What is Aspirin Resistance ?
Aspirin works by irreversibly acetylating the cyclooxygenase (COX)-1 enzyme, thus suppressing thromboxane A . Thromboxane A serves as a potent agonist of platelet aggregation, and aspirin prevents thrombus formation via this mechanism. However, its antiplatelet effect is not uniform in all patients and its inhibition of platelet aggregation is subject to inter-individual and intra-individual variability. This unpredictable response to aspirin can be attributed to clinical, cellular, and genetic factors. Despite appropriate doses of aspirin, many patients develop recurrent ischemic events. This clinical dilemma has often been attributed to aspirin resistance, a broad term that encompasses the wide variety of factors thought to contribute to this phenomenon (figure below ) .
Clinical causes of aspirin resistance can range from patient non-compliance to physicians who display aspirin resistance, that is, physicians who fail to prescribe aspirin appropriately (Figure). Alternatively, patients may take aspirin but not absorb it, or may have interactions because of other medications. Ibuprofen, for example, can adhere to the COX-1 binding site of aspirin, and may via steric hindrance prevent aspirin from exerting its antiplatelet effect and limit its cardioprotective function.
The doseof aspirin may contribute to uninhibited platelet activity depending on the weight and age of patients.It can all be explained by pharmacokinetics, the speed of absorption, which is actually surprisingly slow for the coated version.Coated aspirin will eventually have the desired effect, but onset of action takes a few days. This is no problem for chronic therapy, but the compliance issue may be.
In addition, ACSs and congestive heart failure are associated with increased platelet reactivity. Hyperglycaemia
may decrease the effectiveness of antiplatelet therapy by increasing reactive oxidant species, whereas hypercholesterolaemia may blunt aspirin’s effect on thrombin. Exercise and the catecholamine surge associated with stress can also affect platelet responsiveness. Cellular factors inﬂuencing aspirin efﬁcacy include inadequate suppression of platelet COX-1. In addition, aspirin resistance has been attributed to COX-2 mRNA over-expression by platelets and endothelial cells, though
this remains controversial. 8-iso-PGF generation by catalysed arachidonate peroxidation may also cause aspirin resistance by binding thromboxane receptors. Resolvins, a family of bioactive omega-3 fatty acid metabolites, mediate the inﬂammatory response and are generated via COX-2 acetylation by aspirin. A deﬁciency of these products
could also inﬂuence therapeutic failure. Genetics also play a role in patient response to aspirin as polymorphisms of platelet membrane glycoproteins such as P1 (A1/A2) have been associated with an attenuated response to aspirin. Polymorphisms of von Willebrand Factor (vWF) or the collagen receptor gene have also been postulated to cause aspirin resistance.
Single nucleotide polymorphisms of the P2Y1 gene also can affect response to
aspirin. Despite these ﬁndings, the impact of polymorphisms on aspirin response remains controversial.
One systematic review of 15 studies revealed a wide range in estimates of the prevalence of laboratory aspirin resistance (5% to 65%).The lack of a uniform definition of aspirin resistance and its measurement has limited the understanding of this entity. The “gold standard” test of platelet function, light transmission aggregometry, is the most precise; however, it is time consuming and cannot be performed at the patient’s bedside.
Treating aspirin and clopidogrel resistance
The treatment for failed antiplatelet therapy is as yet undeﬁned. An initial approach would be to correct the clinical factors that may cause therapeutic resistance. Physicians must ensure proper patient compliance while also minimizing Drug –drug interactions. In addition, optimal control of glucose levels and cholesterol levels can reduce platelet reactivity. Currently, there is no good evidence that increasing aspirin dose would be useful.Data from (BRAVO) trial and the CURE trial actually indicate an increased risk of serious bleeding associated with high aspirin doses. However, it remains possible, though unproven, that increased doses of aspirin may overcome aspirin resistance in an individual patient. The addition of clopidogrel to aspirin is logical given its distinct mechanism of action. The Clopidogrel vs. Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study revealed modest superiority of clopidogrel monotherapy over aspirin monotherapy, while also showing an increased beneﬁt in high-risk patients. In terms of dual antiplatelet therapy, aspirin resistant patients have platelets that are more sensitive to ADP. The CURE and CREDO trials support this notion as they revealed the additive clinical beneﬁt of clopidogrel to aspirin.
1-Clinical Aspects of Platelet Inhibitors and Thrombus Formation
2-Pharmacologists question aspirin resistance