PROVE-IT TIMI-22，A to Z ，RIO-EUROPE研究
ESC 2004: Learning as a journey
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
Michael Weber MD
Professor of Medicine
SUNY Downstate College of Medicine
Brooklyn, NY
PROVE-IT TIMI-22 Pravastatin or atorvastatin evaluation and infection therapy
A to Z Aggrastat to Zocor
RIO-EUROPE Rimonabant in Obesity - Europe
Topics
Pravastatin or Atorvastatin Evaluation and Infection Therapy
PROVE-IT TIMI-22
PROVE-IT: Background
Previous studies have shown that patients with high titers of Chlamydia pneumoniae at greater risk of MI
PROVE-IT TIMI-22 and ACES presented at ESC 2004
PROVE-IT: Design
Long-term study of antibiotic therapy against Chlamydia pneumoniae on the occurrence of cardiovascular events in patients with coronary heart disease
4162 patients with ACS (<10 days)
Pravastatin (40 mg daily) vs atorvastatin (80 mg daily)
Patients were randomized a second time to receive treatment with either gatifloxacin 400 mg/day for a full course of 10 days per month followed by 20 days without treatment or placebo
Repeated each month for two years
PROVE IT-TIMI 22: CVD events by treatment group
Cannon C. ESC Congress 2004; August 28-September 1, 2004; Munich, Germany
Primary endpoint a composite of all-cause mortality, MI, unstable angina requiring hospitalization, revascularization, and stroke
PROVE-IT: Great hope
“I think it’s a solid ‘no’ that this doesn’t work.”
Cannon
PROVE-IT: No benefit
“We’ve been at this antibiotic question a couple of times.”
Can these results be extended to patients who have less atherosclerotic burden?
For patients with established coronary disease, three “resounding studies” suggest no benefit
Ferguson
ACES: Design
Study compared treatment with azithromycin 600 mg once a week for a year with placebo in 4012 patients with established coronary disease
Patients were then followed for four years for the occurrence of primary end point events, any one of CHD death, nonfatal MI, coronary revascularization, or hospitalization for unstable angina
RESULTS
Primary end point was almost identical between the groups: 22.4% with placebo and 22.3% with azithromycin)
Antibiotics in CHD
“We’ve come to learn that things like hs-CRP can be produced by non-infectious causes.”
Inflammatory markers do not necessarily reflect an infectious etiology
Still possible that C pneumoniae and other organisms having an earlier etiologic role
Weber
PROVE-IT: 30 days
Difficult to translate into a primary prevention trial
Two other leading infectious organisms are viruses
Antiviral therapies still limited
Cannon
PROVE-IT: Final thoughts
“From the standpoint of using it in people with established coronary disease, I think we have the answer.”
- Ferguson
“It may be that we’ve identified that the process was over at the stage when patients were 60 years old with established disease and the infectious activity had been decades before.”
- Cannon
Aggrastat to Zocor
A to Z
PROVE-IT: Design
Intensive and moderate lipid lowering with statin therapy after acute coronary syndrome (ACS) (N Engl J Med 2004; 350: published March 8th)
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: 30 days
Curves begin to diverge at 30 days
Curves similar in terms of the overall time course
Greater reductions in LDL and CRP levels with atorvastatin 80 mg
PROVE-IT: Understanding CRP
Evolving understanding of lipid-lowering treatment
LDL cholesterol as a major target to prevent major cardiovascular events and death
Increasing focus on reducing CRP as a component of intensive statin therapy
Cannon
A to Z: Design
Z phase of the A to Z trial evaluating aggressive versus conservative statin therapy in 4497 ACS patients
TREATMENT
Early intensive treatment: Simvastatin 40 mg for one month followed by simvastatin 80 mg for the remainder of the trial
Conservative treatment: Placebo for four months followed by simvastatin 20 mg for the remainder of the trial
Primary end point a composite of all-cause mortality, MI, unstable angina requiring hospitalization, revascularization, and stroke
A to Z: Changes in LDL cholesterol
De Lemos J et al. JAMA 2004
A to Z: Primary composite end point
De Lemos J et al. JAMA 2004
A to Z: Results
“Now come the surprises.”
Why do the curves not separate early, when one group was treated with placebo and the other simvastatin 40 mg?
Curves begin to separate between months 4 and 24 – What is going on here?
A to Z: What’s going on here?
Easier to deal with what happens later in the study
Not enough difference in LDL levels to reflect significant differences between the two treatment strategies at 24 months
Effects of different statins beyond lipid lowering
Weber
A to Z: What’s going on here?
“I have no problem with A to Z overall, but that first four months is troubling.”
Is there something unique about atorvastatin that could explain the discrepancy between PROVE-IT and A to Z?
Weber
A to Z: Different patients
“Is it the drug? Is it the population? Or is it the study design?”
DIFFERENCES
Patients in PROVE-IT recruited within 10 days, with many ‘out’ from acute episode versus those in A to Z who were in the midst of ACS
A to Z underpowered
Ferguson
A to Z: No support for early use
A to Z does not support early administration of statins in ACS patients
“I’m a little bit mystified as to how some people have taken this as an endorsement of early administration of statins. It doesn’t support it. PROVE-IT TIMI-22 does, but A to Z goes in exactly the opposite direction.”
Ferguson
A to Z: Two hypotheses
WHY THE DISCREPANCY WITH PROVE-IT?
Final between-group reduction in CRP was 16.7%, whereas as in PROVE-IT, the difference between treated groups was 38%
Different patient population
Different dose
Fuster
PROVE-IT: Role of CRP
CRP does provide a hint as to why no benefit observed at four months
But, CRP issue clouded as A to Z patients stabilized with aggressive medical therapy, possibly resulting in more patients entering the trial with an ongoing thrombotic process
PROVE-IT patients more stable
Cannon<