Baseline Sex Differences in Pulmonary Arterial Hypertension Randomized Clinical Trials

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.

Keywords: body mass index; pulmonary arterial hypertension; sex; sexual dimorphism.

Figure 1.

Study sample. AIR = aerosolized iloprost randomized; CHEST-1 = Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; CTEPH = chronic thromboembolic pulmonary hypertension; FDA = U.S. Food and Drug Administration; IPD = individual participant data; PAH = pulmonary arterial hypertension; WHO = World Health Organization.

Figure 2.

Associations between six-minute-walk distance and (A) age and (B) BMI stratified by sex. Red = females; blue = males. The solid line is the effect estimate; lighter bands are the 95% confidence band. BMI = body mass index.

Figure 3.

Associations between age and (A) RAP, (B) mean PAP, (C) cardiac index (y-axis values are back-transformed but remain in ln scale), (D) PVR (y-axis values are back-transformed but remain in ln scale), and (E ) PCWP, stratified by sex. Red = females; blue = males. The solid line is the effect estimate; lighter bands are the 95% confidence band. PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure.

Figure 4.

Associations between BMI and (A) RAP, (B) mean PAP, (C) cardiac index (y-axis values are back-transformed but remain in ln scale), (D) PVR (y-axis values are back-transformed but remain in ln scale), and (E ) PCWP. Red = females; blue = males. The solid line is the effect estimate; lighter bands are the 95% confidence band. BMI = body mass index; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PVR = pulmonary vascular resistance; RAP = right atrial pressure.