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Aspirin Resistance N = 17

No Aspirin Resistance N = 309

Fig. 8. Excess of serious vascular events among aspirin-resistant patients compared with nonaspirin-resistant patients (53). OR, odds ratio.

definitions of aspirin resistance have varied according to the platelet function tests and platelet agonists used. As a consequence, the range ofaspirin resistance that is quoted varies widely, from 5 to 40% (50). Platelet aggregation by light transmittance (optical aggrego-metry) in PRP is the gold standard method, with aspirin resistance often defined as mean aggregation ©70% in response to 10 pM ADP. However, it is difficult to assess which aggregation technique is the most accurate and valid measure of aspirin resistance without direct comparisons of their clinical relevance.

Aspirin Resistance and Outcomes

In patients with a prior stroke, those with aspirin resistance were 89% more likely to have a recurrent cerebrovascular event within 2 yr than were responders (51). Similar results were seen in patients after peripheral intervention, with an increase in arterial reocclusion among aspirin responders (52). More recently, three separate and well-conducted studies support an association between aspirin resistance and worse clinical outcome in patients with stable coronary artery disease (53-55).

In 2001, Gum et al. (18) reported that 5.5% of a small series of patients with a prior history of coronary or cerebral vascular disease were aspirin resistant. Aspirin resistance was defined as the failure of 325 mg/d of aspirin given for a minimum of 7 d before testing to suppress agonist-induced platelet aggregation, as measured by optical platelet aggrego-metry. The cutoff for the diagnosis of aspirin resistance was derived from screening 40 in-house healthy samples, but details as to how this cutoff was chosen were not provided. After 2 yr of follow-up, they reported that aspirin resistance was associated with a fourfold excess of serious vascular events, which was independent of age, gender, and conventional vascular risk factors (Fig. 8). In addition, this failure to achieve an anticipated effect of aspirin on a laboratory measure was found to be an independent predictor of future risk of serious vascular events.

Baseline aspirin responsiveness in this same patient population was also determined with the PFA-100 (18). The k statistic between these two methods was 0.1 (95% confidence interval: 0.045-0.246), indicating a poor correlation between optical platelet aggregation and the PFA-100 in detection of aspirin resistance. There was a nonsignificant correlation

Fig. 9. Association between quartiles of 11-dehydro TXB2 and outcomes after adjustment for baseline differences between cases and control subjects (p value is for difference between upper and lower quartiles) (54).

between long-term outcomes and baseline aspirin responsiveness as determined by the PFA-100 (12.9% events in aspirin sensitive vs 15.1% in aspirin resistant; p < 0.4). This suggests that the PFA-100 is not as specific compared with optical platelet aggregation for determining clinically relevant aspirin resistance (53,56). However, a real association may have been missed by the small number of events. In addition, the PFA-100 does not provide a specific measure of the antiplatelet effects of aspirin and may lack sensitivity for measuring the antiplatelet effects of low-dose aspirin (57).

Using patients who were taking aspirin from the Heart Outcomes Prevention Evaluation study, Eikelboom et al. (54) measured baseline urinary TXB2, which serves as a marker ofthromboxane generation. Levels were compared between those patients taking aspirin who sustained an ischemic event and those who did not sustain an event. Those in the highest quartile of urinary thromboxane generation had twice the risk of an MI than those in the lowest quartile (Fig. 9). The researchers concluded that the incomplete suppression of thromboxane generation by aspirin—i.e., aspirin resistance—was the cause of the increased risk. However, because the concentration of TXB2 in the urine reflects both platelet and nonplatelet sources of thromboxane generation, this analysis may not provide a specific measure of the antiplatelet effects of aspirin. Furthermore, the predictive value of TXB2 in an individual patient has not been demonstrated and requires further evaluation.

More recently, using the RPFA assay, Chen et al. (55) categorized patients as either aspirin sensitive or aspirin resistant and measured the incidence of myonecrosis after elective percutaneous coronary intervention (PCI) (Fig. 10). By this classification, 19.2% of patients were aspirin resistant. Patients determined to be aspirin resistant were more likely to have periprocedural myonecrosis, highlighting that if a patient about to undergo PCI is determined to be aspirin resistant, some attempt should to be made to intensify anti-platelet therapy.

Remaining Issues

There are several issues regarding aspirin resistance that still need to be addressed. First, existing laboratory measurements of the antiplatelet effects of aspirin are limited. Researchers need to determine which measure is the most relevant. Second, a standardized

Fig. 10. Incidence and magnitude of creatine kinase-myocardial band (CK-MB) and cardiac troponin I (cTnl) elevation in aspirin-resistant and aspirin-sensitive patients after PCI (55). ASA, aspirin.

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