Author + information
- Andrew O. Maree, MSc, MD⁎ (, )
- Hani Jneid, MD and
- Desmond J. Fitzgerald, MD
- ↵⁎Division of Cardiology, Harvard Medical School, Massachusetts General Hospital, 55 Fruit Street, GRB 800, Boston, Massachusetts 02114
We read with interest the comprehensive review of “aspirin resistance” by Mason et al. (1). We suggest, based on our recent experience, that two less well-explored mechanisms may contribute to what is clearly a composite of several processes.
Interindividual pharmocodynamic variability occurs with most drugs. Aspirin is no different; thus aspirin resistance assays may reflect pharmacodynamic heterogeneity. Mason et al. (1) identify genotypic variation in cyclooxygenase (COX)-1 as a potential but unproven pharmacodynamic mechanism. We recently explored this hypothesis in a population with stable coronary artery disease (CAD) and determined that COX-1 haplotype modulates platelet response to aspirin determined by two established laboratory assays of COX inhibition: arachidonic acid-induced platelet aggregation and thromboxane B2generation in serum. Much of the effect, however, was associated with a single COX-1 haplotype carried by 12% of the population, and thus, although contributing to the problem, this does not explain the higher rates of aspirin resistance reported in several studies (2).
Mason et al. (1) also discuss pharmacokinetic resistance to aspirin and specifically the role of drug interaction and dose response; however, variability in aspirin formulation is another possible factor. It is worth recalling that initial dose-finding studies were performed with plain aspirin, which is rapidly absorbed from the stomach and inhibits platelet cyclooxygenase in the presystemic circulation. As mentioned by Mason et al. (1) dosing with 100 mg is sufficient to completely inhibit platelet cyclooxygenase. Accordingly, current American College of Cardiology/American Heart Association guidelines give aspirin a class I indication for use in patients with chronic stable angina (level of evidence A) (3). This recommendation, however, has been interpreted to embrace a myriad of aspirin formulations: various salts, polymer-coated in rapid-release (compressed, soluble), buffered, and enteric-coated preparations, which may influence the bioavailability of the preparation (4). We recently evaluated the effect of low-dose enteric-coated aspirin preparations on platelet COX-1 in both healthy volunteers and patients with stable CAD. Low-dose enteric-coated aspirin failed to inhibit platelet cyclooxygenase in some individuals. Specifically younger, heavier patients and those with a history of prior myocardial infarction were less likely to have an adequate response (5).
Not withstanding the initial uncontrolled studies, we agree that the jury is still out on the clinical relevance of aspirin resistance. However, it is not an unreasonable goal that a drug has its intended pharmacological effect. In the case of aspirin, near complete inhibition of platelet cyclooxygenase is most likely to be achieved with the correct preparation and dose.
- American College of Cardiology Foundation
- Mason P.J.,
- Jacobs A.K.,
- Freedman J.E.
- Gibbons R.J.,
- Chatterjee K.,
- Daley J.,
- et al.
- Maree A.O.,
- Curtin R.J.,
- Dooley M.,
- et al.