Selection Of Antiplatelet Therapy Research Articles

Real-world evaluation of CYP2C19 guided antiplatelet therapy in patients undergoing intracranial aneurysm repair.

Aim: To evaluate the feasibility and impact of using CYP2C19 genotype to guide selection of antiplatelet therapy in patients undergoing intracranial aneurysm treatment with a flow diversion stent in a real-world clinical setting.Patients & methods: A single-center, retrospective, observational cohort study was conducted in 112 patients undergoing intracranial aneurysm repair with flow-diversion stenting from 2014 to2021. Data were abstracted from health records. The frequency of clopidogrel or alternative therapy (ticagrelor or prasugrel) use was compared across CYP2C19 status (intermediate or poor metabolizer [IM/PM] vs. normal, rapid, or ultrarapid metabolizer [NM/RM/UM]).Results: In the study population, CYP2C19 genotype testing was performed on 110 (98.2%) patients; of these, 106 (97.2%) had results available prior to the stent procedure and 28 (25.5%) were IM/PMs. Alternative therapy was used more frequently in IM/PMs compared with NM/RM/UMs (57.1 vs. 8.5%, respectively, p<0.0001). The frequency of thromboembolic events over 12months did not significantly differ across clopidogrel-treated IM/PMs, clopidogrel-treated NM/RM/UMs and patients on alternative therapy (p=0.352); although, event numbers were low.Conclusion: A pre-emptive CYP2C19 genotyping strategy to guide antiplatelet therapy selection in intracranial aneurysm repair patients is feasible in a real-world clinical setting. Larger studies are needed to assess the impact on clinical outcomes.

Optimal anti-platelet therapy for older patients with acute coronary syndrome: a network meta-analysis of randomized trials comprising 59,284 older patients

The aim of this study was to identify the optimal anti-platelet therapy in older acute coronary syndrome (ACS) patients with a mean age ≥ 60 years by comparing the efficacy and safety of different anti-platelet therapies. The selection of antiplatelet therapy in older patients with ACS is a clinical challenge. Numerous evidences indicate that the de-escalation of dual anti-platelet therapy (DAPT) or P2Y12 inhibitor monotherapy may reduce bleeding risk without increasing thrombotic events. However, there is a lack of systematic reviews and optimal strategy analysis regarding older ACS patients. Randomized controlled trials (RCTs) of anti-platelet therapy in older ACS patients were identified. Major adverse cardiovascular events (MACE) were the primary outcome. Secondary outcomes included all death, cardiovascular death, myocardial infarction, stroke, stent thrombosis, and trial-defined major bleeding. Frequentist and Bayesian network meta-analyses were conducted. Treatments were ranked on posterior probability. Summary odds ratios (ORs) were estimated using Bayesian network meta-analysis. A total of 12 RCTs including 59,284 older ACS patients treated with five anti-platelet strategies were included. Ticagrelor monotherapy after 3 months DAPT was comparable to the other strategies (OR 0.73; 95% CI 0.32–1.6) in terms of MACE risk. Additionally, P score analysis and SUCRA Bayesian analysis showed that it was the most beneficial treatment for all deaths, cardiovascular death and revascularization. For safety, although there was no significant difference in direct comparisons, both SUCRA Bayesian (0.806) and P score (0.519) analysis suggested that ticagrelor monotherapy was the safest strategy. The current evidence demonstrated that ticagrelor monotherapy after 3 months DAPT may be a promising approach for achieving a more favorable balance between risk and benefit for older ACS patients, with a relatively low bleeding risk and without an increased risk of MACE events. Moreover, it remains the preferred option for clinical outcomes such as all death, CV death and revascularization. Further high-quality and long-term studies are required to validate anti-platelet therapies among older ACS patients.

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.

Sex-Specific Differences in Clinical Outcomes After Percutaneous Coronary Intervention: Insights from the TAILOR-PCI Trial.

BackgroundTAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study.Methods and ResultsAssociations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P=0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P=0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value (Pint =0.59) or BARC bleeding (P int=0.47) nor for sex and genotype (MACE P int=0.15, and BARC bleeding P int=0.60).Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01742117.

Survey of clinical practice pattern in Germany's certified chest pain units : Adherence to the European Society of Cardiology guidelines on non-ST-segment elevation acute coronary syndrome.

BackgroundWe aimed to analyze the 2020 standard of care in certified German chest pain units (CPU) with a special focus on non-ST-segment elevation acute coronary syndrome (NSTE-ACS) through a voluntary survey obtained from all certified units, using a prespecified questionnaire.MethodsThe assessment included the collection of information on diagnostic protocols, risk assessment, management and treatment strategies in suspected NSTE-ACS, the timing of invasive therapy in non-ST-segment elevation myocardial infarction (NSTEMI), and the choice of antiplatelet therapy.ResultsThe response rate was 75%. Among all CPUs, 77% are currently using the European Society of Cardiology (ESC) 0/3‑h high-sensitive troponin protocol, and only 20% use the ESC 0/1‑h high-sensitive troponin protocol as a default strategy. Conventional ergometry is still the commonly performed stress test with a utilization rate of 47%. Among NSTEMI patients, coronary angiography is planned within 24 h in 96% of all CPUs, irrespective of the day of the week. Prasugrel is the P2Y12 inhibitor of choice in ST-segment elevation myocardial infarction (STEMI), but despite the impact of the ISAR-REACT 5 trial on selection of antiplatelet therapy, ticagrelor is still favored over prasugrel in NSTE-ACS. If triple therapy is used in NSTE-ACS with atrial fibrillation, it is maintained up to 4 weeks in 51% of these patients.ConclusionThis survey provides evidence that Germany’s certified CPUs ensure a high level of guideline adherence and quality of care. The survey also identified areas in need of improvement such as the high utilization rate of stress electrocardiogram (ECG).

Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis

Whether guided selection of antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI) is effective in improving outcomes compared with standard antiplatelet therapy remains controversial. We assessed the safety and efficacy of guided versus standard selection of antiplatelet therapy in patients undergoing PCI. For this systematic review and meta-analysis, from Aug 20 to Oct 25, 2020, we searched MEDLINE (via PubMed), Cochrane, Embase, and Web of Science databases for randomised controlled trials and observational studies published in any language that compared guided antiplatelet therapy, by means of platelet function testing or genetic testing, versus standard antiplatelet therapy in patients undergoing PCI. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. Risk ratios (RRs) and 95% CIs were used with random-effects or fixed-effect models according to the estimated heterogeneity among studies assessed by the I2 index. Coprimary endpoints were trial-defined primary major adverse cardiovascular events and any bleeding. Key secondary endpoints were all-cause death, cardiovascular death, myocardial infarction, stroke, definite or probable stent thrombosis, and major and minor bleeding. This study is registered with PROSPERO (CRD42021215901). 3656 potentially relevant articles were screened. Our analysis included 11 randomised controlled trials and three observational studies with data for 20 743 patients. Compared with standard therapy, guided selection of antiplatelet therapy was associated with a reduction in major adverse cardiovascular events (RR 0·78, 95% CI 0·63-0·95, p=0·015) and reduced bleeding, although not statistically significant (RR 0·88, 0·77-1·01, p=0·069). Cardiovascular death (RR 0·77, 95% CI 0·59-1·00, p=0·049), myocardial infarction (RR 0·76, 0·60-0·96, p=0·021), stent thrombosis (RR 0·64, 0·46-0·89, p=0·011), stroke (RR 0·66, 0·48-0·91, p=0·010), and minor bleeding (RR 0·78, 0·67-0·92, p=0·0030) were reduced with guided therapy compared with standard therapy. Risks of all-cause death and major bleeding did not differ between guided and standard approaches. Outcomes varied according to the strategy used, with an escalation approach associated with a significant reduction in ischaemic events without any trade-off in safety, and a de-escalation approach associated with a significant reduction in bleeding, without any trade-off in efficacy. Guided selection of antiplatelet therapy improved both composite and individual efficacy outcomes with a favourable safety profile, driven by a reduction in minor bleeding, supporting the use of platelet function or genetic testing to optimise the choice of agent in patients undergoing PCI. None.

Guided P2Y12 inhibitor therapy after percutaneous coronary intervention

Antiplatelet treatment regimens for patients after percutaneous coronary intervention (PCI) have undergone major changes and substantial improvements. Extensions or a shortening of treatment as well as the use of various scores have been assessed in numerous trials to maximise anti-ischaemic efficacy and minimise bleeding. 1 Collet JP Thiele H Barbato E et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2020; (published online Aug 29.)https://doi.org/10.1093/eurheartj/ehaa575 Crossref PubMed Scopus (122) Google Scholar , 2 Knuuti J Wijns W Saraste A et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020; 41: 407-477 Crossref PubMed Scopus (1634) Google Scholar The key limitation of these strategies is the inherent time delay in the implementation of any therapy adjustments. At the same time, several clinical trials have investigated tailored and guided antiplatelet treatment. 3 Sibbing D Aradi D Alexopoulos D et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019; 12: 1521-1537 Crossref PubMed Scopus (180) Google Scholar Unfortunately, the pioneering trials of tailored treatment did not meet their primary endpoints or show improvement in patients' outcomes. 4 Price MJ Berger PB Teirstein PS et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011; 305: 1097-1105 Crossref PubMed Scopus (1130) Google Scholar , 5 Trenk D Stone GW Gawaz M et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy with Prasugrel) Study. J Am Coll Cardiol. 2012; 59: 2159-2164 Crossref PubMed Scopus (521) Google Scholar Various explanations have been attributed to these disappointing results, including insufficient intensification of treatment in patients with low response to clopidogrel by limited use of potent P2Y12 inhibitors and preferential inclusion of low-risk patients. 3 Sibbing D Aradi D Alexopoulos D et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019; 12: 1521-1537 Crossref PubMed Scopus (180) Google Scholar To address these issues, a series of recent trials included patients at higher risk and investigated the use of platelet function testing (phenotyping) 6 Sibbing D Aradi D Jacobshagen C et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet. 2017; 390: 1747-1757 Summary Full Text Full Text PDF PubMed Scopus (295) Google Scholar or genetic testing (genotyping) 7 Claassens DMF Vos GJA Bergmeijer TO et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med. 2019; 381: 1621-1631 Crossref PubMed Scopus (212) Google Scholar , 8 Pereira NL Farkouh ME So D et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA. 2020; 324: 761-771 Crossref PubMed Scopus (93) Google Scholar as a strategy by including study groups with a clear distinction of testing versus no testing. Notably, these trials did not provide unequivocal results and were partly limited in sample size and sometimes underpowered to compare specific ischaemic and bleeding endpoints. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysisGuided selection of antiplatelet therapy improved both composite and individual efficacy outcomes with a favourable safety profile, driven by a reduction in minor bleeding, supporting the use of platelet function or genetic testing to optimise the choice of agent in patients undergoing PCI. Full-Text PDF

Evaluating the extent of reusability of CYP2C19 genotype data among patients genotyped for antiplatelet therapy selection

PurposeGenotype-guided antiplatelet therapy is increasingly being incorporated into clinical care. The purpose of this study is to determine the extent to which patients initially genotyped for CYP2C19 to guide antiplatelet therapy were prescribed additional medications affected by CYP2C19. MethodsWe assembled a cohort of patients from eight sites performingCYP2C19 genotyping to inform antiplatelet therapy. Medication orders were evaluated from time of genotyping through one year. The primary endpoint was the proportion of patients prescribed two or more CYP2C19 substrates. Secondary endpoints were the proportion of patients with a drug–genotype interaction and time to receiving a CYP2C19 substrate. ResultsNine thousand one hundred ninety-one genotyped patients (17% nonwhite) with a mean age of 68±3 years were evaluated; 4701 (51%) of patients received two or more CYP2C19 substrates and 3835 (42%) of patients had a drug–genotype interaction. The average time between genotyping and CYP2C19 substrate other than antiplatelet therapy was 25±10 days. ConclusionsMore than half of patients genotyped in the setting of CYP2C19-guided antiplatelet therapy received another medication impacted by CYP2C19 in the following year. Given that genotype is stable for a patient’s lifetime, this finding has implications for cost effectiveness, patient care, and treatment outcomes beyond the indication for which it was originally performed.

Clinical Utility of CYP2C19 Genotype-Guided Antiplatelet Therapy in Patients at Risk of Adverse Cardiovascular and Cerebrovascular Events: A Review of Emerging Evidence.

In patients undergoing percutaneous coronary intervention (PCI), the standard of care is dual antiplatelet therapy with a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin. Current clinical practice guidelines now recommend more potent P2Y12 inhibitors (prasugrel or ticagrelor) over clopidogrel in acute coronary syndrome (ACS). However, clopidogrel remains the most commonly prescribed P2Y12 inhibitor in the setting of PCI and is also the preferred agent in the treatment and secondary prevention of stroke. Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. It has been shown that clopidogrel use in patients who are CYP2C19 no function allele carriers are associated with impaired antiplatelet inhibition and a higher risk of major adverse cardiovascular and cerebrovascular events. Compared to clopidogrel, prasugrel and ticagrelor clinical response is not impacted by CYP2C19 genotype. Even with a demonstrated increased risk of adverse outcomes in CYP2C19 no function allele carriers treated with clopidogrel, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial and has not been widely adopted. Recent results from multiple prospective randomized and nonrandomized clinical trials investigating the use of CYP2C19 genotype-guided antiplatelet therapy following PCI have advanced the evidence base demonstrating the clinical utility of this strategy. Multiple recent studies have examined the effects of CYP2C19 genotype on clopidogrel outcomes in the setting of stroke and neurointerventional procedures. In this review, we discern the clinical utility of using CYP2C19 genotype testing to guide antiplatelet therapy prescribing by evaluating the impact of CYP2C19 genotype-guided selection of antiplatelet therapy on clinical outcomes, summarizing emerging data from cardiovascular and neurology clinical studies, and discussing implications for clinical practice guidelines, remaining knowledge gaps and future research directions.

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

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. 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. 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. 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.

Advances in the Pharmacogenomics of Antiplatelet Therapy.

Acute coronary syndrome (ACS) is a highly thrombotic state, and a sustained antiplatelet effect is vital to the prevention of thrombotic complications. Clopidogrel, the most widely used oral P2Y12 receptor antagonist in ACS, has attracted considerable attention because of significant variability in antiplatelet effect depending on the presence of CYP2C19 allele. Other P2Y12 receptor antagonists offer sustained and more predictable antiplatelet effects than clopidogrel albeit at an increased cost. Several studies have demonstrated the promising application of pharmacogenetics in choosing personalized antiplatelet therapy using the point-of-care genotype assays. Guidelines regarding the genotype-guided approach to the selection of antiplatelet therapy have been conflicting, and studies evaluating the effect of pharmacogenetic-guided selection of antiplatelet therapy on the outcomes have demonstrated mixed results. A literature search was conducted using MEDLINE and EMBASE for studies reporting the association of pharmacogenetic-guided selection of antiplatelet therapy and the outcomes in patients with ACS until December 2018. Presence of specific CYP2C19 allele significantly influences clopidogrel metabolism and associated outcomes in patients with ACS. Thrombotic and bleeding complications are more common in patients with loss-of-function (LOF) and gain-of-function (GOF) alleles, respectively. Although the pharmacogenetic-guided approach to the selection of antiplatelet therapy appears promising in ACS, studies have shown conflicting results, and direct randomized evidence linking this approach with the better outcomes is lacking. Genotype-guided selection of antiplatelet therapy is expected to be useful in patients undergoing percutaneous coronary intervention (PCI) with a high risk of adverse outcomes. The patient-physician discussion should be an essential part of this decision-making process. Large-scale multicenter randomized controlled trials using the point-of-care genotype assay are needed to investigate this approach further before its use can be recommended in all comers.

Clopidogrel as a part of double disaggregant therapy in ACS: a reasonable choice in complex clinical situations

Based on the recommendations of the European Heart Society and the results of clinical and register studies, the article highlights the complex issues that arise when prescribing antiplatelet therapy in patients with acute coronary syndrome, including with concomitant atrial fibrillation (AF); the promising strategies for managing the risk of ischemic and hemorrhagic events are described. Also a clinical case of a patient with acute coronary syndrome and AF is presented, illustrating the objective complexity of correct selection of antiplatelet therapy in such patients.

Clinical Utility of CYP2C19 Genotyping to Guide Antiplatelet Therapy in Patients With an Acute Coronary Syndrome or Undergoing Percutaneous Coronary Intervention.

Current guidelines recommend dual antiplatelet therapy-a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) and aspirin-for patients undergoing percutaneous coronary intervention. Although clopidogrel is the most commonly prescribed P2Y12 inhibitor, it is associated with an increased risk of major adverse cardiovascular events in patients carrying loss-of-function CYP2C19 alleles. In contrast, CYP2C19 genotype does not impact clinical response to prasugrel or ticagrelor. Nevertheless, routine implementation of CYP2C19 genotyping to guide antiplatelet therapy selection has remained controversial because of the lack of large randomized controlled trials evaluating this strategy. Emerging results from registry studies and small clinical trials of CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention offer new insight and contribute to a growing evidence base that supports the clinical utility of a genotyping strategy to personalize antiplatelet therapy selection.

Outcomes associated with dual antiplatelet therapy after myocardial infarction in patients with aortic stenosis

BackgroundAcquired loss of the largest von Willebrand factor multimers is a common hemostatic disturbance in patients with aortic valve stenosis (AS), resulting in impaired platelet adhesion and increased bleeding risk. AS is also associated with atherosclerosis and myocardial infarction (MI). Our aim was to study the clinical outcomes associated with AS in MI patients treated with dual antiplatelet therapy (DAPT) in a nationwide hospital-based register study. MethodsBased on nationwide hospital discharge registers from Sweden (2005–2010) and Denmark (2005–2015), we calculated 1-year incidence rates and hazard ratios of bleeding, recurrent MI, and all-cause mortality in MI patients with and without AS treated with DAPT. Results from both countries were also combined in a meta-analysis. ResultsWe included 50,460 MI patients from Sweden and 50,307 MI patients from Denmark, of which 3% had AS. The bleeding rates (per 100 person-years) in Sweden and Denmark were 3.2 and 3.3 among patients without AS vs. 9.2 and 8.3 among patients with AS. All-cause mortality rates were 7.1 vs. 28.7 in Sweden and 5.8 vs. 30.7 in Denmark among patients without and with AS, respectively. Patients with AS had an increased risk of bleeding, recurrent MI and all-cause mortality. Combined results from both countries were similar for bleeding (hazard ratio 1.59 [0.98–2.59]), recurrent MI (1.78 [1.25–2.54]), and all-cause mortality (1.76 [1.26–2.47]). ConclusionAS was associated with an increased risk of bleeding, recurrent MI and mortality after MI when treated with DAPT. Individualized selection of antiplatelet therapy may be warranted in this high-risk population.

Personalized antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary intervention: A network meta-analysis of randomized clinical trials.

This study aimed to evaluate the efficacy and safety of genotype- and phenotype-guided intensified antiplatelet therapy compared with conventional therapy in patients undergoing stent implantation. Although potent P2Y12 receptor inhibitors are recommended for percutaneous coronary intervention (PCI)-treated acute coronary syndrome, their usage is limited by a high bleeding risk. Therefore, personalized antiplatelet therapy could provide a valuable foundation for selection of antiplatelet therapy in this population. We conducted a Bayesian network meta-analysis for all randomized clinical trials (RCTs) that evaluated genotype- and/or phenotype-guided therapy in PCI-treated coronary artery disease. Thirteen RCTs were included with a total of 6,845 patients. The results showed no significant differences in major adverse cardiovascular events (MACE) between the treatment options ((genotype guided vs. standard of care; OR 0.64; 95% CI: 0.38-1.05) and (phenotype vs. standard of care; OR 0.93; 95% CI: 0.54-1.37)). In addition, no significant differences were demonstrated in bleeding events ((genotype guided vs. standard of care; OR 0.73; 95% CI: 0.45-1.25) and (phenotype vs. standard of care; OR 0.90; 95% CI: 0.62-1.39)). In this mixed treatment meta-analysis of RCTs, neither genotype- nor phenotype-guided antiplatelet therapy in patients with PCI-treated coronary artery disease was superior to conventional therapy.

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta-analysis of randomized clinical trials.

This study aimed to evaluate the efficacy and safety of personalized genotype-guided selection of antiplatelet therapy versus standard of care in patients undergoing percutaneous coronary intervention (PCI). Clopidogrel is the most frequently used P2Y12 receptor antagonist in patients with coronary artery disease. However, genetic variations of clopidogrel are associated with inter-individual response variability which could limit its efficacy. Electronic databases were searched for all randomized clinical trials (RCTs) evaluating genotype-guided therapy versus standard of care in patients undergoing stent implantation. Aggregated risk ratios (RRs) and 95% CIs were calculated using a random-effects model. We included 6 RCTs with a total of 2,371 patients. When compared with standard of care, the use of genotype-guided therapy did not significantly reduce major adverse cardiovascular events (MACE) (RR 0.67; 95% CI: 0.35-1.27; P = 0.22). However, MACE was significantly reduced in the subset of trials which enrolled only acute coronary syndromes (ACS) (P < 0.01). In addition, there was a significant reduction in myocardial infarction in the genotype-guided group (RR 0.44; 95% CI: 0.28-0.70; P < 0.01; I2 = 0%). Other clinical outcomes were not significantly different: cardiovascular mortality (RR 0.68; 95% CI: 0.27-1.74; P = 0.42), stroke (RR 0.62; 95% CI: 0.23-1.65; P = 0.34), stent thrombosis (RR 0.37; 95% CI: 0.13-1.06; P = 0.06), and bleeding (RR 0.68; 95% CI: 0.43-1.06; P = 0.09). In patients undergoing stent implantation, MACE with genotype-guided therapy was not significantly reduced; however, there was a signal towards reduction of MACE in ACS patients, as well as a lower rate of MI, though this will require further confirmation in adequately powered trials.

Clinical outcomes of CYP2C19 genotype-guided antiplatelet therapy: existing evidence and future directions.

It is well established that theCYP2C19nonfunctional *2 and *3 polymorphisms impair the bioactivation and antiplatelet effects of clopidogrel, and increase the risk of adverse cardiovascular events following percutaneous coronary intervention. In contrast,CYP2C19genotype does not impact clinical response to prasugrel or ticagrelor. Recent studies have evaluated the impact ofCYP2C19genotype-guided selection of antiplatelet therapy on clinical outcomes and begun to close some of the gaps in knowledge and uncertainty that have impeded widespread clinical implementation of this precision medicine approach. This review will critically evaluate recent data and offer new insight into the potential clinical utility of genotype-guided antiplatelet therapy in the context of current clinical practice guidelines.

Highlights From the Circulation Family of Journals.

Highlights From the Circulation Family of Journals.

CYP2C19-guided antiplatelet therapy: a cost-effectiveness analysis of 30-day and 1-year outcomes following percutaneous coronary intervention.

Determine whether using CYP2C19 genotype to optimize antiplatelet therapy selection is cost effective over the initial 30 days and 1-year following percutaneous coronary intervention. A cost-effectiveness analysis compared 30-day and 1-year outcomes and cost across three treatment strategies (universal clopidogrel, universal prasugrel, genotype-guided) in a hypothetical cohort. Base-case scenario results at 30 days indicated that the incremental cost per major cardiovascular or bleeding event avoided for genotype-guided treatment was US$8525 and US$42,198 compared with universal clopidogrel and prasugrel, respectively. Probabilistic sensitivity analysis demonstrated that genotype-guided treatment was cost effective over 30 days and 1 year in 62 and 70% of simulations, respectively. Implementing a CYP2C19 genotype-guided approach to antiplatelet therapy could have a positive economic impact by preventing readmissions following percutaneous coronary intervention.

Cost-effectiveness of cytochrome P450 2C19 *2 genotype-guided selection of clopidogrel or ticagrelor in Chinese patients with acute coronary syndrome

The choice of antiplatelet therapy among Asian populations for the treatment of acute coronary syndrome (ACS) is complicated owing to the high prevalence of cytochrome P450 2C19 (CYP2C19) genetic polymorphism that has been associated with reduced efficacy of clopidogrel. Ticagrelor is a potent but more expensive alternative antiplatelet agent that is not affected by CYP2C19 polymorphism. This study aimed to evaluate the cost-effectiveness, from the Hong Kong health-care provider's perspective, of CYP2C19*2 genotype-guided selection of antiplatelet therapy compared with the universal use of clopidogrel or ticagrelor among ACS patients who undergo percutaneous coronary intervention (PCI). In the present study, a two-part model consisting of a 1-year decision tree and a lifetime Markov model was built to simulate the progress of a typical cohort of 60-year-old Chinese patients until age 85 years and compare three treatment strategies: (i) generic clopidogrel or ticagrelor based on CYP2C19*2 genotype, (ii) universal use of generic clopidogrel or (iii) universal use of ticagrelor for all patients. Incremental cost-effectiveness ratios (ICERs) of <1 gross domestic product per capita locally (US dollar (USD)42 423/quality-adjusted life year (QALY)) were considered cost-effective. Base-case results showed universal ticagrelor use was cost-effective compared with universal clopidogrel, but was dominated by genotype-guided treatment. Genotype-guided treatment was cost-effective compared with universal clopidogrel use (ICER of USD2560/QALY). Sensitivity analysis demonstrated that with the cost of genotype testing up to USD400, CYP2C19*2 genotype-guided antiplatelet treatment remained a cost-effective strategy compared with either universal use of generic clopidogrel or ticagrelor in post-PCI ACS patients in Hong Kong.