Genetic Determinants of Response to Clopidogrel and Cardiovascular Events
10 Dec 2009-The New England Journal of Medicine (Massachusetts Medical Society)-Vol. 360, Iss: 4, pp 363-375
TL;DR: Among patients with an acute myocardial infarction who were receiving clopidogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not, particularly marked among the patients undergoing percutaneous coronary intervention.
Abstract: Background Pharmacogenetic determinants of the response of patients to clopidogrel contribute to variability in the biologic antiplatelet activity of the drug. The effect of these determinants on clinical outcomes after an acute myocardial infarction is unknown. Methods We consecutively enrolled 2208 patients presenting with an acute myocardial infarction in a nationwide French registry and receiving clopidogrel therapy. We then assessed the relation of allelic variants of genes modulating clopidogrel absorption (ABCB1), metabolic activation (CYP3A5 and CYP2C19), and biologic activity (P2RY12 and ITGB3) to the risk of death from any cause, nonfatal stroke, or myocardial infarction during 1 year of follow-up. Results Death occurred in 225 patients, and nonfatal myocardial infarction or stroke in 94 patients, during the follow-up period. None of the selected single-nucleotide polymorphisms (SNPs) in CYP3A5, P2RY12, or ITGB3 were associated with a risk of an adverse outcome. Patients with two variant alleles of ABCB1 (TT at nucleotide 3435) had a higher rate of cardiovascular events at 1 year than those with the ABCB1 wild-type genotype (CC at nucleotide 3435) (15.5% vs. 10.7%; adjusted hazard ratio, 1.72; 95% confidence interval [CI], 1.20 to 2.47). Patients carrying any two CYP2C19 loss-offunction alleles (*2, *3, *4, or *5), had a higher event rate than patients with none (21.5% vs. 13.3%; adjusted hazard ratio, 1.98; 95% CI, 1.10 to 3.58). Among the 1535 patients who underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among patients with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none (95% CI, 1.71 to 7.51). Conclusions Among patients with an acute myocardial infarction who were receiving clo pid ogrel, those carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than those who were not. This effect was particularly marked among the patients undergoing percutaneous coronary intervention. (ClinicalTrials. gov number, NCT00673036.)
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Cites background from "Genetic Determinants of Response to..."
...Numerous clinical studies have confirmed that CYP2C19 PMs have significantly lower anticoagulation effect of clopidogrel,which is associatedwith an increased risk of major adverse cardiovascular events (Collet et al., 2009; Mega et al., 2009; Simon et al., 2009; Sofi et al., 2011)....
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References
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TL;DR: The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation, however, the risk of major bleeding is increased among patients treated with clopIDogrel.
Abstract: Background: Despite current treatments, patients who have acute coronary syndromes without ST-segment elevation have high rates of major vascular events. We evaluated the efficacy and safety of the antiplatelet agent clopidogrel when given with aspirin in such patients. Methods: We randomly assigned 12,562 patients who had presented within 24 hours after the onset of symptoms to receive clopidogrel (300 mg immediately, followed by 75 mg once daily) (6259 patients) or placebo (6303 patients) in addition to aspirin for 3 to 12 months. Results: The first primary outcome -- a composite of death from cardiovascular causes, nonfatal myocardial infarction, or stroke -- occurred in 9.3 percent of the patients in the clopidogrel group and 11.4 percent of the patients in the placebo group (relative risk with clopidogrel as compared with placebo, 0.80; 95 percent confidence interval, 0.72 to 0.90; P<0.001). The second primary outcome -- the first primary outcome or refractory ischemia -- occurred in 16.5 percent of the patients in the clopidogrel group and 18.8 percent of the patients in the placebo group (relative risk, 0.86, P<0.001). The percentages of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel. There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7 percent vs. 2.7 percent; relative risk, 1.38; P=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.1 percent vs. 1.8 percent, P=0.13) or hemorrhagic strokes. Conclusions: The antiplatelet agent clopidogrel has beneficial effects in patients with acute coronary syndromes without ST-segment elevation. However, the risk of major bleeding is increased among patients treated with clopidogrel. (N Engl J Med 2001;345:494-502.) Copyright (C) 2001 Massachusetts Medical Society.
5,977 citations
TL;DR: Following PCI, long-term clopidogrel therapy significantly reduced the risk of adverse ischemic events and subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events.
Abstract: ContextFollowing percutaneous coronary intervention (PCI), short-term clopidogrel
therapy in addition to aspirin leads to greater protection from thrombotic
complications than aspirin alone. However, the optimal duration of combination
oral antiplatelet therapy is unknown. Also, although current clinical data
suggest a benefit for beginning therapy with a clopidogrel loading dose prior
to PCI, the practical application of this therapy has not been prospectively
studied.ObjectivesTo evaluate the benefit of long-term (12-month) treatment with clopidogrel
after PCI and to determine the benefit of initiating clopidogrel with a preprocedure
loading dose, both in addition to aspirin therapy.Design, Setting, and ParticipantsThe Clopidogrel for the Reduction of Events During Observation (CREDO)
trial, a randomized, double-blind, placebo-controlled trial conducted among
2116 patients who were to undergo elective PCI or were deemed at high likelihood
of undergoing PCI, enrolled at 99 centers in North America from June 1999
through April 2001.InterventionsPatients were randomly assigned to receive a 300-mg clopidogrel loading
dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter,
all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through
12 months, patients in the loading-dose group received clopidogrel, 75 mg/d,
and those in the control group received placebo. Both groups received aspirin
throughout the study.Main Outcome MeasuresOne-year incidence of the composite of death, myocardial infarction
(MI), or stroke in the intent-to-treat population; 28-day incidence of the
composite of death, MI, or urgent target vessel revascularization in the per-protocol
population.ResultsAt 1 year, long-term clopidogrel therapy was associated with a 26.9%
relative reduction in the combined risk of death, MI, or stroke (95% confidence
interval [CI], 3.9%-44.4%; P = .02; absolute reduction,
3%). Clopidogrel pretreatment did not significantly reduce the combined risk
of death, MI, or urgent target vessel revascularization at 28 days (reduction,
18.5%; 95% CI, −14.2% to 41.8%; P = .23). However,
in a prespecified subgroup analysis, patients who received clopidogrel at
least 6 hours before PCI experienced a relative risk reduction of 38.6% (95%
CI, −1.6% to 62.9%; P = .051) for this end
point compared with no reduction with treatment less than 6 hours before PCI.
Risk of major bleeding at 1 year increased, but not significantly (8.8% with
clopidogrel vs 6.7% with placebo; P = .07).ConclusionsFollowing PCI, long-term (1-year) clopidogrel therapy significantly
reduced the risk of adverse ischemic events. A loading dose of clopidogrel
given at least 3 hours before the procedure did not reduce events at 28 days,
but subgroup analyses suggest that longer intervals between the loading dose
and PCI may reduce events.
2,977 citations
TL;DR: Angina/Non-ST-Elevation Myocardial Infarction : ACC/AHA 2007 Guidelines for the Management of Patients With Unstable ISSN: 1524-4539 Copyright © 2007 American Heart Association.
Abstract: Angina/Non-ST-Elevation Myocardial Infarction : ACC/AHA 2007 Guidelines for the Management of Patients With Unstable ISSN: 1524-4539 Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online 72514 Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX doi: 10.1161/CIRCULATIONAHA.107.18194
2,605 citations
TL;DR: A significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function is observed and this polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of M DR-1.
Abstract: To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.
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TL;DR: In a wide range of patients with acute MI, adding clopidogrel 75 mg daily to aspirin and other standard treatments (such as fibrinolytic therapy) safely reduces mortality and major vascular events in hospital, and should be considered routinely.
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