SCD-HeFT研究,PROVE-IT研究和SYNERGY研究
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
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
Topics
Sudden Cardiac Death in Heart Failure Trial
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?
SCD-HeFT
Design
SCD-HeFT
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
Public and privately sponsored:
Medtronic Inc (Minneapolis, MN)
Wyeth Pharmaceuticals (Madison, NJ)
The National Heart, Lung, and Blood Institute (Bethesda, MD)
Funding
SCD-HeFT
ICD patients
SCD-HeFT
All-cause mortality
SCD-HeFT
Relative risk for all-cause mortality
SCD-HeFT
Relative risk for all-cause mortality
SCD-HeFT
Standard medical therapy
SCD-HeFT
"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."
Impressive trial
SCD-HeFT
Topol
"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."
Difficult question
SCD-HeFT
Califf
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
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
SCD-HeFT
Pravastatin or Atorvastatin Evaluation and Infection Therapy
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
PROVE-IT
Results
N Engl J Med 2004; 350
16% reduction in risk favoring atorvastatin
PROVE-IT
Results
N Engl J Med 2004; 350
28% reduction in risk favoring atorvastatin
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
PROVE-IT
LDL reduction
N Engl J Med 2004; 350
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
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
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
PROVE-IT
PROVE-IT and REVERSAL?
REVERSAL
IVUS study showed a lack of atherosclerotic progression in stable coronary patients JAMA 2004; 291:1071-1080
Benefit broader than ACS
"Until proven otherwise, this would
be an appropriate starting dose in someone who carries significant risk."
PROVE-IT
Topol
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
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
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
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
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."
PROVE-IT
Califf
Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors
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
SYNERGY
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
Enoxaparin in past studies
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
SYNERGY
Results
SYNERGY
Bleeding
H&H=hemoglobin and hematocrit; ICH=intracranial hemorrhage
SYNERGY
No prior treatment
SYNERGY
Thumbs up/Thumbs down – April 2004
Conclusion
"In the end, we're left with a trial that by intention to treat showed noninferiority