Patients who take aspirin but are resistant to its antiplatelet action have a higher risk for myocardial infarction, stroke, or death, according to an article in the March 19th issue of the Journal of the American College of Cardiology.

"Probably there has been no medicine that has had a greater impact in our field than aspirin, but we took for granted that it worked in everyone," said Eric Topol, M.D., senior investigator. The correlation between drug resistance and higher risk for an adverse cardiac outcome during 2 years of follow-up indicates that some patients do not get any benefit from aspirin therapy because even at relatively high doses the drug does not inhibit platelet activity. This apparently inherent resistance to drug action is an important example of pharmacogenomics, the growing study of individual variations in responses to medications.

"We have to increasingly appreciate that aspirin resistance is real and not turn our backs on it," Dr. Topol said. "And we need to hunt this thing down: the cause, the specific ways to more rapidly screen for it, find its genetic basis, which is only a theory at the moment; and protect these patients. They are taking aspirin, but they are not deriving benefit from it. So there are a lot of people out there who have the illusion of being protected by aspirin."

The American researchers enrolled 326 patients between January 1997 and September 1999 who had a history of cardiovascular disease but were stable at time of enrollment. Based on blood tests performed after each patient had been taking 325 mg aspirin for at least a week, 17 patients (5.2 percent) were considered resistant to the antiplatelet effect of aspirin. During an average follow-up period of almost 2 years, aspirin resistant patients were more than 3 times as likely to die or have a myocardial infarction or stroke (24 percent versus 10 percent among patients considered aspirin responsive, producing a hazard ratio of 3.12).

"And we saw this pattern over time, that the patients had a more than 3-fold risk of major events, if they were among the individuals who were unresponsive to aspirin," Dr. Topol said. He added that based on more recent work, he estimates that about 1 in 10 patients on aspirin therapy is resistant; and hence at higher risk for myocardial infarction or stroke. "Obviously there are many implications of this finding. Should we be more aggressive in screening for aspirin resistance? What should we do when we encounter it? What is the precise cause? Is it a genetic defect? There's a lot more work to be done, but this study sets the foundation for further work."

At present it is neither easy nor inexpensive to screen for aspirin resistance or prescribe alternative medicines. Conventional tests are inconvenient for clinicians, while newer screening methods are still under evaluation. If aspirin resistance is related to a genetic mutation, an inexpensive genetic screening test might be possible, but first researchers would need to find the responsible gene.

"There are other ways to treat platelets so they don't develop blood clots. For example, clopidogrel, the trade name is PlavixR, is out there as an alternative. It's considerably more expensive, but it would be something to consider if we had a patient who was proven to be aspirin resistant who had significant risk," Dr. Topol said. He noted that aspirin therapy costs just pennies per day, whereas clopidogrel treatment can cost 2 or 3 dollars per day.

Dr. Topol added that more than 20 million Americans currently take aspirin to prevent adverse cardiovascular events, so identification of aspirin resistant patients and transition to alternative medicines would be expensive. "Our hope for the future is that we will develop these rapid means to detect aspirin resistance and that we'll have other alternatives that are less expensive."

Dr. John Eikelboom, who also has researched aspirin resistance but was not part of the current study team, coauthored an editorial for the journal on the significance of aspirin resistance. "It has long been suspected that some patients may be relatively resistant to the antiplatelet effects of aspirin," Dr. Eikelboom wrote. He said the new study "is important because it confirms, in a prospective study, an association between a commonly available marker of aspirin resistance (optical platelet aggregation) and clinical outcome."

"Nevertheless, important questions remain," Dr. Eikelboom said. "We still do not know how aspirin resistance should be best defined, how it should be diagnosed, and what treatments should be used in patients who may be resistant to aspirin." Until those questions are answered, he noted, "We must continue to prescribe aspirin to all patients who are eligible: that is, those at high risk of future cardiovascular events."