Development of a routine bedside CYP2C19 genotype assessment program for antiplatelet therapy guidance in a community hospital catheterization laboratory.

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1 h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622.

Assessment of Aspirin and Clopidogrel Resistance in Patients Undergoing Cardiovascular Surgery: A Single-Center Cross-Sectional Study

Objective: We aimed to investigate antiplatelet drug resistance utilizing light transmission-lumiaggregometry (LT-LA) and the Platelet Function Analyzer-100 (PFA-100) in patients undergoing cardiovascular surgery. Materials and Methods: The study included 60 patients diagnosed with stable coronary artery disease and peripheral vascular diseases that required surgery. Participants were divided into three groups: patients receiving aspirin (ASA) (n=21), patients receiving clopidogrel (CLO) (n=19), and patients receiving dual therapy (ASA+CLO) (n=20). Aggregation and secretion tests by LT-LA and closure time by the PFA-100 were used to measure antiplatelet drug resistance. Results: Based on the adenosine diphosphate (ADP)-induced aggregation test, 43% of patients were resistant to ASA, 22% to CLO, and 15% to dual therapy. Diabetes, hypertension, and hyperlipidemia were the most commonly identified comorbid disorders. In patients with comorbid risk factors, the median value of platelet aggregation response to ADP was significantly higher in the ASA group than in the CLO and dual therapy groups (p=0.0001). In patients receiving ASA monotherapy, the maximum amplitude of aggregation response to platelet agonists was ≥70% in 43% of patients for ADP and 28% for collagen by LT-LA. Elevated ADP (≥0.29 nmol) and collagen (≥0.41 nmol)-induced adenosine triphosphate release were found by LT-LA in 66% of patients utilizing an ADP agonist and 80% of patients using a collagen agonist undergoing ASA therapy. Closure times obtained with the PFA-100 were normal in 28% of patients using collagen-ADP cartridges and 62% of patients using collagen-epinephrine (CEPI) cartridges who received ASA. Recurrent thrombosis and bleeding were observed in 12 (20%) patients with cardiovascular disease. Three of these individuals (25%) showed ASA resistance with normal responses to ADP-induced aggregation (≥70%) and secretion (≥0.29 nmol), as well as normal CEPI closure times. Conclusion: Our findings suggest that antiplatelet drug monitoring by LT-LA and PFA-100 may be useful for high-risk and complicated cardiovascular patients.

Empiric treatment with aspirin and ticagrelor is the most cost-effective strategy in patients with minor stroke or transient ischemic attack.

BACKGROUND: Patients with minor ischemic stroke or transient ischemic attacks (TIAs) are often treated with dual antiplatelet therapy regimens as part of secondary stroke prevention. Clopidogrel, an antiplatelet used in these regimens, is metabolized into its active form by the CYP2C19 enzyme. Patients with loss of function (LOF) mutations in CYP2C19 are at risk for poorer secondary outcomes when prescribed clopidogrel. AIMS: We aimed to determine the cost-effectiveness of three different treatment antiplatelet regimens in ischemic stroke populations with minor strokes or TIAs and how these treatment regimens are influenced by the LOF prevalence in the population. METHODS: Markov models were developed to look at the cost-effectiveness of empiric treatment with aspirin and clopidogrel versus empiric treatment with aspirin and ticagrelor, versus genotype-guided therapy for either 21 or 30 days. Effect ratios were obtained from the literature, and incidence rates and costs were obtained from the national data published by the Singapore Ministry of Health. The primary endpoints were the incremental cost-effectiveness ratios (ICERs). RESULTS: Empiric treatment with aspirin and ticagrelor was the most cost-effective treatment. Genotype-guided therapy was more cost-effective than empiric aspirin and clopidogrel if the LOF was above 48%. Empiric ticagrelor and aspirin was cost saving when compared to genotype-guided therapy. Results in models of dual antiplatelet therapy for 30 days were similar. CONCLUSION: This study suggests that in patients with minor stroke and TIA planned for dual antiplatelet regimens, empiric ticagrelor and aspirin is the most cost-effective treatment regimen. If ticagrelor is not available, genotype-guided therapy is the most cost-effective treatment regimen if the LOF prevalence in the population is more than 48%.

Cost-effectiveness analysis of CYP2C19 genotype-guided antiplatelet therapy for patients with acute minor ischemic stroke and high-risk transient ischemic attack in China.

AIMS: The study aimed to estimate the cost-effectiveness of CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel, compared to conventional antiplatelet therapy with clopidogrel and aspirin. METHODS: A 90-day decision tree and 30-year Markov model were employed to assess the costs and quality-adjusted life years (QALYs) of personalized antiplatelet therapy for patients with minor ischemic stroke and high-risk transient ischemic attack, compared to conventional antiplatelet therapy in the Chinese healthcare system. The primary outcome was the incremental cost-effectiveness ratio (ICER). The data sources included clinical trials, published literature, official documents and local prices. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to confirm the robustness of the findings. RESULTS: The base-case analysis indicated that the CYP2C19 genotype-guided antiplatelet strategy was cost-effective, and cilostazol group and ticagrelor group yielded an ICER of 3327.40 US dollars (USD)/QALY and 3426.92 USD/QALY, respectively, which were less than threshold. The one-way sensitivity analysis showed the results were robust, where the most sensitive parameter was the disability distribution in the modified Rankin scale 3-5. The probabilistic analysis showed that the CYP2C19 genotype-guided antiplatelet therapy with either cilostazol or ticagrelor was 100% cost-effective under the willingness-to-pay threshold. CONCLUSIONS: CYP2C19 genotype-guided antiplatelet therapy using cilostazol and ticagrelor as an alternative to clopidogrel appeared to be more cost-effective than conventional antiplatelet therapy for acute minor ischemic stroke and high-risk transient ischemic attack patients over 30 years in China.

Utilization of P2Y12 Inhibitors in Older Adults With ST-Elevation Myocardial Infarction and Frailty.

Choosing optimal P2Y12 inhibitor in frail older adults is challenging because they are at increased risk of both ischemic and bleeding events. We conducted a retrospective cohort study of Medicare Advantage Plan beneficiaries who were prescribed clopidogrel, prasugrel, or ticagrelor after percutaneous coronary intervention-treated ST-elevation myocardial infarction from January 1, 2010 to December 31, 2020. Frailty was defined using claims-based frailty index ≥0.25. We conducted multivariable logistic regression to identify factors associated with using potent P2Y12 inhibitors and multivariable-adjusted competing risk analyses to compare the rate of discontinuation of potent P2Y12 inhibitors in frail versus non-frail patients. There were 11,239 patients (mean age 74 years, 39% women). The prevalence of cardiovascular and geriatric co-morbidities was as follows: 32% chronic kidney disease, 28% heart failure, 10% previous myocardial infarction, 6% dementia, 20% anemia, and 12% frailty. The proportion of patients receiving clopidogrel decreased from 78.3% in 2010 to 2013 to 42.1% in 2018 to 2020, with a concurrent increase in those receiving potent P2Y12 inhibitors (mostly ticagrelor) from 21.7% to 57.9%. Frailty was independently associated with reduced odds of initiation (odds ratio 0.78, 95% confidence interval 0.67 to 0.90) but not with discontinuation of potent P2Y12 inhibitors (subdistribution hazard ratio 1.09, 95% confidence interval 0.98 to 1.22). In conclusion, frail older adults are less likely to receive potent P2Y12 inhibitors after percutaneous coronary intervention-treated ST-elevation myocardial infarction, but they are as likely as non-frail patients to continue with the prescribed P2Y12 inhibitor.

Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies.

Background: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting: The study was set in primary and secondary care in England from 2010 to 2017. Participants: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration: This trial is registered as ISRCTN76607611. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients' attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks.

Economic evaluation of pharmacogenomic-guided antiplatelet treatment in Spanish patients suffering from acute coronary syndrome participating in the U-PGx PREPARE study.

BACKGROUND: Cardiovascular diseases and especially Acute Coronary Syndrome (ACS) constitute a major health issue impacting millions of patients worldwide. Being a leading cause of death and hospital admissions in many European countries including Spain, it accounts for enormous amounts of healthcare expenditures for its management. Clopidogrel is one of the oldest antiplatelet medications used as standard of care in ACS. METHODS: In this study, we performed an economic evaluation study to estimate whether a genome-guided clopidogrel treatment is cost-effective compared to conventional one in a large cohort of 243 individuals of Spanish origin suffering from ACS and treated with clopidogrel. Data were derived from the U-PGx PREPARE clinical trial. Effectiveness was measured as survival of individuals while study data on safety and efficacy, as well as on resource utilization associated with each adverse drug reaction were used to measure costs to treat these adverse drug reactions. A generalized linear regression model was used to estimate cost differences for both study groups. RESULTS: Based on our findings, PGx-guided treatment group is cost-effective. PGx-guided treatment demonstrated to have 50% less hospital admissions, reduced emergency visits and almost 13% less ADRs compared to the non-PGx approach with mean QALY 1.07 (95% CI, 1.04-1.10) versus 1.06 (95% CI, 1.03-1.09) for the control group, while life years for both groups were 1.24 (95% CI, 1.20-1.26) and 1.23 (95% CI, 1.19-1.26), respectively. The mean total cost of PGx-guided treatment was 50% less expensive than conventional therapy with clopidogrel [€883 (95% UI, €316-€1582), compared to €1,755 (95% UI, €765-€2949)]. CONCLUSION: These findings suggest that PGx-guided clopidogrel treatment represents a cost-effective option for patients suffering from ACS in the Spanish healthcare setting.

Early Effects of Ticagrelor Versus Clopidogrel on Peripheral Endothelial Function After Non-ST-Elevation Acute Coronary Syndrome and Assessment of Its Relationship With Coronary Microvascular Function.

Peripheral endothelial dysfunction is an independent predictor of adverse long-term prognosis after acute coronary syndrome. Data are lacking on the effects of oral P2Y12-inhibitors on peripheral endothelial function in non-ST-elevation acute coronary syndrome (NSTEACS). Furthermore, the relation between peripheral endothelial function and invasive indexes of coronary microvascular function in NSTEACS is unclear. Between March 2018 and July 2020, hospitalized patients with NSTEACS were randomized (1:1) to ticagrelor or clopidogrel. Peripheral endothelial function was assessed with brachial artery flow-mediated vasodilation (FMD). Invasive indexes of coronary microvascular function were obtained using an intracoronary pressure-temperature sensor-tipped wire. In 70 patients included, mean age was 58.6 years, 78.6% (n = 55) were male and 20% (n = 14) had diabetes mellitus. Compared with clopidogrel, ticagrelor significantly improved FMD (14.2 ± 5.4% vs 8.9 ± 5.3%, p <0.001) after a median treatment time of 41.2 hours. The FMD was significantly correlated with the index of microcirculatory resistance (IMR) measured in the infarct-related artery (r = -0.38, p = 0.001), with a stronger correlation found in those who did not have percutaneous coronary intervention (r = -0.52, p = 0.03). Using receiver operating characteristic curve analysis, an FMD of 8.2% identified an IMR of >34 as the threshold, with 77.6% sensitivity and 52.4% specificity. In patients who did not have a percutaneous coronary intervention, an FMD of 11.49% identified an IMR of >34 with 84.6% sensitivity and 80% specificity. In conclusion, ticagrelor significantly improved peripheral endothelial function compared with clopidogrel in patients with NSTEACS. There was a significant correlation between brachial artery FMD and IMR of the infarct-related artery.

Utilization Trends In Platelet Adenosine Diphosphate P2Y12 Receptor Inhibitor and Cost Among Medicare Beneficiaries.

Recent guidelines regarding acute coronary syndrome (ACS) have advocated for use of prasugrel and ticagrelor over clopidogrel for acute coronary syndrome. However, analyses from multiple databases have shown that clopidogrel continues to be the most commonly prescribed P2Y12 inhibitor. We aimed to evaluate the trends in utilization and cost of P2Y12 inhibitors for Medicare beneficiaries using data from Medicare Part D Prescription Drug Data Event set from 2011 to 2018 for P2Y12 inhibitors. Medicare part D total beneficiaries for P2Y12 receptor inhibitors increased from 2011 to 2018 by 34.8% from 2.45 million to 3.31 million. The total cost for P2Y12 antiplatelets decreased from $ 3.72 billion in 2011 to $ 0.72 billion in 2018 by 80.4%. The availability of generic clopidogrel drove the considerable total cost reduction. Clopidogrel was the most prescribed P2Y12 inhibitor since its introduction accounting for more than 90% of the Medicare beneficiaries from 2013 to 2018. Overall, the number of beneficiaries on newer P2Y12 inhibitors showed a steady increase with 5.9% beneficiaries on brilinta in 2018 and 2.1 % on prasugrel. The total cost of brilinta beneficiaries grew exponentially accounting for 59.2% of total cost in 2018 and average cost per beneficiary increased by 465% in study period. Despite the availability of generic version clopidogrel and prasugrel, 2,161,175 beneficiaries were on brand plavix and 87,174 on effient which contributed to the increased total expenditure. Earlier introduction and transition to generic versions of medication may help to reduce the drug cost and potentially enhance medication compliance.

Cost-effectiveness of testing for CYP2C19 loss-of-function carriers following transient ischemic attack/minor stroke: A Canadian perspective.

BACKGROUND: The CHANCE-2 study compared 3 weeks of aspirin-ticagrelor to aspirin-clopidogrel in CYP2C19 loss-of-function (LOF) allele carriers following a transient ischemic attack (TIA)/minor stroke and demonstrated a modestly lower risk of stroke recurrence with aspirin-ticagrelor. This stroke protection was largely for minor stroke and came at an increased risk of bleeding. The cost-effectiveness of implementing testing for LOF allele status to personalize antiplatelet regimen for secondary stroke prevention after a TIA/minor stroke in the Canadian health care context is unknown. METHODS: Cost-effectiveness analysis using a decision-analytic Markov cohort model with a lifetime horizon was performed to determine the costs and health benefits of testing for LOF allele status compared with no testing (current standard of care). The population of interest was patients living in Canada who suffered a TIA/minor stroke. Outcomes of interest were life-years gained (LYG), quality-adjusted life years (QALY) gained, costs (reported in 2022 Canadian dollars), and the incremental cost-effectiveness ratio (ICER). We adopted the perspective of the Federal, Provincial, and Territorial Ministries of Health and used a 1.5% annual discount rate. Sensitivity analyses were performed to assess uncertainty. RESULTS: Compared to standard of care, LOF allele testing leads to 0.14 LYG (undiscounted), 0.12 QALYs gained (undiscounted), and additional lifetime costs of CAD$432 (discounted) per patient. The ICER of the LOF allele testing strategy is CAD$4310 per QALY gained compared with standard of care. The probabilistic sensitivity analyses demonstrated that LOF allele testing was cost-effective in more than 99.99% of simulations using a willingness-to-pay threshold of CAD$50,000 per QALY. CONCLUSION: Based on available evidence, testing for LOF allele followed by short duration 3 weeks of aspirin-ticagrelor compared to standard-of-care aspirin-clopidogrel can lead to prolonged life and improved quality of life and can be considered very cost-effective when compared with other well-accepted technologies in health and medicine.

Cost-effectiveness of CYP2C19-guided P2Y12 inhibitors in Veterans undergoing percutaneous coronary intervention for acute coronary syndromes.

AIMS: CYP2C19-guided P2Y12 inhibitor selection can reduce cardiovascular (CV) events and bleeding in patients with acute coronary syndromes (ACSs) post-percutaneous coronary intervention (PCI). The 12-month cost-effectiveness of CYP2C19-guided P2Y12 inhibitor selection for Veterans post-ACS/PCI was evaluated from the Veterans Health Administration's (VHA) perspective. METHODS AND RESULTS: Using average annualized PCI volumes and P2Y12 inhibitor use from VA data, a decision-analytic model simulated CYP2C19 testing vs. no testing outcomes in 2800 hypothetical Veterans receiving PY212 inhibitor for 12 months post-ACS/PCI (74% clopidogrel, 5% prasugrel, and 21% ticagrelor use at baseline without testing). CYP2C19 loss-of-function (LOF) carrier prevalence was 28%. Model inputs were from studies (bleeding/ischaemic events, CYP2C19-guided therapy effect, health state utilities, CYP2C19 LOF carrier prevalence) and VHA administrative data (costs of events, drugs, CYP2C19 testing; PCI volumes, and P2Y12 inhibitor prescriptions). The primary outcome was cost (2020 US${\$}$) per quality-adjusted life year (QALY) gained. Base-case scenarios, probabilistic sensitivity analyses, and scenario analyses were completed. CYP2C19-guided therapy resulted in 496 (24%) escalations (clopidogrel to prasugrel/ticagrelor) and 465 (65%) de-escalations (prasugrel/ticagrelor to clopidogrel). CYP2C19 testing averted 1 stroke, 27 myocardial infarctions, 8 CV-related deaths, and caused 3 bleeds. CYP2C19 testing (vs. no testing) was dominant in the base-case scenario (0.0027 QALYs gained, ${\$}$527 saved/person) and in 97.1% of simulations, making it cost-effective and high-value. In scenario analyses, de-escalation in conjunction with escalation is required for CYP2C19 testing to be cost-effective and high-value. CONCLUSION: In Veterans post-ACS/PCI, CYP2C19-guided P2Y12 inhibitor selection can improve CV outcomes and lower costs for the VHA within 12 months of implementation.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

Cost-Effectiveness of Cilostazol Added to Aspirin or Clopidogrel for Secondary Prevention After Noncardioembolic Stroke.

Background The objective of the study was to assess the cost-effectiveness of cilostazol (a selective phosphodiesterase 3 inhibitor) added to aspirin or clopidogrel for secondary stroke prevention in patients with noncardioembolic stroke. Methods and Results A Markov model decision tree was used to examine lifetime costs and quality-adjusted life years (QALYs) of patients with noncardioembolic stroke treated with either aspirin or clopidogrel or with additional cilostazol 100 mg twice daily. Cohorts were followed until all patients died from competing risks or ischemic or hemorrhagic stroke. Probabilistic sensitivity analysis using Monte Carlo simulation was used to model 10 000 cohorts of 10 000 patients. The addition of cilostazol to aspirin or clopidogrel is strongly cost saving. In all 10 000 simulations, the cilostazol strategy resulted in lower health care costs compared with aspirin or clopidogrel alone (mean $13 488 cost savings per patient; SD, $8087) and resulted in higher QALYs (mean, 0.585 more QALYs per patient lifetime; SD, 0.290). This result remained robust across a variety of sensitivity analyses, varying cost inputs, and treatment effects. At a willingness-to-pay threshold of $50 000/QALY, average net monetary benefit from the addition of cilostazol was $42 743 per patient over their lifetime. Conclusions Based on the best available data, the addition of cilostazol to aspirin or clopidogrel for secondary prevention following noncardioembolic stroke results in significantly reduced health care costs and a gain in lifetime QALYs.

Cost Utility of Prasugrel in Postangioplasty Diabetic Patients.

OBJECTIVES: To prevent thrombotic events after angioplasty, current guidelines recommend dual antiplatelet therapy with aspirin and thienopyridine. Clopidogrel is the only thienopyridine currently available in the Brazilian National Health System. The purpose of this study was to determine the cost-effectiveness of prasugrel, an alternative thienopyridine, compared with clopidogrel in patients with acute coronary syndrome and diabetes mellitus who underwent angioplasty. METHODS: A state-transition Markov model was created to simulate the progression of diabetic patients after angioplasty. The model had a lifetime horizon and discounted outcomes at a 5% annual rate. The risks of myocardial infarction and death were calculated using data from the diabetes subgroup, and the risks of bleeding were calculated using data from the overall group from the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction 38 trial. Direct costs were estimated using official Brazilian open data. Quality of life values were obtained through literature search. Univariate and multivariate sensitivity analyses were performed. RESULTS: Prasugrel was associated with more quality-adjusted life-years (QALYs) (5.03 vs 4.94) and higher costs (US$975.11 vs US$575.97), resulting in an incremental cost-utility ratio (ICUR) of US$4303.86/QALY. In one-way sensitivity analysis, the costs of prasugrel had the greatest impact on ICUR, followed by the initial age entering the cohort. In the probabilistic sensitivity analysis, all ICUR values simulations were less than one Brazilian gross domestic product per capita/QALY (US $5802.86). CONCLUSIONS: Given the appealing economic profile, the clinical debate between reducing the risk of myocardial infarction and increasing the risk of bleeding may overcome economic concerns in the Brazilian National Health System.

Treatment Outcomes of Clopidogrel in Patients With ACS and Diabetes Undergoing PCI-Analysis of Beijing Municipal Medical Insurance Database.

Background and Aims: Several clinical trials have proved the efficacy of clopidogrel treatment for patients with percutaneous coronary intervention. There are few large-scale studies to identify the mortality associated with different durations of treatment of clopidogrel in patients with diabetes and ACS undergoing PCI in the Chinese population. The objective of this analysis was to determine the efficacy of long-term clopidogrel therapy (≥12 months) versus short-term use (<12 months) in Chinese patients with diabetes after PCI. Methods and Results: We used the Beijing Municipal Medical Insurance Database provided by the Beijing Municipal Medical Insurance Bureau. The Beijing Municipal Medical Insurance Database contained medical data of about 16 million people, including about 990,000 patients with diabetes and a history of taking antidiabetic medicines. Patients were divided into two groups, one group of 9,116 patients receiving consecutive clopidogrel for one year or more, and another group of 3290 patients receiving consecutive clopidogrel for less than one year. The primary outcomes of this analysis were the risk of all-cause death, myocardial infarction, and revascularization. In patients with diabetes after PCI, long-term clopidogrel treatment was associated with a reduced risk of all-cause death (HR, 0.57[95%CI, 0.49-0.67], P<0.0001), myocardial infarction (HR, 0.79[95%CI, 0.68-0.93], P=0.0035) and an increased risk of angina (HR, 1.18[95%CI, 1.10-1.27], P<0.0001]) and revascularization (HR, 1.07[95%CI, 1.01-1.13], P=0.02]). There was no significant difference in the prevalence of all-cause re-hospitalization, diabetes-related re-hospitalization, and cerebrovascular re-hospitalization. Conclusion: The present study concluded that long-term dual antiplatelet therapy including clopidogrel and aspirin could decrease the risks of all-cause death, myocardial infarction. But it could increase the risks of angina and revascularization. Further studies should interpret the cause of this question.

Cost-Effectiveness of Ticagrelor Compared with Clopidogrel in Patients with Acute Coronary Syndrome from Vietnamese Healthcare Payers' Perspective.

INTRODUCTION: The PLATelet inhibition and patient Outcomes (PLATO) trial (NCT00391872) demonstrated that ticagrelor compared to clopidogrel significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke in patients with acute coronary syndrome (ACS). The aim of this study is to analyze the long-term cost-effectiveness of ticagrelor compared to clopidogrel in ACS patients from a Vietnamese healthcare payers' perspective. METHODS: A two-part cost-effectiveness model was developed to estimate long-term costs and quality-adjusted life-years (QALY). Cardiovascular event rates, hospital bed days, interventions, investigations, study drug utilization and EuroQol 5 Dimension (EQ-5D) data were derived from the PLATO trial. Unit costs of medical services were derived from the Vietnamese governmental price list, and drug costs were based on the weighted average price from the Vietnamese social security report (in VND; 10.000 VND = 0.405 USD). An annual discount rate of 3% was used. Probabilistic and deterministic sensitivity analyses were conducted to evaluate uncertainty of the results. RESULTS: Ticagrelor was associated with an incremental cost of VND 5.34 million (USD 216.49) and a QALY gain of 0.11. This resulted in a cost per QALY gained of VND 49.58 million (USD 2009.96) from the Vietnamese healthcare payers' perspective. Probabilistic sensitivity analysis indicates that ticagrelor has 59% probability of being cost-effective compared with clopidogrel when using a willingness-to-pay threshold of one gross domestic products (GDP) per capita. Deterministic sensitivity analysis using clinical outcomes from the Asian sub-population of PLATO resulted in a cost per QALY of VND 42.25 million (USD 1712.80). CONCLUSION: Ticagrelor can be considered a cost-effective treatment for ACS compared with clopidogrel from a Vietnamese healthcare payers' perspective.

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.

Informe diário de evidências COVID-19: busca realizada em 24 de julho de 2020 / COVID-19 daily evidence report: search conducted on July 24, 2020

O Informe Diário de Evidências é uma produção do Ministério da Saúde que tem como objetivo acompanhar diariamente as publicações científicas sobre tratamento farmacológico e vacinas para a COVID-19. Dessa forma, são realizadas buscas estruturadas em bases de dados biomédicas, referentes ao dia anterior desse informe. Não são incluídos estudos pré-clínicos (in vitro, in vivo, in silico). A frequência dos estudos é demonstrada de acordo com a sua classificação metodológica (revisões sistemáticas, ensaios clínicos randomizados, coortes, entre outros). Para cada estudo é apresentado um resumo com avaliação da qualidade metodológica. Essa avaliação tem por finalidade identificar o grau de certeza/confiança ou o risco de viés de cada estudo. Para tal, são utilizadas ferramentas já validadas e consagradas na literatura científica, na área de saúde baseada em evidências. Cabe ressaltar que o documento tem caráter informativo e não representa uma recomendação oficial do Ministério da Saúde sobre a temática. Foram encontrados 21 artigos e 15 protocolos.

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.