The prognostic utility of tests of platelet function for the detection of 'aspirin resistance' in patients with established cardiovascular or cerebrovascular disease: a systematic review and economic evaluation.

BACKGROUND: The 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. OBJECTIVES: To 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 SOURCES: Bibliographic databases (e.g. MEDLINE from inception and EMBASE from 1980), conference proceedings and ongoing trial registries up to April 2012. METHODS: Standard 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. RESULTS: One 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. LIMITATIONS: Poor 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. CONCLUSIONS: Although 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 REGISTRATION: This study is registered as PROSPERO 2012:CRD42012002151. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Preoperative point-of-care platelet function testing in cardiac surgery.

OBJECTIVE: To investigate if the use of preoperative platelet function testing (PFT) as part of a transfusion algorithm reduced blood product usage in coronary artery bypass surgery (CABG). DESIGN: Prospective, randomized, controlled trial. SETTING: A cardiothoracic hospital. PARTICIPANTS: 249 patients having CABG surgery. INTERVENTIONS: The patients were allocated randomly to PFT preoperatively with Multiple Electrode Aggregometry (MEA, Group A), TEG PlateletMapping (PM, Group B) or none (control, Group C). Post-bypass bleeding management was determined by a transfusion algorithm. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was blood product transfusion in the first 48 hours post-surgery. There was a significant reduction in all blood product transfusion between Groups A (MEA) and B (PM) and Group C (control) (median number of units transfused, 2 (A)/2 (B)/ 4(C), p=0.02). Those in A and B received fewer units of red cells (median number of units, 0 (A)/1 (B) /2 (C), p=0.006) and fresh frozen plasma than the control Group C (median number of units, 0 (A)/0 (B)/2 (C), p<0.001), without receiving significantly more units of platelets (median number of units, 1 (A)/1 (B)/0 (C), p=0.11). In those who had taken an adenosine disphosphate (ADP)-receptor antagonist within 5 days (n=173), these results were amplified, and additionally, there was a significant cost saving (median cost, A=£1738.53, B=£1736.96, C=£3191.80 p=0.006). CONCLUSION: Preoperative PFT as part of a point-of-care testing-based transfusion algorithm led to a reduction in blood transfusion. There is a potential cost saving in those who have taken an ADP-receptor antagonist within 5 days.

Impact of Platelet Functional Assays on the Cost of Treating Suspected Heparin-Induced Thrombocytopenia.

OBJECTIVES: To investigate the potential cost savings of using functional platelet assays to confirm the diagnosis of heparin-induced thrombocytopenia (HIT). METHODS: This was a single-center study conducted in the United States. We performed a retrospective cost of illness analysis of suspected HIT, comparing patients with the serotonin release assay (SRA) ordered as part of their diagnostic evaluation to those who did not. The primary clinical end point was a composite of mortality and major bleed. RESULTS: A total of 147 patients met the study's inclusion criteria. An SRA was ordered in 53 patients of whom 17% were positive. Overall, SRA use did not reduce the composite primary clinical end point (32.1% vs 33%, P = .911). Also, there was no difference in the total cost of hospital stay (US $84781.1 vs US $78534.4, P = .409) nor in the direct medical costs related to HIT management (US $7473.5 vs US $8402.4, P = .393). Early ordering of the SRA (within 48 hours) was associated with shorter length of stay (20 vs 27 days, P = .029) but without a difference in cost of treatment. CONCLUSION: The use of SRA did not reduce the costs or improve clinical outcomes in patients with suspected HIT.

A model-based analysis of the clinical and economic impact of personalising P2Y12-receptor inhibition with platelet function testing in acute coronary syndrome patients.

Although some observational studies reported that the measured level of P2Y12-inhibition is predictive for thrombotic events, the clinical and economic benefit of incorporating PFT to personalize P2Y12-receptor directed antiplatelet treatment is unknown. Here, we assessed the clinical impact and cost-effectiveness of selecting P2Y12-inhibitors based on platelet function testing (PFT) in acute coronary syndrome (ACS) patients undergoing PCI. A decision model was developed to analyse the health economic effects of different strategies. PFT-guided treatment was compared with the three options of general clopidogrel, prasugrel or ticagrelor treatment. In the PFT arm, low responders to clopidogrel received prasugrel, while normal responders carried on with clopidogrel. The associated endpoints in the model were cardiovascular death, stent thrombosis and major bleeding. With a simulated cohort of 10,000 patients treated for one year, there were 93 less events in the PFT arm compared to general clopidogrel. In prasugrel and ticagrelor arms, 110 and 86 events were prevented compared to clopidogrel treatment, respectively. The total expected costs (including event costs, drug costs and PFT costs) for generic clopidogrel therapy were US$ 1,059/patient. In the PFT arm, total costs were US$ 1,494, while in the prasugrel and ticagrelor branches they were US$ 3,102 and US$ 3,771, respectively. The incremental-cost-effectiveness-ratio (ICER) was US$ 46,770 for PFT-guided therapy, US$ 185,783 for prasugrel and US$ 315,360 for ticagrelor. In this model-based analysis, a PFT-guided therapy may have fewer adverse outcomes than general treatment with clopidogrel and may be more cost-effective than prasugrel or ticagrelor treatment in ACS patients undergoing PCI.

Cost-effectiveness of universal and platelet reactivity assay-driven antiplatelet therapy in acute coronary syndrome.

Assays monitoring P2Y12 platelet reactivity can accurately predict which patients will have a poor response to clopidogrel. We sought to determine the cost-effectiveness of using platelet reactivity assays (PRAs) to select a dual-antiplatelet regimen for patients with acute coronary syndrome. A hybrid decision tree Markov model was developed to determine the cost-effectiveness of universal clopidogrel, ticagrelor, or prasugrel (given to all patients) or PRA-driven ticagrelor or prasugrel (given to patients with high platelet reactivity, defined as >230 on the VerifyNow P2Y12 assay; the others received generic clopidogrel). We assumed a cohort of 65-year-old patients with acute coronary syndrome and an incidence of high platelet reactivity of 32% and 13% at ~24 to 48 hours after revascularization and 1 month, respectively. The 5-year costs, quality-adjusted life-years, and incremental cost-effectiveness ratios were calculated for PRA-driven ticagrelor and prasugrel compared with universal clopidogrel, ticagrelor, or prasugrel. PRA-driven ticagrelor and prasugrel were cost-effective compared with universal clopidogrel (incremental cost-effectiveness ratio $40,100 and $49,143/quality-adjusted life-year, respectively); however, universal ticagrelor and prasugrel were not (incremental cost-effectiveness ratio $61,651 and $96,261/quality-adjusted life-year, respectively). Monte Carlo simulation suggested PRA-driven ticagrelor, PRA-driven prasugrel, universal ticagrelor, and universal prasugrel would have an incremental cost-effectiveness ratio <$50,000/quality-adjusted life-year in 52%, 40%, 23%, and 2% of the iterations compared with universal clopidogrel, respectively. Universal ticagrelor and prasugrel were not cost-effective compared with their respective PRA-driven regimens (incremental cost-effectiveness ratio $68,182; $116,875/quality-adjusted life-year, respectively). Monte Carlo simulation suggested universal ticagrelor and prasugrel would have an incremental cost-effectiveness ratio <$50,000/quality-adjusted life-year in 26% and 4% of iterations compared with their respective PRA-driven regimens. The results were most sensitive to differences in agent costs and drug-specific relative risks of death. In conclusion, even with generic clopidogrel, PRA-driven selection of antiplatelet therapy appeared to be a cost-effective strategy with the potential to decrease the overall acute coronary syndrome-associated healthcare costs.

A rapid, automated VWF ristocetin cofactor activity assay improves reliability in the diagnosis of Von Willebrand disease.

INTRODUCTION: The effective diagnosis and monitoring of Von Willebrand Disease (VWD) requires an accurate assessment of ristocetin co-factor activity (VWF:RCo). Current methodologies include automated platelet aggregometry and manual visual agglutination both of which are laborious to perform and notoriously subject to a high degree of inter and intra assay variation. METHODS AND MATERIALS: We have evaluated an automated VWF:RCo assay (BC Von Willebrand Reagent, Siemens, Marberg, Germany) for use on the Sysmex CS2100i analyser (Milton Keynes, UK) and retrospectively compared the results with an in-house manual visual agglutination assay and VWF antigen (Siemens) in normal subjects and in 53 patients with various types of VWD and 23 patients following VWF therapeutic treatment. RESULTS: The intra and interassay CV was improved with the automated assay (2.3% and 3.8% respectively) compared to 7% with the manual VWF:RCo assay. Good correlation was found between the two assays (r=0.91) in 53 patients with VWD. The mean manual VWF:RCo was 0.25IU/ml and mean automated VWF:RCo was 0.27IU/ml. A comparable increase in VWF:RCo following treatment, mostly with Desmopressin, was found in 13 patients with type 1 VWD (mean 3.9 fold increase with manual VWF:RCo and 3.1 fold with the automated VWF:RCo). In 13 patients with type 2 or 3 VWD following treatment mostly with concentrate , a higher increase was found with the automated VWF:RCo assay than the manual assay (mean 11.9 fold manually and mean 20.3 automated). CONCLUSION: The automated VWF:RCo assay shows enhanced precision and analysis time in this difficult and time consuming laboratory test and its introduction should greatly improve the reliability of VWF testing.

Assessing the current role of platelet function testing.

In vitro platelet function tests are commonly applied in research and offer justification for using antiplatelet therapy. However, studies assessing the ability of standardized platelet function tests to predict patients' clinical response to aspirin or clopidogrel have generated contradictory results. At this time, there is no standardized definition for resistance to antiplatelet therapy, and the appropriate treatment of patients who are hyporesponsive to these agents is not known. Although such tests have a role in research, their place in guiding therapy remains to be established, and prospective trials are urgently needed. The ideal platelet function test for clinical practice would be rapid, easy-to-use, inexpensive, and reliable.

Use of the platelet reactivity index by Grotemeyer, platelet function analyzer, and retention test Homburg to monitor therapy with antiplatelet drugs.

In 1974, Wu and Hoak described a method for determining circulating platelet aggregates. This method was modified by Grotemeyer in 1983. The platelet reactivity index (PR) is based on the ratio of platelet aggregates in blood samples obtained in different buffer solutions. Platelet aggregates are resolved when blood is sampled in EDTA-buffer, but remain fixed when EDTA-formalin-buffer is used. Generally, the PR is preferred, because in vitro manipulations of platelets are not necessary, and the results are calculated. PR values above 1.05 are suspicious for elevated platelet aggregation. PR values above 1.2 indicate pathological changes in platelet aggregation. The PR is inexpensive (4.0 euro dollars) and rapid to perform. PR values were used successfully to identify nonresponders to secondary prophylaxis with acetylsalicylic acid (ASA), that is, patients suffering from stroke (33%) and patients after cardiac ischemia (18%). Furthermore, elevated PR values correlated significantly with the incidence of arterial thromboembolic complications. The PR correlated well in our prospective study with values received from the retention test Homburg (RT-H) and the platelet function analyzer (PFA-100). The data indicate that the values of the PR seem to be highly predictive for the evaluation of the ASA therapy. However, the PR is not feasible for the determination of the ASA overdosage.

In vitro tests for assessing heparin-induced thrombocytopenia in patients after elective hip replacement. A medico-economical evaluation.

OBJECTIVES: Considering the previously published incidences of heparin-induced thrombocytopenia (HIT) in patients receiving a thromboprophylactic therapy, the role of the hemostasis laboratory is essential in making a clinical decision. The purpose of this project was to compare the strategies of diagnosis and associated care of patients with suspected HIT after elective hip replacement using platelet aggregation assay, carbon 14-serotonin release, and "doing nothing." METHODS: The authors used an incremental cost-effectiveness analysis based on data extracted from the literature. The effectiveness of the strategies was represented by the number of deep venous thromboses prevented. Cost data were collected from the observation of biological and medical practice at Edouard Herriot University Hospital, Lyon, France, in 1999. RESULTS: In comparison with the strategies of doing nothing using no biological test for diagnosis, and clinical care of HIT-suspected patients, the strategy using platelet aggregation test was more expensive and less effective. With respect to the strategy using carbon 14-serotonin release assay, the incremental cost-effectiveness ratio, expressed as U.S. dollars per deep venous thrombosis prevented, reached $200,000, with a marginal effectiveness of eight deep venous thromboses prevented for 10,000 HIT-suspected patients. CONCLUSION: This study suggests that clinical hemostasis laboratories might consider replacing the platelet aggregation test with the carbon 14-serotonin release assay or should use another functional assay such as the flow cytometric assay for the diagnosis and care of patients with suspected HIT.