ACC 2004: SCD-HeFT, PROVE-IT, and SYNERGY under debate

1. ACC 2004: SCD-HeFT, PROVE-IT, and SYNERGY under debate Eric J Topol MDProvost and Chief Academic Officer Chairman, Department of Cardiovascular Medicine Cleveland Clinic Foundation Cleveland, OH Robert M Califf MDProfessor of Medicine Associate Vice Chancellor for Clinical Research Director, Duke Clinical Research Institute Duke University Medical Center Durham, NC

2. Topics SCD-HEFTSudden Cardiac Death in Heart Failure Trial PROVE-ITPravastatin or Atorvastatin Evaluation and Infection Therapy SYNERGYSuperior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors

3. Sudden Cardiac Death in Heart Failure Trial SCD-HeFT

4. SCD-HeFT Background • Dr Gust Bardy (Seattle Institute for Cardiac Research, WA) and colleagues: • Do defibrillators save lives? • Would they be useful in the more general population of patients with heart failure?

5. SCD-HeFT Design • 2521 patients with NYHA class 2-3 HF and LVEF <35% • 148 centers in North America and New Zealand • Largest internal-cardioverter-defibrillator (ICD) trial ever conducted • ICD vs placebo • Median follow-up of 45 months

6. SCD-HeFT Funding Public and privately sponsored: • Medtronic Inc (Minneapolis, MN) • Wyeth Pharmaceuticals (Madison, NJ) • The National Heart, Lung, and Blood Institute (Bethesda, MD)

7. SCD-HeFT ICD patients

8. SCD-HeFT All-cause mortality

9. SCD-HeFT Relative risk for all-cause mortality

10. SCD-HeFT Relative risk for all-cause mortality

11. SCD-HeFT Standard medical therapy

12. SCD-HeFT Impressive trial • "One of the most impressive trials in sudden cardiac deaths and defibrillators." • "What I thought about this trial, which was so extraordinary, is that it really widened the field of benefit in the population—extending it to the nonischemics." Topol

13. SCD-HeFT Difficult question • "The less symptomatic patients getting the greatest benefit really raises a difficult question of whether we should go out there searching for people with asymptomatic LV dysfunction and put defibrillators in them." Califf

14. SCD-HeFT Call for more ICDs • "As I look at it, we have several million people out there who should have defibrillators put in tomorrow." —Califf • "This is the ultimate collision of evidence-based medicine and the resources to support that." —Topol

15. SCD-HeFT Thumbs • "The only hole, I thought, was the acronym." • "I’m really impressed with this trial, if I had three thumbs, I’d give it that. . . . This is first-rate work." Topol

16. Pravastatin or Atorvastatin Evaluation and Infection Therapy PROVE-IT

17. PROVE-IT Design • Intensive and moderate lipid lowering with statin therapy after acute coronary syndrome (ACS) (N Engl J Med 2004; 350: published March 8, 2004) • 4162 patients with ACS (<10 days) • Pravastatin (40 mg daily) vs atorvastatin (80 mg daily) • Primary end point: a composite of all-cause mortality, MI, unstable angina requiring hospitalization, revascularization, and stroke • Two-year follow-up

18. PROVE-IT Results 16% reduction in risk favoring atorvastatin N Engl J Med 2004; 350

19. PROVE-IT Results 28% reduction in risk favoring atorvastatin N Engl J Med 2004; 350

20. PROVE-IT Early benefit • Event curves began to separate as early as 30 days • In other placebo-controlled studies—4S, Heart Protection Study—there was a lag of approximately 12 to 18 months before event curves separated

21. PROVE-IT LDL reduction N Engl J Med 2004; 350

22. PROVE-IT Thumbs up, but… • "Two thumbs up, but with regrets." • Landmark trial: • Even drugs in the same class require head-to-head comparisons • Need incentives for companies that conduct such trials to be rewarded instead of punished Califf

23. PROVE-IT Underpowered • "I don't have a problem with the result of the study, even though it was underpowered to begin with." • —Califf • "They did have enough events to show a difference." • —Topol

24. PROVE-IT What do the results mean? • "I looked at this trial with interest, being a statin taker myself." • If a drug wins head-to-head, even in an ACS population, then high-dose atorvastatin would be the drug of choice right now • Need for further study against other statins and combinations Califf

25. PROVE-IT PROVE-IT and REVERSAL? • REVERSAL IVUS study showed a lack of atherosclerotic progression in stable coronary patientsJAMA 2004; 291:1071-1080 Benefit broader than ACS "Until proven otherwise, this would be an appropriate starting dose in someone who carries significant risk." Topol

26. PROVE-IT All about the LDL? Does the PROVE-IT trial prove that it's all about the LDL? • What about rosuvastatin? Bigger LDL bang for your buck? • Statin/ezetimibe combination? "It isn't all just LDL." —Topol

27. PROVE-IT "LDL-centric world" • REVERSAL • CRP important to lack of atherosclerotic progression • How low to go with LDL? • If LDL was 80 mg/dL and CRP was quite low, I don't know if I would keep trying to lower LDL • —Topol

28. PROVE-IT Outcome data • Need for more outcome data • It's clear we want to be more aggressive, but too many unknowns with other statins and doses • —Topol • The two statins that are in play from my perspective are simvastatin and atorvastatin • —Califf

29. PROVE-IT More trials • Coming soon • TNTAtorvastatin 80 mg vs atorvastatin 10 mg • IDEALAtorvastatin 80 mg vs simvastatin 20 mg • SEARCHLow-dose vs high-dose simvastatin

30. PROVE-IT Thumbs • "I give this one two thumbs up, but with regrets." • Give 25% of Pfizer's profits to BMS for having done the right thing • "After years of thrashing atorvastatin for not having data, they've got the data and I'm ready to make the switch." Califf

31. Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors SYNERGY

32. SYNERGY Background • Millions of times a year, doctors from around the world are making decisions in acute coronary syndromes about whether to use: • Unfractionated heparin or • Low-molecular-weight heparin

33. SYNERGY Enoxaparin in past studies • ESSENCE, TIMI 11b • Enoxaparin appeared hopeful in terms of easy use, little bleeding • Many patients did not undergo intervention or receive IIb/IIIa inhibitors • SYNERGY • High-risk population with non-ST-segment elevation MI

34. SYNERGY Design • Enoxaparin vs unfractionated heparin • 10 000 high-risk ACS patients in 467 centers • Aged 60 years or older, positive troponin, or ST segment shift • Primary end point of death/MI at 30 days

35. SYNERGY Results

36. SYNERGY Bleeding H&H=hemoglobin and hematocrit; ICH=intracranial hemorrhage

37. SYNERGY No prior treatment Patients with no prior antithrombotic treatment

38. SYNERGY Conclusion • "In the end, we're left with a trial that by intention to treat showed noninferiority for efficacy and a modest excess of bleeding." Califf

39. SYNERGY Disappointing trial • "The question was right, the design was right, the end points were great." • "But I have a problem with the interpretation, or at least some of the perception of the data." • "I think that the trial, if we just call it like it is, says enoxaparin isn't good for aggressive management of acute coronary syndrome—that's how I see the results of this trial." Topol

40. SYNERGY Debating enoxaparin • "I have a disagreement here." • "My interpretation, contrary to yours, is that you ought to stick with what you start with and I think enoxaparin is a bit better to start with." Califf

41. SYNERGY Thumbs • "Obviously we have a divergence of opinion on this one." • "It will be very interesting to follow the clinical-use trends as the people discuss this and the papers come out." Califf