1. Assessing A-HeFT and PEACE Eric J Topol MD Provost and Chief Academic Officer Chair, Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, OH Robert M Califf MD Professor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

2. African-American Heart Failure Trial (A-HeFT)

3. A-HeFT design Randomized 1050 men and women who classified themselves as African American Patients had NYHA class 3-4 HF and reduced LV function Received a fixed-dose combination of isosorbide dinitrate-hydralazine or placebo

4. A-HeFT halted early The trial was terminated before the planned 1100 patients had been randomized Significant mortality increase observed in the placebo group There was a 43% reduction in mortality in the group given isosorbide dinitrate plus hydralazine

5. Outcomes of the primary composite end point and its components End pointISDN- hydralazine (n=518) Placebo (n=532) p Primary end point composite score -0.1-0.50.01 All-cause mortality6.2%10.2%0.02 First HF hospitalization 16.4%24.4%0.001 Change in quality- of-life score at 6 months -5.5-2.70.02

6. A-HeFT "A magnificent effort." "This trial will set a lot of precedents." Califf

7. A-HeFT "A stepping stone to identifying what is the genomic basis for this extraordinary benefit." "Should we be prescribing these to all black patients with heart failure today?" Topol

8. How to apply the results This combination should be added to existing treatments in African Americans with heart failure It is premature to take this action in non-African Americans

9. A-HeFT "It's a very interesting trial—it's one of a kind. I don't know if there's ever been a cardiovascular medical trial like this one." "I would certainly give it two thumbs up for identifying a very important life- saving effect." Topol

10. A-HeFT "I give it two thumbs up too for all of the reasons that you just gave." Califf

11. Prevention of Events with Angiotensin- Converting Enzyme Inhibition (PEACE)

12. PEACE design Would patients with stable coronary artery disease but normal or slightly reduced LVF derive benefit from the addition of ACE inhibitors to conventional therapy? Randomized, double-blind, placebo-controlled study of 8290 patients Patients received either trandolapril 4 mg/day or placebo

13. Findings The incidence of the primary end point—a composite of cardiovascular mortality, nonfatal MI, and coronary revascularization—was nearly identical in the two study arms After an average follow-up of 4.8 years, no subgroup benefited from ACE-inhibitor therapy

14. Incidence of the primary end point and components OutcomeTrandolapril (n=4158) (%) Placebo (n=4132) (%) Hazard ratio (95% CI) p Primary end point 21.922.50.96 (0.88-1.06) 0.43 Death from noncardio- vascular causes 3.74.40.83 (0.67-1.03) 0.09 All-cause mortality 7.28.10.89 (0.76-1.04) 0.13

15. Previous trials Heart Outcomes Prevention Evaluation (HOPE) and European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) High-risk coronary patients could gain additional cardiovascular protection with an ACE inhibitor

16. Evaluating PEACE "When you have two trials that show a significant benefit with pretty much a similar construct as PEACE, you wonder about the third trial." "Perhaps [this is due to] the fact that it is a much lower-risk population and the power of this trial is less than the other two." Topol

17. Evaluating PEACE Possible explanations for the differences between trials: Lower-risk patient cohort limited the power of the trial Different ACE inhibitor with perhaps a different benefit More robust background treatment Bad luck? Califf

18. Applying PEACE ACE inhibitors can be crossed off the required list for patients with coronary disease and good LV function Potentially welcome news in reducing the pharmaceutical toll on patients

19. PEACE "I'm only going to give PEACE one thumb up." "I give the investigators and the originators of PEACE two thumbs up — it was the right question and a very gritty hard-fought-out trial." "I'm going to give the NHLBI only one thumb up for not supporting it with enough money to get it done quickly." Califf

20. PEACE "I think that's the problem here. I think the trial went on for a long time and wound up with, unfortunately, a pretty low-risk population at entry and it's a little more difficult to interpret." "I tend to agree with that assessment." Topol