 kg/m2. Among 1,436 males, the mean age was 49.7 years, and the mean BMI was 26.4 kg/m2. The most common etiology of PAH was idiopathic. Females had shorter 6MWD. For every 1 kg/m2 increase in BMI for females, 6MWD decreased 2.3 (1.6–3.0) meters (P < 0.001), whereas 6MWD did not significantly change with BMI in males (0.31 m [−0.30 to 0.92]; P = 0.32). Females had lower right atrial pressure (RAP) and mean pulmonary artery pressure, and higher cardiac index than males (all P < 0.03). Age significantly modified the sex by RAP and mean pulmonary artery pressure relationships. For every 10-year increase in age, RAP was lower in males (0.5 mm Hg [0.3–0.7]; P < 0.001), but not in females (0.13 [−0.03 to 0.28]; P = 0.10). There was a significant decrease in pulmonary vascular resistance (PVR) with increasing age regardless of sex (P < 0.001). For every 1 kg/m2 increase in BMI, there was a 3% decrease in PVR for males (P < 0.001), compared with a 2% decrease in PVR in females (P < 0.001). Conclusions Sexual dimorphism in subjects enrolled in clinical trials extends to 6MWD and hemodynamics; these relationships are modified by age and BMI. Sex, age, and body size should be considered in the evaluation and interpretation of surrogate outcomes in PAH.