Patients who begin clopidogrel therapy after an acute coronary syndrome event appear to be at increased risk for myocardial infarction and death in the three months after discontinuing the drug, according to an article in the February 6 issue of the Journal of the American Medical Association.

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, MD, PhD, of the Denver Veterans Administration Medical Center, Denver, and colleagues assessed the incidence and timing of death or acute myocardial infarction after stopping treatment with clopidogrel in a group of 3,137 patients discharged from 127 Veterans Affairs hospitals.

Average follow-up after stopping treatment with clopidogrel was 196 days for medically treated patients with an acute syndrome event who were treated without stents (1,568 patients) and 203 days for patients who were treated with stents (1,569 patients).

Among medically-treated patients, average duration of clopidogrel treatment was 302 days. All-cause death (155 patients) or acute infarction (113 patients) occurred in 17.1 percent of patients, with 60.8 percent (163 patients) of events occurring during 0 to 90 days, 21.3 percent (57 patients) occurring during 91 to 180 days, and 9.7 percent (26 patients) 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 than the interval of 91 to 180 days.

Among stent-treated patients, average duration of clopidogrel treatment was 278 days. All-cause death (68 patients) or acute infarction (56 patients) occurred in 7.9 percent of patients, with 58.9 percent (73 patients) occurring during 0 to 90 days, 23.4 percent (29 patients) occurring during 91 to 180 days, and 6.5 percent (8 patients) 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 noted 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 acute coronary syndrome and discharged with post-hospital 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 concluded.