HARVARD GAZETTE ARCHIVES

The new therapy adds a fourth drug to the three-drug regimen that is frequently prescribed after a heart attack to break up clots that block arteries carrying the heart's critical blood supply. The addition of the fourth drug - an antiplatelet medication called clopidogrel, marketed commercially under the name Plavix - reduced the odds of a second heart attack by 31 percent and also reduced the odds of dying from heart-related causes and of needing emergency bypass surgery to restore blood flow to the heart.

The three drugs frequently given after a heart attack include a clot-buster, an anticoagulant, and an antiplatelet medication, typically aspirin.

The new treatment was tested in a large-scale clinical trial run by researchers at Harvard Medical School and Harvard-affiliated Brigham and Women's Hospital. The study's authors said the findings represent the first advance in clot-busting drug treatment for heart attack in more than 10 years that improves mortality.

The clinical trial, supported by a grant from Sanofi-Aventis and Bristol-Myers Squibb, the makers of Plavix, followed 3,491 men and women age 75 and younger who had suffered a heart attack. The trial was conducted at 319 sites in 23 countries.

Trial subjects were treated with the standard clot-busting treatment and aspirin within 12 hours of the heart attack. They then either received clopidogrel or a placebo for the remainder of the trial.

Marc S. Sabatine, an instructor of medicine at Harvard Medical School and associate physician in Brigham and Women's Cardiovascular Division, presented the results this week at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla. Results were also published in the New England Journal of Medicine online on Wednesday (March 9), and are scheduled to be published in the March 24 print issue.

"We have demonstrated that the addition of clopidogrel to standard therapy in patients experiencing an acute myocardial infarction [heart attack] significantly increases the odds of having and maintaining an open coronary artery," Sabatine said. "Clopidogrel offers an effective, simple, inexpensive, and safe means by which to improve reperfusion [restoration of blood flow] and prevent further damage to the heart in these high-risk patients."

Heart attacks are caused by the reduction of blood flow to the heart because of a partially or completely blocked artery. Heart attacks affect 10 million patients worldwide each year, of whom 4 million have a completely blocked coronary artery that requires clot-busting medication or angioplasty, a procedure where a tiny balloon is inserted into the blocked blood vessel and expanded to break up the blockage.

Of those receiving treatment with clot-busting medication, 20 percent to 25 percent still have a blocked artery and are at continued risk of death from a heart attack.

Though bleeding is a concern with antiplatelet medications such as aspirin, the rate of major bleeding in the clopidogrel group was 1.3 percent, similar to the 1.1 percent in the placebo group. The addition of clopidogrel did not increase the risk of intracranial hemorrhage, a rare but dreaded complication of clot-buster therapy and a limiting factor in prior attempts to improve therapy to restore blood flow.

"Patients with acute myocardial infarction (MI) have the highest rate of morbidity and mortality of all patients suffering from atherothrombotic coronary artery disease. Despite treatment with standard fibrinolytic [clot-buster] regimens, many patients still have a blocked artery, putting them at double the risk of death," said the study's senior author, Brigham and Women's Hospital's Eugene Braunwald, Distinguished Hersey Professor of Medicine at Harvard Medical School and chairman of the TIMI Group. "The results of the ... trial constitute a significant step forward in MI management."

Research from a second trial using clopidogrel in patients with acute heart attacks, also presented at the ACC annual meeting, supported the Brigham and Women's Hospital-led results. That trial, involving 46,000 patients, demonstrated a clear survival benefit with the use of clopidogrel.

"These new studies build on prior trials to show that clopidogrel therapy can benefit essentially all types of patients coming to the hospital, including those who have experienced an acute heart attack," said the study's principal investigator, Associate Professor of Medicine Christopher P. Cannon of Brigham and Women's Hospital. "The addition of clopidogrel marks the first addition to fibrinolytic [clot-buster] regimens in more than a decade that improves outcomes and mortality for heart attack patients."