Platelets are inhibited by aspirin, and low dose aspirin improves outcome in patients with an increased risk of occlusive vascular events. The meta-analysis conducted by the Antithrombotic Trialists’ Collaboration shows that treatment with aspirin for 2 years reduces the risk of having an occlusive vascular event from 16.0% to 12.9% (1). However, these findings also imply that approximately one in eight patients treated with aspirin actually will experience an acute, serious vascular event during a 2-year follow-up period. Additionally, the effectiveness of aspirin has been questioned, since several laboratory studies have reported a highly variable response to aspirin treatment, and also that a considerable proportion of patients taking daily aspirin demonstrate a normal platelet function (2,3). These findings have resulted in the emergence of the phenomenon of “aspirin resistance” and “aspirin non-responsiveness”, and it has been hypothesised that patients who do not demonstrate a sufficient platelet inhibition during aspirin therapy are at increased risk of suffering future vascular events.
How to measure aspirin resistance
Aspirin acts by irreversibly acetylating the serine-529 residue at the active site of the cyclooxygenase (COX)-1 enzyme. Thereby COX-1 is inhibited from catalysing the conversion of arachidonic acid to thromboxane A2 (TxA2), prostacyclin, and other prostaglandins. TxA2 is a potent platelet agonist capable of inducing platelet aggregation. Having this mechanism of aspirin in mind, assessment of aspirin resistance can be approached in at least two different ways. Measuring the level of TxA2 and/or metabolites of TxA2 represents the ability of aspirin to inhibit the COX-1 enzyme, whereas assessment of platelet activation and aggregation describes aspirin's ability to inhibit platelet function (2,3,4).
A potential drawback regarding the measurement of the level of TxA2 is that TxA2 can be synthesised by inducible COX-2, which is not sufficiently inhibited by aspirin. Assessment of platelet function is also affected by potential limitations. The most relevant limitation is the fact that several other agents, as for example collagen, epinephrine, and adenosine diphosphate, can induce platelet activation and aggregation. The synthesis of these agents is not inhibited by aspirin, and in clinical conditions associated with elevated levels of these pro-aggregatory agents, they may stimulate platelet aggregation despite effective inhibition of the COX-1 enzyme, thereby mimicking aspirin resistance (5,6,7).
In order to give a more precise description of the phenomenon of aspirin resistance, we recommend to assess both COX-1 inhibition and platelet function, and it should be kept in mind, that ‘aspirin resistance’ may reflect platelet hyper-reactivity.
The ideal test for assessment of aspirin resistance
The optimal platelet function test for assessment of the platelet inhibition exhibited by aspirin should be reproducible, easy to perform, quick and cheap. Additionally, the validity and the power of a potential test should be documented in properly designed studies. There are several point-of-care platelet function test commercially available and also some in development, but at present none of the available tests fullfil all the criteria mentioned above.
Prevalence and clinical relevance of aspirin resistance
Studies have reported a prevalence of aspirin resistance in healthy volunteers and in patients with various manifestations of atherosclerosis in frequencies ranging from 5.5% to 63% (2,3). So far only a few published papers have provided knowledge on the clinical relevance of aspirin resistance (2,3). Overall, these trials support the hypothesis of an association between aspirin resistance and an increased risk of suffering future thrombotic complications. However, the studies were not designed to show whether aspirin resistance was associated with a poor clinical outcome. Therefore, conduction of prospective randomised trials designed with sufficient power to evaluate the prognostic relevance of aspirin resistance is warranted.
At present two international studies are ongoing.
- In the Oxford Vascular Study (OXVASC) 3.000 patients are enrolled in relation to an acute vascular event (stroke, transitory ischemic attack, peripheral vascular disease, or acute coronary syndrome) (8). The platelet function is evaluated by a Platelet Function Analyser–100, and all patients are on 75-300 mg aspirin daily. The pilot study identified 22/120 patients (18%) as aspirin resistant.
- In the ASCET (ASpirin non-responsiveness and Clopidogrel Endpoint Trial) – an on-going single center study from Oslo – 1.000 patients with coronary artery disease treated with aspirin 160 mg are tested for aspirin resistance using the Platelet Function Analyser-100 (9). Irrespective of the test result the patients are randomised to continued therapy with aspirin 160 mg daily or to clopidogrel 75 mg daily, and followed for clinical events for at least 2 years.
Identification of aspirin resistant patients and tailoring antiplatelet treatment may be an important step in the effort to improve morbidity and mortality of patients with atherothrombotic cardiovascular disease in the future. However, at present the validity and power of available data regarding the issue of aspirin resistance are not sufficient to advocate for alternative treatment strategies. This issue should be clarified by careful evaluation of new point-of-care platelet function tests and by the conduction of large-scale clinical randomised trials.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.