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

Mega, Jessica L.; Hochholzer, Willibald; Frelinger, Andrew L.; Kluk, Michael J.; Angiolillo, Dominick J.; Kereiakes, Dean J.; Isserman, Steven; Rogers, William J.; Ruff, Christian T.; Contant, Charles F.; Pencina, Michael J.; Scirica, Benjamin M.; Longtine, Janina A.; Michelson, Alan D.; Sabatine, Marc S.

doi:10.1001/jama.2011.1703

Cited by 328 publications

(250 citation statements)

References 34 publications

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“…Besides acting as a vasodilator, riociguat promotes platelet inhbition by acting synergistically with PGI 2 75. The state of inhibitory pathways can be monitored by measuring intracellular phosphorylation of the PKA/PKG substrate protein VASP in platelets, which has been used to study the efficiency of P2Y12 inhibition in patients 109, 110. Pharmacological studies of P2Y12 receptor based anti‐platelet therapy show that addition of low concentrations of PGI 2 and NO to platelets from volunteers receiving dual anti‐platelet therapy with aspirin and the P2Y12 blocker prasugrel strongly enhances platelet inhibition in the presence of TRAP‐6 or collagen 8.…”

Section: Discussionmentioning

confidence: 99%

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Nagy

Smolenski

2018

Research and Practice in Thrombosis and Haemostasis

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Platelets are regulated by extracellular cues that impact on intracellular signaling. The endothelium releases prostacyclin and nitric oxide which stimulate the synthesis of cyclic nucleotides cAMP and cGMP leading to platelet inhibition. Other inhibitory mechanisms involve immunoreceptor tyrosine‐based inhibition motif‐containing receptors, intracellular receptors and receptor desensitization. Inhibitory cyclic nucleotide pathways are traditionally thought to represent a passive background system keeping platelets in a quiescent state. In contrast, cyclic nucleotides are increasingly seen to be dynamically involved in most aspects of platelet regulation. This review focuses on crosstalk between activating and cyclic nucleotide‐mediated inhibitory pathways highlighting emerging new hub structures and signaling mechanisms. In particular, interactions of plasma membrane receptors like P2Y12 and GPIb/IX/V with the cyclic nucleotide system are described. Furthermore, differential regulation of the RGS18 complex, second messengers, protein kinases, and phosphatases are presented, and control over small G‐proteins by guanine‐nucleotide exchange factors and GTPase‐activating proteins are outlined. Possible clinical implications of signaling crosstalk are discussed.

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Section: Discussionmentioning

confidence: 99%

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Nagy

Smolenski

2018

Research and Practice in Thrombosis and Haemostasis

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“…Alternatively increasing clopidogrel dose may sometimes suffice. Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes, achieved levels of platelet reactivity similar to that seen with the standard 75 mg dose in non-carriers; for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition [5]. …”

mentioning

confidence: 83%

Measuring Platelet Reactivity after Clopidogrel-Has it Reached the End of the Road?

Wong¹

2013

Cardiol Pharmacol

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Clopidogrel is traditionally prescribed at 75 mg daily after a 300 mg loading dose. It is a pro-drug, with a two-step activation process involving a series of cytochrome P-450 (CYP) isoenzymes. Its antiplatelet effect is variable and susceptible to genetic polymorphisms. In particular, patients with either 1 or 2 loss-of-function CYP2C19 alleles have an attenuated pharmacologic response and worse clinical outcomes with standard dose clopidogrel [1]. Among clopidogrel-treated subjects in TRITON-TIMI 38, carriers had higher risk of cardiovascular death, myocardial infarction, or stroke as compared with non-carriers (12.1% vs. 8.0%; P=0.01) and higher risk of stent thrombosis (2.6% vs. 0.8%; p=0.02) [1]. Also, the common polymorphisms in the CYP2C19 gene, seen in approximately 30% of whites, may be more common in other ethnic groups -40% of blacks and >55% of East Asians [2].To achieve higher platelet inhibition, Prasugrel and Ticagrelor are newer P2Y 12 ADP receptor blockers that surpass clopidogrel in platelet inhibition [3,4]. Alternatively increasing clopidogrel dose may sometimes suffice. Among patients with stable cardiovascular disease, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes, achieved levels of platelet reactivity similar to that seen with the standard 75 mg dose in non-carriers; for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition [5]. When is Intense P2Y 12 ADP Receptor Blockade Needed?The CURRENT OASIS-7 trial [6,7], undertaken in 597 centres in 39 countries, randomly assigned, in a 2×2 factorial design, 25086 patients with an acute coronary syndrome who were referred for an invasive strategy to either double-dose clopidogrel (a 600 mg loading dose on day 1, followed by 150 mg daily for 6 days and 75 mg daily thereafter) or standard-dose clopidogrel (a 300 mg loading dose and 75 mg daily thereafter) and either higher-dose aspirin (300 to 325 mg daily) or lower-dose aspirin (75 to 100 mg daily). Aspirin dose had no effect on outcome.These findings illustrate that clopidogrel dosage and consequently the degree of platelet inhibition only matters in patients undergoing stenting but not in those managed medically. This conclusion echoes well with the recent findings from the TRILOGY ACS study [8] and its platelet function sub study [9] showing that both the use of prasugrel and the consequent stronger platelet inhibition as measured by the point-of care Verify Now P2Y 12 testing (Accumetrics, San Diego, California) have no independent relationship to outcome compared to the use of standard dose clopidogrel, in a cohort of medically managed patients.

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“…Recently, Hulot et al, reported that the CYP2C19*2 allele is a major determinant in antiplatelet response in patients with myocardial infarction [11]. This has also been reconfirmed by Mega et al, who have shown that patients with the CYP2C19*2 allele require triple the dose of clopidogrel to achieve the same antiplatelet response as patients with the wildtype alleles [12]. Combined data still point to the CYP2C19*2 allele being a major determinant of response.…”

mentioning

confidence: 89%

Translation of pharmacogenetics to clinical practice: what will it take?

Slaughter

2012

Expert Review of Clinical Pharmacology

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

Abstract: clinicaltrials.gov Identifier: NCT01235351.

Cited by 328 publications

References 34 publications

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Cyclic nucleotide‐dependent inhibitory signaling interweaves with activating pathways to determine platelet responses

Measuring Platelet Reactivity after Clopidogrel-Has it Reached the End of the Road?

Translation of pharmacogenetics to clinical practice: what will it take?

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