The clinical efficacy of aspirin as an antiplatelet agent to prevent occlusive arterial events in patients with atherothrombotic disease is well established; daily administration of aspirin has been shown to reduce the risk of stroke, myocardial infarction (MI) and death by approximately 25% . Despite these proven benefits, many patients continue to experience thrombotic events. Several factors may influence the response of platelets to antiplatelet therapy , including treatment adherence . However, in some patients even in the context of verified compliance, aspirin fails to inhibit platelets as determined by ex vivo laboratory tests, a phenomenon termed “resistance” to antiplatelet therapy .
Many platelet function tests have been used to assess inhibition of platelet function induced by aspirin and their methodologies are diverse [5, 6]. While some assays study global haemostasis, most platelet function assays target a specific phase of platelet function, from platelet adhesion to platelet activation, secretion and aggregation [7, 8]. Methodological differences make it difficult to compare the test results. For example, some of these assays are carried out in whole blood (including whole blood aggregometry, platelet counting, PFA-100, VerifyNow, Impact-R and flow cytometry), while others require sample preparation (such as plasma or serum thromboxane B2 measurement), and others can be performed on urine (levels of the thromboxane B2 metabolite 11-dehydro-thromboxane B2) . Thresholds to determine whether platelet function is within a normal range may vary between studies of the same test depending on how the threshold was established (e.g., thresholds commonly reported in the literature, prescribed by the manufacturer or derived from comparisons with healthy control populations).
Most importantly, some assays are specific to the action of aspirin, by using an agonist that targets the platelet pathway inhibited by aspirin (the cyclooxygenase pathway) or by measuring metabolites of thromboxane A2 (which is the end-product of the pathway blocked by aspirin), while other platelet function assays assess pathways not directly affected by aspirin but measure global platelet reactivity [5, 10, 11]. The effect of aspirin is, of course, more obvious in aspirin-specific assays, but the global platelet reactivity assays could be more clinically relevant as they capture a more global portrait of platelet function . However, for such global assays to be able to determine resistance to aspirin therapy would require aspirin to be the only platelet function modifying agent used by the patient.
There is no official guideline recommending one assay above another, and platelet function testing is not recommended for routine clinical testing in patients requiring aspirin therapy . As a result, many of the available platelet function assays have been used in a research capacity, and part of the uncertainty surrounding the definition and clinical relevance of aspirin resistance is due to the non-interchangeable nature of these assays . As a consequence, there is a need to address basic questions on the prognostic and diagnostic utility and cost-effectiveness of platelet function testing in the context of aspirin therapy before testing can be recommended in clinical practice.
Existing systematic reviews
Three relevant recent systematic reviews were identified, all of which included a meta-analysis [15–17]. The review by Reny et al. looked at the PFA-100 test only to predict cardiovascular events in patients with symptomatic atherosclerosis, and included 8 prospective studies. A statistically significant result was reported for an increased risk of ischemic events in patients defined as ‘aspirin resistant’ by the test. The other reviews included a range of platelet function tests and identified 17 studies  and 20 studies  respectively. Both reviews reported a statistically significant increased risk of cardiovascular events in patients with ‘aspirin resistance’ as defined by the laboratory test(s).
There were some methodological limitations associated with the latter two reviews, including a lack of detail on quality assessment of included studies, the thresholds (cut-off points) used to define ‘aspirin resistance’ for each test, and patient compliance. The diagnostic utility of the tests (e.g., in terms of sensitivity and specificity) was also not considered. Further, heterogeneity between included studies due to differences in platelet function assays, study follow-up periods and aspirin dose, needs to be accounted for and, where possible, investigated in more detail. Since the completion of these reviews, several further studies have been published, particularly due to the emergence of dual/triple antiplatelet therapy regimens (where aspirin is one agent) for treating some at-risk populations with cardiovascular disease, such as those with acute coronary syndrome or undergoing percutaneous coronary intervention.
The aim of the current project is to perform a new systematic review that, in comparison to existing reviews, additionally incorporates any missed studies and/or studies published more recently; implements a more robust and complete meta-analysis of the evidence, including an improved approach to quantifying and examining clinical and statistical heterogeneity; and summarises the evidence in relation to both prognostic association (e.g., odds ratios, hazard ratios) and diagnostic/predictive test accuracy (e.g., sensitivity, specificity) for individual patients.
This systematic review will look at studies which relate platelet function testing to the risk of adverse clinical outcome(s) in patients on aspirin therapy with established cardiovascular or cerebrovascular disease, or diabetes. More specifically, the review will aim to determine the diagnostic/predictive utility and the prognostic utility of different platelet function tests:
to establish whether any of the available platelet function tests to determine “aspirin resistance” has sufficiently high diagnostic/predictive utility (e.g., sensitivity, specificity and positive and negative predictive values close to 1) in order to determine, for individual patients, if treatment modification should be considered based on the test result;
to establish whether any of the available platelet function tests has prognostic ability, i.e., whether it is able to distinguish between groups of patients with different average outcome risks even if it does not accurately predict individual outcome risk.
Further, the potential for a cost-effectiveness analysis will be considered. An economic model will be constructed and the potential for populating the model with data based on the results of the systematic review explored.