The risk of myocardial infarction or death spikes during the 90 days after clopidogrel therapy is discontinued among patients treated for acute coronary syndromes, especially those treated medically.
Clustering of adverse coronary events has been reported after cessation of long-term aspirin and heparin therapy in acute coronary syndrome (ACS) patients. Dr. P. Michael Ho of the Denver Veterans Administration Medical Center and his associates assessed whether clopidogrel withdrawal was associated with a similar “rebound” effect.
The investigators analyzed data on all patients with acute MI or unstable angina who were discharged from any of 127 VA medical centers throughout the country between 2003 and 2005 with prescriptions for clopidogrel. A total of 1,568 of these patients who had been treated medically and 1,569 who had undergone PCI took the drug for a mean of 302 and 203 days, respectively, then discontinued the treatment.
In the medically treated patients, the combined end point of all-cause mortality or ACS occurred in 268 patients (17%) after they stopped taking clopidogrel. Significantly more (163) of those events occurred within 90 days of clopidogrel discontinuation than occurred at 91–180 days (57) or 181–270 days (26).
In PCI-treated patients, who took clopidogrel for an average of 278 days after their procedure, death or ACS occurred in 124 (8%) after discontinuation. As with the medically treated patients, significantly more of the primary end point events occurred within 90 days of cessation (73), compared with days 91–180 (29) and days 181–270 (8). Of the PCI-treated patients, almost two-thirds received bare metal stents, while the rest got drug-eluting stents.
“We found a clustering of death or acute MI in the initial 90-day period after stopping treatment with clopidogrel, compared with later follow-up intervals. These findings were consistent among patient subgroups including those who took shorter vs. longer durations of clopidogrel therapy, among patients with and without diabetes, as well as among PCI-treated ACS patients,” the researchers said.
The rate of adverse events was nearly twice as high immediately after stopping clopidogrel than it was during later periods. The rate was higher by far in the medically treated patients within 90 days of drug cessation, at 1.31 per 1,000 patient-days, than in those patients during days 91–180 (0.69) or in the PCI group during the same period (0.57).
The findings support the hypothesis that there is a rebound hyperthrombotic period after stopping clopidogrel therapy. Additional studies are needed to confirm the findings and to identify the underlying mechanism so that strategies to prevent or attenuate this effect can be devised, they added (JAMA 2008;299:532–9).
Extended clopidogrel therapy might avoid the rebound effect, or other approaches—tapering clopidogrel, “bridging” the cessation of clopidogrel with another antithrombotic drug, or using alternative antiplatelet agents instead of clopidogrel—might attenuate it, they said.
This study was funded by the U.S. Department of Veterans Affairs. One of Dr. Ho's associates receives research support from Bristol-Myers Squibb and Sanofi-Aventis, both of which market clopidogrel.