Clinical trial NCT01184300: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation
Official title: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy Based on GENetic Evaluation (The RAPID GENE Study)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Stable Coronary Artery Disease
Acute Coronary Syndrome
Percutaneous Coronary Intervention
Keywords: CYP2C19*2
Pharmacogenomics
Clopidogrel
Prasugrel
Percutaneous Coronary Intervention
Lead sponsor: Ottawa Heart Institute Research Corporation
Sponsor class: OTHER
Collaborators: name: Spartan Bioscience Inc.
First posted: 2010-08-18
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the RAPID GENE study is to evaluate the feasibility, efficacy and safety of a pharmacogenomic approach to anti-platelet therapy following coronary artery stenting using a CYP2C19\*2 point-of-care genetic test.

Detailed description: Effective medical treatment following acute coronary syndromes and percutaneous coronary intervention (PCI) consists of dual anti-platelet therapy with aspirin and clopidogrel. Despite this treatment approach, a substantial portion of patients continue to experience an increased rate of subsequent adverse cardiovascular events including death, myocardial infarction, and stent thrombosis. This persistent vulnerability has been associated with inadequate platelet inhibition in response to clopidogrel administration, a phenomenon referred to as clopidogrel resistance. Although multiple variables have been implicated in clopidogrel resistance, mounting evidence suggests a crucial role for the loss-of-function CYP2C19\*2 genetic variant. Presence of the \*2 allele has been associated with a 1.5- to 6-fold increased risk of cardiovascular death, myocardial infarction, and stent thrombosis following PCI in patients treated with clopidogrel. These findings, recently bolstered by a meta-analysis, led the American Food and Drug Administration to issue a boxed warning for clopidogrel stating that poor metabolizers may not receive the full benefit of the drug. Consequently, experts have begun to advocate for routine genotyping in the context of dual anti-platelet therapy following PCI. A personalized approach to dual anti-platelet therapy following PCI is feasible given the presence of treatment alternatives such as prasugrel that are capable of overcoming clopidogrel resistance. Selective administration of prasugrel to patients at increased risk of clopidogrel resistance has the potential to successfully minimize adverse ischemic events, while simultaneously minimizing associated bleeding events and health care costs. A prospective pharmacogenomic approach to anti-platelet therapy has been previously hampered by limited access and the time-delay associated with genetic testing. The development of a point-of-care CYP2C19\*2 genetic test that requires minimal training to operate carries the potential to overcome these obstacles and may facilitate the incorporation of pharmacogenomic strategies into routine clinical practice.

Patients receiving percutaneous coronary intervention in the context of non-ST elevation acute coronary syndromes and stable coronary artery disease will be randomized to either a rapid genotyping strategy or standard therapy. Patients in the Rapid Genotyping arm will be screened for the presence of the CYP2C19\*2 allele using a point-of-care genetic test. Carriers of the \*2 allele will receive prasugrel 10 mg daily for 1 week. Non-\*2 carriers in the Rapid Genotyping arm and all patients in the Standard Therapy arm will receive clopidogrel 75 mg daily. At the end of the 1 week period, efficacy of the treatment strategies will be evaluated using VerifyNow platelet function testing.

Eligibility criteria: Inclusion Criteria:

* Males and Females between the ages of 18 and 75 years
* Patients undergoing percutaneous coronary intervention in the context of a non-ST-elevation acute coronary syndrome or stable coronary artery disease
* Able to provide informed consent
* Able to comply with assigned treatment strategy and attend 1 week follow-up visit

Exclusion Criteria:

* Receiving anti-platelet therapy other than aspirin and clopidogrel
* Receiving anti-coagulation with warfarin
* History of stroke or transient ischemic attack
* Platelet count \< 100 000/μL
* Known Bleeding Diathesis
* Hematocrit \<32% or \>52%
* Severe Liver Dysfunction
* Renal Insufficiency (Creatinine Clearance \< 30ml/min)
* Pregnant females

Primary outcomes:
measure: Clopidogrel response status as measured by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) in CYP2C19*2 carriers.
timeFrame: 1 week
Secondary outcomes:
measure: Concordance of point-of-care genetic screening with laboratory based genotyping methods
timeFrame: 1 week
measure: Composite of death from cardiovascular causes, non-fatal myocardial infarction, and re-hospitalization
timeFrame: 1 week and 6 months
measure: Bleeding risk
timeFrame: 1 week and 6 months
measure: Incidence of stent thrombosis
timeFrame: 1 week and 6 months
measure: Feasibility of point-of-care genotyping in randomized setting
timeFrame: 1 week
measure: Influence of Alternate CYP2C19 variants on outcomes
timeFrame: 1 week and 6 months
Other outcomes:
Locations:
city: Ottawa
country: Canada
facility: University of Ottawa Heart Institute
state: Ontario
Study officials:
affiliation: Ottawa Heart Institute Research Corporation
name: Derek Y.F. So, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ottawa Heart Institute Research Corporation
name: Jason D. Roberts, MD
role: STUDY_DIRECTOR
References:
citation: Damani SB, Topol EJ. The case for routine genotyping in dual-antiplatelet therapy. J Am Coll Cardiol. 2010 Jul 6;56(2):109-11. doi: 10.1016/j.jacc.2010.03.029. Epub 2010 May 13.
citation: Hulot JS, Collet JP, Silvain J, Pena A, Bellemain-Appaix A, Barthelemy O, Cayla G, Beygui F, Montalescot G. Cardiovascular risk in clopidogrel-treated patients according to cytochrome P450 2C19*2 loss-of-function allele or proton pump inhibitor coadministration: a systematic meta-analysis. J Am Coll Cardiol. 2010 Jul 6;56(2):134-43. doi: 10.1016/j.jacc.2009.12.071.
citation: Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009 Jan 22;360(4):354-62. doi: 10.1056/NEJMoa0809171. Epub 2008 Dec 22.
citation: Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias WL, Braunwald E, Sabatine MS. Cytochrome P450 genetic polymorphisms and the response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009 May 19;119(19):2553-60. doi: 10.1161/CIRCULATIONAHA.109.851949. Epub 2009 May 4.
citation: Price MJ, Endemann S, Gollapudi RR, Valencia R, Stinis CT, Levisay JP, Ernst A, Sawhney NS, Schatz RA, Teirstein PS. Prognostic significance of post-clopidogrel platelet reactivity assessed by a point-of-care assay on thrombotic events after drug-eluting stent implantation. Eur Heart J. 2008 Apr;29(8):992-1000. doi: 10.1093/eurheartj/ehn046. Epub 2008 Feb 10.
citation: Trenk D, Hochholzer W, Fromm MF, Chialda LE, Pahl A, Valina CM, Stratz C, Schmiebusch P, Bestehorn HP, Buttner HJ, Neumann FJ. 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. J Am Coll Cardiol. 2008 May 20;51(20):1925-34. doi: 10.1016/j.jacc.2007.12.056.
citation: Sibbing D, Stegherr J, Latz W, Koch W, Mehilli J, Dorrler K, Morath T, Schomig A, Kastrati A, von Beckerath N. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. 2009 Apr;30(8):916-22. doi: 10.1093/eurheartj/ehp041. Epub 2009 Feb 4.
citation: Roberts JD, Wells GA, Le May MR, Labinaz M, Glover C, Froeschl M, Dick A, Marquis JF, O'Brien E, Goncalves S, Druce I, Stewart A, Gollob MH, So DY. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. 2012 May 5;379(9827):1705-11. doi: 10.1016/S0140-6736(12)60161-5. Epub 2012 Mar 29.