Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance

Bonello, Laurent; Camoin-Jau, Laurence; Arquès, Stéphane; Boyer, Christian; Panagides, D.; Wittenberg, Olivier; Simeoni, Marie Claude; Barragan, Paul; Dignat-George, Françoise; Paganelli, Franck

doi:10.1016/j.jacc.2007.12.044

Cited by 534 publications

(358 citation statements)

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“…This indicates that the VASP-P assay is insensitive to low levels of P2Y 12 -blockade (46) and might in part explain the poor specificity of the assay, which limits its value for guiding individual therapy. Small randomised controlled trials have recently shown that tailoring clopidogrel LD in non-emergent patients based on a PRI cut-off of 50% significantly improves the patients' outcome (22,23). Translating these results to our data, 62% of patients would require reloading or a change in thienopyridine therapy.…”

Section: Discussionsupporting

confidence: 63%

“…Furthermore, it has been found to be predictive for major adverse cardiovascular events (MACE), including stent thrombosis after PCI and stent implantation (11,21). Recently, small randomised controlled trials have shown that tailoring clopidogrel loading doses (LD) in non-emergent patients based on a platelet reactivity index (PRI) cut-off of 50% significantly improves the patients' outcome (22,23). Taking these data into account, the VASP-P assay, although not a bedside test, might be considered for assessing clopidogrel responsiveness in routine practice.…”

Section: Introductionmentioning

confidence: 99%

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Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events

Freynhofer¹,

Brozovic²,

Bruno³

et al. 2011

Thromb Haemost

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SummaryReduced antiplatelet effect of clopidogrel assessed with multiple electrode aggregometry (MEA) and vasodilator stimulated phosphoprotein-phosphorylation (VASP-P) assay has been proven to predict major adverse cardiovascular events (MACE) after coronary stenting. So far no consecutive registry has evaluated the usefulness of different adenosine diphosphate-based platelet function tests to predict outcome in unselected patients. Hence, our objective was to determine the feasibility of MEA and VASP-P for clinical routine and whether low-response to clopidogrel as determined by MEA and/or the VASP-P assays predicts MACE in a "real-life" population undergoing coronary stenting. Threehundred consecutive patients were included in this prospective registry. Blood was sampled 6-24 hours after stenting to measure MEA and VASP-P. The use of glycoprotein-IIb/IIIa-blockers limited MEA to 196 measurements. Concerning the VASP-P assay, 300 measurements were achieved. Receiver Operating Characteristics (ROC)-curves of sensitiv- ity and specificity estimates for MACE were plotted for VASP-P assay. The area under the ROC-curve was 0.683 (p=0.014) for the platelet reactivity index (PRI) calculated from median fluorescence intensities (FI) with an optimal cut-off at 60.2% PRI. Patients above 60.2% had a significantly increased risk for MACE at six months follow-up (p=0.007). Estimating the cut-offs for the PRI from mean FI (52%) or from geometric mean FI (56.6%) led to clinically relevant differences. VASP-P assay is feasible for clinical routine to measure clopidogrel effects and to predict post-procedural MACE in unselected patients. With regard to differing cut-offs, exact standardisation of the VASP-P assay is mandatory. The use of GP-IIb/IIIa-blockers prevents MEA testing and limits its usability in unselected patients.

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Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events

Freynhofer¹,

Brozovic²,

Bruno³

et al. 2011

Thromb Haemost

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“…31,32 In vitro tests of VASP phosphorylation analysis accurately detect biological clopidogrel resistance that is associated with worse outcome after PCI. 33 -35 Bonello et al 21 demonstrated that PRI using VASP monitoring is safe and significantly improves clinical outcome after a 600-mg LD. Furthermore, a tailored 600-mg clopidogrel LD according to PRI also prevents acute and subacute ST in the same patients.…”

Section: Discussionmentioning

confidence: 99%

“…11 -13 Several methods have been developed to deal with clopidogrel resistance, 14 of which the most popular strategy is increasing the loading dose (LD) utilized in patients undergoing PCI to 600 mg 15 -18 and 900 mg. 19,20 Although clopidogrel response is dose-dependent, there is a threshold to its platelet-inhibitory effect when certain doses are administrated. 19,20 In order to find a better method to tackle clopidogrel resistance, Bonello et al 21 adjusted the clopidogrel LD according to platelet monitoring using the vasodilator-stimulated phosphoprotein (VASP) index in a multicenter randomized prospective study, and observed that it was safe and significantly improved the clinical outcomes after PCI in patients with clopidogrel resistance. In another study, Bonello et al 22 also demonstrated that tailoring the clopidogrel LD according to platelet reactivity monitoring decreased the rate of early stent thrombosis (ST) after PCI without increasing bleeding.…”

Section: Introductionmentioning

confidence: 99%

Modifying Clopidogrel Maintenance Doses According to Vasodilator‐Stimulated Phosphoprotein Phosphorylation Index Improves Clinical Outcome in Patients With Clopidogrel Resistance

Wang

Dai-fu

Zhuang

et al. 2011

Clinical Cardiology

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Background: Despite dual antiplatelet therapy, the rate of major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) remains high. Ex vivo tests of clopidogrel resistance can predict MACE after PCI. The purpose of this study is to evaluate the clinical impact of adjusting phosphorylation analysis in patients with clopidogrel resistance undergoing PCI. Hypothesis: We hypothesized that VASP-guided clopidogrel maintenance doses, compared to fixed doses, improved clinical outcome. Methods: This monocentric, prospective, randomized study was performed on 306 patients undergoing PCI. Patients were randomized to a control group (n = 156) and to a vasodilator-stimulated phosphoprotein (VASP)-guided group (n = 150). In the VASP-guided group, patients received adjusted maintenance doses of clopidogrel to obtain platelet reactivity index (PRI) of <50% during 1 year after PCI. The primary endpoint was the rate of MACE. The secondary endpoints were major and minor bleeding. Results: All patients completed the PCI procedure and 298 patients completed follow-up. The control and VASP-guided groups had similar demographic, clinical, and angiographic characteristics. In the VASP-guided group, PRI was significantly decreased (from 72.1% ± 11.4% to 27.7% ± 8.4%; P = 0.001) in 128 patients (87.1% of all participants). During the 1-year follow-up, 14 MACEs were recorded in the VASP-guided group and 30 MACEs were recorded in the control group (9.3% vs 20.4%, respectively; P = 0.008). There was no difference in the rate of major and minor bleeding in the VASP-guided group compared with the control group (12.9% vs 16.6%; P = 0.06). Conclusions: Modifying clopidogrel maintenance doses according to platelet reactivity monitoring decreases the rate of MACE after PCI without increasing bleeding in patients with clopidogrel resistance during 1-year follow-up.

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“…1,2 However, considerable interindividual variability exists in response to clopidogrel, and those with high on-clopidogrel platelet reactivity are at increased risk of cardiovascular events. 3,4 Several clinical, genetic, and cellular factors have been suggested as mechanisms for clopidogrel response variability. 5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

Park

Her

Kim

et al. 2016

Genetics in Medicine

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Original research article INTRODUCTIONThe identification of individuals at risk of future adverse cardiovascular outcomes is important after percutaneous coronary intervention (PCI). Thus, the use of novel risk markers such as genetic polymorphisms to augment standard risk algorithms, including conventional clinical risk factors, has attracted increasing attention in recent years.Dual antiplatelet therapy with aspirin and clopidogrel is the current standard of treatment after PCI with drug-eluting stent to reduce the rate of recurrent ischemic events. 1,2 However, considerable interindividual variability exists in response to clopidogrel, and those with high on-clopidogrel platelet reactivity are at increased risk of cardiovascular events. 3,4 Several clinical, genetic, and cellular factors have been suggested as mechanisms for clopidogrel response variability. 5 One of the common causes of individual variations in drug response is genetic polymorphism associated with drug absorption and metabolism. [6][7][8] Clopidogrel is a prodrug that requires active enteric absorption and conversion into an active metabolite in the liver. 9 A key protein involved in clopidogrel absorption is the intestinal efflux transporter P-glycoprotein which is encoded by the ABCB1 gene. Purpose: We evaluated the incremental prognostic value of combining the CYP2C19 poor metabolizer (PM) and ABCB1 3435 TT for adverse clinical outcomes over conventional risk factors in a percutaneous coronary intervention (PCI) cohort. Methods:We enrolled 2,188 patients. The primary end point was a composite of death from any cause, nonfatal myocardial infarction (MI), and stroke during 1-year follow-up. The population was stratified into the following four groups: CYP2C19 EM/IM+ABCB1 3435 CC/CT, CYP2C19 EM/IM+ABCB1 3435 TT, CYP2C19 PM+ABCB1 3435 CC/CT, and CYP2C19 PM+ABCB1 3435 TT. Results:A total of 87 (3.97%) primary end-point events occurred (64 deaths, 8 non-fatal MIs and 15 strokes). Multivariate Cox analysis indicated that CYP2C19 PM+ABCB1 3435 TT status was a significant predictor of the primary end point (hazard ratio = 4.51, 95% confidence interval (CI) = 1.92-10.58). However, addition of combined genetic status to the clinical risk model did not improve the model discrimination (C-statistic = 0.786 (95% CI = 0.734-0.837) to 0.785 (95% CI = 0.733-0.838)) or risk reclassification (categorical net reclassification improvement (0.040, P = 0.32), integrated discrimination improvement (0.021, P = 0.026)). Conclusions:In a real-world East Asian PCI population taking clopidogrel, although the concurrent presence of CYP2C19 PM and ABCB1 TT is a strong independent predictor of adverse outcomes, the combined status of two at-risk variants does not have an incremental prognostic value beyond that of the conventional clinical risk factors. Genet Med

show abstract

Adjusted Clopidogrel Loading Doses According to Vasodilator-Stimulated Phosphoprotein Phosphorylation Index Decrease Rate of Major Adverse Cardiovascular Events in Patients With Clopidogrel Resistance

Abstract: This is the first study to suggest that adjusting the clopidogrel loading dose according to platelet monitoring using the VASP index is safe and may significantly improve the clinical outcome after PCI in patients with clopidogrel resistance despite a first 600-mg loading dose.

Cited by 534 publications

References 30 publications

Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events

Multiple electrode aggregometry and vasodilator stimulated phosphoprotein-phosphorylation assay in clinical routine for prediction of postprocedural major adverse cardiovascular events

Modifying Clopidogrel Maintenance Doses According to Vasodilator‐Stimulated Phosphoprotein Phosphorylation Index Improves Clinical Outcome in Patients With Clopidogrel Resistance

Evaluation of the incremental prognostic value of the combination of CYP2C19 poor metabolizer status and ABCB1 3435 TT polymorphism over conventional risk factors for cardiovascular events after drug-eluting stent implantation in East Asians

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