Cost-effectiveness of CYP2C19-guided antiplatelet therapy for acute coronary syndromes in Singapore.

We evaluated the cost-effectiveness of a genotype-guided strategy among patients with acute coronary syndromes using a decision-tree model based on the Singapore healthcare payer's perspective over a 1-year time horizon. Three dual antiplatelet strategies were considered: universal clopidogrel, genotype-guided, and universal ticagrelor. The prevalence of loss-of-function alleles was assumed to be 61.7% and model inputs were identified from the literature. Our primary outcome of interest was incremental cost-effectiveness ratio (ICER) compared to universal clopidogrel. Both genotype-guided (72,158 SGD/QALY) and universal ticagrelor (82,269 SGD/QALY) were considered cost-effective based on a willingness-to-pay (WTP) threshold of SGD 88,991. In our secondary analysis, the ICER for universal ticagrelor was 114,998 SGD/QALY when genotype-guided was taken as a reference. Probabilistic sensitivity analysis revealed that genotype-guided was the most cost-effective strategy when the WTP threshold was between SGD 70,000 to 100,000. Until more data are available, our study suggests that funding for a once-off CYP2C19 testing merits a consideration over 1 year of universal ticagrelor.

Economic Evaluations of CYP2C19 Genotype-Guided Antiplatelet Therapy Compared to the Universal Use of Antiplatelets in Patients With Acute Coronary Syndrome: A Systematic Review.

BACKGROUND AND OBJECTIVES: Clopidogrel is widely used after the percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) and requires activation by cytochrome P450 (CYP), primarily CYP2C19. Patients with CYP2C19 loss-of-function alleles are at increased risk of major adverse cardiovascular events, while more expensive novel antiplatelet agents (ticagrelor and prasugrel) are unaffected by the CYP2C19 mutations. This systematic review aims to answer the question about whether overall evidence supports the genotype-guided selection of antiplatelet therapy as a cost-effective strategy in post-PCI ACS. METHODS: A systematic literature search of PubMed, EMBASE, EconLit, and PharmGKB was done to identify all the economic evaluations related to genotype-guided therapy compared to the universal use of antiplatelets in ACS patients. Quality of Health Economic Studies tool was used for quality assessment. RESULTS: The search identified 13 articles, where genotype-guided treatment was compared to universal clopidogrel, ticagrelor, and/or prasugrel. Six studies showed that genotype-guided therapy was cost-effective compared to universal clopidogrel, while 5 studies showed that it was dominant. One study specified that genotype-guided with ticagrelor is cost-effective only in both CYP2C19 intermediate and poor metabolizers. Genotype-guided therapy was dominant when compared to universal prasugrel, ticagrelor, or both in 5, 1, and 3 studies, respectively. Only 2 studies reported that universal ticagrelor was cost-effective compared to genotype-guided treatment. All the included articles had good quality. CONCLUSION: Based on current economic evaluations in the literature, implementing CYP2C19 genotype-guided therapy is a cost-effective approach in guiding the selection of medication in patients with ACS undergoing PCI.

Cost-effectiveness of CYP2C19-guided antiplatelet therapy in patients with acute coronary syndrome and percutaneous coronary intervention informed by real-world data.

Current guidelines recommend dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitors following percutaneous coronary intervention (PCI). CYP2C19 genotype can guide DAPT selection, prescribing ticagrelor or prasugrel for loss-of-function (LOF) allele carriers (genotype-guided escalation). Cost-effectiveness analyses (CEA) are traditionally grounded in clinical trial data. We conduct a CEA using real-world data using a 1-year decision-analytic model comparing primary strategies: universal empiric clopidogrel (base case), universal ticagrelor, and genotype-guided escalation. We also explore secondary strategies commonly implemented in practice, wherein all patients are prescribed ticagrelor for 30 days post PCI. After 30 days, all patients are switched to clopidogrel irrespective of genotype (nonguided de-escalation) or to clopidogrel only if patients do not harbor an LOF allele (genotype-guided de-escalation). Compared with universal clopidogrel, both universal ticagrelor and genotype-guided escalation were superior with improvement in quality-adjusted life years (QALY's). Only genotype-guided escalation was cost-effective ($42,365/QALY) and demonstrated the highest probability of being cost-effective across conventional willingness-to-pay thresholds. In the secondary analysis, compared with the nonguided de-escalation strategy, although genotype-guided de-escalation and universal ticagrelor were more effective, with ICER of $188,680/QALY and $678,215/QALY, respectively, they were not cost-effective. CYP2C19 genotype-guided antiplatelet prescribing is cost-effective compared with either universal clopidogrel or universal ticagrelor using real-world implementation data. The secondary analysis suggests genotype-guided and nonguided de-escalation may be viable strategies, needing further evaluation.

Cost-effectiveness of CYP2C19 LOF-guided antiplatelet therapy in Chinese patients with acute coronary syndrome.

Aim: This study aimed to evaluate the cost-effectiveness of CYP2C19 loss-of-function(LOF) allele-guided antiplatelet therapy compared with the universal use of clopidogrel or ticagrelor among Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention. Methods: A two-part cost-effectiveness model comprising of a 1-year decision tree and a long-term Markov model was utilized to simulate outcomes of three treatment strategies: universal use of clopidogrel (75 mg daily) or universal use of ticagrelor 90 mg twice daily for all patients and CYP2C19 LOF-guided therapy (LOF allele carriers receiving ticagrelor, LOF allele noncarriers receiving clopidogrel). Model outcomes included quality-adjusted life years (QALYs) gained, direct medical costs and incremental cost-effectiveness ratios (ICERs). ICERs less than one-time gross domestic product per capita in China 59,660 yuan/QALY were considered cost-effective. Results: Base-case analysis showed 'universal ticagrelor use' was cost-effective for an ICER of 33,875 yuan per QALY gained compared with 'universal clopidogrel use' of which gained a 1.6932 QALYs at lowest life-long cost of 2450 yuan. CYP2C19 LOF-guided therapy had an effectiveness of 1.6975 QALYs at a cost of 2812 yuan, for an ICER of 84,118 yuan per QALY gained relative to 'universal clopidogrel use'. Sensitivity analysis demonstrated that base-case results were significantly affected by five factors: the risk ratio of 'non-fatal myocardial infarction', 'non-fatal stroke' and 'cardiovascular death' in ticagrelor versus clopidogrel and the annual costs of clopidogrel and ticagrelor. According to the results of Monte Carlo simulation, when willing to pay is about 32,000 yuan, patients willing to receive clopidogrel or ticagrelor are approximately equal. Conclusion: Optimal antiplatelet treatment is affected by lots of factors. The results of our study demonstrated that 'universal ticagrelor use' was cost-effective compared with 'universal clopidogrel use' for Chinese acute coronary syndrome patients with percutaneous coronary intervention.

Are There Different Evidence Thresholds for Genomic Versus Clinical Precision Medicine? A Value of Information-Based Framework Applied to Antiplatelet Drug Therapy.

BACKGROUND: The threshold of sufficient evidence for adoption of clinically- and genomically-guided precision medicine (PM) has been unclear. OBJECTIVE: To evaluate evidence thresholds for clinically guided PM versus genomically guided PM. METHODS: We develop an "evidence threshold criterion" (ETC), which is the time-weighted difference between expected value of perfect information and incremental net health benefit minus the cost of research, and use it as a measure of evidence threshold that is proportional to the upper bound of disutility to a risk-averse decision maker for adopting a new intervention under decision uncertainty. A larger (more negative) ETC value indicates that only decision makers with low risk aversion would adopt new intervention. We evaluated the ETC plus cost of research (ETCc), assuming the same cost of research for both interventions, over time for a pharmacogenomic (PGx) testing intervention and avoidance of a drug-drug interaction (aDDI) intervention for acute coronary syndrome patients indicated for antiplatelet therapy. We then examined how the ETC may explain incongruous decision making across different national decision-making bodies. RESULTS: The ETCc for PGx increased over time, whereas the ETCc for aDDI decreased to a negative value over time, indicating that decision makers with even low risk aversion will have doubts in adopting PGx, whereas decision makers who are highly risk-averse will continue to have doubts about adopting aDDI. National recommendation bodies appear to be consistent over time within their own decision making, but had different levels of risk aversion. CONCLUSION: The ETC may be a useful metric for assessing policy makers' risk preferences and, in particular, understanding differences in policy recommendations for genomic versus clinical PM.

Lower Copays Sweeten Outcomes-based Deal for Brilinta.

UPMC Health Plan gets a discount if a patient on Brilinta has a heart attack or stroke. The novel sweetener is that UPMC will lower the monthly copay for Brilinta from $45 to $10, which means the patient cost will be about the same as it is for generic Plavix.

Tailoring Antiplatelet Therapy Intensity to Ischemic and Bleeding Risk.

BACKGROUND: Balancing ischemic and bleeding risk is an evolving framework. METHODS AND RESULTS: Our objectives were to simulate changes in risks for adverse events and event-driven costs with use of ticagrelor or prasugrel versus clopidogrel according to varying levels of ischemic and bleeding risk. Using the validated PARIS risk functions, we estimated 1-year ischemic (myocardial infarction or stent thrombosis) and bleeding (Bleeding Academic Research Consortium types 3 or 5) event rates among PARIS study participants who underwent percutaneous coronary intervention with drug-eluting stent implantation for an acute coronary syndrome and were discharged with aspirin and clopidogrel (n=1497). Simulated changes in adverse events with ticagrelor or prasugrel were calculated by applying treatment effects from randomized trials for a 1-year time horizon. Event costs were estimated using National Inpatient Sample data. Net costs were calculated between antiplatelet therapy groups according to level of ischemic and bleeding risk. After weighting events for quality-of-life impact, we calculated event rates and costs for risk-tailored treatment versus clopidogrel under multiple drug pricing assumptions. One-year rates (per 1000 person-years) for ischemic events were 12.6, 24.1, and 66.1, respectively, among those at low (n=630), intermediate (n=536), and high (n=331) ischemic risk. Analogous bleeding rates were 11.0, 23.9, and 66.2, respectively, among low (n=728), intermediate (n=634), and high (n=135) bleeding risk patients. Mean per event costs were $22 174 (ischemic) and $12 203 (bleeding). When risks for ischemia matched or exceeded bleeding, simulated utility-weighted event rates favored ticagrelor/prasugrel, whereas clopidogrel reduced utility-weighted events when bleeding exceeded ischemic risk. One-year costs were sensitive to drug pricing assumptions, and risk-tailored treatment with either agent progressed from cost incurring to cost saving with increasing generic market share. CONCLUSIONS: Tailoring antiplatelet therapy intensity to patient risk may improve health utility and could produce cost savings in the first year after percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00998127.

Is ticagrelor worth its high cost and side-effects?

Ticagrelor is a reversible P2Y12 receptor antagonist that is more potent than clopidogrel. When used in combination with aspirin, it reduces cardiovascular events in patients with acute coronary syndrome. However, unbiased review of 5 randomised controlled trials indicates that although statistically significant, the clinical superiority of ticagrelor over clopidogrel is modest. Thus, identification of patients who benefit the most from ticagrelor is a priority. Besides bleeding issues, ticagrelor can frequently cause bouts of dyspnoea, which requires ticagrelor replacement by another P2Y12 receptor antagonist, with a loading dose.

The use of antiplatelet agents after an acute coronary syndrome in a large community Italian setting of more than 12 million subjects.

BACKGROUND: Antiplatelet agents are the cornerstone of medical treatment in acute coronary syndromes. The aim of this study was to evaluate the clinical epidemiology of patients after an acute coronary syndrome treated with different antiplatelet agent regimens in a large real community setting. METHODS: The ARCO database, including more than 12 million inhabitants, was evaluated. Antiplatelet agent prescriptions were analysed as follows: aspirin, clopidogrel, other antiplatelet agents used alone; the free and fixed combination of clopidogrel and aspirin; the free combination of aspirin with other antiplatelet agents. Healthcare costs included drug prescriptions (prices reimbursed by the Italian National Health System), outpatient specialist services and hospitalisations (Italian national tariffs). RESULTS: From 1 January to 31 December 2014, 26,834 patients were discharged after an acute coronary syndrome. Of these, 19,333 (77%) were prescribed with an antiplatelet agent. Among patients undergoing a revascularisation procedure either percutaneous or surgical (47% of the total population), antiplatelet agents were prescribed in 90% of cases. Dual antiplatelet agent therapy was prescribed in 49.6% of the total population and in 68.5% of those treated invasively. Prescription continuity was observed in just 75% of patients. The highest adherence was observed for the fixed combination of aspirin/clopidogrel (81.5%). Throughout one year of follow-up re-hospitalisation occurred in 47.9% of the patients and the direct cost per patient treated with an antiplatelet agent was €13,297 versus €16,647 in patients not treated with antiplatelet agents. CONCLUSIONS: This study highlights that antiplatelet agent prescriptions, specifically dual antiplatelet agent therapy, are at least suboptimal as well as in prescription continuity. Hospitalisations were frequent and were the main driver of the costs, accounting for 84% of the total costs for the Italian National Health System.

Switching from ticagrelor to clopidogrel in patients with ST-segment elevation myocardial infarction undergoing successful percutaneous coronary intervention in real-world China: Occurrences, reasons, and long-term clinical outcomes.

BACKGROUND: Although switching between ticagrelor and clopidogrel is common in clinical practice, the efficacy and safety of this de-escalation remain controversial. HYPOTHESIS: We assessed the occurrences, reasons, and outcomes of switching from ticagrelor to clopidogrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing successful primary percutaneous coronary intervention (PCI). METHODS: A total of 653 patients with STEMI were randomly assigned to receive loading dose of ticagrelor or clopidogrel before PCI and then received maintenance dose, respectively, for 12 months follow-up. The primary outcome was major adverse cardiac events (MACE), including cardiovascular death, nonfatal myocardial infarction, and stroke. The secondary outcome included unexpected rehospitalization for angina, coronary revascularization, and stent thrombosis. The safety outcome was bleeding described by the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: A total of 602 participants completed the study. The rate of switching from ticagrelor to clopidogrel was 48.6% and the main reason was financial burden. The rate of secondary ischemic events in the de-escalation group was higher than that in the ticagrelor group (15.1% vs 5.6%, P = 0.008), but lower than that in the clopidogrel group (15.1% vs 24.6%, P = 0.03), while there were no significant differences in MACE among the three groups (P = 0.16). De-escalation, ticagrelor, and clopidogrel did not cause significant differences in the rates of major bleeding among the three groups (BARC ≥ 2, P = 0.34). CONCLUSION: Switching from ticagrelor to clopidogrel is very common in patients with STEMI in China. De-escalation might be safe but associated with high risk of ischemic events as compared to ticagrelor.

Prescribing patterns of oral antiplatelets in Wales: evolving trends from 2005 to 2016.

AIM: Antiplatelets have been used for decades to prevent atherothrombotic disease, but there is limited 'real-life' prescribing data. We hereby report the prescribing patterns for oral antiplatelets in Wales, UK. METHODS/RESULTS: Retrospective analysis of anonymized data in Wales from 2005 to 2016 revealed differences in prescribing patterns of oral antiplatelets. Aspirin and dipyridamole use declined with a corresponding increase in clopidogrel prescription. Costs declined with a sharp decrease coinciding with clopidogrel coming off patent. Prasugrel and ticagrelor have shown significant cost contribution (29% of total) despite only forming 1% of total items prescribed in 2016. CONCLUSION: This first-look analysis of real-life antiplatelet data demonstrates a decrease in the overall prescribing costs with varying patterns. This may aid policy-makers in reviewing funding strategies.

Ticagrelor for Secondary Prevention of Atherothrombotic Events After Myocardial Infarction: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited AstraZeneca, the manufacturer of ticagrelor (Brilique®), to submit evidence on the clinical and cost effectiveness of ticagrelor 60 mg twice daily (BID) in combination with low-dose aspirin [acetylsalicylic acid (ASA)] compared with ASA only for secondary prevention of atherothrombotic events in patients with a history of myocardial infarction (MI) and who are at increased risk of atherothrombotic events. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Maastricht University Medical Centre+, was commissioned as the evidence review group (ERG). This paper summarises the company submission (CS), the ERG report and the NICE guidance produced by the appraisal committee (AC) for the use of ticagrelor in England and Wales. The ERG critically reviewed the clinical- and cost-effectiveness evidence in the CS. The systematic review conducted as part of the CS identified one randomised controlled trial (RCT), PEGASUS-TIMI 54. This trial reported the time to first occurrence of any event from the composite of cardiovascular death, MI and stroke as the primary outcome (hazard ratio 0.84 ticagrelor 60 mg BID vs. placebo, 95% confidence interval 0.74-0.95). The population addressed in the CS was a subgroup of the PEGASUS-TIMI 54 trial population, i.e. the 'base-case' population, which comprised patients who had experienced an MI between 1 and 2 years ago, whereas the full trial population included patients who had experienced an MI between 1 and 3 years ago. While the ERG believed the findings of this RCT to be robust, doubts concerning the applicability of the trial to UK patients were raised. The company submitted an individual patient simulation model to estimate the cost-effectiveness of ticagrelor 60 mg BID + ASA versus ASA only. Parametric time-to-event models were used to estimate the time to first and subsequent (cardiovascular) events, time to treatment discontinuation and time to adverse events. The company's base-case analysis resulted in an incremental cost-effectiveness ratio (ICER) of £20,098 per quality-adjusted life-year (QALY) gained. The main issues surrounding the cost effectiveness of ticagrelor 60 mg BID + ASA were the use of parametric time-to-event models estimated based on the full trial population instead of being fitted to the 'label' population (the 'label' population comprised the 'base-case' population and patients who started ticagrelor 60 mg BID within 1 year of previous adenosine diphosphate inhibitor treatment), the incorrect implementation of the probabilistic sensitivity analysis (PSA) of the individual patient simulation, and simplifications of the model structure that may have biased the health benefits and costs estimations of the intervention and comparator. The ERG believed the use of the full trial population to inform the parametric time-to-event models was not appropriate because the 'label' population was the main focus of the scope and CS. The ERG could not investigate the magnitude of the bias introduced by this assumption. The PSA of the individual patient simulation provided unreliable probabilistic results and underestimated the uncertainty surrounding the results because it was based on a single patient. The ERG used the cohort simulation presented in the cost-effectiveness model to perform its base-case and additional analyses and to obtain probabilistic results. The ERG amended the company cost-effectiveness model, which resulted in an ERG base-case ICER of £24,711 per QALY gained. In its final guidance, the AC recommended treatment with ticagrelor 60 mg BID + low-dose ASA for secondary prevention of atherothrombotic events in adults who have had an MI and are at increased risk of atherothrombotic events.