Oriana Ciani1, Massimo Piepoli2, Neil Smart3, Jamal Uddin4, Sarah Walker5, Fiona C Warren5, Ann D Zwisler6, Constantinos H Davos7, Rod S Taylor8. 1. Institute of Health Research, University of Exeter Medical School, Exeter, United Kingdom; Centre for Research on Health and Social Care Management, Bocconi University, Milan, Italy. Electronic address: o.ciani@exeter.ac.uk. 2. Heart Failure Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy. 3. School of Science and Technology, University of New England, Armidale, Australia. 4. Department of Cardiac Surgery, Ibrahim Cardiac Hospital & Research, Institute, Dhaka, Bangladesh; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark. 5. Institute of Health Research, University of Exeter Medical School, Exeter, United Kingdom. 6. National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; Danish Knowledge Centre for Rehabilitation and Palliative Care, University Hospital Odense and University of Southern Denmark, Odense, Denmark. 7. Cardiovascular Research Laboratory, Biomedical Research Foundation Academy of Athens, Athens, Greece. 8. Institute of Health Research, University of Exeter Medical School, Exeter, United Kingdom; National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark; Danish Knowledge Centre for Rehabilitation and Palliative Care, University Hospital Odense and University of Southern Denmark, Odense, Denmark.
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 (ρ), 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 (+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 (Vo2peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; |ρ| < 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.
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 (ρ), 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 (+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 (Vo2peak or 6MWT) and mortality and hospitalization. Moderate levels of correlation between EC with HRQOL were seen (e.g., R2 <52%; |ρ| < 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.
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