Extrapolating from COMMIT, Dr. Chen said that giving this simple, inexpensive, safe, and modestly effective treatment to 1 million acute MI patients would save 5,000 lives and prevent an additional 5,000 strokes or repeat MIs. There are an estimated 10 million acute MIs per year worldwide, a third of which are STEMI, he added.
Discussant Christopher P. Cannon, M.D., said CLARITY and COMMIT are complementary trials that collectively provide important information about how clopidogrel fits into the whole spectrum of STEMI therapy, since the management strategy was 100% noninvasive in COMMIT and entirely invasive in CLARITY.
There was a suggestion of slightly better outcomes with the 300-mg loading dose used in CLARITY. However, CLARITY included patients only up to age 75 years. So a rational, evidence-based approach drawn from the two trials would be to employ a loading dose of clopidogrel in STEMI patients up to age 75 who present within 24 hours of symptom onset, and to skip the loading dose in patients beyond that age, since there is good evidence of efficacy for the 75-mg dose in the very elderly from COMMIT but no safety data for a loading dose in that age group, said Dr. Cannon of Brigham and Women's Hospital, who together with Dr. Sabatine was co-principal investigator in CLARITY.
Dr. Cannon added that the worldwide public health implications of this new addition to the management of STEMI are profound.
Two weeks of clopidogrel costs $50-$100—compared with several thousand dollars for a single dose of a modern fibrinolytic agent—placing dual antiplatelet therapy within reach of many patients, even in developing countries.
“The evidence provided by these two studies with 50,000 randomized patients is very, very strong,” Dr. Cannon told this newspaper. “Obviously I can't speak for the [American College of Cardiology/American Heart Association] guideline committee, but I have heard members of the committee say these studies provide about as strong evidence as you would want to add a new treatment to the guidelines for management of STEMI.”
The combination of clopidogrel and aspirin has previously been shown to reduce coronary risk in patients with unstable angina and in those undergoing percutaneous intervention. An ongoing study that has completed enrollment is examining whether adding long-term clopidogrel is of benefit in a broad group of patients with high-risk vascular disease.
CLARITY was funded by Sanofi-Aventis and Bristol-Myers Squibb Co. Dr. Sabatine and Dr. Cannon have served on paid advisory boards for both companies. COMMIT was funded by those companies along with AstraZeneca, the British Heart Foundation, and the U.K. Medical Research Council.
Don't COMMIT to Quick β-Blocker in MI
Initiation of β-blocker therapy in the setting of acute MI should generally be delayed for several days, until a patient's condition has stabilized, Rory Collins, M.D., said when reporting the main finding of the β-blocker arm of COMMIT/CCS-2, in which patients were immediately randomized double-blind to placebo or three doses of 5 mg IV metoprolol within 15 minutes followed by 200 mg/day of oral metoprolol.
The results indicate optimal use of β-blockers in MI is more complicated than previously appreciated.
Current American College of Cardiology/American Heart Association guidelines, as well as those of the European Society of Cardiology, generally recommend prompt administration of a β-blocker soon after MI onset unless contraindicated. But COMMIT has shown the benefits of doing so are essentially cancelled out by increased harm, said Dr. Collins, professor of medicine and epidemiology and codirector of the clinical trial service unit at the University of Oxford (England).
More specifically, in-hospital mortality was 7.7% in patients in the metoprolol arm and 7.8% with placebo. Early therapy resulted in an 18% reduction in the relative risk of in-hospital reinfarction and a 17% reduction in ventricular fibrillation (VF), which translated into a modest absolute reduction in each of these serious adverse events of five fewer cases per 1,000 treated patients. But these benefits were entirely offset by a 29% increase in the relative risk of developing cardiogenic shock, which occurred in 3.9% of the placebo patients and 5.0% of those on metoprolol, he continued.
The increased risk of cardiogenic shock in the metoprolol group was seen mostly in the first 24 hours following admission. Moreover, it was largely confined to patients who were Killip class 3 upon presentation.
“We're seeing the excess risk largely in people whose heart function is already compromised. Lowering their heart rate and blood pressure further is just pushing them into shock. It's a negative inotropic effect of β-blockade in someone who's got a failing heart,” Dr. Collins explained.