Clopidogrel (Plavix®) responses appear normal in largest data set

Although individual patients respond differently to treatment with the anti-platelet medication clopidogrel (brand name Plavix®), those variations appear normal and may not indicate important differences in the effectiveness of treatment, according to a new study (PDF file) in the Jan. 18, 2005 issue of the Journal of the American College of Cardiology.

“There is nothing unique about clopidogrel, that’s the whole message, in terms of response variability. As with any agent, there are certain people who respond a lot and certain people who respond not a lot. But when you collect large numbers, you see that most people have a normal response, the vast majority have a very nice anti-platelet response on clopidogrel,” said Victor L. Serebruany, MD, PhD, at the HeartDrug Research Laboratories in Towson, Maryland.

In order to investigate reports that some patients were not responding to treatment intended to prevent heart attacks or strokes caused by blood clots, Dr. Serebruany and colleagues at the University of Kentucky in Lexington; Duke Clinical Research Institute in Durham, North Carolina; and the Cleveland Clinic in Ohio analyzed data they had collected over more than seven years during a variety of studies of clopidogrel.

“People started claiming enormously important clinical conclusions, which were based on very vague and very uncertain things,” Dr. Serebruany said.

The data included the results of blood tests that measured how blood platelets aggregated, or clumped together, following treatment with clopidogrel. The study subjects were 94 healthy volunteers, 405 patients treated after coronary stenting, 25 patients with heart failure, and 20 patients treated after strokes. Out of the 544 subjects, 23 (4.2 percent) had a much higher than normal response, while the blood of 26 (4.8 percent) subjects showed very little change in platelet aggregation despite clopidogrel treatment.

An abnormally strong response (hyperresponse) to clopidogrel could raise the risk of bleeding, while a lack of response (hyporesponse) may mean a patient is not adequately protected against dangerous blood clots. However, Dr. Serebruany emphasized that this study did not look at actual health outcomes, and that a low or high response to this laboratory blood test does not necessarily mean a patient is not getting the appropriate benefit from clopidogrel. In addition, he noted that this report was based on combining data from different types of patients and healthy volunteers in studies that were not designed to look at variations in platelet response; so important questions remain to be answered.

“A trial to prove or disprove that certain platelet characteristics have an association with better or worse clinical outcomes absolutely must be done,” he said.

Nevertheless, Dr. Serebruany stressed that large trials involving thousands of patients have demonstrated that clopidogrel can prevent heart attacks, strokes and deaths; so it is premature to alter patient treatment based simply on tests of platelet response.

“There is no reason for people to switch drugs. There have been some anecdotal reports that because of certain platelet measures people were diagnosed with so-called clopidogrel resistance and so then were switched to an earlier drug, Ticlid® (ticlopidine). However, we know that Ticlid is associated with a more toxic side effect profile,” he said. “You certainly should monitor your health; and if you have any bruises or bleeding you should consult with your doctor.”

Pål Aukrust, M.D., Ph.D., at the National Hospital, University of Oslo, Norway, who was not connected with this study, agreed that it is important to investigate whether platelet responses are related to health outcomes.

“Future research will have to clarify if hyporesponders and hyperresponders really are at increased risk for thrombotic and bleeding episodes, respectively. Moreover, more suitable and rapid tests for platelet responsiveness, being able to be performed within minutes or hours, will have to be developed. Finally, such different responsiveness to medications most probably also applies to other anti-platelet drugs and other types of drugs. To identify hyperresponders and hyporesponders will be an important task for future research in clinical medicine. Such research can potentially lead to more ‘tailor-made’ medication for each individual,” Dr. Aukrust said.

Ehtisham Mahmud, M.D., at the University of California in San Diego, who also was not connected with this study, called the study an important step toward investigating what has been called “clopidogrel resistance.”

“This term has come to be used rather freely without any data supporting it. The current study is a first step in the right direction and based on the results of the study it appears that there is a heterogeneous antiplatelet response to treatment with clopidogrel. And rather than clopidogrel resistant, patients may in fact be clopidogrel hyporesponders. Though the term is arbitrary, it does have a physiological basis,” Dr. Mahmud said.