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P2Y12 Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?

ABSTRACT: Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor represents the cornerstone therapy for patients with acute coronary syndromes or undergoing percutaneous interventions, leading to a reduction of subsequent ischemic events. Variable response to clopidogrel has received close attention, and pharmacokinetic, pharmacodynamic, and pharmacogenomic factors have been identified as culprits. This led to the introduction of newer, potentially safer, and more effective antiplatelet agents (prasugrel and ticagrelor). Additionally, several point-of-care assays of platelet function have been developed in recent years to rapidly screen individuals on antiplatelet therapy. While the routine use of platelet function testing is uncertain and not currently recommended, it may be useful in instances when the degree of platelet inhibition may be uncertain such as high-risk patients undergoing percutaneous coronary intervention or when there may be a suspected pharmacodynamic interaction with other drugs. The current paper focuses on the P2Y12 receptor inhibitors and their pharmacogenetics and indications in patients with acute coronary syndromes or receiving percutaneous coronary interventions as well as the applicability of platelet function testing in this clinical context.

SUBMITTER: Oprea AD

PROVIDER: S-EPMC3590496 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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P2Y12 Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?

Oprea Adriana Dana AD Popescu Wanda M WM

Cardiology research and practice 20130219

Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor represents the cornerstone therapy for patients with acute coronary syndromes or undergoing percutaneous interventions, leading to a reduction of subsequent ischemic events. Variable response to clopidogrel has received close attention, and pharmacokinetic, pharmacodynamic, and pharmacogenomic factors have been identified as culprits. This led to the introduction of newer, potentially safer, and more effective antiplatelet age ...[more]

PMID: 23533940

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Project description:ImportancePretreatment of patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) with P2Y12 receptor antagonists is a common practice despite the lack of definite evidence for its benefit.ObjectiveTo investigate the association of P2Y12 receptor antagonist pretreatment vs no pretreatment with mortality, stent thrombosis, and in-hospital bleeding in patients with NSTE-ACS undergoing percutaneous coronary intervention (PCI).Design, setting, and participantsThis cohort study used prospective data from the Swedish Coronary Angiography and Angioplasty Registry of 64 857 patients who underwent procedures between 2010 and 2018. All patients who underwent PCI owing to NSTE-ACS in Sweden were stratified by whether they were pretreated with P2Y12 receptor antagonists. Associations of pretreatment with P2Y12 receptor antagonists with the risks of adverse outcomes were investigated using instrumental variable analysis and propensity score matching. Data were analyzed from March to June 2019.ExposuresPretreatment with P2Y12 receptor antagonists.Main outcomes and measuresThe primary end point was all-cause mortality within 30 days. Secondary end points were 1-year mortality, stent thrombosis within 30 days, and in-hospital bleeding.ResultsIn total, 64 857 patients (mean [SD] age, 64.7 [10.9] years; 46 809 [72.2%] men) were included. A total of 59 894 patients (92.4%) were pretreated with a P2Y12 receptor antagonist, including 27 867 (43.7%) pretreated with clopidogrel, 34 785 (54.5%) pretreated with ticagrelor, and 1148 (1.8%) pretreated with prasugrel. At 30 days, there were 971 deaths (1.5%) and 101 definite stent thromboses (0.2%) in the full cohort. Pretreatment was not associated with better survival at 30 days (odds ratio [OR], 1.17; 95% CI, 0.66-2.11; P = .58), survival at 1 year (OR, 1.34; 95% CI, 0.77-2.34; P = .30), or decreased stent thrombosis (OR, 0.81; 95% CI, 0.42-1.55; P = .52). However, pretreatment was associated with increased risk of in-hospital bleeding (OR, 1.49; 95% CI, 1.06-2.12; P = .02).Conclusions and relevanceThis cohort study found that pretreatment of patients with NSTE-ACS with P2Y12 receptor antagonists was not associated with improved clinical outcomes but was associated with increased risk of bleeding. These findings support the argument that pretreatment with P2Y12 receptor antagonists should not be routinely used in patients with NSTE-ACS.

Project description:ImportancePhysician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown.ObjectiveTo investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial.Design, setting, and participantsThe GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019.InterventionsInvestigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization.Main outcomes and measuresReasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected.ResultsOf 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated.Conclusions and relevancePhysicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach.Clinical trial registrationClinicalTrials.gov identifier: NCT02293395.

Project description:ImportanceThe practice of pretreatment with oral P2Y12 inhibitors in non-ST elevation acute coronary syndromes (NSTEACS) remains common; however, its association with improved cardiovascular outcomes is unclear.ObjectiveTo assess the association between oral P2Y12 inhibitor pretreatment and cardiovascular and bleeding outcomes in patients with NSTEACS.Data sourcesOn March 20, 2021, PubMed, MEDLINE, Embase, Scopus, Web of Science, Science Direct, clinicaltrials.gov, and the Cochrane Central Register for Controlled Trials were searched from database inception.Study selectionRandomized clinical trials of patients with NSTEACS randomized to either oral P2Y12 inhibitor pretreatment (defined as prior to angiography) or no pretreatment (defined as following angiography, once coronary anatomy was known) among patients undergoing an invasive strategy.Data extraction and synthesisThis study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data on publication year, sample size, clinical characteristics, revascularization strategy, P2Y12 inhibitor type and dosage, time from pretreatment to angiography, and end point data were independently extracted by 2 authors. A random-effects model was used, including stratification by (1) P2Y12 inhibitor type, (2) revascularization strategy, and (3) access site.Main outcomes and measuresThe primary end point was 30-day major adverse cardiac events (MACEs). Secondary end points were 30-day myocardial infarction (MI) and cardiovascular death. The primary safety end point was 30-day major bleeding (defined according to individual studies).ResultsA total of 7 trials randomizing 13 226 patients to either pretreatment (6603 patients) or no pretreatment (6623 patients) were included. The mean age of patients was 64 years and 3598 (27.2%) were female individuals. Indication for P2Y12 inhibitors was non-ST elevation myocardial infarction in 7430 patients (61.7%), radial access was used in 4295 (32.6%), and 10 945 (82.8%) underwent percutaneous coronary intervention. Pretreatment was not associated with a reduction in 30-day MACE (odds ratio [OR], 0.95; 95% CI, 0.78-1.15; I2 = 28%), 30-day MI (OR, 0.90; 95% CI, 0.72-1.12; I2 = 19%), or 30-day cardiovascular death (OR, 0.79; 95% CI, 0.49-1.27; I2 = 0%). The risk of 30-day major bleeding was increased among patients who underwent pretreatment (OR, 1.51; 95% CI, 1.16-1.97; I2 = 41%). The number needed to harm to bring about 1 major bleeding event with oral P2Y12 inhibitor pretreatment was 63 patients.Conclusions and relevanceIn this study, pretreatment with oral P2Y12 inhibitors among patients with NSTEACS prior to angiography, compared with treatment once coronary anatomy is known, was associated with increased bleeding risk and no difference in cardiovascular outcomes. Routine pretreatment with oral P2Y12 inhibitors in patients with NSTEACS receiving an early invasive strategy is not supported by this study.

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P2Y12 Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?

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P2Y12 Receptor Inhibitors in Acute Coronary Syndromes: What Is New on the Horizon?

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