Conference: 2010 International PHA Conference and Scientific Sessions
Release Date: 06.24.2010
Presentation Type: Abstracts
Brar SS, Madabushi R, Stockbridge N, Gobburu JV, Jadhav PR.
Center for Drug Evaluation and Research, U.S. Food and Drug Administration, USA
BACKGROUND: New treatments for PAH are routinely approved based on effects on exercise capacity as measured by six-minute-walk distance (6MWD). The endpoints for vascular remodeling and pulmonary hemodynamic benefit have been routinely collected, but play little regulatory role in approval. The objective of this investigation is to assess the relationship between hemodynamic measures and exercise capacity. The research aims to provide a framework to support approval of PAH treatments in patients who may be unable to perform the commonly used 6MWD.
METHODS: Patient-level data from 13 pivotal clinical trials, incorporating seven PAH therapies of differing mechanisms, were used for the analysis. The adult patient population included those with varying degrees of PAH severities of idiopathic or familial PAH. The data from active and control arms were used. Changes from baseline ( ) in standard pulmonary hemodynamic measures (e.g., CO, mPAP, PVRI, RAP, etc.) were investigated for a relation with 6MWD. Univariate regression between 6MWD and each individual hemodynamic variable was performed to allow comparison across trials and therapies. For each regression model, parameter estimates were evaluated for statistical significance and consistency among trials. In addition, multivariate regression was performed on the pooled data using various linear combinations of hemodynamics to explain 6MWD.
RESULTS: A significant relationship was observed between the change in hemodynamic measures ( CI, mPAP, RAP, SVRI, and PVRI) and exercise capacity, 6MWD (univariate, p-value all < 0.05) across 13 trials (n=1096 subjects). The strongest association was with PVRI, where the slope (-0.032 [-0.039, -0.024] m•cm5/dyne•sec; mean ± 95%CI) for PVRI and 6MWD relationship was consistent across all trials of different drug classes and for placebo. Multivariate analysis showed that the combination of PVRI and RAP were significant predictors of 6MWD in adult patients with PAH.
CONCLUSIONS: In a systematic analysis of hemodynamic and 6MWD data from 1096 patients, PVRI was found to be a significant and consistent predictor of 6MWD. Most importantly, the investigation demonstrated consistency of relationship across independent trials, drugs with differing mechanisms of action, and placebo. The relationship between PVRI is supported by a priori physiological reasoning where an improvement in pulmonary resistance is expected to improve the exercise capacity.