Low-dose aspirin increases aspirin resistance in patients with coronary artery disease

The American Journal of Medicine (2005) 118, 723-727 CLINICAL RESEARCH STUDY AJM Theme Issue: CARDIOLOGY Low-dose aspirin increases aspirin resistance in patients with coronary artery disease Pui-Yin Lee, MBBS, Wai-Hong Chen, MBBS, FACC, William Ng, MBBS, FACC, Xi Cheng, MD, Jeanette Yat-Yin Kwok, RN, Hung-Fat Tse, MD, FACC, Chu-Pak Lau, MD, FACC Department of Medicine, The University of Hong Kong, Queen Mary Hospital. KEYWORDS: Aspirin; Coronary disease; Platelets ABSTRACT PURPOSE: We sought to investigate the association of aspirin dose and aspirin resistance in stable coronary artery disease patients measured by a point-of-care assay. METHODS: We studied 468 consecutive stable coronary artery disease patients in a referral cardiac center who were taking aspirin 80 to 325 mg daily for 4 weeks. The VerifyNow Aspirin (Ultegra RPFA-ASA, Accumetrics Inc, San Diego, Calif) was used to determine aspirin responsiveness. An aspirin reaction unit (ARU) 550 indicates the absence of aspirin-induced platelet dysfunction, based on correlation with epinephrine-induced light transmission aggregometry. Demographic and clinical data were collected to analyze the predictors of aspirin resistance. RESULTS: Aspirin resistance was noted in 128 (27.4%) patients. Univariate predictors of aspirin resistance include elderly (P 0.002), women (P 0.001), anemia (P 0.001), renal insufficiency (P 0.009) and aspirin dose 100mg (P 0.004). Multivariate analysis revealed hemoglobin (odds ratio [OR] 0.6; 95% confidence interval [CI] 0.51 to 0.69; P 0.001) and aspirin dose 100 mg (OR 2.23; 95% CI 1.12 to 4.44; P 0.022) to be independent predictors of aspirin resistance. Daily aspirin dose 100 mg was associated with increased prevalence of aspirin resistance compared with 150 mg and 300 mg daily (30.2% vs 16.7% vs 0%, P 0.0062). CONCLUSION: A 100 mg or less daily dose of aspirin, which may have lower side effects, is associated with a higher incidence of aspirin resistance in patients with coronary artery disease. Prospective randomized studies are warranted to elucidate the optimal aspirin dosage for preventing ischemic complications of atherothrombotic disease. 2005 Elsevier Inc. All rights reserved. Requests for reprints should be addressed to Wai-Hong Chen, MBBS, FACC, Division of Cardiology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. E-mail address: whchen@hku.hk. The pivotal role of platelet in the initiation of atherothrombosis supports the clinical usefulness of aspirin in reducing ischemic cardiovascular events in patients with atherosclerosis. 1 However, aspirin has been shown to have variable antiplatelet activity in individual patients. 2 4 Recent studies showed that patients with inadequate platelet inhibition by aspirin are associated with a higher incidence of reocclusion after peripheral angioplasty, 5 more myonecrosis after elective percutaneous coronary intervention, 3 and more myocardial infarction, stroke, and cardiovascular death among stable cardiovascular patients. 4,6 Although low-dose aspirin (50-100 mg daily) was suggested to be the rational strategy in order to maximize its efficacy and to minimize its toxicity, 1,7 the effect of aspirin dose on the prevalence of aspirin resistance has not been studied. This 0002-9343/$ -see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.03.041

724 The American Journal of Medicine, Vol 118, No 7, July 2005 study examines the prevalence, predictors, and the effect of aspirin dose on aspirin resistance in patients with documented coronary artery disease using the point-of-care VerifyNow Aspirin (Ultegra RPFA-ASA, Accumetrics, San Diego, Calif). Methods Study group A total of 468 patients with stable coronary artery disease and aspirin use of 80 to 325 mg daily for 4 weeks were prospectively enrolled between October 2002 and May 2004. Because all patients had regular follow-up in our institution, the aspirin dose could be retrieved from computer prescription record. Aspirin dose and compliance were verified with patients before recruitment. Coronary artery disease was documented by cardiac catheterization, previous history of myocardial infarction, or previous percutaneous coronary intervention or coronary artery bypass surgery. Exclusion criteria included: ingestion of nonsteroidal anti-inflammatory drugs, dipyridamole, clopidogrel, or ticlopidine within 7 days before enrollment; administration of heparin or low-molecularweight heparin within 24 hours before enrollment; family or personal history of bleeding disorders; platelet count 150 10 3 / L or 450 10 3 / L; hemoglobin 8 g/dl; and major surgery a week before enrollment. Patient records were reviewed and patients were interviewed to determine the dose of aspirin taken over the past 4 weeks. Renal insufficiency was defined as serum creatinine 140 mol/l. Blood samples All patients recruited would have blood sample collection on the same day. Aspirin-induced platelet inhibition was measured using a commercially available point-of-care assay, the VerifyNow Aspirin. Two milliliters citratedanticoagulated blood was added to 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-naïve patient tested prior to and 2 to 30 h after aspirin (325 mg) ingestion, and is defined as aspirin-resistant (Ultegra RPFA-ASA package insert). Compared with light aggregometry, the sensitivity and the specificity of this assay were 92% and 85%, respectively. 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% for post-aspirin samples. Statistical analysis Categorical variables are presented as frequencies and percentages. Continuous variables are presented as means SD. Categorical variables were compared using chi-squared tests or Fisher s exact tests if appropriate. Student s t test or Mann-Whitney U test (if not normally distributed) were used to compare the continuous variables between 2 groups. A logistic regression analysis using forward technique was employed to determine significant predictors of aspirin resistance. A P value 0.05 was considered statistically significant. All analyses were performed using SPSS 12.0 (SPSS Inc., Chicago, Ill). Results The baseline clinical characteristics of the patients are listed in Table 1. Of a total of 468 patients enrolled, 128 (27.4%) were found to be aspirin resistant. Patients who were aspirin resistant were older (66.7 10.2 years vs 63.2 11.7 years, P 0.002), more likely to be women (46.1% vs 25.3%, P 0.001), and had a slightly lower hemoglobin level (12.7 1.5 years vs 14.0 1.5 g/dl, P 0.001) compared with patients who were aspirin sensitive. Renal insufficiency was associated with aspirin resistance (18.8% vs 9.7%, P 0.009). The mean dosage of aspirin taken was lower in aspirin-resistant patients (101.95 17.84 mg vs 114.40 42.17 mg, P 0.001). The 2 groups had similar prevalence of cardiovascular risk factors and severity of coronary artery disease. To further evaluate the effect of different aspirin dosages, we performed analysis to determine the percentage of aspirin-sensitive patients in accordance with the aspirin dosage (Figure). In this cohort, 384 (82.1%) patients were taking 80-100 mg aspirin daily, whereas 72 (15.4%) and 12 (2.5%) patients were taking 150 mg and 300 mg aspirin daily, respectively. It was noted that 69.8% of patients taking 100 mg were aspirin sensitive, compared with 83.3% and 100% of patients who were taking 150 mg and 300 mg, respectively (P 0.0062). Univariate and multivariate analysis of predictors for aspirin resistance are shown in Table 2. Variables associated with aspirin resistance by univariate analysis were age (P 0.002), women (P 0.001), hemoglobin level (P 0.001), renal insufficiency (P 0.009) and aspirin dose (P 0.004). Multivariate analysis revealed hemoglobin level (odds ratio [OR] 0.6; 95% confidence interval [CI] 0.51 to 0.69; P 0.001) and aspirin dose 100 mg (OR 2.23; 95% CI 1.12 to 4.44; P 0.022) to be independent predictors of aspirin resistance in this cohort of patients with documented coronary artery disease.

Lee et al Aspirin dose, aspirin resistance and coronary artery disease 725 Table 1 Baseline clinical characteristics according to aspirin sensitivity status ASA-S (n 340) ASA-R (n 128) P value Age, years 63.2 11.7 66.7 10.2 0.002 Women, n (%) 86 (25.3%) 59 (46.1%) 0.001 Weight, kg 66.7 12.0 65.0 11.5 0.200 Body mass index, kg/m 2 25.4 3.6 25.7 3.8 0.590 Diabetes, n (%) 117 (34.4%) 50 (39.1%) 0.350 Hypertension, n (%) 223 (65.6%) 93 (72.7%) 0.146 Hyperlipidemia, n (%) 233 (68.5%) 88 (68.8%) 0.963 Current smoker, n (%) 48 (14.1%) 14 (10.9%) 0.366 Prior myocardial infarction, n (%) 104 (30.6%) 43 (33.6%) 0.533 Hemoglobin, g/dl 14.0 1.5 12.7 1.5 0.001 White cell count, 109/L 7.3 2.1 6.9 2.0 0.060 Platelet count, 109/L 235.3 68.2 232.4 66.4 0.684 2- or 3-vessel coronary artery disease, n (%) 161 (47.4%) 65 (50.8%) 0.508 Serum creatinine, mol/l 112.3 87 118.3 68.3 0.482 Renal insufficiency, n (%) 33 (9.7%) 24 (18.8%) 0.009 Aspirin reaction unit (ARU) 473.6 54.1 597.2 39.0 Aspirin dosage (mg) 114.4 42.2 102.0 17.8 0.001 ASA-S aspirin-sensitive; ASA-R aspirin-resistant. Body mass index is calculated as the weight in kilograms divided by the square of height in meters. Discussion Our results showed that up to 27.4% of patients with stable coronary artery disease were aspirin resistant as measured by the VerifyNow Aspirin. This is the largest study so far studying the prevalence of aspirin resistance in patients with coronary artery disease. We also showed that low hemoglobin level and aspirin dose predicted aspirin resistance in this cohort. Gum et al, using optical platelet aggregation, showed that 29.3% of the patients taking 325 mg aspirin daily were either aspirin resistant or semiresponder. 8 Similar to our findings, they found aspirin-resistant patients or aspirin Figure Effect of aspirin dose on percentage of aspirin-sensitive patients (ARU 550). ASA aspirin; ASA-S aspirin sensitive; ASA-R aspirin resistant. semiresponders were more likely to be women, be an older age, and have a lower hemoglobin. However, no significant demographic differences between aspirin-resistant and sensitive patients were identified using the platelet function analyzer-100 to define aspirin responsiveness. Wang et al, using also the VerifyNow Aspirin, found that low platelet count and low hematocrit were significant predictors of aspirin resistance. 9 Aspirin dose was not predictive of aspirin resistance. However, the patients recruited (n 422) were more heterogeneous in that 64% of patients had coronary artery disease, 7% had cerebral vascular accidents, and 8% had peripheral vascular disease. In addition, in contrast to our study, most (66%) of their patients were taking higher doses of aspirin ( 162 mg) and only 33% were taking 81 mg daily aspirin. Together with our data, all these observational studies showed that around 1 in 4 patients were aspirin resistant as determined by different platelet assays. The underlying mechanism for association between low hemoglobin and aspirin resistance was not clear, but this may explain the observation that anemia was related to poor clinical outcomes in patients with established coronary artery disease. 10,11 The use of low-dose versus intermediate- or high-dose aspirin is still controversial. In the recent Antithrombotic Trialists Collaboration, 1 which was a meta-analysis of 287 studies, high-dose aspirin had a similar proportional risk reduction as low-dose aspirin. Because high-dose aspirin was associated with more gastrointestinal side effects and bleeding, low-dose aspirin was generally preferred and recommended. However, laboratory tests showed that highdose aspirin was associated with more complete platelet inbibition. 12,13 Recently, in a pooled analysis of more than

726 The American Journal of Medicine, Vol 118, No 7, July 2005 Table 2 Univariate and multivariate analysis of predictors of aspirin resistance Variables -coefficient Standard Error P value OR 95% CI Univariate predictors Age 0.03 0.01 0.002 1.03 1.01, 1.05 Female 0.93 0.22 0.001 2.53 1.65, 3.86 Hemoglobin 0.54 0.08 0.001 0.58 0.50, 0.68 Renal insufficiency 0.76 0.29 0.009 2.15 1.21, 3.80 ASA dose 100 mg 0.95 0.33 0.004 2.60 1.36, 4.96 Multivariate predictors Hemoglobin 0.52 0.08 0.001 0.60 0.51, 0.69 ASA dose 100 mg 0.80 0.35 0.022 2.23 1.12, 4.44 20 000 patients with unstable angina and acute myocardial infarction, Quinn et al 14 observed that intermediate-dose aspirin, compared with low-dose aspirin, was associated with less frequent myocardial infarction. There was no difference in the incidence of death and there were more strokes among patients with high-dose aspirin. In a randomized study involving an oral glycoprotein IIb/IIIa antagonist lotrafiban, Topol et al found that high-dose ( 162 mg/day) aspirin was associated with decreased mortality. 15 On the contrary, in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study, Peters et al showed that high-dose aspirin, with or without clopidogrel, was not associated with fewer clinical events 16 but more major bleedings. Our study showed that low-dose aspirin was associated with more aspirin resistance. Whether or not escalating the aspirin dose among aspirin-resistant patients would reverse their aspirin responsiveness and hence their clinical risks remains to be proved. A large-scale prospective study on aspirin dose and aspirin resistance, preferably together with clinical outcomes, will be needed. Meanwhile, further studies in female, elderly, and chronic renal failure patients are needed to elucidate the role of aspirin responsiveness in these high-risk groups of patients. Our data also showed that, with the use of the VerifyNow Aspirin, aspirin-resistant patients would be readily identified. Compared with conventional laboratory methods for evaluation of platelet function, which are complicated and time consuming, the VerifyNow Aspirin is easy to use and readily accessible to physicians in clinical practice. This assay was recently reported to have a high correlation with conventional aggregometry in assessing platelet function among patients with stable cardiovascular disease. 17 Last, further studies on the long-term outcomes of aspirin-resistant patients would be needed. Although we believe that antiplatelet therapy should be individualized, the use of higher dose aspirin or alternative antiplatelet (eg, clopidogrel) in these patients will not be advocated until more data are available. There are some limitations to this study. First, this is a nonrandomized observational study. Unrecognized confounders may influence the prevalence of parameters among aspirin-sensitive and resistant patients. Second, we relied on computer prescription records to determine the aspirin dose patients were taking. However, we did try to confirm the dose of aspirin taken by verifying with the patients. Meanwhile, patients compliance to take aspirin was not ascertained. Conclusion Aspirin resistance is noted in a significant number of stable coronary artery disease patients, and low aspirin dose is associated with a higher incidence of aspirin resistance. Prospective randomized studies to evaluate the safety and efficacy of higher dose aspirin or alternative antiplatelet agents in aspirin-resistant patients are warranted. References 1. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324:71 86. 2. 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A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. JAm Coll Cardiol. 2003;41:961 965. 7. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:234S 264S. 8. Gum PA, Kottke-Marchant K, Poggio ED, et al. Profile and prevalence of aspirin resistance in patients with cardiovascular disease. Am J Cardiol. 2001;88:230 235.

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