Validation of Exercise Capacity as a Surrogate Endpoint in Exercise-Based Rehabilitation for Heart Failure A Meta-Analysis of Randomized Controlled Trials

OBJECTIVES This study sought to validate exercise capacity (EC) as a surrogate for mortality, hospitalization, and health-related quality of life (HRQOL). BACKGROUND EC is often used as a primary outcome in exercise-based cardiac rehabilitation (CR) trials of heart failure (HF) via direct cardiorespiratory assessment of maximum oxygen uptake (VO(2)peak) or through submaximal tests, such as the 6-min walk test (6MWT). METHODS After a systematic review, 31 randomized trials of exercise-based CR compared with no exercise control (4,784 HF patients) were included. Outcomes were pooled using random effects meta-analyses, and inverse variance weighted linear regression equations were fitted to estimate the relationship between the CR on EC and all-cause mortality, hospitalization, and HRQOL. Spearman correlation coefficient (rho), R-2 at trial level, and surrogate threshold effect (STE) were calculated. STE represents the intercept of the prediction band of the regression line with null effect on the final outcome. RESULTS Exercise-based CR is associated with positive effects on EC measured through VO(2)peak (+3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (+41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (VO(2)peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R-2 < 52%; vertical bar rho vertical bar < 0.72). Estimated STE was an increase of 5 ml/kg/min for VO(2)peak and 80 m for 6MWT to predict a significant improvement in HRQOL. CONCLUSIONS The study results indicate that EC is a poor surrogate endpoint for mortality and hospitalization but has moderate validity as a surrogate for HRQOL. Further research is needed to confirm these findings across other HF interventions. (C) 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.