Sex and Menopause Differences in Response to Tadalafil: 6‐Minute Walk Distance and Time to Clinical Worsening

Abstract

Pulmonary arterial hypertension (PAH) is a female-predominant disease, but there are little data on treatment response by sex and menopausal status. In this retrospective analysis of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) randomized clinical trial, we assessed treatment response between the sexes by examining change in 6-minute walk distance (6MWD) and time to clinical worsening (TCW). We examined the effect of menopausal status on the same treatment measures. 6MWD was recorded before and after 16 weeks of treatment with tadalafil or placebo in the PHIRST study cohort of 340 subjects (264 females, 76 males). A univariate analysis was used to assess the effect of sex on change in 6MWD and TCW. Multivariate linear regression and Cox proportional hazards models were built for 6MWD and TCW, respectively. Women were subdivided by age as a surrogate for menopausal status. The linear trend test and the log-rank test were performed on change in 6MWD and TCW by age. For tadalafil-treated patients, a significant difference in change in 6MWD by sex (mean: 48.6 m for males vs. 34.7 m for females; P = 0.01) was found, but it was not significant in multivariate analysis (P = 0.08). There was a trend toward a female age-dependent effect in change in 6MWD; the premenopausal group showed the greatest improvement. A significant sex-or age-dependent effect on TCW was not present. In conclusion, this retrospective analysis of the PHIRST trial suggests that men and premenopausal women may experience greater functional improvement when treated with tadalafil than older women, but there was no consistent sex or menopausal effect on TCW.Keywords: pulmonary arterial hypertension, sex differences, tadalafil, 6-minute walk distance, menopause. Pulmonary arterial hypertension (PAH) is a group of disorders that are characterized by elevated pulmonary arterial resistance, leading to eventual right heart failure. 1,2 PAH is a female-predominate disease; according to the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) Registry, group 1 PAH is four times more likely in female patients than in male patients. [3][4][5][6] While the exact cause of the observed female predominance is unknown, it may potentially relate to a disruption in the protective effect of estrogen on the pulmonary vasculature and myocardium. [7][8][9][10][11] A recent study examining patient factors as a predictor of treatment response with tadalafil found male sex to be predictive of improved change in 6-minute walk distance (6MWD). 12 Despite this, there is a paucity of literature investigating the effect of menopause on response to PAH treatment. Providing more tailored therapy to patients may allow for more cost-conscious, targeted, and safer treatment for patients with PAH.Two prior sex-specific treatment response studies found opposing results for response to tadalafil and endothelin receptor antagonists (ERAs). ERAs have demonstrated a more robust change in 6MWD in female patients, while tadalafil has d...

Sex differences in hemodynamic responses and long-term survival to optimal medical therapy in patients with pulmonary arterial hypertension

“…These findings may be explained by sexual dimorphism in NO metabolism, as urinary 15 N nitrate excretion, which reflects total NO biosynthesis, was significantly higher in females compared with males, suggesting that males may benefit more from the NO pathway and PDE-5 inhibitors than females [ 48 ]. In the present study, no significant sex interaction was noted for PDE-5 inhibitors use as in the previous study [ 47 ]. This is probably because medication is effective for both sexes in different ways.…”

“…This sex difference in clinical responses to ERAs may be related, at least in part, to higher levels of circulating ET-1 and greater vasoconstriction mediated by ET receptor type A in males [ 44 , 45 ]. Sex differences in the effects of PDE-5 inhibitors have also been reported; male and premenopausal female patients were able to achieve clinically relevant responses in 6MWD and health-related quality of life [ 46 , 47 ]. These findings may be explained by sexual dimorphism in NO metabolism, as urinary 15 N nitrate excretion, which reflects total NO biosynthesis, was significantly higher in females compared with males, suggesting that males may benefit more from the NO pathway and PDE-5 inhibitors than females [ 48 ].…”

Tadalafil once daily: Narrative review of a treatment option for female sexual dysfunctions (FSD) in midlife and older women

“…Treatment with tadalafil in elderly women for its metabolic and micro-vascular effects on skeletal muscle and adipose tissue in type 2 diabetic patients (23), for the treatment of pulmonary hypertension (30). Little evidence is reported on its efficacy in the treatment of FSD, specially in particular populations such as women treated with antidepressant drugs (31) or women affected by type 1 Diabetes Mellitus (DM) with sexual arousal disorders (28).…”

Novel approach to classifying patients with pulmonary arterial hypertension using cluster analysis

“…In addition, gender, cardiovascular risk factors and age have recently been identified as potential predictors of therapeutic response. 2 – 5 …”

“…In addition, gender, cardiovascular risk factors and age have recently been identified as potential predictors of therapeutic response. [2][3][4][5] Clustering, also referred to as phenomapping, is a statistical technique that utilizes unbiased machine learning and has been recently applied as a proof-of-concept strategy for classifying patients with heart failure. [6][7][8] We aimed to use cluster analysis on PAH participants included in clinical trials to identify distinct clinical phenotypes in PAH.…”