Clopidogrel dose adjustment after outpatient screening for CYP2C19 variant alleles: a pilot study.

This pilot study examined the feasibility of outpatient screening and clopidogrel dose adjustment for patients with previous percutaneous coronary intervention and at least one CYP2C19 loss-of-function allele. After screening a total of 211 outpatients, 50 patients were enrolled in a crossover study comparing 30 days of standard dose (75 mg) to 30 days of high-dose clopidogrel (150 mg). Platelet function was assessed with the VerifyNow P2Y12 assay. In patients with CYP2C19*2, 150 mg daily of clopidogrel was associated with improved ADP-specific platelet inhibition (217 vs 258 P2Y12 reaction units, p = 0.01). Outpatient screening for CYP2C19 loss-of-function polymorphisms is feasible, and a strategy of clopidogrel dose escalation may improve platelet inhibition in appropriately selected patients.

[1]  R. Horenstein,et al.  The CYP2C19*17 variant is not independently associated with clopidogrel response , 2013, Journal of Thrombosis and Haemostasis.

[2]  J. Mega,et al.  Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update , 2013, Clinical pharmacology and therapeutics.

[3]  A. Schmaier,et al.  Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the platelet physiology subcommittee of SSC/ISTH , 2013, Journal of thrombosis and haemostasis : JTH.

[4]  E. Vicaut,et al.  Bedside monitoring to adjust antiplatelet therapy for coronary stenting. , 2012, The New England journal of medicine.

[5]  M. Pencina,et al.  Dosing clopidogrel based on CYP2C19 genotype and the effect on platelet reactivity in patients with stable cardiovascular disease. , 2011, JAMA.

[6]  Hani Jneid,et al.  2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in c , 2011, Journal of the American College of Cardiology.

[7]  G. Montalescot,et al.  High doses of clopidogrel to overcome genetic resistance: the randomized crossover CLOVIS-2 (Clopidogrel and Response Variability Investigation Study 2). , 2011, JACC. Cardiovascular interventions.

[8]  N. Schork,et al.  Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. , 2011, JAMA.

[9]  E. Antman,et al.  Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. , 2010, JAMA.

[10]  A. Kastrati,et al.  Cytochrome 2C19*17 Allelic Variant, Platelet Aggregation, Bleeding Events, and Stent Thrombosis in Clopidogrel-Treated Patients With Coronary Stent Placement , 2010, Circulation.

[11]  Claes Held,et al.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes. , 2009, The New England journal of medicine.

[12]  S. Steinhubl,et al.  Considerable variability in platelet activity among patients with coronary artery disease in response to an increased maintenance dose of clopidogrel , 2009, Coronary artery disease.

[13]  E. Antman,et al.  Cytochrome p-450 polymorphisms and response to clopidogrel. , 2009, The New England journal of medicine.

[14]  G. Montalescot,et al.  Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study , 2009, The Lancet.

[15]  N. Farid,et al.  Quantitative determination of clopidogrel active metabolite in human plasma by LC-MS/MS. , 2008, Journal of pharmaceutical and biomedical analysis.

[16]  M. Fromm,et al.  Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. , 2008, Journal of the American College of Cardiology.

[17]  P. Barragan,et al.  Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. , 2008, Journal of the American College of Cardiology.

[18]  Li Zhang,et al.  A double-blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. , 2008, European heart journal.

[19]  Jeffrey L. Anderson,et al.  2007 Focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. , 2008, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[20]  E. Antman,et al.  Prasugrel versus clopidogrel in patients with acute coronary syndromes. , 2007, The New England journal of medicine.

[21]  H. White,et al.  Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. , 2007, Journal of the American College of Cardiology.

[22]  D. Angiolillo,et al.  Randomized Comparison of a High Clopidogrel Maintenance Dose in Patients With Diabetes Mellitus and Coronary Artery Disease: Results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) Study , 2007, Circulation.

[23]  F. Neumann,et al.  Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. , 2006, Journal of the American College of Cardiology.

[24]  G. Montalescot,et al.  A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. , 2006, Journal of the American College of Cardiology.

[25]  P. Gurbel,et al.  Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. , 2005, Journal of the American College of Cardiology.

[26]  A. Kastrati,et al.  Loading With 600 mg Clopidogrel in Patients With Coronary Artery Disease With and Without Chronic Clopidogrel Therapy , 2004, Circulation.

[27]  H. Hod,et al.  Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction , 2004, Circulation.

[28]  P. Morange,et al.  FOCUS ISSUE: CARDIAC INTERVENTION Benefit of a 600-mg Loading Dose of Clopidogrel on Platelet Reactivity and Clinical Outcomes in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Coronary Stenting , 2006 .