Issue 117 Item 15 Some Patients Resistant to Action of Aspirin

The response to aspirin is sub-optimal in many patients. Urinary concentrations of a thromboxane metabolite can be used to identify cardiovascular and diabetic patients who may be resistant to the antiplatelet action of aspirin, according to a study published in the April 9 issue of the journal Circulation. “This [discovery] should lead to studies to try and overcome aspirin resistance,” says John W. Eikelboom, lead author of the study and a senior clinical lecturer in the Department of Medicine at the University of Western Australia and a hematologist at Royal Perth Hospital.

Previous research had identified three possible explanations for the syndrome known as “aspirin resistance”: Platelets might be activated by pathways not blocked by aspirin, some patients may need doses of aspirin higher than the 75 mg to 325 mg currently used, or some patients generate thromboxane Alpha2 despite the aspirin doses.

Eikelboom and colleagues evaluated the third of these three options. Working with morning urine samples collected from 5,529 high-risk Canadians who participated in the Heart Outcomes Prevention Evaluation (HOPE) study, the researchers assessed whether failure of aspirin to suppress thromboxane generation increased the risk of cardiovascular events such as myocardial infarction and stroke. For patients who were aged 55 and over and had known coronary artery disease, peripheral vascular disease, or stroke, or diabetes and at least one coronary risk factor, the researchers measured urinary 11-dehydro thromboxane Beta2 levels, a stable metabolite of thromboxane Alpha2 whose urinary excretion reflects the extent of aspirin-mediated thromboxane inhibition. Aspirin-treated patients who had a confirmed myocardial infarction, stroke, or cardiovascular death after randomization were defined as cases, while other patients were controls.

In patients whose urinary excretion of 11-dehydro thromboxane Beta2 was increased, more cardiovascular events occurred. Those patients whose urinary levels fell into the highest quartile had 1.8 times as many cardiovascular events as those in the lowest quartile. These findings support the theory that aspirin resistance is a failure of suppression of thromboxane generation, the third possibility listed above. This raises the prospect that a pharmacogenetic test might someday be used to identify patients prone to aspirin resistance, but no such gene has yet been found.

This study could have two immediate effects on clinical practice. First, a clinical test may soon be available for detecting elevated urinary levels of thromboxane’s metabolite. Currently a test is available for use in research labs. Second, in patients who appear to be aspirin resistant or whose urinary levels are high, other antiplatelet agents such as clopidogrel may be used in addition to aspirin.

However, Eikelboom cautioned, until more tests are available and more studies conducted, the risks and concerns identified in the HOPE study should not cause patients to overhaul current therapies: “It’s vitally important that patients at risk for future cardiovascular events continue to take aspirin, as there are overwhelming data that aspirin is effective. What our article demonstrates is that the response to aspirin is suboptimal in many patients.”