Halting Plavix can create adverse effects. Source: Bloomberg

Among patients with ACS medically treated or PCI-treated, a clustering of adverse events in the initial three months after stopping clopidogrel (Plavix) can occur, supporting the possibility of its rebound effect, according to a study published in the Feb. 6 issue of the Journal of the American Medical Association.

P. Michael Ho, MD, PhD, of the Denver VA Medical Center in Denver, and colleagues, said they undertook the trial because it is unknown whether patients are at increased short-term risk for adverse events following clopidogrel cessation. They sought to assess the rates of adverse events after stopping treatment with clopidogrel in a national sample of patients with ACS.

The researchers noted that the study did not address how long clopidogrel may safely be taken. The current indication is that it should be administered for nine months after a heart attack, and 12 months after a stent is implanted

Plavix is the world's second-biggest selling drug, generating $1.37 billion in the fourth quarter of 2007, only second to Pfizer’s cholesterol pill Lipitor. Plavix is the current gold-standard anti-platelet therapy for post-PCI patients. Prasugrel from Eli Lilly and Daiichi Sankyo, the only potential U.S. competitor, is currently awaiting approval since their FDA submission in mid-January.

In this retrospective cohort study, researchers examined 3,137 patients with ACS discharged from 127 Veterans Affairs hospitals between Oct. 1, 2003, and March 31, 2005, with post-hospital treatment with clopidogrel. 

The primary outcome measure was the rate of all-cause mortality or acute MI (AMI) after stopping treatment with clopidogrel.

The mean follow-up after stopping treatment with clopidogrel was 196 days for medically treated patients with ACS without stents (1,568 patients) and 203 days for patients with ACS treated with PCI (1,569 patients), the authors wrote.

Among medically treated patients, Ho and colleagues said the mean duration of clopidogrel treatment was 302 days and death or AMI occurred in 17.1% of patients, with 60.8% of events occurring during day one to three months, 21.3% during 91 to 180 days, and 9.7% during 181 to 270 days after stopping treatment with clopidogrel.

In a multivariable analysis including adjustment for duration of clopidogrel treatment, the researchers said the first three-month interval after stopping treatment with clopidogrel was associated with a significantly higher risk of adverse events (1.46-2.69 vs. the interval of 91-180 days).

Similarly, among PCI-treated patients with ACS, the mean duration of clopidogrel treatment was 278 days and death or AMI occurred in 7.9% of patients, with 58.9% of events occurring during the first day to three months, 23.4% during 91 to 180 days, and 6.5% during 181 to 270 days after stopping clopidogrel treatment, the researchers said.

In multivariable analysis including adjustment for duration of clopidogrel treatment, the researchers found that the first three-month interval after stopping clopidogrel treatment was associated with a significantly higher risk of adverse events.

“Even though the absolute rates were low, the relative increase in adverse events in the early period after stopping treatment with clopidogrel was nearly twofold higher than later periods,” the authors wrote.

However, the researchers said that additional studies are needed to confirm the clustering of events after stopping clopidogrel, including associations with cardiovascular mortality and reasons for stopping clopidogrel, as well as to determine the mechanism of the phenomenon and to identify strategies to reduce early events after clopidogrel cessation.