1. 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 - 3318

2. 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

3. O’Connor - 3318 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

4. O’Connor - 3318 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

5. O’Connor - 3318 Time to All-Cause Mortality or All-Cause Hospitalization HR 0.93 (95% CI: 0.84, 1.02), P=0.13

6. O’Connor - 3318 Summary of Major Outcomes Hazard Ratio 95% CIp-value All-cause mortality and hospitalization (primary) Main analysis0.930.84, 1.020.13 Adjusted analysis0.890.81, 0.990.03 CV mortality and CV hospitalization Main analysis0.920.83, 1.030.14 Adjusted analysis0.910.82, 1.010.09 CV mortality and HF hospitalization Main analysis0.870.75, 1.000.06 Adjusted analysis0.850.74, 0.990.03

7. O’Connor - 3318 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

8. O’Connor - 3318 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.