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Combination therapy benefits those with unstable angina

The results of the CURE trial, reported at the recent American College of Cardiology meeting, have some important implications for the large number of patients who suffer from ACS or acute coronary syndrome (unstable angina or non-Q wave MI). When taken in combination with aspirin, study subjects who took clopidogrel enjoyed a 20 percent reduction in heart attack, stroke and coronary disease-related deaths. This benefit was in addition to the benefit aspirin alone provides, as well as other standard therapies such as beta blockers and cholesterol-lowering drugs. These are very important findings.

Acute coronary syndrome (ACS)
ACS affects millions of people. In the U.S. alone, 1.5 to 2 million patients present with ACS every year. About 10 percent of these patients experience recurrent chest pain or a heart attack within 30 days of discharge from the hospital even though they are being treated with contemporary medications.

ACS is characterized by recurrent or prolonged chest pain that can occur either with minimal exertion or at rest. The chest pain or angina is a result of insufficient blood supply and blood clots in the coronary arteries and may lead to heart attacks. Researchers have been trying a variety of formulations to block this clotting mechanism.

Blocking the clotting mechanism
Aspirin is one very effective way to block the clotting mechanism, and clopidogrel, like aspirin, prevents components of the blood, known as platelets, from sticking together; but it does it in a different way, so combining the two drugs produces an additive benefit.

This is good news for patients and physicians who treat people with heart disease. It is particularly significant for patients who are aspirin resistant. About 10 percent of all Americans and 25 percent of Asian Americans do not experience the anticlotting benefits of aspirin, but they may benefit from clopidogrel.

The CURE study
Since the study has not yet been published, we don't have all of the data; but preliminary indications are very positive. This was the largest study of ACS patients, including more than 12,500 individuals. Half received standard therapy, which includes aspirin (75-325 mg per day), and the other half received the same standard therapy plus clopidogrel. Patients were given an initial dose of 300 mg of clopidogrel followed by a daily dose of 75 mg per day. In the control group, death, stroke and heart attacks occurred in 11.47 percent compared to 9.28 percent in the group who received clopidogrel, a relative risk reduction of 20 percent. Heart attacks were reduced by 23 percent, strokes by 15 percent.

A benefit could be measured within two hours of taking the drugs, and the benefit continued for the length of the study. There could be an additional benefit beyond that period, but we'll need additional research to determine that.

Side effects
Like aspirin, clopidogrel can cause bleeding. Of the 6,303 control patients who took aspirin alone, 1.8 percent experienced a life-threatening bleed, compared to 2.1 percent in the aspirin plus clopidogrel group. This is considered a statistically insignificant increase in risk, but minor bleeding increases were higher—8.6 percent in the aspirin group and 15.3 percent in the combination therapy group. Minor bleeds are those that occur at the site of an IV or catheter insertion and are easily treated.

The study's lead researcher, points out that treating 1,000 patients with clopidogrel and aspirin for nine months prevents 28 major events in 23 patients at a cost of three life-threatening bleeds.

Also, 1,500 study patients underwent coronary bypass surgery. As expected, bleeding rates increased in both the aspirin-alone and the aspirin-clopidogrel group, but there was no additional bleeding risk in the aspirin-clopidogrel group.

The bottom line
Aspirin is a wonderful drug for people with ACS, reducing adverse events by 25 to 50 percent; but even with aspirin, 10 to 15 percent of patients have a heart attack or die within one year and 20 percent of patients are readmitted to the hospital. The addition of clopidogrel offers patients an even greater benefit. Patients with ACS need to talk to their physicians about whether this drug should be added to their regimen.

Barriers to treatment, including costs and bleeding risks, need to be assessed for each individual patient. Clopidogrel is particularly important to consider for those at high risk such as patients with diabetes, those who are aspirin resistant and patients who have suffered recurrent bouts of severe angina or minor heart attacks in spite of ongoing treatment.

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Dr. Mukherjee is a partner with Cardiology Associates of New Haven, an attending physician at Yale-New Haven Heart Center and an assistant clinical professor of medicine and cardiology at the Yale School of Medicine.