Aspirin failure, defined as occurrence of an acute coronary syndrome despite aspirin use, has been associated with a higher cardiovascular risk profile and worse prognosis. Whether this phenomenon is a manifestation of patient characteristics or failure of adequate platelet inhibition by aspirin has never been studied. We evaluated 174 consecutive patients with acute myocardial infarction. Of them, 118 (68%) were aspirin naive and 56 (32%) were regarded as having aspirin failure. Platelet function was analyzed after ≥72 hours of aspirin therapy in all patients. Platelet reactivity was studied by light-transmitted aggregometry and under flow conditions. Six-month incidence of major adverse coronary events (death, recurrent acute coronary syndrome, and/or stroke) was determined. Those with aspirin failure were older (p = 0.002), more hypertensive (p <0.001), more hyperlipidemic (p <0.001), and more likely to have had a previous cardiovascular event and/or procedure (p <0.001). Cumulative 6-month major adverse coronary events were higher in the aspirin-failure group (14.3% vs 2.5% p <0.01). Patients with aspirin failure had lower arachidonic acid–induced platelet aggregation (32 ± 24 vs 45 ± 30, p = 0.003) after aspirin therapy compared to their aspirin-naive counterparts. However, this was not significant after adjusting for differences in baseline characteristics (p = 0.82). Similarly, there were no significant differences in adenosine diphosphate–induced platelet aggregation and platelet deposition under flow conditions. In conclusion, our results suggest that aspirin failure is merely a marker of higher-risk patient profiles and not a manifestation of inadequate platelet response to aspirin therapy.
Although aspirin has been found to significantly decrease arterial thrombotic events, acute coronary events continue to occur despite aspirin use. This phenomenon, which has been termed “aspirin failure,” is associated with a higher cardiovascular risk profile including older age, a higher incidence of diabetes and hypertension, previous heart failure, and previous cardiovascular events and/or revascularization. Most previous studies have suggested that aspirin failure is a predictor of worse prognosis with a higher incidence of recurrent cardiac events, a need for urgent revascularization, and death. More recent studies, however, have failed to show an association between aspirin failure and worse prognosis. Because atherothrombosis is multifactorial, no cardiovascular drug can offer complete prevention from subsequent events. Thus, aspirin failure might be the result of various factors, other than merely resistance to drug effect. We sought to evaluate whether aspirin failure reflects inadequate inhibition of cyclo-oxygenase-1 and platelet aggregation in response to arachidonic acid (AA) (aspirin resistance) or whether it is simply a manifestation of higher-risk patient characteristics.
Methods
We evaluated 174 consecutive patients who presented with an acute myocardial infarction (AMI) within 12 hours of symptom onset. Diagnosis of AMI was based on troponin I increase and typical anginal pain and/or electrocardiographic (ECG) changes suggestive of acute ischemia. All patients with ST-elevation MI (STEMI) underwent primary percutaneous coronary intervention and all patients without STEMI underwent coronary angiography and percutaneous coronary intervention within 48 hours of admission. All patients were treated initially with a loading dose of aspirin 300 mg and a loading dose of clopidogrel 300 mg, followed by aspirin 100 mg/day and clopidogrel 75 mg/day. Patient baseline characteristics, including previous aspirin use, were recorded on admission. Use of aspirin including daily dose and compliance were recorded based on a patient’s interview on admission. Those treated with aspirin for ≥1 week before the qualifying AMI were defined as having aspirin failure, whereas all others were classified as aspirin naive. Patients who were on nonsteroidal anti-inflammatory drugs and treated with aspirin intermittently or for <1 week before the qualifying AMI were excluded from the study. All patients were treated with unfractionated heparin starting at admission and until completion of percutaneous coronary intervention, at which time heparin was routinely discontinued. Of the 118 aspirin-naive patients, 102 (86%) were treated with glycoprotein IIb/IIIa inhibitors compared to 46 patients (82%, p = 0.8) with aspirin failure.
To determine whether aspirin failure is associated with an inadequate platelet response to aspirin, the 2 study groups were compared with respect to platelet reactivity including aggregation in response to AA after aspirin treatment (≥72 hours)
Blood for platelet reactivity was drawn with a loose tourniquet through a short venous catheter on the fourth day after AMI. Blood was collected into tubes containing 3.2% sodium citrate and was assessed for platelet function immediately after it was drawn. Blood samples were centrifuged and the upper fraction collected as platelet-rich plasma. Remaining blood was centrifuged again to obtain platelet-poor plasma. Platelet aggregation was evaluated by a turbidimetric PACKS-4 aggregometer (Helena Laboratories, Beaumont, Texas) using adenosine diphosphate (5.5 μmol/L) and AA 1.6 mol/L as agonists. Changes in light transmission were recorded for 5 minutes and maximal amplitude of aggregation was measured. Platelet deposition under flow conditions was studied using Cone and Plate(let) Analyzer technology (DiaMed AG, Cressier, Switzerland), as described in detail elsewhere. Briefly, citrated whole blood 130 μL was placed in a polystyrene well and subjected to a shear rate of 1,800/s using a rotating conical disk for 2 minutes. The well was washed and stained with May-Gruenwald stain. Stained wells were analyzed by an image analyzer connected to a microscope. Platelet deposition was monitored by percent total area covered with platelet aggregates and was designated as surface coverage (percentage). All blood samples were evaluated in the same laboratory and by the same operator who was blinded to patients’ therapy and clinical status.
Patients were followed during their hospital stay for reinfarction, development of congestive heart failure (functional class ≥III), malignant arrhythmia, stroke, and death. To determine reinfarction during hospitalization, cardiac biomarkers had to be re-increased to ≥2 times that of the last level measured with recurrence of anginal pain and/or new ECG changes compatible with ischemia. Patients were followed for 6 months after discharge by routine outpatient clinic visits or telephone call and were evaluated for recurrent angina, reinfarction, recurrent acute coronary syndrome (ACS), need for revascularization, new-onset congestive heart failure, stroke, and death. Reinfarction was defined as troponin increase with ECG changes compatible with ischemia or recurrent anginal pain. Recurrent ACS was defined as any MI or a recurrent ischemic event necessitating rehospitalization or unscheduled revascularization. For this study major acute coronary events comprising all-cause death, recurrent ACS, and/or stroke at 6 months were prespecified.
Continuous variables are presented as mean ± SD or median and interquartile range, and categorical variables are expressed as percentages. Continuous variables were compared using Student’s t test if data followed normal distribution and Mann-Whitney test if data were skewed. Categorical variables were compared using Pearson chi-square test or Fisher’s exact test when indicated. To account for the nonrandomized character of the study we applied a propensity-score approach. The propensity score was estimated using logistic regression on covariates that could have affected the decision to use aspirin before the qualifying AMI (age, previous ACS, previous revascularization, previous angina, hyperlipidemia, diabetes mellitus, and hypertension). We applied weighting for balance of subsamples of patients treated and not treated with aspirin before the qualifying AMI. Weight was equal to the inverse propensity score for those treated with aspirin and equal to 1/(1 − propensity score) for those who were not treated with aspirin.
Independent predictors of AA-induced platelet aggregation were determined using linear regression including the following variables: previous aspirin use, gender, age, previous ACS, previous angina, previous revascularization, diabetes mellitus, hypertension, angiographic multivessel coronary artery disease, with and without propensity score as a covariate.
All tests were 2-sided and a p value <0.05 was considered statistically significant. All calculations were done using STATA SE 10 (STATA Corporation, College Station, Texas).
Results
In total 174 consecutive patients presenting with an AMI were evaluated. Of them, 118 patients (68%) were aspirin naive and 56 (32%) were regarded as having aspirin failure. All those 56 patients were treated with aspirin ≥100 mg/day. Patient baseline characteristics are listed in Table 1 . Patients with aspirin failure were older, more likely to be hypertensive and hyperlipidemic, to have had a previous cardiovascular event and/or procedure, and to be treated with angiotensin-converting enzyme inhibitors, β blockers, and statins at onset of the qualifying AMI ( Table 1 ). Most patients in the 2 groups presented with STEMI (75% with aspirin failure and 80% aspirin naive, p = 0.41). Patients in the 2 groups were also similar with regard to indexes of infarct size and extent of angiographic coronary artery disease ( Table 2 ).
| Variable | Aspirin Naive | Aspirin Failure | p Value |
|---|---|---|---|
| (n = 118) | (n = 56) | ||
| Age (years), mean ± SD | 58 ± 11 | 63 ± 11 | 0.003 |
| Men | 85% | 80% | 0.5 |
| Smoker | 45% | 32% | 0.1 |
| Hyperlipidemia | 34% | 68% | <0.001 |
| Diabetes mellitus | 22% | 36% | 0.051 |
| Hypertension | 41% | 71% | <0.001 |
| Creatinine (mg/dl), mean ± SD | 1.02 ± 0.18 | 1.04 ± 0.3 | 0.62 |
| Previous myocardial infarction | 6% | 34% | <0.001 |
| Previous coronary bypass | 1.7% | 11% | 0.007 |
| Previous percutaneous coronary intervention | 4% | 23% | <0.001 |
| Previous medications | |||
| Angiotensin-converting enzyme inhibitors | 8% | 41% | <0.001 |
| β blocker | 7% | 32% | <0.001 |
| Statins | 9% | 63% | <0.001 |
| Variable | Aspirin Naive | Aspirin Failure | p Value |
|---|---|---|---|
| ST-elevation myocardial infarction | 80% | 75% | 0.41 |
| Primary ventricular fibrillation | 1.7% | 3.5% | 0.4 |
| Multivessel coronary disease | 41% | 48% | 0.26 |
| Peak creatine phosphokinase (IU/L) | 1,808 ± 339 | 1,428 ± 215 | 0.35 |
| Medication at discharge | |||
| Angiotensin-converting enzyme inhibitors | 86% | 83% | 0.7 |
| β blocker | 83% | 85% | 0.8 |
| Statins | 80% | 88% | 0.2 |
Despite an equally benign in-hospital course and similar medical therapy at discharge, patients with aspirin failure had a higher incidence of major acute coronary events at 6-month follow-up (2.5% vs 14.3%, p <0.01), driven mainly by a higher incidence of recurrent infarction ( Table 3 ). Table 4 presents platelet reactivity results on the fourth day after aspirin loading and maintenance therapy of 100 mg for ≥72 hours in previous aspirin users and aspirin-naive patients. Previous aspirin users compared to aspirin-naive patients had lower AA-induced platelet aggregation (32 ± 24 vs 45 ± 30, p = 0.003). However, after weighing for propensity score the difference was not significant (p = 0.82). When all 174 study patients were plotted based on AA-induced platelet aggregation we found a bimodal distribution with 1 peak around 20% and another around 80%. These 2 subpopulations were best dichotomized using an AA-induced platelet aggregation of 50% as a cut-off point. Previous aspirin users had a lower incidence of high (>50%) residual AA-induced platelet aggregation after aspirin therapy (12, 21%, vs 50, 42%, p <0.01). In multivariate logistic regression (including propensity score as a covariate) previous aspirin use was not an independent predictor of AA-induced platelet aggregation (p = 0.2) and the only independent predictor was male gender (odds ratio −40, 95% confidence interval −55 to −25, p <0.01).
| Variable | Aspirin Naive | Aspirin Failure | p Value |
|---|---|---|---|
| (n = 118) | (n = 57) | ||
| In-hospital outcome | |||
| Heart failure | 19% | 12% | 0.3 |
| Reinfarction | 0 | 1.8% | 0.14 |
| Postinfarction angina pectoris | 0.8% | 0 | 0.5 |
| Stroke | 0 | 1.7% | 0.14 |
| Postdischarge follow-up ⁎ | |||
| Recurrent angina pectoris | 6% | 14% | 0.06 |
| Recurrent acute coronary syndrome | 2.5% | 9% | 0.057 |
| Recurrent myocardial infarction | 0.8% | 7% | 0.019 |
| Heart failure | 2.5% | 1.8% | 0.8 |
| Revascularization | 3.4% | 8.8% | 0.12 |
| Stroke | 0 | 0 | 0.9 |
| Death | 0 | 1.8% | 0.15 |
| Combined end point | |||
| Major adverse coronary events | 2.5% | 14.3% | <0.01 |
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