BackgroundThe use of aspirin is well established for secondary prevention of cardiovascular disease. However, a proportion of patients suffer repeat cardiovascular events despite being prescribed aspirin treatment. It is uncertain whether or not this is due to an inherent inability of aspirin to sufficiently modify platelet activity. This report aims to investigate whether or not insufficient platelet function inhibition by aspirin (‘aspirin resistance‘), as defined using platelet function tests (PFTs), is linked to the occurrence of adverse clinical outcomes, and further, whether or not patients at risk of future adverse clinical events can be identified through PFTs.ObjectivesTo review systematically the clinical effectiveness and cost-effectiveness evidence regarding the association between PFT designation of ‘aspirin resistance’ and the risk of adverse clinical outcome(s) in patients prescribed aspirin therapy. To undertake exploratory model-based cost-effectiveness analysis on the use of PFTs.Data sourcesBibliographic databases (e.g. MEDLINE from inception and EMBASE from 1980), conference proceedings and ongoing trial registries up to April 2012.MethodsStandard systematic review methods were used for identifying clinical and cost studies. A risk-of-bias assessment tool was adapted from checklists for prognostic and diagnostic studies. (Un)adjusted odds and hazard ratios for the association between ‘aspirin resistance’, for different PFTs, and clinical outcomes are presented; however, heterogeneity between studies precluded pooling of results. A speculative economic model of a PFT and change of therapy strategy was developed.ResultsOne hundred and eight relevant studies using a variety of PFTs, 58 in patients on aspirin monotherapy, were analysed in detail. Results indicated that some PFTs may have some prognostic utility, i.e. a trend for more clinical events to be associated with groups classified as ‘aspirin resistant’. Methodological and clinical heterogeneity prevented a quantitative summary of prognostic effect. Study-level effect sizes were generally small and absolute outcome risk was not substantially different between ‘aspirin resistant’ and ‘aspirin sensitive’ designations.No studies on the cost-effectiveness of PFTs for ‘aspirin resistance’ were identified. Based on assumptions of PFTs being able to accurately identify patients at high risk of clinical events and such patients benefiting from treatment modification, the economic model found that a test–treat strategy was likely to be cost-effective. However, neither assumption is currently evidence based.LimitationsPoor or incomplete reporting of studies suggests a potentially large volume of inaccessible data. Analyses were confined to studies on patients prescribed aspirin as sole antiplatelet therapy at the time of PFT. Clinical and methodological heterogeneity across studies precluded meta-analysis. Given the lack of robust data the economic modelling was speculative.ConclusionsAlthough evidence indicates that some PFTs may have some prognostic value, methodological and clinical heterogeneity between studies and different approaches to analyses create confusion and inconsistency in prognostic results, and prevented a quantitative summary of their prognostic effect. Protocol-driven and adequately powered primary studies are needed, using standardised methods of measurements to evaluate the prognostic ability of each test in the same population(s), and ideally presenting individual patient data. For any PFT to inform individual risk prediction, it will likely need to be considered in combination with other prognostic factors, within a prognostic model.Study registrationThis study is registered as PROSPERO 2012:CRD42012002151.FundingThe National Institute for Health Research Health Technology Assessment programme.

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IMPORTANCEIt is unclear whether patients with advanced cancer value surrogate end points, particularly progression-free survival (PFS). Despite this uncertainty, surrogate end points form the basis of regulatory approval for the majority of new cancer treatments.OBJECTIVE To summarize and qualitatively assess studies evaluating whether patients with advanced cancer understand and value PFS.EVIDENCE REVIEW MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature databases were searched from database inception to November 12, 2018. Articles eligible for inclusion investigated patient understanding, preference, or perceived value of disease progression or PFS in the setting of advanced cancer. Three authors independently reviewed and extracted data from all studies eligible for inclusion. FINDINGS In total, 17 studies representing 3646 patients were included. Of these studies, 15 specifically aimed to assess patients' values toward, and their willingness to trade off toxic effects for gains or losses in the end point of PFS. All studies examined used widely disparate definitions when attempting to describe the meaning of PFS to patients. Ten studies specifically presented patients with the term progression-free survival as an attribute choice. In the words used to define the attribute of PFS, 6 studies used the term survival. Five studies clarified that PFS may not translate into better overall survival, and 5 studies explained that improvements in PFS may not reflect how well the patient may feel. No study clarified that a PFS event could represent either progression or death, and no study defined for the patient what constituted progression. The studies assessed herein underrepresented ethnic and racial minorities (mean percentage of white patients, 88%; range, 77%-96%). Values and preferences may vary across cultural backgrounds given that different relative preferences were assigned to cost and efficacy outcomes in North American vs Asian studies, although only a few studies were evaluated. CONCLUSIONS AND RELEVANCEThe existing literature evaluating patients' understanding, preferences, and values toward the end point of PFS was severely limited by the heterogeneity of methods, attribute selection, and descriptions used to define PFS to patients. High-quality studies are needed that clearly define PFS for patients and that systematically document their understanding of the term. Only then can it be assessed whether PFS is an end point of value to patients with advanced cancer.

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Our QI initiative was successful in improving rates of GOC documentation in patients with advanced cancer.