Daniel M. F. Claassens

Introduction The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2Y₁₂ inhibitor strategy reduced bleeding rates compared with standard treatment with ticagrelor or prasugrel without increasing thrombotic event rates after primary percutaneous coronary intervention (PCI). Objective In this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel. Methods A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2Y₁₂ inhibitor strategy in patients with myocardial infarction undergoing primary PCI. The cost-effectiveness analysis was conducted from a Dutch healthcare system perspective. Within-trial survival and utility data were combined with lifetime projections to evaluate lifetime cost effectiveness for a cohort of 1000 patients. Costs and utilities were discounted at 4 and 1.5%, respectively, according to Dutch guidelines for health economic studies. Besides deterministic and probabilistic sensitivity analyses, several scenario analyses were also conducted (different time horizons, different discount rates, equal prices for P2Y₁₂ inhibitors, and equal distribution of thrombotic events between the two strategies). Results Base-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant. Conclusion In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings. Trial Registration Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872

Background: Whether factor V Leiden is associated with lower bleeding risk in patients with acute coronary syndromes using (dual) antiplatelet therapy has yet to be investigated. Methods and Results: We pooled data from 3 randomized clinical trials, conducted in patients with acute coronary syndromes, with adjudicated bleeding outcomes. Cox regression models were used to obtain overall and cause‐specific hazard ratios (HRs) to account for competing risk of atherothrombotic outcomes (ie, composite of ischemic stroke, myocardial infarction, and cardiovascular death) in each study. Estimates from the individual studies were pooled using fixed effect meta‐analysis. The 3 studies combined included 17 623 patients of whom 969 (5.5%) were either heterozygous or homozygous (n=23) carriers of factor V Leiden. During 1 year of follow‐up, a total of 1289 (7.3%) patients developed major (n=559) or minor bleeding. Factor V Leiden was associated with a lower risk of combined major and minor bleeding (adjusted cause‐specific HR, 0.75; 95% CI, 0.56–1.00; P =0.046; I ² =0%) but a comparable risk of major bleeding (adjusted cause‐specific HR, 0.93; 95% CI, 0.62–1.39; P =0.73; I ² =0%). Adjusted pooled cause‐specific HRs for the association of factor V Leiden with atherothrombotic events alone and in combination with bleeding events were 0.75 (95% CI, 0.55–1.02; P =0.06; I ² =0%) and 0.75 (95% CI, 0.61–0.92; P =0.007; I ² =0%), respectively. Conclusions: Given that the lower risk of bleeding conferred by factor V Leiden was not counterbalanced by a higher risk of atherothrombotic events, these findings warrant future assessment for personalized medicine such as selecting patients for extended or intensive antiplatelet therapy.

Background: Guidelines favor ticagrelor or prasugrel over clopidogrel in patients with myocardial infarction. However, the POPular Genetics trial (Patient Outcome After Primary Percutaneous Coronary Intervention [PCI]) showed that in patients with primary PCI, a CYP2C19 genotype–guided strategy was associated with a lower bleeding risk without increasing thrombotic risk, compared with routine ticagrelor/prasugrel treatment. Nevertheless, optimal P2Y ₁₂ inhibitor treatment in specific CYP2C19 genetic subgroups is still a subject of debate. Methods: A prespecified subanalysis of the POPular Genetics trial was performed, using patients in whom CYP2C19 *2, *3, and *17 genotypes was determined. Two different analyses were planned. The first assessed the effect of the CYP2C19 *17 allele in clopidogrel-treated patients. The second compared the effect of clopidogrel in noncarriers of a loss-of-function allele with ticagrelor/prasugrel–treated patients, irrespective of CYP2C19 genotype. Main outcomes were a thrombotic outcome (cardiovascular death, myocardial infarction, stent thrombosis, and stroke) and a bleeding outcome (PLATO [Platelet Inhibition and Patient Outcomes] major and minor bleeding) after 12 months. Results: A total of 2429 patients were used for analyses. In the first analysis, the CYP2C19 *17 polymorphism was not found to have a significant influence on thrombotic (adjusted hazard ratio, 0.95 [95% CI, 0.45–2.02]) or bleeding outcomes (adjusted hazard ratio, 0.74 [95% CI, 0.48–1.18]). In the second analysis, clopidogrel was associated with a lower number of bleeding events compared with ticagrelor/prasugrel (9.9% versus 11.7%, adjusted hazard ratio, 0.74 [95% CI, 0.56–0.96]), without a significant increase in thrombotic events (3.4% versus 2.5%, adjusted hazard ratio, 1.14 [95% CI, 0.68–1.90]). Conclusions: In patients with primary PCI not carrying a CYP2C19 loss-of-function allele, the use of clopidogrel compared with ticagrelor or prasugrel was associated with lower bleeding rates, without an increase in thrombotic events. No effect on clinical outcomes was found for the CYP2C19 *17 polymorphism. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01761786. URL: https://www.trialregister.nl/ ; Unique identifier: NL2872.

Diagnostic and treatment strategies for acute coronary syndrome have improved dramatically over the past few decades, but mortality and recurrent myocardial infarction rates remain high. An aging population with increasing co-morbidities heralds new clinical challenges. Therefore, in order to evaluate and improve current treatment strategies, detailed information on clinical presentation, treatment and follow-up in real-world patients is needed. The Future Optimal Research and Care Evaluation in patients with Acute Coronary Syndrome (FORCE-ACS) registry (ClinicalTrials.gov Identifier: NCT03823547) is a multi-center, prospective real-world registry of patients admitted with (suspected) acute coronary syndrome. Both non-interventional and interventional cardiac centers in different regions of the Netherlands are currently participating. Patients are treated according to local protocols, enabling the evaluation of different diagnostic and treatment strategies used in daily practice. Data collection is performed using electronic medical records and quality-of-life questionnaires, which are sent 1, 12, 24 and 36 months after initial admission. Major end points are all-cause mortality, myocardial infarction, stent thrombosis, stroke, revascularization and all bleeding requiring medical attention. Invasive therapy, antithrombotic therapy including patient-tailored strategies, such as the use of risk scores, pharmacogenetic guided antiplatelet therapy and patient reported outcome measures are monitored. The FORCE-ACS registry provides insight into numerous aspects of the (quality of) care for acute coronary syndrome patients.

In acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI), treatment with the P2Y₁₂ inhibitors ticagrelor or prasugrel is recommended over clopidogrel due to a better efficacy, albeit having more bleeding complication. These higher bleeding rates have provoked trials investigating de-escalation from ticagrelor or prasugrel to clopidogrel in the hope of reducing bleeding without increasing thrombotic event rates. In this review, we sought to present an overview of the major trials investigating several different options for de-escalation; unguided, platelet function testing- and genotype-guided. Based on these results, and on other established literature sources, such as guidelines and expert consensus papers, we provide an overview to help decide when and how to de-escalate antiplatelet therapy in ACS patients undergoing PCI.

It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y₁₂ inhibitors.

Early recognition of myocardial infarction (MI) remains a challenge, especially in patients presenting with non-ST-segment elevation MI. Heart-type fatty acid binding protein (hFABP) has shown to be a more sensitive marker for myocardial necrosis as compared to non-high sensitive troponins (4th generation and older). However, since high sensitive troponin (hs TnT) assays are available, it is questionable whether hFABP still has value as a diagnostic tool for MI. A systematic search was conducted in Medline, Embase and Cochrane. After selecting the articles, they were assessed for risk of bias according to the QUADAS-2 criteria. Negative predictive value, positive predictive value, sensitivity and specificity were extracted or calculated if possible. Nine studies met the inclusion criteria. Overall, hs TnT showed higher sensitivity than hFABP, while hFABP had higher specificity. In patients presenting within 3 hours after onset of symptoms, sensitivity is low for both hFABP and hs TnT (19-63% vs 25-55%, respectively), while specificity seems higher for hFABP than for hs TnT (70-99% vs 57-86%, respectively). In these patients, the area under the curve for hs TnT is equal or better than that for hFABP (0.67-0.92 for hs TnT vs 0.69-0.85 for hFABP). The addition of hFABP to hs TnT did not improve sensitivity and specificity. This systematic review finds no advantage for using hFABP over hs TnT in either early presenting patients or overall. Furthermore, no advantage was found if a combination of hFABP and hs TnT was used for the diagnosis of MI.