Prevalence of poor biological response to clopidogrel

Mallouk, Nora; Labruyère, Carine; Reny, Jean-Luc; Chapelle, Céline; Piot, Michèle; Fontana, Pierre; Gris, Jean‐Christophe; Delavenne, Xavier; Mismetti, Patrick; Laporte, Silvy

doi:10.1160/th11-03-0202

Cited by 73 publications

(18 citation statements)

References 183 publications

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“…Horizontal lines represent medians, the long broken line indicates the lower limit of reference interval, the long dotted line on panel B shows the cut-off for clopidogrel resistance established in clinical studies [4,5,12]. NR: non-responder, WR: weak responder, SR: strong responder.…”

Section: Resultsmentioning

confidence: 99%

“…The active metabolite covalently binds to the P2Y12 receptor and thereby inhibits the amplification mechanism of ADP-induced platelet activation and aggregation. Despite its potent antiplatelet effect, clinical studies suggest that approximately 10-50% of patients are resistant to therapy and it is not clear, which laboratory test is most suitable to identify such patients [2–5]. A number of methods are available for monitoring the effect of clopidogrel.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of a New P2Y12 Receptor Specific Platelet Aggregation Test with Other Laboratory Methods in Stroke Patients on Clopidogrel Monotherapy

et al. 2013

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BackgroundClinical studies suggest that 10-50% of patients are resistant to clopidogrel therapy. ADP induced platelet aggregation, a widely used test to monitor clopidogrel therapy, is affected by aspirin and is not specific for the P2Y12 receptor inhibited by clopidogrel.ObjectivesTo develop a P2Y12-specific platelet aggregation test and to compare it with other methods used for monitoring clopidogrel therapy.Patients/MethodsStudy population included 111 patients with the history of ischemic stroke being on clopidogrel monotherapy and 140 controls. The effect of clopidogrel was tested by a newly developed ADP(PGE1) aggregation test in which prostaglandin E1 treated platelets are used. Results of conventional ADP induced platelet aggregation, VerifyNow P2Y12 assay and ADP(PGE1) aggregation were compared to those obtained by flow cytometric analysis of vasodilator stimulated phosphoprotein (VASP) phosphorylation. Reference intervals for all assays were determined according to the guidelines of Clinical Laboratory Standards Institute.ResultsThe P2Y12-specificity of ADP(PGE1) test was proven by comparing it with ADP aggregation in the presence of P2Y1 antagonist, adenosine 3’, 5’-diphosphate. The method was not influenced by aspirin treatment. Approximately 50% of patients were clopidogrel resistant by conventional ADP aggregation and VerifyNow tests. The ADP(PGE1) method and the VASP phosphorylation assay identified 25.9% and 11.7% of patients as non-responders, respectively. ADP(PGE1) aggregation showed good correlation with VASP phosphorylation and had high diagnostic efficiency. ConclusionThe new ADP(PGE1) method is a reliable test for monitoring P2Y12 receptor inhibition by platelet aggregation. As a subset of patients are non-responders, monitoring clopidogrel therapy by adequate methods is essential.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of a New P2Y12 Receptor Specific Platelet Aggregation Test with Other Laboratory Methods in Stroke Patients on Clopidogrel Monotherapy

et al. 2013

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“…Recent studies have demonstrated wide variability of individual patient responsiveness to the inhibitory effects of clopidogrel on platelet aggregation, 6–8 with potentially important implications for its clinical effectiveness and safety. Following percutaneous coronary intervention (PCI) or ACS, patients with low clopidogrel responsiveness and consequent high on-treatment platelet reactivity have a higher risk of recurrent ischemic events, 9–12 while patients with enhanced platelet inhibition have lower risk of cardiovascular events 13 but a higher risk of bleeding.…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 Gene Variants, Race, and Mortality Among Clopidogrel-Treated Patients After Acute Myocardial Infarction

Cresci

Depta

Lenzini

et al. 2014

Circ Cardiovasc Genet

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Background Clopidogrel is recommended after acute myocardial infarction (AMI) but has variable efficacy and safety, in part related to the effect of cytochrome P450 (CYP) polymorphisms on its metabolism. The effect of CYP polymorphisms on cardiovascular events among clopidogrel-treated patients after AMI remains controversial, and no studies to date have investigated the association of CYP variants with outcomes in African American patients. Methods and Results 2732 subjects (2062 Caucasians; 670 African Americans) hospitalized with AMI enrolled in the prospective, multicenter TRIUMPH study were genotyped for CYP polymorphisms. The majority of Caucasians (79%) and African Americans (64.4%) were discharged on clopidogrel. Among Caucasians, carriers of the loss-of-function CYP2C19*2 allele had significantly increased 1-year mortality (adjusted HR: 1.70; CI: 1.01 to 2.86; p=0.046), and a trend toward increased rate of recurrent MI (adjusted HR: 2.10; CI 0.95 to 4.63; p= 0.066). Among African Americans, increased 1-year mortality was associated with the gain of function CYP2C19*17 allele (adjusted HR for *1/*17 vs. *1/*1: 2.02; CI: 0.92 to 4.44; *17/*17 vs. *1/*1: 8.97; CI: 3.34 to 24.10; p< 0.0001) and the CYP1A2*1C allele (adjusted HR for *1/*1C vs. *1/*1: 1.89; CI: 0.85 to 4.22; *1C/*1C vs. *1/*1: 4.96; CI: 1.69 to 14.56; p= 0.014). Bleeding events were significantly more common among African American carriers of CYP2C19*17 or CYP1A2*1C. Conclusions Both loss of function and gain of function CYP polymorphisms affecting clopidogrel metabolism are associated with increased mortality among clopidogrel treated patients following AMI; the specific polymorphism and the putative mechanism vary according to race.

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“…Recent systematic reviews have estimated the prevalence of HTPR to be between 16–50% among patients treated with clopidogrel. 21,22 However, proposed HTPR cutoff values are imprecise, and are likely highly dependent on the unique clinical and pharmacogenetic characteristics of each specific studied population. 23 Using the VerifyNow P2Y12 assay, a PRU cutoff value between 230–240 has been reported as prognostic for subsequent major adverse cardiovascular events (MACEs).…”

Section: Discussionmentioning

confidence: 99%

Clinical determinants of clopidogrel responsiveness in a heterogeneous cohort of Puerto Rican Hispanics

Hernández-Suárez

Scott

Tomey

et al. 2017

Therapeutic Advances in Cardiovascular Disease

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Background Clopidogrel is by far the most prescribed platelet adenosine diphosphate (ADP) antagonist in Puerto Rico despite the advent of newer agents (prasugrel and ticagrelor). Given the paucity of data on clopidogrel responsiveness in Hispanics, we sought to determine the association between clinical characteristics and platelet reactivity in Puerto Rican patients on clopidogrel therapy. Study population A total of 100 Puerto Rican patients on clopidogrel therapy were enrolled and allocated into two groups: Group I, without high on-treatment platelet reactivity (HTPR); and Group II, with HTPR. Platelet function was measured ex vivo using the VerifyNow® P2Y12 assay. Results The cohort was comprised of Hispanic patients with coronary artery disease (57%), peripheral artery disease (32%), carotid artery stenosis (7%), cerebral artery aneurysm (2%), and stroke (2%). Mean platelet reactivity was 200 ± 61 P2Y12 reaction units (PRUs) (range: 8–324), and 35% of patients had HTPR (PRUs ≥ 230). Multivariable logistic regression analysis determined that diabetes mellitus (DM) [odds ratio (OR) = 3.27; 95% confidence interval (CI): 1.20–8.96], use of proton-pump inhibitors (PPIs) (OR = 3.60; 95% CI: 1.09–11.82), and calcium channel blockers (CCBs) (OR = 3.10; 95% CI: 1.09–8.83) were independent predictors of HTPR (p < 0.05) after adjusting for other clinical variables. Conclusions In a sample of 100 Puerto Rican Hispanic patients on clopidogrel, 35% had HTPR. Furthermore, DM, PPIs and CCBs predicted HTPR. Clinical outcome data are needed to identify appropriate PRU thresholds for risk prediction in the Puerto Rican population.

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Prevalence of poor biological response to clopidogrel

Cited by 73 publications

References 183 publications

Comparison of a New P2Y12 Receptor Specific Platelet Aggregation Test with Other Laboratory Methods in Stroke Patients on Clopidogrel Monotherapy

Comparison of a New P2Y12 Receptor Specific Platelet Aggregation Test with Other Laboratory Methods in Stroke Patients on Clopidogrel Monotherapy

Cytochrome P450 Gene Variants, Race, and Mortality Among Clopidogrel-Treated Patients After Acute Myocardial Infarction

Clinical determinants of clopidogrel responsiveness in a heterogeneous cohort of Puerto Rican Hispanics

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