Aspirin resistance: myth or major problem?

Abstract

Cardiovascular disease is a major cause of long-term disability and, globally, is the number one cause of death according to the World Health Organization. Aspirin (acetylsalicylic acid), initially launched as a painkiller, is now widely used in the prevention of occlusive arterial events and has become one of the most commonly used drugs world-wide. It inhibits platelet aggregation and reduces the risk of myocardial infarction, stroke and vascular mortality by approximately 25 % among high-risk patients [1]. Platelet aggregation is inhibited by irreversible acetylation of the cyclooxygenase (COX)-1 enzyme, whereby platelet production of thromboxane A2 (TxA2) is effectively reduced. TxA2 is a vasoconstrictor and, in addition, acts synergistically with other platelet-derived products, such as ADP, to augment platelet activation and aggregation. This is essential to thrombus formation. The inhibition of COX-1 is irreversible, rapid, saturable and permanent for the life span of the anucleate platelets that are not able to synthesize new proteins. Even low daily doses of aspirin (75–150 mg) suppress thromboxane biosynthesis and reduce the risk of ischaemic events and vascular death among high-risk patients [1]. However, despite treatment with aspirin, 1 in 8 patients experiences a recurrent vascular event within 2 years [1], and this fact, together with laboratory findings of a low aspirin response, has given rise to the term ‘‘aspirin resistance’’ [2,3]. The prevalence of ‘‘aspirin resistance’’ ranges from only a few percent to 65 % of individuals tested in previous studies. One possible explanation for these divergent findings is the fact that ‘‘aspirin resistance’’ is being used to describe a number of different phenomena, including the clinical inability to protect patients from thrombotic events or the failure of aspirin to inhibit platelet aggregation as indicated by bleeding time, thromboxane measurements or determination of platelet aggregation. It has been suggested that the term ‘‘residual platelet reactivity’’ more completely covers these phenomena. Certainly, the considerable number of events among high-risk patients despite optimal anti-platelet therapy constitutes a major problem in clinical cardiology. Arterial thrombosis is multifactorial, however, and, accordingly, most adverse thrombotic events likely reflect treatment failure due to mechanisms other than actual resistance to anti-platelet therapy. A recent meta-analysis has shown that patients identified as being biochemically ‘‘aspirin resistant’’, defined as platelet aggregation despite aspirin treatment, are more likely to be clinically ‘‘aspirin resistant’’ in that they carry a significantly higher risk of vascular events compared with biochemically aspirin-sensitive patients [4]. In this meta-analysis, the mean prevalence of biochemical ‘‘aspirin resistance’’ was 27 %, and the odds ratio of cardiovascular outcomes in these patients was 3.8 [2.3–6.1]. This analysis lends support to the hypothesis of an association between biochemical ‘‘aspirin resistance’’ and an increased risk of thrombotic events. However, important differences between the included studies must be considered: study population, endpoints, follow-up time and the methods used to evaluate the biochemical aspirin response. Furthermore, most studies were fairly small and were not specifically designed to show whether biochemical ‘‘aspirin resistance’’ is associated with a poor clinical outcome. Therefore, conduction of large, prospective, randomized trials designed with sufficient power to evaluate the prognostic relevance of biochemical ‘‘aspirin resistance’’ is warranted. Currently, the results of a number of trials are awaited. Among these is the Norwegian ASCET (ASpirin nonresponsiveness and Clopidogrel Endpoint Trial) in which 1000 patients with coronary artery disease are randomized to continued treatment with either aspirin 160 mg/d or clopidogrel 75 mg/d after initial