Aspirin Resistance (Anti-Inflammatory Antithrombotic Effect) in Unstable Angina or Clinical Bias? A Pathophysiological Exploration of the Mechanisms of Higher Ischaemic Recurrence in Prior Aspirin Users in Unstable Angina

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Abstract

In the ENAI study (enalapril in unstable angina),a multicentre trial in 1,028 patients, those previously treated with aspirin had a worse outcome. Though this finding could be partially explained by a higher risk profile of the patients, the independent predictive value of previous use of aspirin for ischaemic recurrence in the multivariate analysis even in the subgroup without a coronary history, suggested a different pathophysiology, probably due to aspirin resistance. The mechanisms of this finding have not been explored. Recent findings showed that primary prevention of myocardial infarction with aspirin use is only seen in patients with initial high plasma levels of C reactive protein, but the interaction of aspirin and C reactive protein in unstable angina is unknown. Objectives To explore in unstable angina patients 1) the influence of prior aspirin use on plasma levels of markers of tissue injury (troponin), inflammation (C reactive protein) and thrombotic activity (PAI, tPA,D dimer, ATM, fibrinogen; 2) the interaction of prioraspir in use with predictive value of this markers. Methods Eighty seven patients were prospectively included in 8 centers. On admission, a blood sample was obtained and levels of the different markers were centrally analyzed. A combined clinical end point was defined (ischaemic recurrence [IRI defined as new anginal episodes with ECG changes, myocardial infarction [MI], need of urgent coronary surgery [CABG] or death) at 7 days after admission. Correlation of the plasma markers with the combined endpoint was analyzed in a double way: a) comparing plasma levels of the patients with or without coronary events, and b) evaluation of a cut-off point level for high risk through ROC curves analysis. The same analysis was repeated accord-ing to previous aspirin use. Univariate and multiple logistic regression analyses were performed. Results Thirty six patients (41.4%) were previous aspirin users (AAS+). A combined end point developed in38.9% of the AAS+ group and in 15.7% of AAS-,odds and 95% CI: 3.4 (1.11 to 10.7), p = 0.027. Patients in AAS+ group were older, with more coronary antecedents and higher previous use of betablockers. In the logistic regression analysis AAS+remained a significant predictor of worse evolution, but only when previous use of beta blockers was excluded from the model. Higher plasma lev-els of PAI, troponin, C reactive protein and D dimer were seen in patients with the combined end point. There was no influence of AAS+ and plasma levels of these markers:   _{p NS      PCR mg/dl    DIM nglml   TROPnglml     PAI ng/ml} AAS+     1.2±2        642 ±384   0.176±0.5    58.4 ±28 AAS±     0.89±1,8   577 ± 304  0.128±0.134 49.3 ± 2   With the ROC curve, cut off point levels were determined for D dimer >_ 850 ng/ml, odds for combined end point 3.3, 95% CI 1.1-10, and CRP ? 0.4 mg/dl, odds 3 (1.1-9), both p < 0.05. AAS+ were more likely to be included in the D dimer elevated lev-els group (odds 2, p = 0.1), but the odds for combined event for D dimer was similar in patients with or without AAS+. Odds for combined event in CRP groups was modified with AAS+: patients with elevated CRP levels and AAS+ odds 1.1 versus odds 13 with CRPT and AAS-, p interaction 0.05. Conclusions Prior aspirin use in patients with unstable angin awas associated with worse outcome in the univariate and multivariate analysis. 2) Prior aspirin use had a weak association with plasma levels of inflammatory activity, tissue injury and thrombotic activity, with a trend for higher levels of D dimer. (...)