Pharmacogenetic Approach to Anti-platelet Therapy for the Treatment of ST-segment Elevation Myocardial Infarction (STEMI) (RAPID STEMI)

This study has been completed.
Sponsor:
Collaborator:
Spartan Bioscience Inc.
Information provided by (Responsible Party):
Derek So, University of Ottawa Heart Institute
ClinicalTrials.gov Identifier:
NCT01452139
First received: September 27, 2011
Last updated: April 23, 2013
Last verified: April 2013
  Purpose

The objective of the RAPID STEMI study is to evaluate the feasibility, efficacy, and safety of a pharmacogenetic approach to anti-platelet therapy for the treatment of ST-segment elevation myocardial infarction (STEMI) patients following percutaneous coronary intervention (PCI) using point-of-care genetic testing for the CYP2C19*2, *17, and ABCB1 3435 C>T alleles.


Condition Intervention Phase
STEMI
Genetic: Point-of-Care Genetic Testing
Drug: Prasugrel
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: ReAssessment of Anti-Platelet Therapy Using an InDividualized Strategy in Patients With ST-segment Elevation Myocardial Infarction

Resource links provided by NLM:


Further study details as provided by University of Ottawa Heart Institute:

Primary Outcome Measures:
  • The rates of high on-treatment platelet reactivity as measured by the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) in CYP2C19*2 and ABCB1 3435 TT carriers treated with prasugrel relative to clopidogrel. [ Time Frame: 1 month ] [ Designated as safety issue: No ]
    High on-treatment platelet reactivity as measured by the VerifyNow P2Y12 assay with evidence based cutoffs.


Secondary Outcome Measures:
  • Composite of death from cardiovascular causes, non-fatal myocardial infarction, and re-hospitalization. [ Time Frame: 1 month ] [ Designated as safety issue: No ]
  • Bleeding risk [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]
    Defined by TIMI major/minor

  • Concordance of point-of-care genetic screening with laboratory based genotyping methods [ Time Frame: 1 month ] [ Designated as safety issue: No ]
    Genotyping results from the Spartan RX device will be compared with the results of direct DNA sequencing.

  • Effect of the CYP2C19*17 allele on platelet inhibition. [ Time Frame: 1 month ] [ Designated as safety issue: No ]
    As measured by VerifyNow in P2Y12 Reaction Units (PRU) and percent platelet inhibition.

  • Effect of CYP2C19*17 allele on bleeding events [ Time Frame: 1 month ] [ Designated as safety issue: Yes ]
    Comparison of TIMI major & minor bleeding rates in carriers and non-carriers of the CYP2C19*17 allele.

  • Mean PRU and percent platelet inhibition in CYP2C19*2 and ABCB1 3435 TT carriers treated with prasugrel relative to clopidogrel [ Time Frame: 1 month ] [ Designated as safety issue: No ]
  • Between-group change in PRU and percent platelet inhibition in CYP2C19*2 and ABCB1 3435 TT carriers treated with prasugrel relative to clopidogrel. [ Time Frame: 1 month ] [ Designated as safety issue: No ]

Enrollment: 102
Study Start Date: September 2011
Study Completion Date: March 2013
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: At-Risk Genetics Arm: Prasugrel
Treatment of STEMI patients carrying at least 1 at-risk genetic variant with prasugrel 10mg daily for 1 month.
Genetic: Point-of-Care Genetic Testing
Point-of-Care Genetic Testing for Genetic Variants Linked to Adverse Outcomes with Clopidogrel (CYP2C19*2 & ABCB1 3435 TT)
Other Name: Spartan RX
Drug: Prasugrel
Treatment of STEMI patients carrying at least one high risk genetic variant with prasugrel 10mg daily.
Other Name: Effient
Active Comparator: At-Risk Genetics Arm: Clopidogrel
Treatment of STEMI patients carrying at least 1 at-risk genetic variant with clopidogrel 150mg daily for 1 week followed by 75mg daily.
Genetic: Point-of-Care Genetic Testing
Point-of-Care Genetic Testing for Genetic Variants Linked to Adverse Outcomes with Clopidogrel (CYP2C19*2 & ABCB1 3435 TT)
Other Name: Spartan RX
Active Comparator: Low Risk Genetics Arm: Clopidogrel
Treatment of STEMI patients with no at-risk genetic variants with clopidogrel 75mg daily.
Genetic: Point-of-Care Genetic Testing
Point-of-Care Genetic Testing for Genetic Variants Linked to Adverse Outcomes with Clopidogrel (CYP2C19*2 & ABCB1 3435 TT)
Other Name: Spartan RX

Detailed Description:

Dual anti-platelet therapy following percutaneous coronary intervention (PCI) for the treatment of STEMI has traditionally consisted of aspirin and clopidogrel. Despite this treatment approach, a substantial portion of patients experience recurrent 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 high on-treatment platelet reactivity. Although multiple variables have been implicated in altered clopidogrel response, mounting evidence has suggested a crucial role for common genetic variants including: CYP2C19*2, *17, and ABCB1 3435 C>T alleles.

Presence of the CYP2C19*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 2 separate meta-analyses, 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. The ABCB1 3435 TT genotype has also been linked with increased adverse cardiovascular events in individuals treated with clopidogrel following PCI for an acute coronary syndrome. In contrast, the CYP2C19*17 gain-of-function allele appears to enhance the activity of clopidogrel and has been associated with reduced ischemic events but increased bleeding.

As a result of these findings, experts have begun to advocate for routine genotyping in the context of 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 point-of-care genetic testing for the CYP2C19*2, *17, and ABCB1 3435 C>T alleles that requires minimal training to perform carries the potential to overcome these obstacles and may facilitate the incorporation of pharmacogenetic strategies into routine clinical practice.

Patients receiving PCI in the context of STEMI will undergo point-of-care genetic testing for the CYP2C19*2, *17, and ABCB1 3435 C>T alleles. CYP2C19*2 carriers and individuals homozygous for the ABCB1 3435 T allele will subsequently be randomized to prasugrel 10mg daily for 1 month or clopidogrel 150mg daily for 1 week followed by 75mg daily. The remaining individuals without an at-risk genotype will receive standard therapy with clopidogrel. At the end of the 1 month period, efficacy of the treatment strategies will be evaluated using VerifyNow platelet function testing. The effect of the CYP2C19*17 allele will be prospectively evaluated during the treatment period.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males and Females between the ages of 18 and 75 years
  • STEMI patients treated with percutaneous coronary intervention
  • Able to provide informed consent
  • Able to comply with assigned treatment strategy and attend 1 month follow-up visit

Exclusion Criteria:

  • Receiving anti-platelet therapy other than aspirin and clopidogrel
  • Receiving anti-coagulation with warfarin or dabigatran
  • History of stroke or transient ischemic attack
  • Platelet count < 100 000/μL
  • Known Bleeding Diathesis
  • Hematocrit <30% or >52%
  • Severe Liver Dysfunction
  • Renal Insufficiency (Creatinine Clearance < 30ml/min)
  • Pregnant females
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01452139

Locations
Canada, Ontario
University of Ottawa Heart Institute
Ottawa, Ontario, Canada, K1N 4W7
Sponsors and Collaborators
University of Ottawa Heart Institute
Spartan Bioscience Inc.
Investigators
Principal Investigator: Derek Y F So, MD University of Ottawa Heart Institute
Study Director: Jason D Roberts, MD University of Ottawa Heart Institute
  More Information

Publications:

Responsible Party: Derek So, Assistant Professor, University of Ottawa Heart Institute
ClinicalTrials.gov Identifier: NCT01452139     History of Changes
Other Study ID Numbers: 2010364-01H
Study First Received: September 27, 2011
Last Updated: April 23, 2013
Health Authority: Canada: Health Canada

Keywords provided by University of Ottawa Heart Institute:
STEMI
Pharmacogenetics
Prasugrel
Clopidogrel
Percutaneous Coronary Intervention

Additional relevant MeSH terms:
Infarction
Myocardial Infarction
Ischemia
Pathologic Processes
Necrosis
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Clopidogrel
Prasugrel
Platelet Aggregation Inhibitors
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions
Purinergic P2Y Receptor Antagonists
Purinergic P2 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 28, 2014