Clot-Preventing Drug Can Cause Potentially Fatal Blood Disorder

The disorder, which causes mass destruction of blood platelets, anemia, neurologic changes, including stroke, seizures and loss of consciousness, kidney failure and fever, almost always appears within two weeks of starting clopidogrel therapy.

Northwestern University researchers Charles L. Bennett, M.D., and Charles J. Davidson, M.D., and colleagues reported these findings today in an article in the online version of The New England Journal of Medicine (http://www.nejm.org). The findings were released online weeks before the print version of the article because of the important implications of the study for clinicians worldwide.

Ironically, clopidogrel was developed to be a less toxic, but chemically similar, replacement for ticlopidine, a first-generation antiplatelet drug that was found to cause TTP and other toxic reactions.

Bennett, a hematologist/oncologist and associate professor of medicine, and Davidson, a cardiologist and associate professor of medicine at Northwestern University Medical School, previously reported 98 cases of ticlopidine-associated TTP and 30 deaths, almost always following three months or less of ticlopidine therapy.

Clopidogrel, with over 3 million users since its launch in 1998, has replaced ticlopidine as one of the most popular antiplatet drugs today, Bennett said.

In the current study, Bennett, Davidson and several of the country's leading TTP investigators reported the cases of 11 patients age 35 to 70 with clopidogrel-associated TTP. Five patients also were given cholesterol-lowering drugs, including Lipitor® (Warner Lambert and Pfizer).

While all but one patient responded to plasmapheresis, a procedure that is similar to filtering the blood, two patients had to undergo the procedure 20 or more times and required almost a month in intensive care. Two other patients, including one who had received a cholesterol-lowering drug, had two recurrent episodes of TTP. One patient died after taking clopidogrel for five days.

Davidson, an interventional cardiologist, acknowledged that while the number of clopidogrel- associated TTP cases is small at this time, the group's findings raise concern that clopidogrel-related TTP may be hard to diagnose, can occur early after starting the drug therapy, can take as long as a month to treat and may be prone to relapse.

He cautioned that most cardiologists and neurologists have been unaware of the association of clopidogrel and TTP. He also raised concern that some individuals may have taken the drug and developed fatal, but unrecognized, cases of TTP. He said that prescribers of clopidogrel should closely monitor patients taking this drug, a practice that is rarely done today.

The Food and Drug Administration approved clopidogrel for use in 1998. Over 20,000 patients have received the drug on closely monitored clinical trials, and no cases of TTP were identified, leading clinicians to conclude that the drug is safe and monitoring patients is not necessary.

The 11 cases the researchers reported in The New England Journal of Medicine were obtained by active surveillance from blood banks, medical directors (three cases), hematologists who specialize in TTP care (six cases) and the pharmaceutical manufacturer of clopidogrel (two cases), using a system that was designed during the investigation of ticlopidine-associated TTP cases.

Bennett, with active support from Bristol Myers Squibb and Sanofi pharmaceuticals, the manufacturers of clopidogrel, currently is pursuing extending the active surveillance program to Europe to look for additional cases of clopidogrel-related TTP.

Bennett and Davidson reported in 1998 that TTP occurred in 1 in 1,600 persons who took ticlopidine, 100 times more frequently than in the general population, and carried a mortality rate of 33 percent.

Yet, ticlopidine-associated TTP was not widely recognized by cardiologists or neurologists until seven years after the drug had received FDA approval, even after being used by several million individuals, Davidson said.

Fortunately, with physicians being more aware of the possible diagnosis of TTP, regardless of its cause, and timely use of plasma exchange, the mortality rate is now in the range of 10 to 20 percent.

Bennett is the director of health services research at the Veterans Administration Healthcare System/Lakeside Division and a member of the Institute for Health Services Research and Policy Studies and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Davidson is the director of the interventional cardiology program at Northwestern Memorial Hospital.

Their collaborators on this study were from Harvard, Johns Hopkins, Indiana University, Case Western Reserve, Albert Einstein University, the University of Nebraska and Baylor University.

This study was supported in part by grants from the National Heart, Lung, and Blood Institute.