ACC 2005: Message from the trials
Valentin Fuster MD
Director, Cardiovascular Institute
Mount Sinai Medical Center
New York, NY
Christopher Cannon MD
Staff cardiologist
Brigham and Women's Hospital
Boston, MA
James Ferguson MD
Associate Director, Cardiology
St Luke's Episcopal Hospital and Texas Heart Institute
Houston, TX
Women's Health Study Use of aspirin for primary prevention
COMMIT and CLARITY Use of clopidogrel in acute-MI patients
TNT High-dose atorvastatin in stable CHD patients
ASCOT-BPLA
Calcium channel blocker plus ACE inhibitor reduced all-cause mortality and other cardiovascular end points
Topics
Women's Health Study
Use of aspirin for primary prevention
Women's Health Study: Design
Use of aspirin for primary prevention in women
(N Engl J Med 2005: published March 7th)
39 876 initially healthy women 45 years of age or older
Randomized to 100 mg of aspirin on alternate days or placebo
Monitored for first major CV event (nonfatal MI, nonfatal stroke, or death from CV causes)
10-year follow-up
WHS: Cardiovascular end points
WHS: Stroke end points
WHS: Ambitious trial
Glass half-full vs half-empty
Reduces stroke in a primary- prevention population
But does not reduce mortality, which may have been an ambitious end point, in retrospect
Ferguson
WHS: Surprising results
Benefit in stroke and myocardial infarction reduction in women older than 65 years
"You do have to be at risk to get benefit from aspirin."
Cannon
Gender differences
Significant differences in stroke reduction in the Women's Health Study and the Physician's Health Study
Does stroke occur earlier in women than it does in men?
Gender differences
Mean ages roughly the same, but different follow-up
Physician's Health Study: 5-year follow-up
Women's Health Study: 10-year follow-up
"These are not apples and apples we're comparing."
- Ferguson
WHS: Aspirin dose
"We don't know what the right dose of aspirin is right now."
- Ferguson
Physician's Health Study used 325-mg dose
Antithrombotic Trialist Collaboration suggests doses less than 75 mg/day not as effective
WHS: The guidelines
Changing guidelines? No need . . .
Aspirin used in primary prevention only when patient's risk-factor profile is intermediate based on Framingham risk score
But may need to revisit the stroke reduction benefit
Fuster
WHS: Who gets aspirin?
How low down the risk spectrum do we go?
No benefit in younger patients
Need to categorize women at high risk for stroke to direct aspirin therapy to them
Cannon
WHS: Not change practice
"It's telling us what we sort of knew already. Not everybody needs to be taking aspirin."
Benefits tied to the degree of risk
Stroke-prevention data need to be teased out further
Ferguson
COMMIT Clopidogrel and Metoprolol in Myocardial Infarction Trial
CLARITY Clopidogrel as Adjunctive Reperfusion Therapy - Thrombolysis in Myocardial Infarction (TIMI) 28
New data about clopidogrel
CLARITY
(N Engl J Med 2005: published March 9, 2005)
3500 patients
Clopidogrel improved infarct-related artery patency in MI patients receiving thrombolysis
-Reduced occluded arteries by 36%
-Reduced death, MI, or recurrent ischemia requiring revascularization at 30 days by 20%
New data about clopidogrel
COMMIT
46 000 patients
Addition of clopidogrel in patients with ST-segment-elevation MI with or without thrombolysis
-Death/MI/stroke reduced by 9%
-Death reduced by 7%
CLARITY and COMMIT
This adds the final piece of the puzzle that clopidogrel is beneficial in ST-segment-elevation MI
- Cannon
CLARITY and COMMIT
Substantial clinical benefit in keeping vessels open
COMMIT counterintuitive: most of the benefit in patients presenting within first 12 hours
Trend toward benefit in patients also treated with fibrinolytics
Ferguson
Mechanisms
Same mechanism as aspirin?
After 180 minutes, the arteries open more and stay open because of the combination
Prevention of reocclusion is likely the operative mechanism
"Two agents are better than one."
Cannon
CLARITY and COMMIT
If you have risk, more antiplatelet therapy provides incremental benefit
Opportunity to significantly improve aspirin
Ferguson
TNT
Treating to New Targets
High-dose atorvastatin in stable CHD patients
TNT: Design
Lowering LDL cholesterol levels in stable CHD patients substantially below current guidelines
(N Engl J Med 2005: published March 8, 2005)
Parallel-group study randomizing 10 001 patients to atorvastatin 10 mg or 80 mg
Patients included were men and women aged 35 years to 75 years with clinically evident CHD
Primary end point was first major CV event (death from CHD, nonfatal MI, nonfatal and fatal stroke, or resuscitation after cardiac arrest)
5-year follow-up
TNT: LDL cholesterol levels
TNT: Primary efficacy outcomes
TNT: What does it add?
PROVE-IT showed that lower is better in ACS patients, but did it apply to stable CHD patients?
Yes! Confirms and supports that lower LDL cholesterol is better, but also expands the principle to more than 30 million US patients
Cannon
TNT: What does it add?
Baseline LDL cholesterol levels low in TNT
No longer good enough to simply "put a statin in the drinking water"
Level of LDL cholesterol matters— need to get it down even further than we thought we did
Is it all about the LDL?
Looking down the road to tease out benefit
What happens when patients are stratified by LDL cholesterol levels coming into the study?
Is it all LDL? What happens above and beyond LDL lowering?
Ferguson
Beyond the guidelines
Patient with angina and prior MI
Goal to bring LDL cholesterol level to 70 mg/dL
Do I start treatment at the maximum 80-mg dose of atorvastatin?
Fuster
ACS vs stable CHD
In ACS patients, start with a high-dose statin, as PROVE-IT showed benefit emerged after 10 days
In stable CHD patients, slower titration is an option, but getting control of LDL and CRP is key
Cannon
TNT: Safety issues
1.2% of patients treated with atorvastatin 80 mg had a persistent elevation in alanine aminotransferase, aspartate aminotransferase, or both, compared with 0.2% of patients receiving atorvastatin 10 mg (p<0.001)
TNT: Safety issues
99% of the patients didn't need any dose adjustment with atorvastatin 80 mg
"It seems to me that in t