Physical Functioning, Six-Minute Walk Distance, and Pulmonary Vascular Resistance in Adult Patients With Pulmonary Arterial Hypertension Treated With Sildenafil: Examining the Distributions of Outcomes

Abstract

PURPOSE: Pulmonary arterial hypertension (PAH) is characterized by increasing pulmonary vascular resistance (PVR) and is lethal if untreated. Therapies that improve exercise capacity (typically assessed by 6-minute walk distance [6MWD]) and hemodynamic parameters, including PVR, exist. Perceived improvement in patients' quality of life (QoL), especially Physical Functioning (PF), may influence treatment selection. We examined the distribution of PVR, 6MWD, and QoL changes. METHODS: In two double-blind sildenafil trials in adult PAH patients, placebo was compared with sildenafil alone (12-week study; n=256) or added to epoprostenol therapy (16-week study; n=265). The Short Form (SF)-36 assessed QoL, including the PF domain. For each study, cumulative distribution functions (CDFs) plotted the cumulative percentage of patients (y-axis) against numeric (and, separately, percentage) changes in 6MWD, SF-36 PF, and PVR (x-axis) from baseline to end-of-study. Kolmogorov-Smirnov tests assessed differences between sildenafil and placebo CDFs. RESULTS: For all outcomes in both studies, CDFs for numeric and percentage changes were similarly shaped for placebo and sildenafil groups. The CDF for change in SF-36 PF favored sildenafil vs placebo in both 12-and 16-week studies for numeric (P=0.01 and P=0.03, respectively) and percentage change (P=0.02 for both). In the 12-week study, 89% of sildenafiltreated patients had >5-point improvements in SF-36 PF vs 49% of placebo-treated patients; improvements were 61% and 46%, respectively, in the 16-week study. Similarly, CDFs for change in PVR favored sildenafil vs placebo in the 12-and 16-week studies using numeric or percentage change (P<0.001 for all); change in 6MWD also favored sildenafil vs placebo using numeric and percentage change (P<0.001 for all). CONCLUSION: In two large controlled trials, we observed a consistent and robust effect of sildenafil, alone or in combination with epoprostenol, compared with placebo across the entire distribution of values for exercise capacity, physical function, and hemodynamics. Applying CDFs to these outcomes can enrich their interpretation. CLINICAL IMPLICATIONS: Sildenafil significantly improves SF-36 PF, PVR, and 6MWD in adult PAH patients, alone or in combination with epoprostenol therapy.