What question did this study set out to answer?

To assess whether escalating clopidogrel maintenance doses up to 300 mg daily improves platelet inhibition in cardiovascular disease patients harboring CYP2C19 loss-of-function alleles.

November 17, 2011JAMA

Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease

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Why the study?

Does higher maintenance dosing of clopidogrel (up to 300 mg daily) improve platelet reactivity in patients with stable cardiovascular disease and loss-of-function CYP2C19 genotypes?

Population

333 patients with stable cardiovascular disease, including 247 noncarriers of a CYP2C19*2 loss-of-function…

Comparison

Clopidogrel maintenance doses of 150, 225, and… vs Standard clopidogrel 75 mg daily maintenance dose

Design

RCT, randomized, double-blind

Follow-up

4 treatment periods, each lasting approximately 14 days

Authors

JMJessica L. MegaGeneral Cardiology WHWillibald HochholzerFondazione Edmund Mach AFAndrew L. FrelingerCross-Cutting Cardiology

Discussion

Member takes

Implication

Supports 225 mg clopidogrel in CYP2C19*2 heterozygotes; confirms pharmacodynamic equivalence to standard dosing in noncarriers.

Key Points

To assess whether escalating clopidogrel maintenance doses up to 300 mg daily improves platelet inhibition in cardiovascular disease patients harboring CYP2C19 loss-of-function alleles.
Multicenter, randomized, double-blind trial (ELEVATE-TIMI 56; NCT01235351) conducted across 32 sites enrolling 333 genotyped patients with stable cardiovascular disease.
Participants completed four 14-day treatment periods: 247 noncarriers received 75 mg and 150 mg daily, while 86 carriers (80 heterozygotes, 6 homozygotes) received 75 mg, 150 mg, 225 mg, and 300 mg daily.
Platelet reactivity was evaluated using VASP phosphorylation (platelet reactivity index, PRI) and the VerifyNow P2Y12 assay (reaction units, PRU).
With standard 75-mg daily dosing, CYP2C19*2 heterozygotes exhibited significantly higher platelet reactivity than noncarriers (mean VASP PRI: 70.0% vs 57.5%; mean PRU: 225.6 vs 163.6; P < .001 for both).
Tripling the clopidogrel dose to 225 mg daily in heterozygotes lowered platelet reactivity to levels comparable to standard 75-mg dosing in noncarriers (PRU ratio 0.94; 90% CI, 0.84-1.04; nonresponder rate fell from 52% to 10%, P < .001).
In CYP2C19*2 homozygotes, escalating therapy to 300 mg daily failed to achieve effective platelet inhibition, leaving high residual platelet reactivity (mean VASP PRI: 68.3%, 95% CI 44.9%-91.6%; mean PRU: 287.0, 95% CI 170.2-403.8).

Structured PICO

Does higher maintenance dosing of clopidogrel (up to 300 mg daily) improve platelet reactivity in patients with stable cardiovascular disease and loss-of-function CYP2C19 genotypes?

Population

333 patients with stable cardiovascular disease, including 247 noncarriers of a CYP2C19*2 loss-of-function allele and 86 carriers (80 heterozygotes, 6 homozygotes)

Intervention

Clopidogrel maintenance doses of 150, 225, and 300 mg daily for approximately 14 days per treatment period

Comparator

Standard clopidogrel 75 mg daily maintenance dose

Outcome

Platelet function test results (vasodilator-stimulated phosphoprotein [VASP] phosphorylation and VerifyNow P2Y(12) assays) and adverse eventssurrogate

In patients with stable cardiovascular disease, tripling the clopidogrel maintenance dose to 225 mg daily overcomes high on-treatment platelet reactivity in CYP2C19*2 heterozygotes, but doses up to 300 mg remain insufficient for homozygotes.

Cite This Study

Mega et al. (2011) studied this question.

synapsesocial.com/papers/6a7cde35854948aad28d19e2 https://doi.org/10.1001/jama.2011.1703

Topics

Dual antiplatelet therapy Women and heart disease

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Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Topics

Dosing Clopidogrel Based on CYP2C19 Genotype and the Effect on Platelet Reactivity in Patients With Stable Cardiovascular Disease

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Also Consider

Topics

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