Escalating Clopidogrel by Involving a Genetic Strategy–Thrombolysis In Myocardial Infarction 56 - ELEVATE-TIMI 56


The goal of the trial was to evaluate a strategy of tailored clopidogrel therapy by genotyping for CYP2C19*2 among patients with stable cardiovascular disease.


Administration of higher doses of clopidogrel according to CYP2C19*2 genotype will reduce platelet reactivity.

Study Design

  • Randomized
  • Blinded
  • Parallel
  • Stratified

Patient Populations:

  • Patients with clinically stable cardiovascular disease with an indication for daily clopidogrel (prior myocardial infarction and/or percutaneous coronary intervention within the last 4 weeks to 6 months)

    Number of enrollees: 333
    Mean patient age: 60 years
    Percentage female: 25%


  • Use of anticoagulation therapy
  • Use of proton pump inhibitors
  • Current smoking
  • Prior stent thrombosis
  • Increased risk for bleeding
  • End-stage renal or liver disease
  • Procedure or hospitalization planned within the next 12 weeks

Primary Endpoints:

  • On-treatment VASP PRI and PRU

Drug/Procedures Used:

Patients with stable cardiovascular disease had blinded genotyping performed for CYP2C19*2. Carriers were treated with clopidogrel 75 mg, 150 mg, 225 mg, and 300 mg daily for 14 days each (in various sequences), whereas noncarriers were treated with clopidogrel 75 mg, and 150 mg daily for 14 days each (two periods for each dose).

Principal Findings:

Overall, 333 patients were enrolled. The mean age was 60 years, 25% were women, 35% had diabetes, 57% had prior myocardial infarction, mean body mass index was 31 kg/m2, and mean blood pressure was 127/76 mm Hg.

Vasodilator-stimulated phosphoprotein platelet reactivity index (VASP PRI) among noncarriers (p for trend < 0.001):
58% with clopidogrel 75 mg
47% with clopidogrel 150 mg

VASP PRI among CPY2C19*2 heterozygote carriers (p for trend < 0.001):
70% with clopidogrel 75 mg
61% with clopidogrel 150 mg
53% with clopidogrel 225 mg
49% with clopidogrel 300 mg

VASP PRI among CPY2C19*2 homozygote carriers (p for trend = 0.003):
87% with clopidogrel 75 mg
79% with clopidogrel 150 mg
73% with clopidogrel 225 mg
68% with clopidogrel 300 mg

Nonresponse to clopidogrel 75 mg daily (P2Y12 reactivity unit [PRU] ≥230): 23% among noncarriers, 52% among CYP2C19*2 heterozygotes, and 80% among CYP2C19*2 homozygotes.

PRU among noncarriers (p for trend < 0.001):
164 with clopidogrel 75 mg
127 with clopidogrel 150 mg

PRU among CPY2C19*2 heterozygote carriers (p for trend < 0.001):
226 with clopidogrel 75 mg
188 with clopidogrel 150 mg
153 with clopidogrel 225 mg
128 with clopidogrel 300 mg

PRU among CPY2C19*2 homozygote carriers (p for trend = 0.32):
329 with clopidogrel 75 mg
310 with clopidogrel 150 mg
286 with clopidogrel 225 mg
287 with clopidogrel 300 mg


Among patients with stable cardiovascular disease, carriers of CYP2C19*2 had higher platelet reactivity to clopidogrel 75 mg daily than noncarriers. In heterozygotes, increasing clopidogrel to 225 mg daily resulted in a similar degree of platelet reactivity as noncarriers with clopidogrel 75 mg daily. On the other hand, homozygotes retained a high degree of platelet reactivity, even with clopidogrel 300 mg daily.

The role of genetic testing in patients with cardiovascular disease who are treated with clopidogrel is currently unclear since antiplatelet therapy can be directly tailored to platelet reactivity (for example, VASP PRI or PRU). Such a strategy was tested in the GRAVITAS trial; however, extra higher loading dose (clopidogrel 600 mg) and higher maintenance dose (clopidogrel 150 mg daily) was not effective at reducing adverse cardiovascular events. In that trial, it is unknown if an even higher daily dose of clopidogrel or a newer adenosine diphosphate (ADP) receptor antagonist would have resulted in different results.


Mega JL, Hochholzer W, Frelinger AL III, et al. Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease. JAMA 2011;306:2221-8.

Presented by Dr. Jessica Mega at the American Heart Association Scientific Sessions, Orlando, FL, November 16, 2011.

Clinical Topics: Invasive Cardiovascular Angiography and Intervention

Keywords: Myocardial Infarction, Body Mass Index, Platelet Aggregation Inhibitors, Blood Pressure, Ticlopidine, Blood Platelets, Genetic Testing, Genotype, Diabetes Mellitus, Vasodilator Agents, Percutaneous Coronary Intervention

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