The current study represents a two-year follow-up of an original aspirin-resistance study first published in 2001 and showing 5% of 326 patients to have evidence of aspirin resistance, as measured by optical platelet aggregation.2 For the follow-up study, Gum et al performed telephone interviews, backed up by medical chart reviews and queries of the social security death index, to confirm rates of death, MI, and CVA, the combined primary end point of the study.

The investigators report that the composite primary outcome was significantly higher in patients determined to be aspirin resistant at baseline, compared with aspirin responders. Of the 17 patients with aspirin resistance (aspirin nonresponders), four (24%) died or had an MI or a CVA, compared with 30 of 309 (10%) of aspirin responders. When individual end points were assessed in both groups, nonresponders showed a trend toward worse outcomes, but these did not reach statistical significance.

In multivariate analyses, aspirin resistance proved to be a significant independent predictor of longer-term adverse events, with a hazard ratio of 4.14.

"The work of Gum et al indicates that failure to achieve an anticipated effect of aspirin on a laboratory measure of platelet aggregation, which is present in about one in 20 high-risk patients, is an independent predictor of future risk of serious vascular events," Drs John W Eikelboom and Graeme J Hankey write in an accompanying editorial.3 Eikelboom and colleagues have previously demonstrated a link between aspirin resistance, as measured by increasing levels of urinary 11-dehydro thromboxane B2 generation, and risk of future MI, stroke, and CV death, in a HOPE trial substudy, as reported by heartwire.4

The Eikelboom study, in combination with Gum et al's findings, lays the groundwork for exploring the next key questions in aspirin resistance. As Gum described it to heartwire, "The first question was, does aspirin resistance exist? And I think that's indisputable at this point. The second question is, is aspirin resistance clinically important? I think with our study, along with Dr Eikelboom's study and other preliminary work, we are establishing that now. The third and most important question to the average citizen is, what do I do about it?"

Eikelboom and Hankey point out that a fundamental first step will be to standardize a definition of aspirin resistance, given the different tools and methods by which aspirin resistance is determined today. "A suitable definition of aspiring resistance should not only incorporate an absent or attenuated laboratory response to a therapeutic antiplatelet dose of aspirin in a compliant patients that correlated significantly and independently with its effects in preventing atherothrombotic vascular events," they propose, "it also requires a specific, accurate, and reproducible laboratory measure of the antiplatelet effects of aspirin, the results of which can be generalized to other laboratories and patients," they write.

Asked about the standardization issue, Gum told heartwire, "I would say that it's the biggest issue in aspirin resistance today. Anybody involved in the research of aspirin resistance is convinced that aspirin resistance is an important clinical diagnosis, but what we really are looking for is a standardization to measure it so that we can all agree on the diagnosis of it and be assured that what we are diagnosing has clinical relevance across the board."

What is needed to establish accepted standards, Gum said, are larger-scale studies using a bedside device to measure aspirin resistance and linking these measurements to clinical events. Studies comparing different aspirin-resistance-testing devices will also be required.

The problem here, of course, is study funding for an old drug, she noted. "Sponsorship will be an issue: Wal-Mart-brand aspirin does not have a financial incentive in this. Unfortunately this is one of those areas that is very important but difficult to fund."

The next question is how to act on a diagnosis of aspirin resistance, since there is no specific treatment for the condition, Eikelboom and Hankey point out. They propose that clinicians must first ascertain that the underlying cause of a vascular event in an aspirin-resistant patient is atherothrombotic disease. It is also important to confirm that the patient was taking aspirin as prescribed. At this point a clinician could consider alternative antithrombotic strategies, including clopidogrel, dipyridamole plus aspirin, or warfarin plus aspirin, they write.

Researchers also need to establish whether clopidogrel and potentially newer antiplatelet agents effectively "treat" aspirin resistance, or whether they provide added benefit in all patients, regardless of their response to aspirin.

"There have been studies that indicate that aspirin plus clopidogrel is beneficial in patients who have atherosclerotic disease, peripheral vascular disease, and cerebrovascular disease," Gum said. "And an important question is, is it beneficial because some of those people are aspirin resistant? If so, would we be better off specifically treating the people with aspirin resistance?"

In cardiology today, most people with cardiovascular disease are already getting a medicine cabinet's worth of drugs, Gum pointed out, including beta blockers, statins, ACE inhibitors, and aspirin. Ideally, physicians would prefer to give additional drugs only to the patients who need them.

"If we could figure out who benefits most from additional therapies, we would have better patient compliance, a lower side-effect profile, and from a cost standpoint it would be phenomenal," Gum said.