Efficacy and Safety of Exercise Training as a Treatment Modality in Patients With Chronic Heart Failure: Results of A Randomized Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) David J. Whellan, MD, MHS Jefferson Medical College, Philadelphia, PA Christopher M. O’Connor, MD Duke University Medical Center, Durham, NC on behalf of the HF-ACTION Steering Committee, Investigators, and Coordinators Funded by NHLBI Ancillary studies funded by GE Healthcare and Roche Diagnostics Financial Disclosures: Research Support: GE Healthcare, Roche Diagnostics O’Connor

Background n In past studies, exercise training has l Increased exercise capacity l Improved quality of life l Improved biomarkers l Possibly improved survival n Limitations l Relatively small l Majority single-center l Underpowered to evaluate mortality and morbidity l Lack of adequate control groups l Limited safety data

O’Connor n All-cause mortality + hospitalization: Primary n CV mortality + CV hospitalization n CV mortality + HF hospitalization n Mortality n Safety n Physiologic endpoints: CPX and 6MW n QOL n Cost HF-ACTION Outcomes

O’Connor Study Design Chronic heart failure, NYHA Class II-IV, LVEF ≤ 35%, optimal medical therapy, and capable of exercising Chronic heart failure, NYHA Class II-IV, LVEF ≤ 35%, optimal medical therapy, and capable of exercising Pre-randomization CPX and ECHO Randomization 1:1 (Stratified by center and HF etiology) Randomization 1:1 (Stratified by center and HF etiology) Exercise Training Usual Care Optimized medical treatment Patient education Phone calls Recommendation: Moderate intensity activity 30 minutes/day activity 30 minutes/day Optimized medical treatment Patient education Phone calls Recommendation: Moderate intensity activity 30 minutes/day activity 30 minutes/day Optimized medical treatment Patient education Phone calls Supervised training Home training Optimized medical treatment Patient education Phone calls Supervised training Home training

O’Connor Time to All-Cause Mortality or All-Cause Hospitalization HR 0.93 (95% CI: 0.84, 1.02), P=0.13

O’Connor Summary of Major Outcomes Hazard Ratio 95% CIp-value All-cause mortality and hospitalization (primary) Main analysis , Adjusted analysis , CV mortality and CV hospitalization Main analysis , Adjusted analysis , CV mortality and HF hospitalization Main analysis , Adjusted analysis ,

O’Connor Limitations  Adherence in exercise training group and physical activity by the usual care group may have diminished the identified benefit of exercise training  Blinding of subjects and research personnel not possible  Core labs blinded  Clinical Endpoint Committee blinded  Home exercise adherence data are difficult to collect and to precisely quantify

O’Connor Conclusions n The HF- ACTION Trial is the largest and most comprehensive study of exercise training in patients with heart failure. n Based on the protocol-specified primary analysis, exercise training produced a modest, non-significant decrease in the primary endpoint (all-cause mortality or all-cause hospitalization) and key secondary clinical endpoints. n In secondary analyses, with adjustment for the most significant, objectively-determined prognostic factors, the adjusted treatment effect was statistically significant for the primary endpoint and for the secondary endpoint of CV mortality or HF hospitalization. n The HF-ACTION study results support a structured exercise training program for patients with reduced LV function and HF symptoms in addition to evidence-based therapy.