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

Abstract

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 (Vo₂peak) 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 (r), R2 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 Vo₂peak (þ3.10 ml/kg/min; 95% confidence interval [CI]: 2.01 to 4.20) or 6MWT (þ41.15 m; 95% CI: 16.68 to 65.63) compared to control. The analyses showed a low level of association between improvements in EC (Vo₂peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; jrj < 0.72). Estimated STE was an increase of 5 ml/kg/min for Vo₂peak 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.