Platelets play a pivotal role in mediating thrombotic complications of atherosclerotic vascular disease. Oral antiplatelet agents are the cornerstone of pharmacologic therapy for preventing ischemic events of atherothrombotic disease. Aspirin and clopidogrel, by blocking thromboxane A 2 (TXA 2 )- and adenosine diphosphate (ADP)-induced platelet activation pathways, respectively, are the most commonly used oral antiplatelet drugs in clinical practice. Variability in the response to antiplatelet drugs has been recognized for decades. Antiplatelet drug resistance or nonresponsiveness is used to describe the clinical observation of the inability of the antiplatelet agent to prevent thrombotic vascular events or the laboratory phenomenon of reduced effect of the antiplatelet agent on one or more tests of platelet function.
Using nonstandardized definitions of nonresponsiveness based on a variety of platelet function tests including, among others, light transmission aggregometry (LTA), impedance aggregometry, urinary metabolites of TXA 2 , flow cytometry, fibrinogen-coated bead agglutination, thromboelastography, and shear-induced measures of platelet function, the prevalence of aspirin nonresponsiveness ranges from 5% to 60% and the prevalence of clopidogrel nonresponsiveness ranges from 17% to 32%. Although LTA is frequently cited as the “gold standard” for platelet function testing, there is lack of consensus on whether percent inhibition of a particular platelet function test or persistent high platelet reactivity is the more appropriate determinant of nonresponsiveness. The mechanisms of aspirin and clopidogrel resistance are incompletely defined. Multiple cellular, clinical, and genetic factors likely contribute to both aspirin and clopidogrel nonresponsiveness ( Figs. 21-1 and 21-2 ). Nonadherence to drug regimens (i.e., noncompliance) is likely responsible for a significant proportion of nonresponsiveness as assessed by platelet function testing. , Increasing clopidogrel dose , or hepatic cytochrome P-450 (CYP450) activity enhances the platelet inhibitory response of clopidogrel by increasing the concentration of the active metabolite ( Fig. 21-3 ). Conditions or risk factors associated independently with clopidogrel nonresponsiveness include congestive heart failure, body weight (>100 kg), myocardial infarction (MI) presentation, and diabetes mellitus. Genetic polymorphisms, particularly of genes responsible for the metabolism of clopidogrel, such as the *2 allele of CYP4502C19, result in loss-of-function leading to reduced conversion of clopidogrel to its active metabolite, and are associated with a higher rate of adverse cardiovascular events in patients presenting with acute coronary syndromes and after percutaneous coronary intervention (PCI) ( Fig. 21-4 ). The CYP2C19*2 allele is common in the general population (approximately 30% of whites, 40% of African-Americans, and more than 55% of East Asians) , and, therefore, is likely to have clinical significance that will need to be explored in future clinical trials. An additional limitation of clopidogrel involves drug-drug interactions. Use of drugs that inhibit the activity of CYP2C19, including several of the proton pump inhibitors (PPI), could result in reduced drug levels of the active metabolite and a possible reduction in clinical efficacy. A retrospective cohort study of more than 16,700 patients who received clopidogrel post-stenting reported an increase in the 1-year risk of cardiovascular events in patients taking omeprazole, esomeprazole, pantoprazole, and lansoprazole on top of clopidogrel as compared with patients not taking a PPI, indicating that the risk may be a class effect (hazard ratio [HR] 1.51; 95% confidence interval [CI] 1.39-1.64; P < .0001). The risk of adverse outcomes associated with the concomitant use of clopidogrel and PPIs has been confirmed in additional studies, and in general is also found in the placebo group of clopidogrel trials. , Such data have prompted a specific label change for clopidogrel indicating that concomitant use of drugs that inhibit CYP2C19 (e.g., omeprazole and other PPIs) should be discouraged.
In contrast to clopidogrel, there is little evidence that increasing aspirin dose influences responsiveness to aspirin as assessed by tests of platelet function or clinical outcomes, except possibly for diabetic patients in whom resistance may be partially overcome by higher aspirin doses. The preparation of aspirin does not appear to affect platelet inhibitory responses in the chronic phase; however, attenuated platelet inhibition by low-dose (81 mg) enteric-coated preparations has been observed within the first week.
Aspirin Nonresponsiveness and Clinical Outcomes
An increasing number of prospective studies linking laboratory measures of antiplatelet drug nonresponsiveness to adverse clinical outcomes have been reported. It is important to note that there are major limitations of the currently available data. The number of patients studied in all of the reports is small. The study designs are not adequate for controlling confounding variables. The dosage of aspirin varied, treatment compliance was not verified, and the definition of aspirin resistance is not uniform. Key historical studies are summarized below.
Grotemeyer and coworkers determined aspirin responsiveness in 180 stroke patients 12 hours after an oral intake of 500 mg aspirin. Patients with a platelet reactivity index of less than or equal to 1.25 were categorized as aspirin responders while those with an index of greater than or equal to 1.25 were defined as being secondary aspirin nonresponders (i.e., aspirin-resistant). All patients were prescribed aspirin 500 mg three times daily and were followed for 24 months. Stroke, MI, or vascular death were major outcome measures. The incidence of aspirin resistance was 33%. Complete follow-up was obtained in 174 patients (96%). Major events were noted in 29 patients: 5 (4.4%) in the aspirin-responder group versus 24 (40%) in the aspirin-resistant group ( P < .0001).
Mueller and coworkers studied 100 patients with intermittent claudication undergoing elective percutaneous balloon angioplasty. Aspirin was prescribed at a dose of 100 mg daily. Using corrected whole blood aggregometry they defined a normal response to aspirin as at least 20% reduction in platelet function with both ADP and collagen as agonists. Fluctuations in aspirin responsiveness among the studied population were noted on serial monitoring. The incidence of aspirin resistance was about 60% at each time point of measurement. At 52-week follow-up, 8 patients in the aspirin-resistance group were noted to have reocclusion at the angioplasty site, compared with none of the patients with a normal response to aspirin (87% increase in risk, P = .0093).
Eikelboom and coworkers performed a nested case-control study on 976 aspirin-treated patients, with documented or at high-risk of cardiovascular disease, from the Heart Outcomes Prevention Evaluation database. Aspirin responsiveness was divided into quartiles by urinary 11-dehydrothromboxane B 2 levels, a marker of in vivo thromboxane generation. After 5 years of follow-up, those patients in the highest quartile had 1.8-fold increase in risk for the composite of MI, stroke, or cardiovascular death (odds ratio [OR] 1.8; 95% CI 1.2-2.7; P = .009; Fig. 21-5 ) when compared to those in the lowest quartile. The risks of MI (OR 2.0; 95% CI 1.2-2.7; P = .006) and cardiovascular death (OR 3.50; 95% CI 1.7-7.4; P < .001) were likewise significantly increased.
Gum and colleagues enrolled 326 stable patients with cardiovascular disease taking aspirin 325 mg daily for 7 days or less and defined aspirin resistance as a mean aggregation of more than 70% with 10 µm ADP and a mean aggregation of more than 20% with 0.5 mg/mL arachidonic acid by optical platelet aggregation. Aspirin resistance was noted in 17 patients (5.2%). After a mean follow-up of 1.8 years, major events (death, MI, or stroke) occurred in 4 (24%) patients in the aspirin-resistant group, compared with 30 (10%) patients in the aspirin-sensitive group ( P = .03). The Kaplan-Meier time-to-event curves for event-free survival showed late divergence of the event curves that remained to be explained ( Fig. 21-6 ). Multivariate analysis demonstrated that, in addition to other risk factors such as increasing age, history of congestive heart failure, and elevated platelet count, aspirin resistance was an independent predictor of adverse outcomes (hazard ratio [HR] 4.14; 95% CI 1.42-12.06; P = .009).
Chen and coworkers tested aspirin responsiveness in patients undergoing elective PCI treated with aspirin at 80 to 300 mg daily for at least 7 days. Using the aggregation-based point-of-care Rapid Platelet Function Assay-Aspirin (VerifyNow Aspirin), 29 (19.2%) out of the 151 enrolled patients were found to be aspirin-resistant, as defined by an aspirin reaction unit (ARU) of greater than 550. Despite clopidogrel pretreatment with a loading dose of 300 mg at least 12 hours prior to the intervention and procedural anticoagulation using heparin, patients with aspirin resistance had a 2.9-fold increased risk of myocardial necrosis determined by creatine kinase-MB elevation when compared with aspirin-sensitive patients.
After reporting the predictors and prevalence of aspirin resistance among 468 stable patients with coronary artery disease using VerifyNow Aspirin, Chen and coworkers followed this cohort prospectively and found that after a mean follow-up of 379 ± 200 days, patients with aspirin resistance ( n = 128; 27.4%) were at increased risk of the composite outcome of cardiovascular (CV) death, MI, unstable angina requiring hospitalization, stroke, and transient ischemic attack compared with patients who were aspirin-sensitive (15.6% vs. 5.3%; HR 3.12; 95% CI 1.65-5.91; P < .001). Cox proportional hazard regression modeling identified aspirin resistance, diabetes, prior MI, and a low hemoglobin to be independently associated with major adverse long-term outcomes (HR for aspirin resistance 2.46; 95% CI 1.27-4.76; P = .007).
A systematic review and meta-analysis of aspirin “resistance” and risk of cardiovascular morbidity is highlighted in Figure 21-7 . Twenty studies totaling 2930 patients with cardiovascular disease and treated with aspirin 75 to 325 mg were included. Compliance was confirmed directly in only 14 out of 20 studies and 28% were classified as aspirin resistant using a variety of ex vivo platelet function assays and non-uniform definitions of resistance. Aspirin resistant compared to aspirin sensitive patients were at a greater risk of any cardiovascular event (OR 3.85; 95% CI 3.08-4.80), death (OR 5.9; 95% CI 2.28-15.72), or acute coronary syndrome (OR 4.06; 95% CI 2.96-5.56).
Clopidogrel Nonresponsiveness and Clinical Outcomes
The first prospective study linking clinical outcome to clopidogrel responsiveness was reported by Barragan and coworkers. Using assay of vasodilator-stimulated phosphoprotein phosphorylation (VASP), a marker of platelet inhibition that exhibited an inverse relationship to thienopyridine treatment efficacy, platelet reactivity was evaluated in consecutive patients (n = 16) undergoing coronary stenting treated with ticlopidine (n = 9) or clopidogrel (n = 7) who experienced subacute stent thrombosis (ST) and compared these with other patients (n = 30; 22 received ticlopidine, 8 received clopidogrel) free of subacute ST. A significant difference in platelet reactivity was noted between these two groups of patients (63.28% ± 9.56% vs. 39.80% ± 10.9%, respectively; P < .001).
Matetzky and coworkers evaluated clopidogrel responsiveness in 60 patients with ST-segment elevation MI undergoing primary PCI with stent implantation. The antithrombotic regimen included 300 mg aspirin on admission, heparin, eptifibatide, and clopidogrel 300 mg on completion of PCI and 75 mg daily for 3 months. Patients were stratified into quartiles according to the percentage reduction of ADP (5 µmol/L)-induced platelet aggregation at day 6 compared to baseline and those in the first quartile ( n = 15) were considered resistant to clopidogrel. At 6-month follow-up, six out of the 15 patients (40%) resistant to clopidogrel developed 7 recurrent ischemic cardiovascular event (acute coronary syndromes [ACS], acute peripheral arterial occlusion, mortality from ischemic stroke), whereas only 1 patient (6.7%) in the second quartile and no patients in quartiles 3 or 4 experienced an event ( P for trend = .007) ( Fig. 21-8 ).
