Some heart attack patients may be resistant to blood thinner

American Heart Association
Monday, 7 June 2004

A substantial proportion of heart attack patients may be resistant to the blood thinner clopidogrel and face an increased risk of recurrent blockages, researchers report in today's rapid access issue of Circulation: Journal of the American Heart Association.

Researchers studied clopidogrel, a commonly used drug that helped prevent blood clotting in 60 patients, average age 58, who were treated with angioplasty and stenting after heart attacks.

All patients received chewable aspirin throughout the study. They got an initial high dose of 300 milligrams of clopidogrel after angioplasty and received smaller doses of 75 mg for three months.

"This is the first study to find an association between clopidogrel resistance and cardiovascular risk," said Hanoch Hod, M.D., senior investigator of the study and director of the Intensive Coronary Care Unit Heart Institute, Sheba Medical Center in Israel.

Shlomi Matetzky, M.D., is the lead author and principal investigator of the study.

Patients were examined at clinics three and six months after hospital discharge. Patients confirmed drug therapy compliance via telephone calls one month after discharge and again at the first clinic visit.

Clopidogrel resistance was measured by a platelet aggregation tests. Platelets are disk-shaped blood components that clump together to form blood clots. Patients who are resistant to clopidogrel will have a higher score for platelet aggregation.

Patients were split into four groups based on inhibition of platelet activity after six days of treatment compared to platelet activity before the blood-thinning drug was administered. Patients in quartiles two through four had varying levels of response, with levels of 69 percent, 58 percent and 33 percent of baseline values.

During the six-month follow-up, seven patients in quartile one (non responders) had eight recurrent blockages and eight had clinical events, including stent thrombosis and myocardial infarction. None of the patients in quartiles three or four had recurrent events.

"We were surprised by the extent of the clinical impact of clopidogrel resistance on the course of these patients," Hod said. "This study suggests that patients might benefit from more frequent evaluation and monitoring of platelet activity soon after a cardiac event."

The study found that patients with recurrent blockages were older and had higher Killip Class upon admission and a lower-percent reduction of clotting as early as the third day of treatment.

Killip Class is a scoring method used for patients who have suffered heart attack. It is based on the existence of signs and symptoms of heart failure.

"The only difference we found between patients' characteristics was a lower incidence of smokers in the fourth quartile," Hod said.

This finding might suggest that individual variability in response to clopidogrel is related to how the liver enzymes convert clopidogrel to its active form," Hod said.

Researchers noted limitations to the study. "The current study is an observational one and of a relatively small sample size, and therefore does not allow for definitive conclusions," Hod said.

"The question of whether increased doses of clopidogrel might overcome this resistance in non-responsive patients warrants further investigation."

Stephen Wiviott, M.D., and Elliott Antman, M.D., investigators in the TIMI Study Group, Cardiovascular Division at Brigham and Women's Hospital in Boston, reviewed the findings and wrote in an editorial for Circulation that the study adds "a new and important piece to the emerging clopidogrel resistance picture." They comment, "To allow these observations to improve the care of patients, therapies must be found that can overcome this resistance. One approach may be to treat with higher doses of clopidogrel, another may be to utilize alternate antiplatelet agents."

Hod's co-authors are Boris Shenkman, M.D., Ph.D.; Victor Guetta, M.D.; Michael Shechter, M.D.; Roy Bienart, M.D.; Ilan Goldenberg, M.D.; Ilya Novikov, Ph.D.; Hanna Pres, M.Sc.; Naphatali Savion, Ph.D.; and David Varon, M.D.

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