Investigating the "sex paradox" in pulmonary arterial hypertension: Results from the Pulmonary Hypertension Association Registry (PHAR)

Background: Female sex is a significant risk factor for pulmonary arterial hypertension (PAH), yet males with PAH have worse survival - a phenomenon referred to as the "sex paradox" in PAH.

Methods: All adult PAH patients in the Pulmonary Hypertension Association Registry (PHAR) with congruent sex and gender were included. Baseline differences in demographics, hemodynamics, functional parameters, and quality of life were assessed by sex. Kaplan-Meier survival analysis was used to evaluate survival by sex. Mediation analysis was conducted with Cox proportional hazards regression by comparing the unadjusted hazard ratios for sex before and after adjustment for covariates. The plausibility of collider-stratification bias was assessed by modeling how large an unmeasured factor would have to be to generate the observed sex-based mortality differences. Subgroup analysis was performed on idiopathic and incident patients.

Results: Among the 1,891 patients included, 75% were female. Compared to men, women had less favorable hemodynamics, lower 6-minute walk distance, more PAH therapies, and worse functional class; however, sex-based differences were less pronounced when accounting for body surface area or expected variability by gender. On multivariate analysis, women had a 48% lower risk of death compared to men (Hazard Ratio 0.52, 95% Confidence interval 0.36 - 0.74, p < 0.001). Modeling found that under reasonable assumptions collider-stratification could account for sex-based differences in mortality.

Conclusions: In this large registry of PAH patients new to a care center, men had worse survival than women despite having more favorable baseline characteristics. Collider-stratification bias could account for the observed greater mortality among men.