Recent studies have suggested that clopidogrel response may vary significantly with age. Limited data are available exploring the age dependency of ex vivo aspirin response in young and old patients with stable coronary artery disease. Patients with stable coronary artery disease (n = 583) who had been treated with aspirin 75 to 325 mg/day for ≥1 week were recruited from a general cardiology practice. The study cohort was divided into 2 groups: patients aged <75 years (n = 438) and patients aged ≥75 years (n = 145). Aspirin response was determined using the VerifyNow Aspirin Test, and resistance was defined as ≥500 or 550 aspirin reaction units (ARU). The independent predictive value of age on VerifyNow score (as a continuous function) was determined using multivariate linear regression, adjusted for gender, body mass index, and diabetes mellitus. Younger and older patients had similar baseline clinical profiles, including relative doses of aspirin therapy. The mean VerifyNow Aspirin Test score was significantly higher in patients aged ≥75 years: 450 ± 54 versus 434 ± 53 ARU (p = 0.0007). After accounting for the primary covariates, age remained a predictor of VerifyNow score (p = 0.007). Aspirin resistance on the basis of the 500-ARU cutoff was higher in older patients (19% vs 11%, p = 0.009), but there was no difference when the 550-ARU cutoff was used (7% vs 5%, p = 0.40). In conclusion, aspirin response differs significantly by age in patients with stable CAD.
In recent years, it has become apparent that the biologic response to aspirin therapy is not uniform; rather, there is wide variability among individuals in platelet-level responsiveness. The prevalence of suboptimal response or “resistance” to the antiplatelet effects of aspirin is estimated to be 1% to 45%. Low response to aspirin has been consistently associated with an increased risk for adverse clinical outcomes, including cardiovascular mortality, myocardial infarction, and postprocedural myonecrosis. In addition, meta-analyses have demonstrated that low response to aspirin is associated with an almost fourfold increased risk for the development of subsequent cardiovascular events. A landmark meta-analysis conducted by the Antiplatelet Trialists’ Collaboration in the early 1990s including 145 randomized controlled clinical trials and 70,000 high-risk patients for ischemic events showed a robust risk reduction of approximately 25% in serious vascular events. This risk reduction was consistently demonstrated in patient subgroups, regardless of age, gender, and co-morbid illnesses. The use of aspirin is also associated with increased risk for bleeding, which appears to be higher in older adults, in whom the drug is commonly used for the treatment of cardiovascular disease. Studies have indicated increased risk for bleeding even with low doses of the drug. Recent data have revealed reduced response to clopidogrel in older patients with coronary artery disease (CAD). Despite the high rates of ischemic disease and bleeding events in this segment of the population, there are no established data regarding the proportion of aspirin low response rates in older adults. Our aim, therefore, was to evaluate the response to aspirin by age in patients with stable CAD.
Methods
In this cross-sectional study, patients with known stable CAD (n = 583) aged >18 years who had been treated with aspirin 75 to 325 mg/day for ≥1 week were included. CAD was defined as a history of myocardial infarction, coronary artery bypass graft, percutaneous coronary intervention (PCI) with or without stenting, or previous angiographically proved obstructive coronary lesion ≥50%. Patients were recruited from outpatient cardiology clinics from 2007 to 2009. Compliance with aspirin (taken for ≥1 week) was verified separately by the patient’s attending physician, study nurse, and study physician using a dedicated study questionnaire. Exclusion criteria were PCI and/or acute coronary syndromes within 1 month of enrollment; concomitant treatment with omega-3 fatty acid–containing products; concomitant treatment with ibuprofen, naproxen, or warfarin; thrombocytopenia (<100 × 10 3 cells/mm 3 ); anemia (hemoglobin <10 g/dl); or renal insufficiency (creatinine >2.5 mg/dl). The study cohort was divided into 2 groups, patients aged <75 years (n = 438) and patients aged ≥75 years (n = 145), on the basis of previously used age cutoffs. The study was approved by the Investigational Review Board of the Rabin Medical Center, and all subjects provided written informed consent.
All blood samples were obtained from an antecubital vein, with a 21-gauge needle, and collected in tubes containing 3.2% citrate. The tubes were filled to capacity and gently mixed. The blood samples were processed <2 hours after collection.
The VerifyNow Aspirin Test (Accumetrics, Inc., San Diego, California) was used to assess response to aspirin treatment. This assay is a point-of-care, turbidimetric-based system that uses citrate-anticoagulated blood and cartridges containing fibrinogen-coated beads and 1 mmol/L arachidonic acid as the platelet agonist. Results are expressed as aspirin reaction units (ARU). According to the manufacturer’s recommendation, a cutoff of ≥550 ARU indicates resistance to the antiplatelet effects of aspirin. Previous studies showed that the cutoff level of 550 ARU has sensitivity of 70% and specificity of 90% for the detection of aspirin resistance compared with arachidonic acid–induced platelet aggregation. A lower cutoff level of 500 ARU has sensitivity of 90% and specificity of 75% for the detection of aspirin resistance. Rates of aspirin resistance according to the 2 cutoff levels are presented.
For internal consistency, turbidimetric platelet aggregation was performed in a randomly selected subgroup of 149 patients (25.6% of the study sample). Aggregation was performed in platelet-rich plasma using a BioData PAP-4 platelet aggregometer (BioData, Horsham, Pennsylvania). Platelets were stimulated with 0.5 mg/ml (1.6 mmol/L) arachidonic acid. The extent of aggregation was defined as the maximal light transmission ≤6 minutes after addition of the agonist, with platelet-poor plasma used as a reference.
Continuous variables are presented as mean ± SD, and categorical variables are presented as number (percentage). Comparisons between younger and older patients were performed using unpaired Student’s t tests and chi-square tests for continuous and categorical variables, respectively. Two subset analyses were performed on the basis of (1) stratification by gender, and (2) availability of turbidimetric aggregometry data. Furthermore, these results were assessed as a continuous variable and a categorical variable (using cutoffs of 500 and 550 ARU). The independent correlation between age and VerifyNow Aspirin Test continuous scores was analyzed using multivariate linear regression, adjusted for gender, body mass index, and diabetes mellitus. Multivariate analysis and Pearson’s correlation analysis were performed using SPSS version 11.0 (SPSS, Inc., Chicago, Illinois). Statistical significance was set at p <0.05.
Results
A total of 583 patients (67 ± 11 years, 80% men) were included. The age and gender distribution in the 2 groups were as follows: age <75 years (n = 438 patients, average age 62 ± 9 years, range 33 to 74, 78% men) and age ≥75 years (n = 145, average age 80 ± 4 years, range 75 to 92, 83% men). Patients in the 2 groups had similar clinical characteristics, except for higher body mass indexes in younger patients (29 ± 12 vs 26 ± 4 kg/m 2 , p <0.001; Table 1 ). The 2 groups had similar rates of previous myocardial infarction or previous PCI. Invasive revascularization was performed in most patients, but coronary artery bypass grafting was significantly more prevalent in the older group (27% in patients aged <75 years vs 41% in those aged ≥75 years, p = 0.002; Table 1 ). Importantly, the aspirin doses used were similar in the 2 groups, with most patients in the 2 groups (81.5%) receiving low-dose aspirin (75 to 100 mg/day). Patients in the 2 groups were also treated with similar medications, except for a lower rate of calcium channel blocker use in the younger group (13% vs 26%, p = 0.003). Of note, serum creatinine levels were higher in patients aged ≥75 years ( Table 1 ).
| Variable | Age (yrs) | p Value | |
|---|---|---|---|
| <75 (n = 438) | ≥75 (n = 145) | ||
| Age (yrs) | 62 ± 9 | 80 ± 4 | <0.0001 |
| Men | 342 (78%) | 120 (83%) | 0.22 |
| Body mass index (kg/m 2 ) | 29 ± 12 | 26 ± 4 | <0.0001 |
| Diabetes mellitus | 245 (40%) | 80 (38%) | 0.93 |
| Hypertension ∗ | 129 (69%) | 34 (77%) | 0.17 |
| Hyperlipidemia † | 75 (80%) | 26 (78%) | 0.86 |
| Current smokers | 44 (11%) | 13 (10%) | 0.3 |
| Previous myocardial infarction | 205 (47%) | 76 (52%) | 0.28 |
| Previous coronary artery bypass graft | 120 (27%) | 60 (41%) | 0.002 |
| Previous PCI | 319 (73%) | 110 (76%) | 0.54 |
| Creatinine level (mg/dl) | 1.1 ± 0.3 | 1.3 ± 0.4 | 0.001 |
| Medications | |||
| Aspirin 75–100 mg | 357 (82%) | 118 (81%) | 0.97 |
| Aspirin 160–325 mg | 78 (18%) | 25 (17%) | 0.97 |
| Clopidogrel | 23 (5.3%) | 5 (3.4%) | 0.4 |
| Statins | 376 (86%) | 120 (83%) | 0.58 |
| β blockers | 284 (65%) | 95 (66%) | 0.9 |
| Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers | 241 (55%) | 80 (55%) | 0.98 |
| Calcium channel blockers | 58 (13%) | 37 (26%) | 0.03 |
∗ Screening blood pressure ≥140/90 mm Hg or use of previous antihypertensive medications.
† Screening total cholesterol level ≥200 mg/dl or use of previous lipid-lowering agents.
The mean VerifyNow Aspirin Test score was significantly higher in the older group: 450 ± 54 versus 434 ± 53 ARU (p = 0.0007). After accounting for the primary covariates of gender, body mass index, and diabetes mellitus, age remained a predictor of VerifyNow score expressed as a continuous variable in the final multivariate linear regression model (p = 0.007). In the categorical analysis, the 2 groups were compared using 2 separate VerifyNow cutoffs (>500 and >550 ARU). The analysis indicated a greater prevalence of aspirin resistance on the basis of the 500-ARU cutoff in the older patients (19% vs 11%, p = 0.009) but no difference when the 550-ARU cutoff was used (7% vs 5%, p = 0.40).
In a subanalysis of the 2 groups according to gender, men and women aged ≥75 years had higher VerifyNow scores than younger patients (aged <75 years; Table 2 ). However, no differences were found between the genders within each age group ( Table 2 ). In the quarter of patients with available aggregometry measurement (n = 149), response to aspirin, as assessed by the 2 methodologies in this subgroup, is presented in Table 3 . The 2 methods showed concordant lower platelet inhibition by aspirin in patients aged ≥75 years.
| Variable | Age <75 yrs | Age ≥75 yrs | p Value |
|---|---|---|---|
| Total cohort | 434 ± 53 (438) | 450 ± 54 (135) | 0.0007 |
| Men | 435 ± 51 (343) | 448 ± 52 (121) | 0.02 |
| Women | 429 ± 59 (95) | 459 ± 64 (24) | 0.048 |
| p value for men vs women | 0.35 | 0.45 |
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