Patients Appear to Be at Increased Risk of Adverse Events Within 3 Months After Stopping Clopidogrel Therapy for Acute Coronary Syndrome

CHICAGO, Feb. 5, 2008—Patients who receive the anti-platelet medication clopidogrel following an acute coronary syndrome (such as heart attack) appear to be at greater risk of a heart attack or death in the first 90 days after stopping clopidogrel treatment, according to a study in the February 6 issue of JAMA.

Randomized trials have established the effectiveness of clopidogrel therapy following hospitalization for acute coronary syndrome (ACS) for patients treated either medically or with percutaneous coronary intervention (PCI - procedures such as balloon angioplasty or stent placement used to open narrowed coronary arteries). Current cardiology guidelines recommend clopidogrel therapy for ideally up to 1 year for patients treated medically or with a bare metal stent, according to background information in the article. It is unknown whether there may be a "rebound effect" or concentration of thrombotic events shortly after stopping treatment with clopidogrel, as has been found for patients after long-term aspirin therapy.

P. Michael Ho, M.D., Ph.D., of the Denver VA Medical Center, Denver, and colleagues assessed the incidence and timing of death or acute myocardial infarction (AMI; heart attack) after stopping treatment with clopidogrel in a group of 3,137 patients with ACS discharged from 127 Veterans Affairs hospitals. Average follow-up after stopping treatment with clopidogrel was 196 days for medically treated patients with ACS without stents (n = 1,568) and 203 days for patients with ACS treated with PCI (n = 1,569).

Among the medically-treated patients, the average duration of clopidogrel treatment was 302 days. The researchers found that all-cause death (n = 155) or AMI (n = 113) occurred in 17.1 percent (n = 268) of patients, with 60.8 percent (n = 163) of events occurring during 0 to 90 days, 21.3 percent (n = 57) occurring during 91 to 180 days, and 9.7 percent (n = 26) occurring during 181 to 270 days after stopping treatment with clopidogrel. Further analysis indicated that the interval of 0 to 90 days was associated with nearly twice the risk of adverse events after stopping treatment with clopidogrel compared with the interval of 91 to 180 days.

Among the PCI-treated patients, average duration of clopidogrel treatment was 278 days. All-cause death (n = 68) or AMI (n = 56) occurred in 7.9 percent (n = 124) of the patients, with 58.9 percent (n = 73) of the events occurring during 0 to 90 days, 23.4 percent (n = 29) occurring during 91 to 180 days, and 6.5 percent (n = 8) occurring during 181 to 270 days after stopping treatment with clopidogrel. After adjustment for total duration of clopidogrel treatment following hospital discharge, the interval of 0 to 90 days after stopping treatment with clopidogrel was associated with an 82 percent increased risk of adverse events compared with the interval of 91 to 180 days.

The authors write that there is in vitro and physiological evidence to support a short-term increase in platelet activation and associated thrombotic risk immediately after stopping antiplatelet therapy.

"There are several potential implications of this study. Even though the absolute event rates were low, the relative increase in adverse events in the early period after stopping treatment with clopidogrel was nearly 2-fold higher than later periods. In addition, the absolute number of adverse events attributable to this event clustering is significant when extrapolated to a population level, considering the number of patients admitted with ACS and discharged with posthospital treatment with clopidogrel therapy both in the United States and worldwide."

"These findings, however, do not necessarily offset the benefits of clopidogrel therapy. Rather, additional studies are needed to confirm the presence of the event clustering after cessation of clopidogrel and to better understand the pathophysiology of this phenomenon. If these findings are subsequently confirmed, guideline recommendations may need to be reconsidered in terms of duration of clopidogrel therapy and perhaps the means of drug cessation," the researchers conclude.
(JAMA. 2008;299[5]:532-539. Available pre-embargo to the media at www.jamamedia.org)

Editor's Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

For More Information: Contact the JAMA/Archives Media Relations Department at 312/464-JAMA (5262) or email: mediarelations@jama-archives.org .

Posted: February 2008


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