Introduction

Approximately a fifth of all persons in the USA currently take aspirin on a routine basis, irrespective of age or indication. This proportion increases to almost 50% in patients over the age of 65 [1]. Despite ongoing debate regarding the utility of chronic aspirin use for primary prophylaxis in patients at high risk for developing cardiovascular disease [2], its central cardioprotective role in patients with coronary artery disease (CAD), peripheral vascular disease, and/or cerebrovascular disease has been well established. A landmark meta-analysis conducted by the Antiplatelet Trialists’ Collaboration [3] in the early 1990s including 145 randomized controlled clinical trials and 70,000 high-risk patients showed a robust risk reduction of approximately 25% in serious vascular events (defined as nonfatal myocardial infarction (MI), nonfatal stroke, or vascular death). This risk reduction was consistently demonstrated in patient subgroups, regardless of age, sex, and comorbid illnesses [3]. Indeed, the most recent American Heart Association (AHA)/American College of Cardiology (ACC) guidelines strongly favor the use of aspirin (75–162 mg daily) indefinitely for secondary prevention against atherosclerotic disease (class I, level of evidence A) [4]. In addition, aspirin (with the addition of a thienopyridine) has become the standard therapeutic regimen for patients with acute coronary syndromes (ACS) and for those undergoing percutaneous coronary intervention (PCI) [5].

Over the last decade, however, a preponderance of data has accrued that suggest that the antiplatelet effects of aspirin are nonuniform. In fact, a small, but substantial, proportion of patients may experience suboptimal platelet inhibition despite guideline-recommended dosing of this antiplatelet agent. In recent years, this phenomenon of “aspirin resistance” has transformed from a transient laboratory finding into a potentially clinically relevant entity. Reduced responsiveness to aspirin therapy may place patients at higher risk for adverse ischemic events, highlighting the importance of investigating the mechanisms underlying this phenomenon. The biological response to aspirin therapy is influenced by a number of factors including alterations in drug metabolism and distribution, genetic polymorphisms of molecular pathways, platelet hyperreactivity, and pharmacological interactions. This chapter will focus on the (i) definition and relative prevalence of aspirin resistance, (ii) clinical implications of this phenomenon, (iii) mechanisms of variability and suboptimal response, and (iv) potential methods to overcome aspirin resistance.

Definition, prevalence, and clinical implications of aspirin resistance

The overall definition of “aspirin resistance” is highly dependent on the specific assay, cutoffs (for abnormal values), and patient population. Although consensus working group has established a set of criteria for defining high on-treatment platelet reactivity (HTPR) for clopidogrel [6], to our knowledge, no such standardized definitions exist for aspirin. Most definitions rely on strict laboratory criteria based on various in vitro and ex vivo platelet assays. It should be noted that a number of studies have defined suboptimal response to aspirin as the upper fraction (e.g., quartile or quintile) of posttreatment residual platelet function in order to avoid issues with arbitrary, nonstandardized definitions. Furthermore, determination of aspirin responsiveness has largely been examined at a single-time point, generally before or after PCI. Platelet function may dynamically change in the periprocedural time period, and thus, platelet response to aspirin may vary with time. Definitive data are lacking regarding the stability of the aspirin resistance phenomenon over time. This emphasizes the dependence of test results on the particular patient setting, clinical status, and population.

Due to these factors, a wide range of prevalence rates have been reported in the literature ranging from less than 1% in certain population to over 60% of patients studied [7, 8, 9]. A well-conducted cross-sectional study by Lordkipanidzé et al. [10] compared the prevalence of aspirin resistance in 201 patients with stable CAD using six commonly utilized platelet assays (including light transmission aggregometry (LTA), whole blood aggregometry, Platelet Function Analyzer (PFA)-100, VerifyNow Aspirin assay, urine 11-dehydro-TXB₂ concentrations). Approximately 4% of patients were found to be aspirin resistant based on the gold standard LTA stimulated by arachidonic acid (AA). The relative frequency of aspirin resistance for other assays ranged from 6.7% (with VerifyNow Aspirin assay) to 59.5% (with PFA-100). Only few patients were identified by multiple assays to be resistant, and the agreeability between assays was poor [10]. There is especially poor correlation between direct measures of thromboxane metabolites and indirect assays of platelet function [11].

Mounting evidences over the last decade suggest that aspirin resistance is associated with a significantly increased risk of adverse cardiovascular events. In fact, three recent meta-analyses [12, 13, 14] consistently showed that patients with aspirin resistance, measured by a number of laboratory assays, had significantly worse prognosis compared to patients who were aspirin sensitive. Each meta-analysis included over 2000 patients and over 10 independent studies [12, 13, 14]. The pooled odds ratios for combined cardiovascular end points in each meta-analysis were 3.85 (3.08–4.80) [12], 3.8 (2.3–6.1) [13], and 3.11 (1.88–5.15) [14].