Aspirin/Plavix Combo Tx Improved STEMI

IMNG News Service

May 2005

ORLANDO, FLA. -- Adding a brief course of clopidogrel to standard aspirin therapy in patients with ST-elevation MI improves arterial patency and saves lives, according to two major studies presented at the annual meeting of the American College of Cardiology.

Marc S. Sabatine, M.D., presented the results of the Clopidogrel as Adjunctive Reperfusion Therapy-Thrombolysis in Myocardial Infarction trial (CLARITY-TIMI 28), a double-blind study in which 3,491 patients presenting with ST-elevation MI (STEMI) within 12 hours of symptom onset received a fibrinolytic agent, aspirin, and heparin and were then randomized to oral clopidogrel (Plavix) or placebo. The clopidogrel regimen consisted of a 300-mg loading dose followed by 75 mg once daily. By study design, all patients underwent coronary angiography 2-8 days later. Clopidogrel was then stopped unless a stent was implanted, as occurred in nearly 60% of patients, in which case open-label clopidogrel was recommended, as is standard therapy.

The primary end point in CLARITY was a composite comprising an occluded infarct-related artery upon angiography a mean of 3.5 days after starting clopidogrel, repeat MI prior to angiography, or death. The rates were 15.0% in the clopidogrel arm and 21.7% with placebo, for a highly significant 36% reduction in the risk of the end point with clopidogrel (N. Engl. J. Med. 2005;352:1179-89).

The secondary end point was the 30-day combined rate of cardiovascular death, recurrent MI, or recurrent ischemia leading to urgent revascularization. The rates were 11.6% of patients in the clopidogrel arm and 14.1% on placebo, for a significant 20% risk reduction favoring clopidogrel.

There was no excess in major or minor bleeding or intracranial hemorrhage in the clopidogrel group. Surprisingly, there was no significant increase in the rate of major bleeding even among patients who underwent coronary artery bypass graft surgery less than 5 days after discontinuing clopidogrel, added Dr. Sabatine of Brigham and Women's Hospital, Boston.

A few days of clopidogrel prevented one primary event for every 16 patients treated. The number of patients needed to be treated to avoid one secondary study end point was 36.

The rationale for CLARITY was that the efficacy of fibrinolytic therapy is limited by inadequate reperfusion and/or early reocclusion in one-quarter of treated patients. An occluded infarct-related artery is associated with a twofold increase in long-term mortality.

CLARITY was designed to mimic how STEMI is managed at the 80% of U.S. hospitals lacking the capability to perform primary percutaneous intervention within a 90-minute window. Patients presenting to these hospitals receive thrombolytic therapy. Roughly three-quarters of them are referred for angiography a few days later, as a result of which two-thirds undergo a coronary revascularization procedure.

The other major clopidogrel study was the mammoth Clopidogrel and Metoprolol in Myocardial Infarction Trial/Second Chinese Cardiac Study (COMMIT/CCS-2). Unlike CLARITY, COMMIT was powered to detect a short-term mortality benefit for the antiplatelet agent. It involved 45,852 acute MI patients, 93% with STEMI, who presented to 1,250 Chinese hospitals within 24 hours of symptom onset. They were randomized to 75 mg/day of clopidogrel or placebo for an average of 16 days in addition to aspirin and other standard medications.

COMMIT featured a two-by-two factorial design in which patients were also randomized to intravenous metoprolol or placebo, with mixed results.

In-hospital mortality occurred in 7.7% of the clopidogrel group and in 8.1% of those on placebo. This represents a highly significant 7% relative risk reduction favoring clopidogrel, reported principal investigator Zhengming Chen, M.D., of the University of Oxford (England).

The other primary outcome was the combined rate of death, repeat MI, or stroke within 28 days. The rate was 9.3% in the clopidogrel arm and 10.1% with placebo, for a significant 9% relative risk reduction. Rates of major cerebral and noncerebral in-hospital bleeding, at just over 0.5%, were not significantly increased with clopidogrel.

Clopidogrel showed a consistent benefit regardless of patient gender, age, or use of thrombolytic therapy.

The main difference between the clopidogrel regimens in CLARITY and COMMIT was the use of a loading dose in CLARITY in order to achieve a more rapid antiplatelet effect. Nevertheless, a significant outcome benefit was seen with the 75 mg/day used in COMMIT even on the day of randomization.

COMMIT showed that, on average, roughly 2 weeks of clopidogrel produced an absolute benefit of 10 fewer deaths, repeat MIs, or strokes per 1,000 treated patients, with no increased risk of bleeding. Among the 12,000 participants aged 75-100 years, the absolute benefit was even greater, at 13 fewer events per 1,000 participants.

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.

"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."

Clopidogrel has been somewhat controversial, said Michael J. Bresler, M.D., director of the department of emergency medicine at Mills-Peninsula Health Services in San Mateo, Calif., and clinical professor in the division of emergency medicine at Stanford University.

It costs more than aspirin, although much less than other antiplatelet agents such as glycoprotein Ib/IIIa inhibitors, he said, and a previous smaller study showed a significant increase in bleeding when clopidogrel was added to aspirin.

The net clinical benefit, however, has been felt by many experts to be worth the added risk of bleeding, Dr. Bresler said. These two new larger studies, however, did not demonstrate any increased bleeding risk, he noted.

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. Dr. Bresler is on a presenters panel that receives funding from the two companies. COMMIT was funded by those companies along with AstraZeneca, the British Heart Foundation, and the U.K. Medical Research Council.

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