Despite continuing improvements in treatment and prevention, atherosclerotic coronary artery disease (CAD) remains the single most important cause of mortality in all industrialized nations.

Percutaneous coronary intervention (PCI) is one of the most frequently used treatments for this condition. The procedure is performed in approximately 5 million patients worldwide every year. Clopidogrel, along with aspirin, is part of routine treatment for all patients who undergo PCI today, but it typically limited to short-term therapy of only 2 to 4 weeks.

Until recently, physicians have not fully appreciated the long-term high risk of atherosclerotic events in patients who receive percutaneous intervention. The first randomized trial to evaluate the effect of long-term clopidogrel treatment in a PCI population is Clopidogrel for the Reduction of Events During Observation (CREDO).

99 hospitals in the United States and Canada participated in this double blind, randomized trial. Investigators evaluated extended clopidogrel therapy in the prevention of long-term thrombotic events of a PCI population. They randomized 2,116 patients from the United States and Canada to a treatment arm or placebo.

The treatment arm included a 300 mg loading dose of clopidogrel 3 to 24 hours before the procedure, while the control arm received placebo. Both groups received clopidogrel and aspirin at the time of the procedure and for 28 days after that. Then, the treatment arm continued on clopidogrel and aspirin for a total of 1 year of treatment, while the control group received placebo and aspirin for the same time period.

The primary outcome measure was the composite rate of death, myocardial infarction or stroke. In this patient population, investigators reported a 27% relative reduction in risk of death, myocardial infarction or stroke among the patients who received long-term clopidogrel therapy (p=0.02).

This represented a 3% absolute reduction in risk, from 11.5% to 8.5%. Importantly, the benefit occurred in all subgroups studied. This included women vs. men, diabetics and non-diabetics, patients with acute coronary syndromes and those without, and patients who received glycoprotein IIb/IIIa inhibitors at the time of the procedure, and those who did not.

In addition, the degree of benefit in the combined endpoint was nearly identical to the benefit seen in the individual endpoint components. There was a relative risk reduction of approximately 25% for rate of death, myocardial infarction and stroke.

There was no difference between groups in incidence of minor bleeding. However, there was a non-significant trend toward an increase in major bleeding. Almost all of the major bleeding occurred in patients who had an invasive procedure. About 4% of patients in both clopidogrel and placebo groups received a coronary artery bypass graft. Over half of all patients undergoing bypass had a diagnosis of major bleeding.

Dr. Steinhubl said the clinical implications of these results are potentially enormous. If physicians applied these results to the millions of patients who undergo percutaneous intervention, clopidogrel could save patients from 50,000 heart attacks, strokes or deaths each year. In addition, even longer treatment with clopidogrel could lead to even greater benefit.