Escalating Clopidogrel by Involving a Genetic Strategy - Thrombolysis In Myocardial Infarction 56 (ELEVATE)

TIMI Study Group

Status and phase: Completed; Phase 2

Conditions: Percutaneous Coronary Intervention; Myocardial Infarction

Treatments: Drug: Clopidogrel

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT01235351

TIMI 56

Details and patient eligibility

About

To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele.

Full description

Clopidogrel blocks the P2Y12 ADP receptor on platelets and has been shown to reduce cardiovascular events in acute coronary syndrome (ACS) patients.However, inter-patient variability in the pharmacodynamic response to clopidogrel is well recognized, and patients with lesser degrees of platelet inhibition in response to clopidogrel have been shown to be at increased risk of cardiovascular events.

One potential source of this variability is the metabolism of clopidogrel, which is a pro-drug requiring biotransformation to become an active antiplatelet compound. Cytochrome P-450 (CYP) enzymes play a role in the metabolism, and carriers of reduced-function genetic variants in CYP2C19 (~30% of the population) have lower active clopidogrel metabolite levels, diminished platelet inhibition, and higher rates of adverse cardiovascular events as compared with non-carriers in the setting of treatment with standard maintenance doses of clopidogrel.

Aim: To determine whether higher as compared with lower maintenance doses of clopidogrel can adequately improve the degree of platelet inhibition in carriers of a reduced-function CYP2C19 allele.

Hypotheses: The primary hypothesis is that subjects who carry a reduced-function CYP2C19 allele will have improvement in platelet inhibition with higher maintenance doses of clopidogrel.The secondary hypothesis is that higher maintenance doses of clopidogrel in carriers of a reduced-function CYP2C19 allele will result in similar platelet inhibition as compared to a standard maintenance dose of clopidogrel in non-carriers.

Enrollment: 335 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria (major):

1. Between 18 and 75 years of age, inclusive.
2. Have an indication for the use of clopidogrel defined as either spontaneous MI [hospitalized with final diagnosis of MI, excluding periprocedural or definite secondary MI (e.g., due to anemia or hypertensive emergency)] or PCI within the past 6 months.
3. Clinically stable and at least 4 weeks following the MI or PCI.

Exclusion Criteria (major):

1. Conditions that alter platelet function.
2. Conditions that increase bleeding risk.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Quadruple Blind

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335 participants in 2 patient groups

Clopidogrel - for CYP2C19*2 carriers

Active Comparator group

Description:

Clopidogrel for CYP2C19\*2 gene carriers

Treatment:

Drug: Clopidogrel

Drug: Clopidogrel

Clopidogrel - for CYP2C19*2 non-carriers

Active Comparator group

Description:

Clopidogrel for CYP2C19\*2 gene NON-carriers

Treatment:

Drug: Clopidogrel

Drug: Clopidogrel