Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis

Objective To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel

The Clinical Implementation of CYP2C19 Genotyping in Patients with an Acute Coronary Syndrome:Insights From the FORCE-ACS Registry

BACKGROUND: Guidelines recommend prasugrel or ticagrelor for acute coronary syndrome (ACS) patients. However, these P2Y12 inhibitors increase bleeding risk compared to clopidogrel. Although genotype-guided P2Y12-inhibitor selection has been shown to reduce bleeding risk, data on its clinical implementation is lacking. METHODS: The study included ACS patients receiving genotype-guided antiplatelet therapy, utilising either a point-of-care (POC) device or laboratory-based testing. We aimed to collect qualitative and quantitative data on genotyping, eligibility for de-escalation, physician adherence to genotype results, time to de-escalation and cost reduction. RESULTS: Of the 1,530 patients included in the ACS registry from 2021 to 2023, 738 ACS patients treated with ticagrelor received a CYP2C19 genotype test. The median turnover time of genotyping was 6.3 hours (interquartile range [IQR], 3.2-16.7), with 82.3% of the genotyping results known within 24 hours after admission. POC genotyping exhibited significantly shorter turnaround times compared to laboratory-based testing (with respective medians of 5.7 vs 47.8 hours; P &lt; .001). Of the genotyped patients, 81.7% were eligible for de-escalation which was carried out within 24 hours in 70.9% and within 48 h in 93.0%. The time to de-escalation was significantly shorter using POC (25.4 hours) compared to laboratory-based testing (58.9 hours; P &lt; .001). Implementing this strategy led to a reduction of €211,150.50 in medication costs. CONCLUSIONS: CYP2C19 genotype-guided-de-escalation in an all-comers ACS population is feasible. POC genotyping leads to shorter turnaround times and quicker de-escalation. Time to de-escalation from ticagrelor to clopidogrel in noncarriers was short, with high physician adherence to genotype results.</p

aspirin therapy in primary cardiovascular disease prevention a position paper of the european society of cardiology working group on thrombosis

Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit-to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as $2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding. (J Am Coll Cardiol 2014;64:319–27) © 2014 by the American College of Cardiology Foundation

Dabigatran dual therapy versus warfarin triple therapy post-PCI in patients with atrial fibrillation and diabetes

OBJECTIVES: The aim of this study was to evaluate dabigatran dual therapy versus warfarin triple therapy in patients with or without diabetes mellitus in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial.BACKGROUND: It is unclear whether dual therapy is as safe and efficacious as triple therapy in patients with atrial fibrillation with diabetes following percutaneous coronary intervention.METHODS: In RE-DUAL PCI, 2,725 patients with atrial fibrillation (993 with diabetes) who had undergone PCI were assigned to warfarin triple therapy (warfarin, clopidogrel or ticagrelor, and aspirin) or dabigatran dual therapy (dabigatran 110 mg or 150 mg twice daily and clopidogrel or ticagrelor). Median follow-up was 13 months. The primary outcome was the composite of major bleeding or clinically relevant nonmajor bleeding, and the main efficacy outcome was the composite of death, thromboembolic events, or unplanned revascularization.RESULTS: Among patients with diabetes, the incidence of major bleeding or clinically relevant nonmajor bleeding was 15.2% in the dabigatran 110 mg dual therapy group versus 27.5% in the warfarin triple therapy group (hazard ratio [HR]: 0.48; 95% confidence interval [CI] 0.35 to 0.67) and 23.8% in the dabigatran 150 mg dual therapy group versus 25.1% in the warfarin triple therapy group (HR: 0.87; 95% CI: 0.62 to 1.22). Risk for major bleeding or clinically relevant nonmajor bleeding was also reduced with both dabigatran doses among patients without diabetes (dabigatran 110 mg dual therapy: HR: 0.54; 95% CI: 0.42 to 0.70; dabigatran 150 mg dual therapy: HR: 0.63; 95% CI: 0.48 to 0.83). Risk for the efficacy endpoint was comparable between treatment groups for both patients with and those without diabetes. No interaction between treatment and diabetes subgroup could be observed, either for bleeding or for composite efficacy endpoints.CONCLUSIONS: In this subgroup analysis, dabigatran dual therapy had a lower risk for bleeding and a comparable rate of the efficacy endpoint compared with warfarin triple therapy in patients with atrial fibrillation with or without diabetes following percutaneous coronary intervention.</p

Effects of CYP3A4*22 and CYP3A5 on clinical outcome in patients treated with ticagrelor for ST-segment elevation myocardial infarction: POPular Genetics sub-study

Aims: To determine the clinical efficacy, adverse events and side-effect dyspnea of CYP3A4*22 and CYP3A5 expressor status in ticagrelor treated patients.Methods and results: Ticagrelor treated patients from the POPular Genetics randomized controlled trial were genotyped for CYP3A4*22 and CYP3A5*3 alleles. Patients were divided based on their genotype. In total 1,281 patients with ST-segment elevation myocardial infarction (STEMI) were included. CYP3A4*22 carriers (n = 152) versus CYP3A4*22 non-carrier status (n = 1,129) were not found to have a significant correlation with the primary thrombotic endpoint: cardiovascular death, myocardial infarction, definite stent thrombosis and stroke [1.3% vs. 2.5%, adjusted hazard ratio 1.81 (0.43–7.62) p = 0.42], or the primary bleeding endpoint: PLATO major and minor bleeding [13.2% vs. 11.3%, adjusted hazard ratio 0.93 (0.58–1.50) p = 0.77]. Among the CYP3A4*1/*1 patients, CYP3A5 expressors (n = 196) versus non-expressors (n = 926) did not show a significant difference for the primary thrombotic [2.6% vs. 2.5%, adjusted hazard ratio 1.03 (0.39–2.71) p = 0.95], or the primary bleeding endpoint [12.8% vs. 10.9%, adjusted hazard ratio 1.13 (0.73–1.76) p = 0.58]. With respect to dyspnea, no significant difference was observed between CYP3A4*22 carriers versus CYP3A4*22 non-carriers [44.0% vs. 45.0%, odds ratio 1.04 (0.45–2.42) p = 0.93], or in the CYP3A4*1/*1 group, CYP3A5 expressors versus CYP3A5 non-expressors [35.3% vs. 47.8%, odds ratio 0.60 (0.27–1.30) p = 0.20].Conclusion: In STEMI patients treated with ticagrelor, neither the CYP3A4*22 carriers, nor the CYP3A5 expressor status had a statistical significant effect on thrombotic and bleeding event rates nor on dyspnea.Clinical Trial Registration:ClinicalTrials.gov, identifier NCT01761786

Cost-effectiveness of clopidogrel vs. ticagrelor in patients of 70 years or older with non-ST-elevation acute coronary syndrome

OBJECTIVE: The POPular AGE trial showed that clopidogrel significantly reduced bleeding risk compared with ticagrelor without any signs of an increase in thrombotic events. The aim of this analysis was to estimate the long-term cost-effectiveness of clopidogrel compared with ticagrelor in these patients aged 70 years or older with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS AND RESULTS: A 1-year decision tree based on the POPular AGE trial in combination with a lifelong Markov model was developed to compare clopidogrel with ticagrelor in terms of clinical outcomes, costs, and quality-adjusted life years (QALYs) in elderly patients (above 70 year) with NSTE-ACS. Cost-effectiveness was assessed from a Dutch healthcare system perspective. Events rates and utility data observed in the POPular AGE trial were combined with lifetime projections to evaluate costs and effects for a fictional cohort of 1000 patients. Treatment with clopidogrel instead of ticagrelor led to a cost saving of €1484 575 (€1485 per patient) and a decrease of 10.96 QALYs (0.011 QALY per patient) in the fictional cohort. In an alternative base case with equal distribution over health states in the first year, treatment with clopidogrel led to an increase in QALYs. In all scenario analyses, treatment with clopidogrel was cost-saving. CONCLUSION: Clopidogrel is a cost-saving alternative to ticagrelor in elderly patients after NSTE-ACS, though regarding overall cost-effectiveness clopidogrel was not superior to ticagrelor, as it resulted in a small negative effect on QALYs. However, based on the results of the alternative base case and clinical outcomes of the POPular AGE trial, clopidogrel could be a reasonable alternative to ticagrelor for elderly NSTE-ACS patients with a higher bleeding risk

NT-proBNP level before primary PCI and risk of poor myocardial reperfusion: Insight from the On-TIME II trial.

Background N-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP), a marker for neurohumoral activation, has been associated with adverse outcome in patients with myocardial infarction. NT-proBNP levels may reflect extensive ischemia and microvascular damage, therefore we investigated the potential association between baseline NTproBNP level and ST-resolution (STR), a marker of myocardial reperfusion, after primary percutaneous coronary intervention (pPCI).Methods we performed a post-hoc analysis of the On-TIME II trial (which randomized ST-elevation myocardial infarction (STEMI) patients to pre-hospital tirofiban administration vs placebo). Patients with measured NT-proBNP before angiography were included. Multivariate logistic-regression analyses was performed to investigate the association between baseline NTproBNP level and STR one hour after pPCI.Results Out of 984 STEMI patients, 918 (93.3%) had NT-proBNP values at baseline. Patients with STR 70% had higher NT-proBNP values compared to patients with complete STR (70%) [Mean +/- SD 375.2 +/- 1021.7 vs 1007.4 +/- 2842.3, Median (IQR) 111.7 (58.4-280.0) vs 168.0 (62.3-601.3), P < .001]. At multivariate logistic regression analysis, independent predictors associated with higher risk of poor myocardial reperfusion (STR < 70%) were: NT-proBNP (OR 1.17, 95%CI 1.041.31, P = .009), diabetes mellitus (OR 1.87, 95%CI 1.14-3.07, P = .013), anterior infarct location (OR 2.74, 95% CI 2.00-3.77, P < .001), time to intervention (OR 1.06, 95%CI 1.01-1.11, P = .021), randomisation to placebo (OR 1.45, 95%CI 1.05-1.99, P = .022).Conclusions In STEMI patients, higher baseline NT-proBNP level was independently associate with higher risk of poor myocardial reper fusion, suppor ting the potential use of NT-proBNP as an early marker for risk stratification of myocardial reperfusion after pPCI in STEMI patients

Adding Surgical Edge-to-Edge Mitral Valve Repair to Myectomy in Hypertrophic Obstructive Cardiomyopathy: Long-Term Functional and Echocardiographic Outcome

This study evaluates the early and long-term clinical and echocardiographic outcome of edge-to-edge (E2E) mitral valve repair (MVr) concomitant to septal myectomy (SM) in patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM). A retrospective single-center analysis was performed of patients who underwent isolated SM or SM with E2E MVr from 2011 to 2022. Exclusion criteria were primary mitral valve (MV) disease or concomitant valve surgery. Early and long-term safety, functional and echocardiographic outcomes were compared between groups. Between January 2011 and April 2022, 76 consecutive patients underwent SM for HOCM: 42 patients (55%) underwent SM without additional E2E MVr (Group 1) and 34 patients (45%) underwent SM with additional E2E MVr (Group 2). At latest follow-up, 87% of patients were in New York Heart Association (NYHA) class I-II with no significant differences in NYHA class between groups. Incidence of safety events was comparable between groups. Echocardiographic relief of left ventricular outflow tract (LVOT) obstruction was comparable at early follow-up (P = 0.68), with a significant but small difference in maximum LVOT pressure gradient at latest follow-up in favor of E2E MVr (P = 0.04). Furthermore, patients who underwent SM with E2E MVr showed less residual systolic anterior motion at early and latest follow-up (P = 0.020; P = 0.178). Reintervention on the MV was absent in both groups at 1 year and equally low at follow-up (P = 0.27). This study demonstrates that adding E2E MVr to septal myectomy is as safe as isolated myectomy for the treatment of HOCM. Moreover, the addition of E2E MVr is associated with similar excellent functional improvement and freedom from MV reintervention