Author + information
- Received October 12, 2003
- Revision received November 30, 2003
- Accepted December 9, 2003
- Published online March 17, 2004.
- Wai-Hong Chen, MBBS*,* (, )
- Pui-Yin Lee, MBBS*,
- William Ng, MBBS*,
- Hung-Fat Tse, MD, FACC* and
- Chu-Pak Lau, MD, FACC*
- ↵*Reprint requests and correspondence:
Dr. Wai-Hong Chen, Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
Objectives We sought to investigate the effect of aspirin resistance on the incidence of myonecrosis after non-urgent percutaneous coronary intervention (PCI) among patients pretreated with clopidogrel.
Background Oral antiplatelet therapy using aspirin and a thienopyridine is the standard of care for preventing thrombotic complications of PCI. The effect of aspirin resistance on the outcomes of patients undergoing PCI is unknown.
Methods We used the Ultegra Rapid Platelet Function Assay-ASA (Accumetrics Inc., San Diego, California) to determine aspirin responsiveness of 151 patients scheduled for non-urgent PCI. All patients received a 300-mg loading dose of clopidogrel >12 h before and a 75-mg maintenance dose in the morning of the PCI. The incidence of myonecrosis was measured by creatine kinase-myocardial band (CK-MB) and by troponin I (TnI) elevations after PCI.
Results A total of 29 (19.2%) patients were noted to be aspirin-resistant. There was a significantly higher incidence of female subjects in the aspirin-resistant versus aspirin-sensitive groups. The incidence of any CK-MB elevation was 51.7% in aspirin-resistant patients and 24.6% in aspirin-sensitive patients (p = 0.006). Elevation of TnI was observed in 65.5% of aspirin-resistant patients and 38.5% of aspirin-sensitive patients (p = 0.012). Multivariate analysis revealed aspirin resistance (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.2 to 6.9; p = 0.015) and bifurcation lesion (OR 2.8; 95% CI 1.3 to 6.0; p = 0.007) to be independent predictors of CK-MB elevation after PCI.
Conclusions Despite adequate pretreatment with clopidogrel, patients with aspirin resistance as measured by a point-of-care assay have an increased risk of myonecrosis following non-urgent PCI.
Early complications of percutaneous coronary intervention (PCI) are caused by arterial thrombosis at the site of vessel injury (1). More complete platelet inhibition using aspirin and a thienopyridine during PCI offers protection against ischemic complications (2–7). However, 8% to 45% (8–11)of patients do not respond to aspirin therapy as determined by different laboratory tests, and these aspirin-resistant patients are at increased risk of thrombotic events (8,12–14). The contribution of aspirin, a relatively weak antiplatelet agent, to the prevention of thrombotic complications of PCI in the presence of the full effect of a thienopyridine is unknown. This study was designed to compare the incidence of myonecrosis after PCI between aspirin-resistant and aspirin-sensitive patients pretreated with clopidogrel >12 h before PCI.
Consecutive patients with aspirin use of 80- to 325-mg daily for ≥1 week and who were scheduled for PCI were enrolled. Exclusion criteria included saphenous vein graft intervention, chronic total occlusions that could not be crossed by guidewires, preprocedural elevation of creatine kinase-myocardial band (CK-MB) or troponin I (TnI), planned use of glycoprotein IIb/IIIa inhibitors, and the use of antiplatelet drugs other than aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) within two weeks of the PCI. The local ethics committee on human research approved the protocol, and all patients provided written informed consent.
After collecting baseline blood samples for CK-MB, TnI, and aspirin responsiveness, all patients received an oral loading dose of 300-mg clopidogrel 12 to 24 h before the procedure. The PCI procedure was performed on the following day according to standard practice, after the patients received an additional 75-mg maintenance dose of clopidogrel. Unfractionated heparin 70 U/kg or enoxaparin 1 mg/kg was used for procedural anticoagulation at operator discretion. Following the procedure, blood samples for TnI were collected at 12 to 24 h, whereas those for CK-MB were collected at 6 to 8 h. If CK-MB was elevated, serial measurements every 8 h were obtained and the peak level was recorded. The CK-MB was considered elevated if ≥16 U/l, which was further subdivided into 1 to 3 × (16 to 48 U/l), 3 to 5 × (49 to 80 U/l), and >5 × (>80 U/l) normal. A TnI value of ≥2.0 ng/ml was considered elevated. Aspirin-induced platelet inhibition was measured using a commercially available point-of-care assay, the Ultegra Rapid Platelet Function Assay-ASA (RPFA-ASA) (Accumetrics Inc., San Diego, California). Citrate-anticoagulated blood 2 ml was added to RPFA-ASA cartridges, which contain fibrinogen-coated beads and platelet agonists. If aspirin has produced the expected antiplatelet effect, fibrinogen-coated beads will not agglutinate, and light transmission will not increase. The result is expressed as aspirin reaction unit (ARU). An ARU ≥550 indicates the absence of aspirin-induced platelet dysfunction, based on correlation with epinephrine-induced light transmission aggregometry in aspirin-naive patient tested prior to and between 2 to 30 h after aspirin (325 mg) ingestion (15), and is defined as aspirin-resistant. From this study, both the sensitivity (92%) and the specificity (85%) of this assay were determined. The coefficient of variance was 2.5% on repeated measures within patients. The between-patient coefficient of variance was 12.5% for baseline samples and 15.0% for post-aspirin samples. Digital angiograms were analyzed off-line using a computer-based edge-detection program (CMS-GFT, MEDIS, Leiden, The Netherlands) by experienced cardiologists who were unaware of the patient characteristics and outcomes.
Comparisons between the two groups were performed by the Mann-Whitney Utest for continuous variables and by the Fisher exact test for dichotomous variables. A logistic regression analysis using forward technique was employed to determine significant independent predictors of CK-MB elevation. A significant level was defined when p < 0.05. All analyses were performed using SPSS 10.0 (SPSS Inc., Chicago, Illinois).
The clinical, angiographic, and procedural characteristics of the patients are listed in Tables 1 and 2. ⇓⇓A total of 29 (19.2%) out of 151 enrolled patients were found to be aspirin-resistant. The characteristics were matched in the two groups except for the higher incidence of female patients (44.8% vs 19.7%; p = 0.007) in the aspirin-resistant group. All patients underwent successful PCI with <50% diameter stenosis at the target lesion(s) and Thrombolysis In Myocardial Infarction flow grade 3 after the intervention. There was no bailout use of glycoprotein IIb/IIIa inhibitors in any of the patients; no clinical bleeding events occurred. The ratios of hemoglobin pre- and post-PCI in the aspirin-sensitive and -resistant groups were identical at 0.96. None of the patients developed contrast nephropathy. Post-PCI myonecrosis occurred more frequently in the aspirin-resistant patients than in the aspirin-sensitive patients. The incidence of any CK-MB elevation was 51.7% versus 24.6% in the aspirin-resistant and -sensitive groups, respectively (p = 0.006) (Fig. 1). Elevation of TnI occurred in 65.5% of aspirin-resistant patients and 38.5% of aspirin-sensitive patients (p = 0.012) (Fig. 1). The median peak values of CK-MB and TnI in the aspirin-resistant and -sensitive groups, respectively, were 20 and 17 U/l and 6.3 and 0.85 ng/ml. The continuous relationship between ARU and CK-MB, TnI, or bleeding index was not observed. No in-hospital mortality or urgent target vessel revascularization occurred among any of the patients. Variables associated with CK-MB elevation by univariate analysis were aspirin resistance (p = 0.006), bifurcation lesion (p = 0.035), B2/C lesion (p = 0.029), and number of stents used (p = 0.04). Multivariate analysis revealed aspirin resistance (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.2 to 6.9; p = 0.015) and bifurcation lesion (OR 2.8; 95% CI 1.3 to 6.0; p = 0.007) to be independent predictors of CK-MB elevation after PCI.
This is the first study to demonstrate that, despite adequate pretreatment with clopidogrel, patients undergoing non-urgent PCI are at increased risk of myonecrosis when they are determined to be aspirin-resistant using a point-of-care assay, compared with those who are aspirin-sensitive. Elevation of CK-MB has been shown to be associated with a higher incidence of death, myocardial infarction, and repeat revascularization after PCI (16). Prevention of post-PCI myonecrosis, therefore, is of clinical importance. Aspirin has been shown to reduce acute thrombotic complications of balloon angioplasty (17–19). Thienopyridine pretreatment (2–7)and the addition of intravenous glycoprotein IIb/IIIa inhibitors (20–23)further improve the outcomes of patients undergoing elective or urgent PCI. However, the role of aspirin in PCI has not been defined in the contemporary era using double or triple antiplatelet therapy.
Aspirin resistance describes the clinical observation of the inability of aspirin to prevent thrombotic complications or the laboratory phenomenon of absence of the effect of aspirin on platelet inhibition tests. Four prior studies demonstrated the association of adverse clinical events in patients with aspirin resistance as determined by different assays (8,12–14). Our study extends these observations and provides further evidence on the clinical significance of aspirin resistance. We collected the data prospectively in stable patients undergoing PCI while interventionalists and laboratory personnel performing assays for myonecrosis were blinded to platelet inhibition results. The relatively high percentages of CK-MB and TnI elevations in our population may be due to the high rates of diabetes (≥40%) and complex lesions (≥75% B2/C lesions), and diffuse atherosclerosis as reflected by small reference diameters of ∼2.6 mm. Despite receiving the maximal antiplatelet effect of clopidogrel with a 300-mg loading dose given >12 h before non-urgent PCI, aspirin-resistant patients had a 2.9-fold increased risk of CK-MB elevation compared with aspirin-sensitive patients.
Our study has several potential limitations. First, the study population was small and Asian in origin. Important trends may not be detected because of a lack of statistical significance and it is not known whether ethnicity plays a role in the differences in aspirin resistance. Second, our study did not have a prospective randomized design, and there might be unrecognized confounders that may influence the occurrence of myonecrosis in addition to aspirin responsiveness. Third, the antiplatelet effect of aspirin may fluctuate in patients at the same dosage. A single baseline measurement may not reflect the extent of platelet inhibition over long periods of time. However, during PCI when maximal antithrombotic action is desirable, a point-of-care platelet inhibition assay may give instant information on the efficacy of aspirin, regardless of previous antiplatelet effect.
Finally, we conclude that aspirin resistance is associated with a 2.9-fold increased incidence of myonecrosis as evidenced by CK-MB elevation following non-urgent PCI with adequate clopidogrel pretreatment. Our results may have implications for the need of identification of aspirin resistance in patients undergoing PCI and the use of alternative or additional antithrombotic therapy to minimize procedural complications.
- aspirin reaction unit
- creatine kinase-myocardial band
- non-steroidal anti-inflammatory drugs
- odds ratio
- percutaneous coronary intervention
- troponin I
- Received October 12, 2003.
- Revision received November 30, 2003.
- Accepted December 9, 2003.
- American College of Cardiology Foundation
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