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      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

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          Abstract

          After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown.

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          Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis.

          Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes. To define the risk of major adverse cardiovascular outcomes among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel. A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained. Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype. Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P < .0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P = .001) CYP2C19 reduced-function alleles, as compared with noncarriers. Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.
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            Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge.

            Intravenous administration of 80 mg of recombinant tissue plasminogen activator (rt-PA, 40, 20, and 20 mg in successive hours) and streptokinase (SK, 1.5 million units over 1 hr) was compared in a double-blind, randomized trial in 290 patients with evolving acute myocardial infarction. These patients entered the trial within 7 hr of the onset of symptoms and underwent baseline coronary arteriography before thrombolytic therapy was instituted. Ninety minutes after the start of thrombolytic therapy, occluded infarct-related arteries had opened in 62% of 113 patients in the rt-PA and 31% of 119 patients in the SK group (p less than .001). Twice as many occluded infarct-related arteries opened after rt-PA compared with SK at the time of each of seven angiograms obtained during the first 90 min after commencing thrombolytic therapy. Regardless of the time from onset of symptoms to treatment, more arteries were opened after rt-PA than SK. The reduction in circulating fibrinogen and plasminogen and the increase in circulating fibrin split products at 3 and 24 hr were significantly less in patients treated with rt-PA than in those treated with SK (p less than .001). The occurrence of bleeding events, administration of blood transfusions, and reocclusion of the infarct-related artery was comparable in the two groups. Thus, in patients with acute myocardial infarction, rt-PA elicited reperfusion in twice as many occluded infarct-related arteries as compared with SK at each of seven serial observations during the first 90 min after onset of treatment.
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              A Genotype-Guided Strategy for Oral P2Y 12 Inhibitors in Primary PCI

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

                Journal
                JAMA
                JAMA
                American Medical Association (AMA)
                0098-7484
                August 25 2020
                August 25 2020
                : 324
                : 8
                : 761
                Affiliations
                [1 ]Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
                [2 ]Peter Munk Cardiac Centre and Heart and Stroke Richard Lewar Centre, University of Toronto, Toronto, Ontario, Canada
                [3 ]University of Ottawa Heart Institute, Ottawa, Ontario, Canada
                [4 ]Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
                [5 ]National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
                [6 ]Department of Medicine, Loyola University, Maywood, Illinois
                [7 ]Department of Internal Medicine, Division of Cardiology, Konyang University, Seo-gu, Taejon, South Korea
                [8 ]Heart Research Center, Chonnam National University, Gwangju, South Korea
                [9 ]Department of Cardiology, Minneapolis Heart Institute Foundation, Minneapolis, Minnesota
                [10 ]Division of Cardiology, The Miriam Hospital, Providence, Rhode Island
                [11 ]Division of Cardiology, Rhode Island Hospital, Providence, Rhode Island
                [12 ]Mayo Clinic Health System—La Crosse, La Crosse, Wisconsin
                [13 ]Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
                [14 ]St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
                [15 ]Canadian VIGOUR Centre, University of Alberta, Edmonton, Alberta
                [16 ]Division of Cardiology, Department of Medicine, Albany Medical Center and Albany Medical College, Albany, New York
                [17 ]Montreal Heart Institute and Université de Montréal, Montreal, Quebec, Canada
                [18 ]Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
                [19 ]Department of Medicine, Mazankowski Alberta Heart Institute and University of Alberta, Edmonton, Alberta, Canada
                Article
                10.1001/jama.2020.12443
                7448831
                32840598
                5d8a8e4f-2a95-42d1-bb53-fb30256c3625
                © 2020
                History

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