1. ACC 2004: SCD-HeFT, PROVE-IT, and SYNERGY under debate
Eric J Topol MD Provost and Chief Academic Officer Chairman, 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. Topics SCD-HEFT Sudden Cardiac Death in Heart Failure Trial
PROVE-IT Pravastatin or Atorvastatin Evaluation and Infection Therapy
SYNERGY Superior 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. Design 2521 patients with NYHA class 2-3 HF and LVEF <35%
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. Funding Public and privately sponsored:
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. All-cause mortality All-cause mortality ICD Amiodarone Placebo
SCD-HeFT
All-cause mortality
All-cause mortality
ICD
Amiodarone
Placebo
3 years (%)
17.1
24.0
22.3
5 years (%)
28.9
34.1
35.8

9. Relative risk for all-cause mortality
SCD-HeFT
Relative risk for all-cause mortality
Population
Number (ICD+control)
HR*
97.5% CI
All patients
1676
0.77**
NYHA class 2
1160
0.54
NYHA class 3
516
1.16
Ischemic HF
884
0.79
Nonischemic HF
794
0.73
*HR=hazard ratio
**p=0.007

10. Relative risk for all-cause mortality
SCD-HeFT
Relative risk for all-cause mortality
Population
Number (ICD+control) HR
97.5% CI
LVEF <30%
1390
0.73
LVEF >30%
285
1.08
QRS <120 ms
977
0.84
QRS >120 ms
699
0.67
On beta blockers
1157
0.68
Not on beta blockers
519
0.92

11. Standard medical therapy
SCD-HeFT
Standard medical therapy
Medication
Baseline rate (%)
Rate at last follow-up (%)
ACE inhibitors 85 72
ACE inhibitors or angiotensin receptor blockers 96 87
Beta blockers 69 78
Statins 38 47

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. Thumbs "The only hole, I thought, was the acronym."
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. Results 16% reduction in risk favoring atorvastatin PROVE-IT End point
Pravastatin 40 mg (n=1973)
(%)
Atorvastatin 80 mg (n=2003) p
Primary composite end point
26.3
22.4
0.005
16% reduction in risk favoring atorvastatin
N Engl J Med 2004; 350

19. Results 28% reduction in risk favoring atorvastatin PROVE-IT End point
Pravastatin 40 mg (n=1973)
(%)
Atorvastatin 80 mg (n=2003) p
Death from any cause
3.2
2.2
0.07
28% reduction in risk favoring atorvastatin
N Engl J Med 2004; 350

20. Early benefit Event curves began to separate as early as 30 days
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. LDL reduction PROVE-IT LDL cholesterol Pravastatin 40 mg (n=1973)
Atorvastatin 80 mg (n=2003)
Final LDL cholesterol (mg/dL)
95.0
62.0
N Engl J Med 2004; 350

22. Thumbs up, but… "Two thumbs up, but with regrets." Landmark trial:
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. What do the results mean?
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 and REVERSAL? REVERSAL
IVUS study showed a lack of atherosclerotic progression in stable coronary patients JAMA 2004; 291:
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. "LDL-centric world" REVERSAL
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. Outcome data Need for more outcome data
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. More trials Coming soon TNT Atorvastatin 80 mg vs atorvastatin 10 mg
PROVE-IT
More trials
Coming soon
TNT Atorvastatin 80 mg vs atorvastatin 10 mg
IDEAL Atorvastatin 80 mg vs simvastatin 20 mg
SEARCH Low-dose vs high-dose simvastatin

30. Thumbs "I give this one two thumbs up, but with regrets."
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. Enoxaparin in past studies
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. Design Enoxaparin vs unfractionated heparin
SYNERGY
Design
Enoxaparin vs unfractionated heparin
high-risk ACS patients in 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. Bleeding SYNERGY Bleeding Enoxaparin (%) UFH (%) p
GUSTO severe bleeding
2.9
2.4
0.107
H&H drop/ICH
15.2
12.5
0.001
TIMI major bleeding
9.1
7.6
0.008
Transfusions
17.0
16.0
0.155
H&H=hemoglobin and hematocrit; ICH=intracranial hemorrhage

37. Patients with no prior antithrombotic treatment
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. Debating enoxaparin "I have a disagreement here."
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. Thumbs "Obviously we have a divergence of opinion on this one."
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