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Background: Clopidogrel associated with aspirin is the recommended treatment for patients undergoing elective percutaneous coronary intervention (PCI). Although severe PCI-related events are rare, evidence suggests that PCI-related myocardial infarction and myocardial injury are frequent complications that can impact the clinical prognosis of the patients. Antiplatelet therapy with a potent P2Y 12 receptor inhibitor such as ticagrelor may reduce periprocedural ischemic complications while maintaining a similar safety profile as compared with conventional dual antiplatelet therapy by aspirin and clopidogrel in this setting., Methods: Assessment of Loading with the P2Y 12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting (ALPHEUS) (NCT02617290) is an international, multicenter, randomized, parallel-group, open-label study in patients with stable coronary artery disease who are planned for an elective PCI. In total, 1,900 patients will be randomized before a planned PCI to a loading dose of ticagrelor 180 mg or a loading dose of clopidogrel (300 or 600 mg) in addition to aspirin. Patients will then receive a dual antiplatelet therapy with aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary ischemic end point is PCI-related myocardial infarction (myocardial infarction type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after elective PCI/stent. Safety will be evaluated by major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 48 hours (or discharge if it occurs earlier)., Conclusion: ALPHEUS is the first properly sized trial comparing ticagrelor to clopidogrel in the setting of elective PCI and is especially designed to show a reduction in periprocedural events, a surrogate end point for mortality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Prior Studies have suggested better outcomes in smokers compared with nonsmokers receiving clopidogrel ("smoker's paradox"). The impact of a more intensive clopidogrel regimen on ischemic and bleeding risks in smokers with acute coronary syndromes requiring percutaneous coronary interventions remains unclear., Methods and Results: We analyzed 17 263 acute coronary syndrome patients undergoing percutaneous coronary intervention from the CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events-Seventh Organization to Assess Strategies in Ischemic Symptoms) trial, which compared double-dose (600 mg day 1;150 mg days 2-7; then 75 mg daily) versus standard-dose (300 mg day 1; then 75 mg daily) clopidogrel in acute coronary syndrome patients. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Interactions between treatment allocation and smoking status (current smokers versus nonsmokers) were evaluated. Overall, 6394 patients (37.0%) were current smokers. For the comparison of double- versus standard-dose clopidogrel, there were significant interactions in smokers and nonsmokers for the primary outcome ( P =0.031) and major bleeding ( P =0.002). Double- versus standard-dose clopidogrel reduced the primary outcome among smokers by 34% (hazard ratio [HR] 0.66, 95% confidence interval [CI], 0.50-0.87, P =0.003), whereas in nonsmokers, there was no apparent benefit (HR 0.96, 95% CI, 0.80-1.14, P =0.61). For major bleeding, there was no difference between the groups in smokers (HR 0.77, 95% CI, 0.48-1.24, P =0.28), whereas in nonsmokers, the double-dose clopidogrel regimen increased bleeding (HR 1.89, 95% CI, 1.37-2.60, P <0.0001). Double-dose clopidogrel reduced the incidence of definite stent thrombosis in smokers (HR 0.41, 95% CI, 0.24-0.71) and nonsmokers (HR 0.63, 95% CI, 0.42-0.93; P for interaction=0.19)., Conclusions: In smokers, a double-dose clopidogrel regimen reduced major cardiovascular events and stent thrombosis after percutaneous coronary intervention, with no increase in major bleeding. This suggests that clopidogrel dosing in patients with acute coronary syndromes should be personalized, taking into consideration both ischemic and bleeding risk., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00335452., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Acute coronary syndrome (ACS) mortality increases when the culprit lesion is in the left anterior descending (LAD) artery. We investigated the effects of prasugrel versus clopidogrel according to site of culprit lesion causing ACS treated with percutaneous coronary intervention (PCI) in the TRITON-TIMI 38 study., Methods: Patients were divided into three groups based on the native coronary artery culprit lesion location. The LAD artery group included also patients with the culprit lesion in the left main (LM) artery., Results: In the whole ACS population, prasugrel recipients had lower rates of the primary endpoint that included cardiovascular (CV) death, non-fatal myocardial infarction (MI) or non-fatal stroke without significant differences across vessel groups. CV death was significantly decreased with prasugrel in the whole ACS population (p=0.03) and in ST-elevation MI (STEMI) patients undergoing primary PCI (p=0.04), with pronounced differences in favour of prasugrel versus clopidogrel when the LAD-LM was the culprit vessel (relative risk reduction 50% in the whole ACS population, 57% in STEMI treated with primary PCI, p for interaction 0.07 and 0.08 respectively)., Conclusions: Prasugrel effects were particularly favourable when LAD-LM was the culprit vessel, resulting in CV mortality reduction in the whole ACS population and in STEMI patients when treated with primary PCI., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort (n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation (P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery (P = 0.0298) and replication (n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion., (© 2016 American Society for Clinical Pharmacology and Therapeutics.)

Background: The extent of P2Y12 inhibition during coronary intervention is an important determinant of ischemic complications. The currently available oral P2Y12 inhibitors are limited by a relatively slow onset of action and variable on-treatment response., Objective: Our objective was to determine the pharmacodynamic (PD) dose-antiplatelet response relationship and the pharmacokinetics of MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, and to identify the dose level of MDCO-157 that matches the PD effect of oral clopidogrel 300 mg., Methodology: A randomized open-label crossover study was performed in 33 healthy adult volunteers to determine the pharmacokinetic (clopidogrel and clopidogrel H4 thiol active metabolite) and the PD (vasodilator-stimulated phosphoprotein [VASP]) effects of MDCO-157 at doses of 75, 150, and 300 mg and of oral clopidogrel 300 mg., Results: Data are presented as %, mean (standard deviation). The maximum effect of P2Y12 receptor inhibition assessed by flow cytometry using VASP was 70.42 (6.7), 69.45 (7.1), and 65.58 (12.6) for intravenous MDCO-157 at doses of 75, 150, and 300 mg, respectively, compared with 56.6 (17.5) with oral clopidogrel 300 mg administration (p < 0.0001). Intravenous administration of MDCO-157 led to a stepwise increase in plasma exposure of clopidogrel, higher than with administration of an oral dose of 300 mg (p < 0.0001). Plasma exposure of H4-thiol also increased with intravenous dose (3.6 ± 2.6, 6.9 ± 4.6, and 12.4 ± 9.1 h·ng/ml for intravenous 75, 150, and 300 mg, respectively) but was lower than with oral administration of a 300-mg dose (34.0 ± 16.0 h.ng/ml; pairwise p < 0.0001)., Conclusions: MDCO-157, an intravenous formulation of clopidogrel complexed with sulphobutylether betacyclodextrin, did not show significant platelet inhibition when administered at doses up to 300 mg. Higher doses with longer infusion may be needed to reach a sufficient threshold of active metabolite generation., Trial Registration: ClinicalTrials.gov identifier: NCT01860105.

Background: The ARCTIC study randomized 2440 patients scheduled for stent implantation to a strategy of platelet function monitoring with drug adjustment in patients who had a poor response to antiplatelet therapy or to a conventional strategy without monitoring and drug adjustment. No significant improvement in clinical outcomes with platelet function monitoring was observed., Objective: The purpose of this study is to assess the relationships between CYP2C19 genotypes, clopidogrel pharmacodynamic response, and clinical outcome., Methods and Results: In the ARCTIC-GENE study, 1394 patients were genotyped for loss- and gain-of-function CYP2C19 alleles. Randomization of treatment strategy was well balanced. Slow metabolizers identified as carriers of at least one loss-of-function allele CYP2C19*2 (n = 459) were more likely poor responders at randomization (41.6 vs. 31.6%, p = 0.0112) and 14 days later (23.8 vs. 10.4%, p < 0.0001) and more frequently on prasugrel (11.5 vs. 8.1%, p = 0.039) as compared with rapid metabolizers (n = 935). Intensification of antiplatelet treatment did not differ between slow and rapid metabolizers according to the study algorithm based on platelet function only. The primary study outcome defined as the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization 1 year after stent implantation did not differ between slow and rapid metabolizers (HR 0.988, 95% CI [0.812;1.202], p = 0.90). Likewise, the primary safety outcome did not differ between rapid and slow metabolizer phenotype., Conclusions: The genetic clopidogrel profile was a good marker of platelet function response on clopidogrel but was not related to clinical outcome suggesting that the genetic added little to the pharmacodynamic information used in the study to adjust antiplatelet therapy. ClinicalTrials.gov: NCT00827411.

Purpose: Proton-pump Inhibitors use and CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses and increased cardiovascular events., Methods: Post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 41) or homozygous (*2/*2, n = 7) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel loading dose. A PK/PD model was defined using the variation of the P2Y12 reaction unit relative to baseline., Results: Carriage of CYP2C19*2 allele and the use of omeprazole/esomeprazole were associated with the inter-individual variability in the active metabolite clearance. The relationship between inhibition of platelet aggregation (IPA, %) and the active metabolite AUC (h*μg/L) was described by a sigmoid function (Emax 56 ± 5%; EAUC50 15.9 ± 0.8 h*μg/L) with a gamma exponent (7.04 ± 2.26)., Conclusion: This on/off shape explains that a small variation of exposure may have a clinical relevance.

Objectives: This study compared the timing of onset of antiplatelet action after treatment with clopidogrel and prasugrel at first medical contact in patients with ST-segment elevation myocardial infarction (STEMI) scheduled for primary percutaneous coronary intervention (PPCI)., Background: Little is known about the timing of onset of antiplatelet action after a pre-percutaneous coronary intervention (PCI) loading dose of clopidogrel or prasugrel in patients with STEMI., Methods: This double-blind, prospective study randomized 62 patients with STEMI scheduled for PPCI in the ambulance or the emergency department to 60 mg prasugrel (n = 31) or 600 mg clopidogrel (n = 31). The primary endpoint was the platelet reactivity index (PRI) measured with the vasodilator-stimulated phosphoprotein assay 2 h after intake of the study medication. Secondary endpoints were PRI after 4 h, TIMI (Thrombolysis In Myocardial Infarction) patency of the infarct-related artery before and after PCI, and clinical events until day 30., Results: The PRI after 2 h (50.4 ± 32.7% vs. 66.3 ± 22.2%; p = 0.035) and after 4 h (39.1 ± 27.5% vs. 54.5 ± 49.3%; p = 0.038) were significantly lower with prasugrel compared with clopidogrel. In addition, the rate of patients with a PRI <50% tended to be higher with prasugrel compared with clopidogrel after 2 h (46.7% vs. 28.6%; p = 0.15) and after 4 h (63.0% vs. 38.9%; p = 0.06). There were no significant differences in TIMI 2/3 patency before PCI (39.2% vs. 31.0%; p = 0.43) and TIMI 3 patency after PCI (88.5% vs. 89.3%; p = 0.92)., Conclusions: The pre-PCI administration of prasugrel in patients with STEMI undergoing PPCI was associated with a significant faster platelet inhibition compared with clopidogrel. Therefore, prasugrel should be preferred to clopidogrel in this setting. (ETAMI-Study: Early Thienopyridine Treatment to Improve Primary PCI in Patients With Acute Myocardial Infarction; NCT01327534)., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: The potential negative metabolic interaction between proton pump inhibitors and clopidogrel is an unsolved issue. We hypothesized that doubling the clopidogrel maintenance dose (150 mg) would be less effective than switching to prasugrel 10 mg maintenance dose (MD) to overcome this negative interaction., Method and Results: In a randomized study with a factorial design, 82 stable coronary artery disease patients treated with 75 mg clopidogrel MD and aspirin were assigned to receive in a double blind fashion lansoprazole (30 mg/day) or placebo and to receive in an open fashion 150 mg clopidogrel MD or 10 mg prasugrel MD. The primary endpoint was the relative change in residual platelet reactivity over the 14-day study period [(RPA14day-RPAbaseline)/RPAbaseline]. The effect of doubling the clopidogrel MD on relative change in RPA was neutralized by lansoprazole (-53.6±48.4% versus +0.8±53.7% without and with lansoprazole, respectively, p = 0.02) whereas 10 mg of prasugrel MD dramatically reduced RPA irrespective of lansoprazole co-administration (-81.8 %±24.8% vs. -72.9%±32.9% without and with lansoprazole, respectively, p = NS). Lansoprazole exposure was the only parameter with a significant interaction with RPA among subgroups., Conclusion: The higher platelet inhibitory effect obtained by doubling the clopidogrel MD was totally neutralized by the co-administration of lansoprazole. This drug interaction was not observed with prasugrel 10 mg.

Objectives: This study sought to evaluate the efficacy of prasugrel versus clopidogrel in ST-segment elevation myocardial infarction (STEMI) by the timing of percutaneous coronary intervention (PCI)., Background: Treatment strategies and outcomes for patients with STEMI may differ when treated with primary compared with secondary PCI., Methods: STEMI patients in the TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis In Myocardial Infarction 38) were randomized to prasugrel or clopidogrel on presentation if primary PCI was intended or later during secondary PCI. Primary PCI was defined as within 12 h of symptom onset. The primary endpoint was cardiovascular death, myocardial infarction (MI), or stroke. Because periprocedural MI is difficult to assess in the setting of STEMI, we performed analyses excluding these events., Results: Reductions in the primary endpoint with prasugrel versus clopidogrel (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.65 to 0.97; p = 0.022) were consistent between primary and secondary PCI patients at 15 months (HR: 0.89; 95% CI: 0.69 to 1.13 vs. HR: 0.65; 95% CI: 0.46 to 0.93; p interaction = 0.15). However, a tendency toward a difference in treatment effect at 30 days (HR: 0.68; 95% CI: 0.54 to 0.87; p = 0.002) was observed between primary and secondary PCI patients (HR: 0.81; 95% CI: 0.60 to 1.09 vs. HR: 0.51; 95% CI: 0.34 to 0.76; p interaction = 0.06). When periprocedural MI was excluded, the efficacy of prasugrel remained consistent among primary and secondary PCI patients at 30 days (HR: 0.53; 95% CI: 0.34 to 0.81 vs. HR: 0.44; 95% CI: 0.22 to 0.88; p interaction = 0.68) and 15 months (HR: 0.76; 95% CI: 0.56 to 1.03 vs. HR: 0.75; 95% CI: 0.46 to 1.21; p interaction = 0.96)., Conclusions: The efficacy of prasugrel versus clopidogrel was consistent irrespective of the timing of PCI, particularly in preventing nonprocedural events. (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38; NCT00097591)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Dual antiplatelet therapy, comprising aspirin and clopidogrel, is recommended in patients undergoing coronary stenting to avoid the occurrence of stent thrombosis and others ischaemic events. Interindividual response to clopidogrel varies, however, with poor response associated with an increased risk of ischaemic events. New assays are available for testing aspirin and clopidogrel response routinely at the bedside., Aim: To evaluate the prognostic value of testing antiplatelet response in an intermediate-risk population undergoing stent implantation., Methods: We prospectively assessed clopidogrel and aspirin response using the VerifyNow assay at the time of coronary stenting in 1001 patients who presented with stable coronary disease or non-ST-segment elevation acute coronary syndrome. The main ischaemic endpoint was the composite of definite and probable stent thrombosis, cardiovascular death or spontaneous myocardial infarction at one year. The safety endpoint was major bleeding., Results: Overall, 36.0% of patients had high on-clopidogrel platelet reactivity (OCR) and 8.6% had high on-aspirin platelet reactivity (OAR). The main ischaemic composite endpoint occurred in 3.9% of patients with high vs. 2.3% of patients with normal OCR (hazard ratio 1.66, 95% confidence interval 0.78-3.54; P=0.18). Definite or probable stent thrombosis occurred in 1.1% of patients with high vs. 0.3% of patients with normal OCR (P=0.86). There was no significant difference in ischaemic endpoints according to OAR and there was no difference in rates of major bleeding between patients with high versus normal on-treatment platelet reactivity., Conclusions: On-treatment platelet reactivity was not associated with 1-year ischaemic or bleeding events in an intermediate-risk population undergoing stent implantation., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

Platelet P2YI2 receptor inhibition with clopidogrel, prasugrel or ticagrelor plays a key role to prevent recurrent ischaemic events after percutaneous coronary intervention in acute coronary syndromes or elective settings. The degree of platelet inhibition depends on the antiplatelet medication used and is influenced by clinical and genetic factors. A concept of therapeutic window exists. On one side, efficient anti-aggregation is required in order to reduce cardio-vascular events. On the other side, an excessive platelet inhibition represents a risk of bleeding complications. This article describes the current knowledge about some platelet function tests and genetic tests and summarises their role in the clinical practice.

A new ELISA technique has been developed to measure the vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) in clopidogrel-treated patients. This technique has not been evaluated in acute coronary syndrome (ACS) patients or in prasugrel-treated patients. We assessed the accuracy of ELISA-VASP to identify high on-treatment platelet reactivity (HPR) in ACS patients in comparison with established platelet function tests. Platelet reactivity was measured in 240 ACS patients treated with clopidogrel (75 or 150 mg) or prasugrel (5 or 10 mg) using flow cytometry (FC-VASP) and the ELISA-VASP technique, light transmission aggregometry (LTA) and VerifyNow-P2Y12 assay (VN-P2Y12). When using the ELISA-VASP PRI, the rate of patients with HPR in the overall ACS population was 15.5%, including a 27% rate in clopidogrel-treated patients and a 4% rate in prasugrel-treated patients. There was a strong correlation between ELISA-VASP PRI and FC-VASP PRI (r = 0.83, r2 = 0.68 p < 0.0001) with an area under the receiver-operating characteristics (ROC) curve to identify HPR (VASP-PRI >50% with FC-VASP) of 0.94, p<0.0001. The threshold of 60% for ELISA-VASP PRI provided the best accuracy (likelihood ratio= 23.67) to identify patients with HPR when compared to FC-VASP, LTA or VN-P2Y12 assays. In conclusion, ELISA-VASP is a fast, easy-to-use and specific test to identify HPR in ACS patients on thienopyridines. A 60% threshold value displays the best accuracy to identify HPR in these patients.

Objectives: This study sought to assess the consequences of switching prasugrel to clopidogrel on platelet inhibition and clinical outcomes after an acute coronary syndrome (ACS)., Background: Many ACS patients are switched from prasugrel to clopidogrel within the recommended 1-year duration of treatment., Methods: Platelet reactivity was measured with the VerifyNow P2Y(12) assay (Accumetrics, San Diego, California) in 300 ACS patients treated for 15 days with prasugrel 10 mg. Patients displaying low on-treatment platelet reactivity (LPR) and/or at high risk of bleeding were switched to clopidogrel 75 mg and tested again 15 days later. The rate of patients with high on-treatment platelet reactivity (HPR), P2Y(12) reaction units (PRU) >208, and LPR (PRU <0) were evaluated before and after the switch. Bleeding and ischemic events were also recorded., Results: On a regimen of prasugrel 10 mg, the rate of patients with LPR was 45.6% (n = 137), whereas 4.3% (n = 13) had HPR. A group of 31 patients (10.3%) was switched to clopidogrel 75 mg, of whom 29 had LPR (93.5%) on a regimen of prasugrel. On-treatment platelet reactivity (PRU) increased from 14 ± 4 on a regimen of prasugrel to 155 ±15 on a regimen of clopidogrel (p = 0.0001), resulting in a much lower rate of patients with LPR (9.7%). The rate of patients with HPR increased from 0% with prasugrel to 29% (n = 9) with clopidogrel. The rate of minor bleeding decreased after the switch from 32.2% to 9.7%; p = 0.03., Conclusions: An LPR is frequent in patients treated with prasugrel 10 mg. Early switching from prasugrel 10 mg to clopidogrel 75 mg reduces the number of patients with LPR and minor bleeding events but unmasks a group of nonresponders to clopidogrel with unknown consequences on clinical outcomes., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Context: Clopidogrel pretreatment is recommended for patients with acute coronary syndromes (ACS) and stable coronary artery disease who are scheduled for percutaneous coronary intervention (PCI), but whether using clopidogrel as a pretreatment for PCI is associated with positive clinical outcomes has not been established., Objective: To evaluate the association of clopidogrel pretreatment vs no treatment with mortality and major bleeding after PCI., Data Sources: MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and reference lists of qualifying articles. STUDY SELECTION Studies reporting clinical data on mortality and major bleeding were included. Of the 392 titles identified, 15 articles published between August 2001 and September 2012 met the inclusion criteria: 6 randomized controlled trials (RCTs), 2 observational analyses of RCTs, and 7 observational studies., Data Extraction: Quality of studies was assessed with the Ottawa Scale and the Jadad Score as appropriate. Results were independently extracted by 2 reviewers. A random-effect model was applied. Pretreatment was defined as the administration of clopidogrel before PCI or catheterization. The main analysis was performed on RCTs and confirmed by observational analyses and observational studies. Prespecified subgroups--clinical presentation and clopidogrel loading dose--were analyzed. The primary efficacy and safety end points were all-cause mortality and major bleeding. Secondary end points included major cardiac events., Results: Of the 37 814 patients included in the meta-analysis, 8608 patients had participated in RCTs; 10,945, in observational analyses of RCTs; and 18,261, in observational studies. Analysis of RCTs showed that clopidogrel pretreatment was not associated with a reduction of death (absolute risk, 1.54% vs 1.97%; OR, 0.80; 95% CI, 0.57-1.11; P = .17) but was associated with a lower risk of major cardiac events (9.83% vs 12.35%; OR, 0 .77; 95% CI, 0.66-0.89; P < .001). There was no significant association between pretreatment and major bleeding overall (3 .57% vs 3.08%; OR, 1.18; 95% CI, 0.93-1.50; P = .18). Analyses from observational analyses of RCTs and observational studies were consistent for all results., Conclusions: Among patients scheduled for PCI, clopidogrel pretreatment was not associated with a lower risk of mortality but was associated with a lower risk of major coronary events.

Aims: The aim of this study was to compare on-thienopyridine platelet reactivity of elderly patients (≥75 years) vs. younger patients (<75 years). Elderly patients represent a growing and challenging segment of the coronary population for whom the effect of dual antiplatelet therapy on platelet inhibition has not been specifically addressed., Methods and Results: The SENIOR-PLATELET study included 1331 coronary patients chronically (>14 days) treated with aspirin and a thienopyridine (clopidogrel 75 mg, n= 1027; clopidogrel 150 mg, n= 139; or prasugrel 10 mg, n= 165). Platelet response to clopidogrel and prasugrel was assessed by the VerifyNow assay and light transmission aggregrometry (LTA). Response to treatment, rate of high platelet reactivity (HPR), and inhibition (HPI) were compared in the two age categories. On-treatment platelet reactivity with clopidogrel 75 mg, 150 mg or prasugrel 10 mg was higher in elderly patients (n= 205) than in younger patients (n= 1126) whichever the test used. The difference in P2Y(12) reaction units (PRU) between the two populations was +45 in patients treated with clopidogrel 75 mg (P< 0.0001), +30 in patients treated with clopidogrel 150 mg (P= 0.17), and +20 with prasugrel 10 mg (P= 0.10). Differences in residual platelet aggregation were consistent when measured by LTA. Elderly patients treated with clopidogrel 75 mg were more likely to have HPR than younger patients (38.2 vs. 18.2%, OR: 2.58, 95% CI: 1.76-3.79; P< 0.0001) even after adjustment for potential confounders (adj OR: 1.83, 95% CI: 1.16-2.87; P= 0.009)., Conclusion: Elderly patients present an impaired response to clopidogrel with a high rate of HPR. Clopidogrel 150 mg or prasugrel 10 mg blunt, but do not eliminate the difference in response observed between old and young patients.

Clopidogrel used in conjunction with aspirin has a central role in the treatment of patients with an acute coronary syndrome (ACS) and/or undergoing percutaneous coronary intervention (PCI). The pharmacokinetic and pharmacodynamic responses to this drug are highly variable leaving up to one third of patients with inadequate platelet inhibition or high on-treatment platelet reactivity (HPR), and subsequent increased ischemic cardiovascular events. Genetic variability in drug absorption and metabolism is a key factor responsible for the inefficient generation of the active drug metabolite. The two-step hepatic cytochrome P450 (CYP)-dependant oxidative metabolism of the prodrug appears to be of particular importance. Pharmacogenomic analyses have identified loss-of-function variant alleles of CYP 2C19 and specifically the 2C19*2 allele, to be the predominant genetic mediators of the antiplatelet effect of clopidogrel. Carriers were have been shown to have lower active metabolite levels of clopidogrel, higher platelet reactivity and associated poorer outcomes. Rapid and accurate point-of-care genetic tests to identify these alleles are currently in development but several questions about the role of such testing remain such as patient selection and whether personalized treatment based on genotype has a positive impact on clinical outcome. At present, genetic testing cannot be recommended in routine clinical practice due to insufficient prospective data. However, the significant body of research published to date suggests a likely role when used in combination with platelet function analysis in ACS patients undergoing stenting who have other known risk factors for recurrent ischemic events.

Background: Reduced concentrations of clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post-myocardial infarction (MI) patients treated with clopidogrel., Methods and Results: We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to clopidogrel after either loading dose. Using multivariable linear regression analyses, the CYP2C19*2 allele was the only predictor of clopi-H4 generation and platelet response irrespective of the platelet function assay. CYP2C19 loss-of-function but not PON1 variants were significantly associated with increased risk of major cardiovascular events (death, MI, and urgent coronary revascularization) occurring during long-term clopidogrel exposure in 371 young post-MI patients (age <45 years) enrolled in the AFIJI cohort (CYP2C19 loss-of-function allele carrier versus noncarrier: hazard ratio, 2.26; 95% confidence interval, 1.15-4.41, P=0.02; PON1 QQ192 versus QR/RR192: hazard ratio, 1.03; 95% confidence interval, 0.50-2.11, P=0.93; PON1 LL55 versus LM/MM55: hazard ratio, 1.52; 95% confidence interval, 0.75-3.08, P=0.24)., Conclusions: Our study does not confirm that PON1 Q192R or L55M can influence clopidogrel pharmacokinetics or pharmacodynamics in post-MI patients.

The thienopyridines inhibit platelet activation and aggregation by directly inhibiting the platelet P2Y12 adenosine diphosphate receptor. The available thienopyridines are prodrugs and must be converted into active forms by the cytochrome P450 (CYP) enzyme system. An important portion of the variability in platelet response to clopidogrel is explained by the variability in plasma concentrations of the clopidogrel active metabolite. Several reports have thus progressively raised concerns about potential drug interactions as a result of inhibition or induction of CYP450 enzymes. Pharmacokinetics and pharmacodynamics studies have notably shown that concomitant use of clopidogrel and some proton pump inhibitors reduces the antiplatelet effect of clopidogrel. Several other drugs (metabolized through CYP3A4 such as statins or antifungals) similarly impact the pharmacologic response to clopidogrel. Conversely, agents that induce CYP activity increase clopidogrel responsiveness. However, the data supporting the clinical relevance of such pharmacological drug interactions have been controversial. This review will provide an overview of the mechanisms underlying thienopyridine-associated drug-drug interactions, and highlight the most recent developments in the field and propose guidance for the practitioner.

Background: The association between bleeding severity and cause of mortality in the non-acute setting is unclear. We sought to investigate the association between bleeding and mortality subtype, and assess whether this association differs in patients on dual antiplatelet therapy (DAPT) versus aspirin alone., Methods: Using multivariable Cox proportional hazards survival regression, we examined the association between moderate or severe bleeding and all-cause, cardiovascular, and cancer mortality in 15,603 patients with cardiovascular disease or multiple risk factors enrolled in the CHARISMA trial., Results: Patients with moderate or severe bleeding had a higher incidence of all-cause, cardiovascular, and cancer mortality (P < .001 for each). After multivariable adjustment, moderate/severe bleeding remained independently associated with not only all-cause mortality (adjusted hazard ratio [HR] 1.66; 95% confidence interval [CI] 1.24-2.21) and cardiovascular mortality (HR 2.05, 95% CI 1.38-3.04) but also cancer mortality (HR 4.76, 95% CI 2.60-8.69). However, there was a significant interaction between bleeding and potency of antiplatelet therapy for all-cause (P = .002), cardiovascular (P = .02), and cancer mortality (P = .03); in subjects on aspirin alone, moderate/severe bleeding was associated with all-cause (HR 5.27, 95% CI 3.56-7.80), cardiovascular (HR 4.33, 95% CI 2.55-7.37), and cancer mortality (HR 9.01, 95% CI 4.41-18.43), but not in subjects on DAPT (all-cause: HR 1.48, 95% CI 0.93-2.34; cardiovascular: HR 1.04, 95% CI 0.58-1.86; and cancer mortality: HR 1.79, 95% CI 0.56-5.74)., Conclusions: In stable patients, moderate or severe bleeding is associated with a significantly increased risk of all-cause, cardiovascular, and cancer mortality. However, this risk appeared different in subjects on single antiplatelet therapy versus DAPT., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objectives: This study sought to determine whether the pharmacokinetic (PK) and pharmacodynamic (PD) responses to high or standard clopidogrel loading doses (LDs) differ according to CYP2C19*2 allele., Background: CYP2C19 loss-of-function alleles are associated with reduced responsiveness to standard clopidogrel doses., Methods: Young post-myocardial infarction patients heterozygous (wild type [wt]/*2, n = 43) or homozygous (*2/*2, n = 8) for the CYP2C19*2 genetic variant were matched with patients not carrying the variant (wt/wt, n = 58). All patients were randomized to a 300- or 900-mg clopidogrel LD. The relative reduction in residual platelet aggregation (RR-RPA, %) and the area under the plasma concentration time curve of active metabolite from baseline to 6 h after loading (AUC(0-6)) were compared according to both LD and CYP2C19*2 carriage., Results: The 300-mg LD led to a gene-dose effect for RR-RPA (-65.7% ± 35.9% in wt/wt vs. -48.0% ± 38.4% in wt/*2 vs. -14.6% ± 32.4% in *2/*2; overall p value = 0.003, p = 0.03 for wt/wt versus wt/*2, p = 0.04 for wt/*2 versus *2/*2) with minor effect in *2/*2 carriers. After the 900-mg LD, the effect of the CYP2C19*2 variant on platelet inhibition was fully compensated in wt/*2 carriers but not in *2/*2 carriers (-83.6% ± 25.8% in wt/wt vs.-77.2% ± 26.9% in wt/*2 vs. -29.5% ± 26.8% in *2/*2; overall p value = 0.0003, p = 0.20 for wt/wt versus wt/*2, p < 0.001 for wt/*2 versus *2/*2). A similar pattern was observed for the active metabolite AUC(0-6) according to carriage of CYP2C19*2 for both LDs. There was a significant correlation between PK and PD responses irrespective of the LD., Conclusions: Carriers of CYP2C19*2 display significantly lower responses to clopidogrel with a gene-dose effect. Clopidogrel resistance can be overcome by increasing the dose in heterozygous carriers but not in homozygous carriers. (Clopidogrel and Response Variability Investigation Study 2 [CLOVIS-2]; NCT00822666)., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: This study investigated the effect of clopidogrel treatment on inflammatory activity as evidenced by the change in high-sensitivity C-reactive protein (hsCRP) levels in a broad population of patients who are at high risk of atherothrombotic events. The predictive value of hsCRP levels for a treatment benefit of clopidogrel was also explored., Methods: The study included 8021 patients with established atherosclerotic disease or multiple cardiovascular risk factors enrolled in the CHARISMA trial. Patients were randomly assigned either to clopidogrel plus aspirin or placebo plus aspirin. HsCRP was measured at study entry and at study termination (median 28&emsp14;months). The predefined primary composite endpoint was myocardial infarction, stroke, or death from cardiovascular causes., Results: There was a stepwise increase in the event rate of the combined primary endpoint with increasing quartiles of hsCRP at baseline (4.0%, 6.1%, 7.4% and 8.7% for the highest quartile). In both treatment groups the changes in hsCRP levels over time were identical. In patients with low hsCRP levels (<3 mg/l) clopidogrel treatment was associated with a lower event rate compared with placebo (4.0% vs 6.0%, log rank p=0.005). In contrast no treatment effect was observed in patients with high hsCRP levels (8.1% vs 8.0%, ns)., Conclusions: In this broad population, hsCRP is a powerful predictor of ischaemic events. Compared with placebo, clopidogrel was without effect on inflammatory markers. The reduction in cardiovascular events by antiplatelet treatment with clopidogrel was isolated to patients with low levels of hsCRP.

Background: In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use., Methods and Results: In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P=0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P=0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata., Conclusions: Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.

Background: individual response to oral antiplatelet therapy is subject to variability, and bedside monitoring offers the opportunity of individualizing therapy for stent implantation. Time and consequence of discontinuation of thienopyridine after stenting is also an unsolved issue after drug eluting stent (DES) implantation., Study Design: the ARCTIC trial is designed to demonstrate the superiority of a strategy of platelet function monitoring with dose adjustment in suboptimal responders as compared to a more conventional strategy without monitoring and without dose adjustment to reduce the primary end point evaluated 1 year after DES implantation. At the end of the 1-year follow-up, all patients will be randomized again to test the superiority of a strategy of pursuit of dual antiplatelet therapy beyond 1 year as compared to a strategy of interruption. ARCTIC is a multicenter, prospective, open-label study with parallel arms and a double randomization. Two thousand four hundred sixty-six patients with stable angina/ischemia or non-ST-elevation Acute Coronary Syndrome undergoing percutaneous coronary intervention (PCI) with DES implantation are being enrolled. The primary end point for the 2 tested hypotheses is the time to first occurrence of all-cause mortality, nonfatal myocardial infarction, definite/probable stent thrombosis, urgent revascularization, or nonfatal stroke. Platelet function analyses will be performed at the time of PCI and repeated 2 to 4 weeks after PCI., Conclusion: ARCTIC tests the hypothesis of personalized oral antiplatelet therapy at the time of and after DES implantation. It also examines the clinical impact of thienopyridine interruption 1 year after DES implantation.

Objectives: The purpose of this study was to perform a meta-analysis of randomized trials that compare new P2Y(12) inhibitors with clopidogrel to determine whether they improve clinical outcomes after percutaneous intervention (PCI)., Background: Ticlopidine/clopidogrel prevents major adverse cardiac events after PCI, but no trials have shown an effect on mortality. New P2Y(12) inhibitors are more potent and evaluated in PCI. Whether they decrease mortality after PCI compared with clopidogrel is unknown., Methods: MEDLINE and Cochrane Controlled Trials Register databases were searched from January 1980 through January 2010. Randomized, placebo-controlled trials that compared new P2Y(12) antagonists with clopidogrel in PCI were selected. Data from 8 studies were evaluated and analyses performed for all randomized patients, PCI patients (any PCI), and PCI for ST-segment elevation myocardial infarction (STEMI) patients. All-cause mortality was the primary efficacy end point. Thrombolysis In Myocardial Infarction major bleeding was the primary safety end point., Results: A total of 48,599 patients were included with 94% of patients with acute coronary syndrome and 84% of patients undergoing PCI. New P2Y(12) inhibitors significantly decreased death (odds ratio [OR]: 0.83, 95% confidence interval [CI]: 0.75 to 0.92, p < 0.001 for the whole cohort; OR: 0.85, 95% CI: 0.75 to 0.96, p = 0.008 for any PCI; and OR: 0.78, 95% CI: 0.66 to 0.92, p = 0.003 for PCI for STEMI). In PCI patients, new P2Y(12) inhibitors also significantly decreased major adverse cardiac events by 18% (p < 0.001) and stent thrombosis by 40% (p < 0.001). Although there was an increase in Thrombolysis In Myocardial Infarction major bleeding for any PCI (OR: 1.23, 95% CI: 1.04 to 1.46, p = 0.01), no difference was observed in PCI for STEMI (OR: 0.98, 95% CI: 0.85 to 1.13, p = 0.76), with similar outcomes in primary PCI for STEMI. Results were confirmed in sensitivity analyses that removed the largest study., Conclusions: New P2Y(12) inhibitors decrease mortality after PCI compared with clopidogrel. The risk/benefit ratio is particularly favorable in PCI for STEMI patients., (Copyright © 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Smoking induces CYP1A2, thereby enhancing clopidogrel conversion to its active metabolite. We sought to determine the association between clopidogrel use and clinical outcomes in smokers versus nonsmokers with a broad spectrum of acute coronary syndrome (ACS)., Methods: We examined the association between early clopidogrel use in-hospital and 6-month outcomes among 44,426 patients with ACS in relation to smoking status in the Global Registry of Acute Coronary Events. We tested for heterogeneity of clopidogrel effect among smokers versus nonsmokers in separate multivariable models that adjusted for (1) established prognosticators in the Global Registry of Acute Coronary Events risk score and (2) independent predictors of major bleeding., Results: Rates of in-hospital mortality, death/myocardial infarction, and major bleeding were 4.3%, 5.9%, and 2.5%, respectively. Current smokers (n = 12,149) were more likely to be younger men without documented vascular disease; had lower rates of hypertension, hyperlipidemia, and diabetes; and more frequently presented with ST elevation (all P < .0001). Early clopidogrel use (55%) was associated with a reduction in the composite endpoint of mortality and myocardial infarction both in-hospital and at 6 months among current smokers and nonsmokers. There was no interaction between current smoking and clopidogrel use for ischemic endpoints. Major bleeding associated with early clopidogrel use was actually lower among current smokers compared with nonsmokers., Conclusions: Despite prior observations of smoking-enhanced clopidogrel effects, early clopidogrel use among smokers presenting with ACS compared with nonsmokers was not independently associated with a greater reduction in cardiovascular events. In contrast with nonsmokers, clopidogrel use among smokers was not associated with excess bleeding, perhaps because of unmeasured confounders., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Content: Clopidogrel, one of the most commonly prescribed medications, is a prodrug requiring CYP450 biotransformation. Data suggest its pharmacologic effect varies based on CYP2C19 genotype, but there is uncertainty regarding the clinical risk imparted by specific genotypes., Objective: To define the risk of major adverse cardiovascular outcomes among carriers of 1 (≈ 26% prevalence in whites) and carriers of 2 (≈ 2% prevalence in whites) reduced-function CYP2C19 genetic variants in patients treated with clopidogrel., Data Sources and Study Selection: A literature search was conducted (January 2000-August 2010) in MEDLINE, Cochrane Database of Systematic Reviews, and EMBASE. Genetic studies were included in which clopidogrel was initiated in predominantly invasively managed patients in a manner consistent with the current guideline recommendations and in which clinical outcomes were ascertained., Data Extraction: Investigators from 9 studies evaluating CYP2C19 genotype and clinical outcomes in patients treated with clopidogrel contributed the relevant hazard ratios (HRs) and 95% confidence intervals (CIs) for specific cardiovascular outcomes by genotype., Results: Among 9685 patients (91.3% who underwent percutaneous coronary intervention and 54.5% who had an acute coronary syndrome), 863 experienced the composite end point of cardiovascular death, myocardial infarction, or stroke; and 84 patients had stent thrombosis among the 5894 evaluated for such. Overall, 71.5% were noncarriers, 26.3% had 1 reduced-function CYP2C19 allele, and 2.2% had 2 reduced-function CYP2C19 alleles. A significantly increased risk of the composite end point was evident in both carriers of 1 (HR, 1.55; 95% CI, 1.11-2.17; P = .01) and 2 (HR, 1.76; 95% CI, 1.24-2.50; P = .002) reduced-function CYP2C19 alleles, as compared with noncarriers. Similarly, there was a significantly increased risk of stent thrombosis in both carriers of 1 (HR, 2.67; 95% CI, 1.69-4.22; P < .0001) and 2 (HR, 3.97; 95% CI, 1.75-9.02; P = .001) CYP2C19 reduced-function alleles, as compared with noncarriers., Conclusion: Among patients treated with clopidogrel for percutaneous coronary intervention, carriage of even 1 reduced-function CYP2C19 allele appears to be associated with a significantly increased risk of major adverse cardiovascular events, particularly stent thrombosis.

Background: Clopidogrel and aspirin are the most commonly used antiplatelet therapies for percutaneous coronary intervention (PCI). We assessed the effect of various clopidogrel and aspirin regimens in prevention of major cardiovascular events and stent thrombosis in patients undergoing PCI., Methods: The CURRENT-OASIS 7 trial was undertaken in 597 centres in 39 countries. 25,086 individuals with acute coronary syndromes and intended early PCI were randomly assigned to double-dose (600 mg on day 1, 150 mg on days 2-7, then 75 mg daily) versus standard-dose (300 mg on day 1 then 75 mg daily) clopidogrel, and high-dose (300-325 mg daily) versus low-dose (75-100 mg daily) aspirin. Randomisation was done with a 24 h computerised central automated voice response system. The clopidogrel dose comparison was double-blind and the aspirin dose comparison was open label with blinded assessment of outcomes. This prespecified analysis is of the 17,263 individuals who underwent PCI. The primary outcome was cardiovascular death, myocardial infarction, or stroke at 30 days. Analyses were by intention to treat, adjusted for propensity to undergo PCI. This trial is registered with ClinicalTrials.gov, number NCT00335452., Findings: 8560 patients were assigned to double-dose and 8703 to standard-dose clopidogrel (8558 and 8702 completed 30-day follow-up, respectively), and 8624 to high-dose and 8639 to low-dose aspirin (8622 and 8638 completed 30-day follow-up, respectively). Compared with the standard dose, double-dose clopidogrel reduced the rate of the primary outcome (330 events [3·9%] vs 392 events [4·5%]; adjusted hazard ratio 0·86, 95% CI 0·74-0·99, p=0·039) and definite stent thrombosis (58 [0·7%] vs 111 [1·3%]; 0·54 [0·39-0·74], p=0·0001). High-dose and low-dose aspirin did not differ for the primary outcome (356 [4·1%] vs 366 [4·2%]; 0·98, 0·84-1·13, p=0·76). Major bleeding was more common with double-dose than with standard-dose clopidogrel (139 [1·6%] vs 99 [1·1%]; 1·41, 1·09-1·83, p=0·009) and did not differ between high-dose and low-dose aspirin (128 [1·5%] vs 110 [1·3%]; 1·18, 0·92-1·53, p=0·20)., Interpretation: In patients undergoing PCI for acute coronary syndromes, a 7-day double-dose clopidogrel regimen was associated with a reduction in cardiovascular events and stent thrombosis compared with the standard dose. Efficacy and safety did not differ between high-dose and low-dose aspirin. A double-dose clopidogrel regimen can be considered for all patients with acute coronary syndromes treated with an early invasive strategy and intended early PCI., Funding: Sanofi-Aventis and Bristol-Myers Squibb., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this study was to assess the association between the loss-of-function cytochrome P450 2C19 (CYP2C19)*2 variant (10 studies, 11,959 patients) or the use of proton pump inhibitors (PPIs) (13 studies, 48,674 patients) and ischemic outcomes (major adverse cardiovascular events [MACE]) in patients treated with clopidogrel., Background: In clopidogrel-treated patients, increased cardiovascular risk has been identified with the loss-of-function CYP2C19*2 allele or the use of PPIs, some of them CYP2C19 inhibitors. To further estimate the effect of a reduction in activity of this enzyme, the authors performed a meta-analysis of the studies available., Methods: The meta-analysis was performed on 23 studies using the odds ratio (OR) as the parameter of efficacy, with a fixed-effect model. The end points were MACE, mortality, or stent thrombosis., Results: Of the 11,959 patients, carriers of the loss-of-function CYP2C19*2 allele (28% [n = 3,418]) displayed a 30% increase in the risk for MACE compared with noncarriers (9.7% vs. 7.8%; OR: 1.29; 95% confidence interval [CI]: 1.12 to 1.49; p < 0.001). This single gene variant (CYP2C19*2) was also associated with an excess of mortality (1.8% vs. 1.0%; OR: 1.79; 95% CI: 1.10 to 2.91; p = 0.019; n = 6,225) and of stent thrombosis (2.9% vs. 0.9%; OR: 3.45; 95% CI: 2.14 to 5.57; p < 0.001; n = 4,905). This increased risk was apparent in both heterozygotes and homozygotes and was independent of the baseline cardiovascular risk. PPI users (42% [n = 19,614]) displayed increased risk for MACE (21.8% vs. 16.7%; OR: 1.41; 95% CI: 1.34 to 1.48; p < 0.001) and mortality (12.7% vs. 7.4%; OR: 1.18; 95% CI: 1.07 to 1.30; p < 0.001; n = 23,977) compared with nonusers. The impact of PPI use was, however, significantly influenced by baseline cardiovascular risk, being significant only in high-risk patients., Conclusions: In this global meta-analysis, reduced CYP2C19 function appears to expose clopidogrel-treated patients to excess cardiovascular risk and mortality. Conflicting results among studies may be explained by differences in types and/or levels of risk of patients., (Copyright 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality., Methods and Results: We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria. Severe bleeding occurred in 1.7% of the clopidogrel group versus 1.3% on placebo (P=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (P<0.001). The risk of bleeding was greatest the first year. Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter. The frequency of bleeding was similar in patients with established disease and risk factors only. In multivariable analysis, the relationship between moderate bleeding and all-cause mortality was strong (hazard ratio, 2.55; 95% confidence interval, 1.71 to 3.80; P<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18; P<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77; P<0.0001)., Conclusions: In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.

Objectives: The purpose of this study was to determine whether the speed of response to clopidogrel loading predicts the final degree of response., Background: Fast inhibition of platelet aggregation is important in the setting of acute coronary syndromes and percutaneous coronary intervention, but its association with the final degree of inhibition is not well established., Methods: We performed a post hoc analysis of the ALBION study; early kinetic profiles of adenosine diphosphate 20 micromol/l maximal platelet aggregation (MPA) and DeltaMPA (with baseline sample as reference) were studied at 8 time points within the 24 h after clopidogrel loading (300, 600, or 900 mg) in non-ST-segment elevation acute coronary syndrome patients. Low response was defined as DeltaMPA <10% over the first 24 h, fast response as DeltaMPA > or =10% at 1 h or before loading (the others being slow responders), and high post-treatment platelet reactivity as MPA > or =56.56% (fourth quartile). Inflammatory markers (PAC-1 and P-selectin) and vasodilator-stimulated phosphoprotein (VASP) were also evaluated according to onset of action., Results: Fifty-five percent of patients were slow responders. Noncurrent smoking and body mass index > or =25 kg/m(2) were associated with slower and lower responses. High post-treatment platelet reactivity was more frequent in slow responders (28% vs. 14%, p < 0.0001). There was a clopidogrel dose-effect relationship on DeltaMPA, with a trend toward faster onset of platelet inhibition in the 900-mg loading dose group. Slow responders had a slower and lower decrease in PAC-1 and P-selectin and higher VASP index at 6 h (76.5% vs. 66.4%, p = 0.019) and 24 h (70.3% vs. 61.5%, p = 0.049)., Conclusions: Slow response to clopidogrel, within the first hour of administration, is a reliable marker of low response at 24 h and high post-treatment platelet reactivity., (Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Compared with the approved dose regimen of clopidogrel (300-mg loading dose [LD], 75-mg maintenance dose [MD]), prasugrel has been demonstrated to reduce ischaemic events in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). In ACS, antiplatelet effects of a prasugrel MD regimen have not been previously compared with either a higher clopidogrel MD or after switching from a higher clopidogrel LD. The objective of this study was to evaluate the antiplatelet effect of a prasugrel 10-mg MD versus a clopidogrel 150-mg MD in patients with ACS who had received a clopidogrel 900-mg LD. Patients with non-ST elevation ACS, treated with aspirin and a clopidogrel 900-mg LD, were randomised within 24 hours post-LD to receive a prasugrel 10-mg or clopidogrel 150-mg MD. After 14 days of the initial MD, subjects switched to the alternative treatment for 14 days. The primary endpoint compared maximum platelet aggregation (MPA, 20 microM adenosine diphosphate [ADP]) between prasugrel and clopidogrel MDs for both periods. Responder analyses between treatments were performed using several platelet-function methods. Of 56 randomised subjects, 37 underwent PCI. MPA was 26.2% for prasugrel 10 mg and 39.1% for clopidogrel 150 mg (p<0.001). The prasugrel MD regimen reduced MPA from the post-900-mg LD level (41.2% to 29.1%, p=0.003). Poor response ranged from 0% to 6% for prasugrel 10 mg and 4% to 34% for clopidogrel 150 mg. Thus, in ACS patients a prasugrel 10-mg MD regimen resulted in significantly greater platelet inhibition than clopidogrel at twice its approved MD or a 900-mg LD.

Background: Smoking increases platelet aggregability and the degree of platelet inhibition by clopidogrel on ex vivo platelet function tests. Whether smoking status affects the relationship between clopidogrel and clinical outcomes is unknown., Methods and Results: We evaluated the relationship between smoking status (current smoker, former smoker, or never-smoker) and treatment with clopidogrel on the risk of all-cause, cardiovascular, and cancer mortality among the 12 152 participants from the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial who had established cardiovascular disease. Current smoking was associated with an increase in all-cause (adjusted hazard ratio [HR] 2.58, 95% confidence interval [CI] 1.85 to 3.60), cardiovascular (HR 2.26, 95% CI 1.48 to 3.45), and cancer (HR 3.56, 95% CI 1.96 to 6.46) mortality compared with never smoking. The impact of clopidogrel on mortality differed by smoking status (P for interaction=0.018 for current smokers). Among current smokers, clopidogrel was associated with a reduction in all-cause mortality (HR 0.68, 95% CI 0.49 to 0.94); clopidogrel did not reduce all-cause mortality among former smokers (HR 0.95, 95% CI 0.75 to 1.19) or never-smokers (HR 1.14, 95% CI 0.83 to 1.58). A similar pattern was noted for cardiovascular mortality. As expected, no relationship was observed between clopidogrel and cancer mortality by smoking status. The risk of bleeding appeared to differ according to smoking status; randomized clopidogrel was associated with a significantly increased risk of severe or moderate bleeding (HR 1.62, P=0.04) among current smokers but a smaller and nonsignificant increase among never-smokers (HR 1.31, P=0.15)., Conclusions: Clopidogrel therapy may be more effective in current smokers, but it may also confer a greater bleeding risk than in nonsmokers. Further studies are needed to investigate this possibility.

Background: There are limited contemporary data on the early use of clopidogrel or glycoprotein (Gp) IIb/IIIa inhibitors, alone versus combination therapies, in non-ST-elevation acute coronary syndrome (NSTE-ACS)., Methods: This study included 5,806 Canadian NSTE-ACS patients with elevated cardiac biomarker and/or ST deviation on presentation in the prospective GRACE between 2003-2007. We stratified the study population according to the management strategy (non-invasive vs invasive) and into low-(GRACE risk score or=141)., Results: Overall, 3,893 patients (67.1%) received early (

Background: Late discontinuation of clopidogrel after an acute coronary syndrome or stent placement may be associated with a clinical rebound effect., Aims: To describe the characteristics and evolution of patients non-compliant to study drug in the prospective, randomized, double-blind CHARISMA trial., Methods: Of 15,603 patients aged 45 or older years with established atherothrombotic disease (coronary artery disease, stroke, peripheral arterial disease) or multiple cardiovascular risk factors, 2999 permanently interrupted (withdrawers) study drug (clopidogrel or placebo) during follow-up. The primary endpoint was first occurrence since randomization of myocardial infarction, stroke or cardiovascular death., Results: Withdrawers displayed a higher risk profile and rates of death/myocardial infarction/stroke (13.5% versus 5.6%; hazard ratio [HR]: 3.18; 95% confidence interval [CI]: 3.05-3.32; p<0.001) and severe bleeding (4.9% versus 0.7%; odds ratio [OR]: 7.42; 95% CI: 5.67-9.70; p<0.001) versus non-withdrawers. Death/myocardial infarction/stroke occurred after an average of 228 days (95% CI: 197-258) and was less frequent in patients assigned to clopidogrel versus placebo (9.7% versus 11.9%; HR: 0.80; 95% CI: 0.64-1.00; p=0.051); the rate of severe bleeding was the same (4.0% versus 4.3%; OR: 0.92; 95% CI: 0.65-1.32; p=0.66). Among withdrawers, initial clopidogrel treatment was an independent correlate of survival (HR: 0.74, 95% CI: 0.59-0.93; p=0.011), but not severe bleeding (OR: 0.94; 95% CI: 0.65-1.35; p=0.74). Kaplan-Meier curves for the primary endpoint suggested no rebound effect or disease reactivation after discontinuation of clopidogrel compared with placebo., Conclusions: Patients who stopped medication had increased rates of ischaemic and bleeding events and mortality. Patients initially on clopidogrel had fewer ischaemic events than those on placebo; discontinuation was not associated with any clinically detectable rebound effect.

No prospective randomized trial has specifically examined the long-term outcomes of clopidogrel use in patients with chronic kidney disease. This study aimed to determine the risks and benefits of long-term clopidogrel administration in patients with diabetic nephropathy, the most common form of chronic kidney disease. We performed a post hoc analysis of the CHARISMA trial, which randomly assigned patients without active acute coronary syndrome, but with established atherosclerotic disease (symptomatic) or multiple risk factors for atherosclerotic disease (asymptomatic), to clopidogrel plus aspirin versus placebo plus aspirin. All CHARISMA patients (n = 15,603) were separated into the 3 groups: nondiabetic patients, diabetic patients without nephropathy, and diabetic patients with nephropathy. Within each group, outcomes of patients randomly assigned to clopidogrel were compared with those of patients randomly assigned to placebo. Outcomes in the prespecified CHARISMA subgroups of asymptomatic and symptomatic patients were also compared with respect to study drug assignment and nephropathy status. Patients with nephropathy who received clopidogrel had no difference in bleeding, but experienced significantly increased cardiovascular (CV) and overall mortality compared with those randomly assigned to placebo. There were no differences in bleeding, overall mortality, or CV mortality for nondiabetic or diabetic patients without nephropathy who received clopidogrel versus placebo. In the asymptomatic cohort, patients with nephropathy randomly assigned to clopidogrel had significantly increased overall and CV mortality compared with placebo, whereas asymptomatic patients without nephropathy randomly assigned to clopidogrel had no significant mortality difference compared with placebo. In conclusion, this post hoc analysis suggested that clopidogrel may be harmful in patients with diabetic nephropathy. Additional studies are needed to investigate this possible interaction.

Most guidelines recommend indefinite use of aspirin in patients at increased atherothrombotic risk. Dual antiplatelet therapy (aspirin/clopidogrel) is significantly more effective than aspirin monotherapy in reducing cardiovascular risk in a number of patient populations. As a result, dual therapy is recommended in many patient groups, including those with acute coronary syndromes and those who have undergone percutaneous coronary intervention. The recommended duration of clopidogrel/aspirin treatment is generally less than one year and, in some cases, as little as one month. However, there is evidence from a range of patient populations that more prolonged clopidogrel/aspirin therapy may be more effective than short-term treatment in reducing cardiovascular risk in some patients. The effects of discontinuing clopidogrel after an event-free period of one year require examination in clinical trials. Trial data are also needed to guide management of patients in whom early antiplatelet withdrawal is being considered (e.g. those who require non-cardiac surgery). This review discusses the benefits and risks of long-term dual antiplatelet therapy in a range of clinical situations.

Background: The optimal aspirin dose for the prevention of cardiovascular events remains controversial., Objective: To assess the incidence of and risk factors for adverse clinical outcomes by investigator-determined aspirin dose in a primary prevention trial., Design: Post hoc observational analyses of data from a double-blind, placebo-controlled, randomized trial., Setting: Outpatient., Patients: 15 595 patients with cardiovascular disease or multiple risk factors., Intervention: Clopidogrel, 75 mg/d, or placebo, with aspirin, 75 to 162 mg/d, as selected by the investigators., Measurements: Incidence of the composite outcome of myocardial infarction, stroke, or cardiovascular death (efficacy end point), and incidence of severe or life-threatening bleeding (safety end point), at a median of 28 months (interquartile range, 23 to 31 months) of follow-up., Results: Daily aspirin doses were categorized as less than 100 mg (75 or 81 mg) (n = 7180), 100 mg (n = 4961), and greater than 100 mg (150 or 162 mg) (n = 3454). The hazard of the primary efficacy end point was the same regardless of dose (adjusted hazard ratio, 0.95 [95% CI, 0.80 to 1.13] for 100 mg vs. less than 100 mg, and 1.0 [CI, 0.85 to 1.18] for greater than 100 mg vs. less than 100 mg). The hazard of the primary safety end point also did not depend on dose (adjusted hazard ratio, 0.85 [CI, 0.57 to 1.26] for 100 mg vs. less than 100 mg and 1.05 [CI, 0.74 to 1.48] for greater than 100 mg vs. less than 100 mg). In patients also receiving clopidogrel, daily aspirin doses greater than 100 mg seemed to be non-statistically significantly associated with reduced efficacy (adjusted hazard ratio, 1.16 [CI, 0.93 to 1.44]) and increased harm (adjusted hazard ratio, 1.30 [CI, 0.83 to 2.04])., Limitation: The analysis was post hoc, and aspirin use was not randomized or blinded., Conclusion: Daily aspirin doses of 100 mg or greater were associated with no clear benefit in patients taking aspirin only and possibly with harm in patients taking clopidogrel. Daily doses of 75 to 81 mg may optimize efficacy and safety for patients requiring aspirin for long-term prevention, especially for those receiving dual antiplatelet therapy., Primary Funding Source: None.

Background: Mechanical reperfusion with stenting for ST-elevation myocardial infarction (STEMI) is supported by dual antiplatelet treatment with aspirin and clopidogrel. Prasugrel, a potent and rapid-acting thienopyridine, is a potential alternative to clopidogrel. We aimed to assess prasugrel versus clopidogrel in patients undergoing percutaneous coronary intervention (PCI) for STEMI., Methods: We undertook a double-blind, randomised controlled trial in 707 sites in 30 countries. 3534 participants presenting with STEMI were randomly assigned by interactive voice response system either prasugrel (60 mg loading, 10 mg maintenance [n=1769]) or clopidogrel (300 mg loading, 75 mg maintenance [n=1765]) and were unaware of the allocation. The primary endpoint was cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Efficacy analyses were by intention to treat. Follow-up was to 15 months, with secondary analyses at 30 days. This trial is registered with ClinicalTrials.gov, number NCT00097591., Findings: At 30 days, 115 (6.5%) individuals assigned prasugrel had met the primary endpoint compared with 166 (9.5%) allocated clopidogrel (hazard ratio 0.68 [95% CI 0.54-0.87]; p=0.0017). This effect continued to 15 months (174 [10.0%] vs 216 [12.4%]; 0.79 [0.65-0.97]; p=0.0221). The key secondary endpoint of cardiovascular death, myocardial infarction, or urgent target vessel revascularisation was also significantly reduced with prasugrel at 30 days (0.75 [0.59-0.96]; p=0.0205) and 15 months (0.79 [0.65-0.97]; p=0.0250), as was stent thrombosis. Treatments did not differ with respect to thrombolysis in myocardial infarction (TIMI) major bleeding unrelated to coronary-artery bypass graft (CABG) surgery at 30 days (p=0.3359) and 15 months (p=0.6451). TIMI life-threatening bleeding and TIMI major or minor bleeding were also similar with the two treatments, and only TIMI major bleeding after CABG surgery was significantly increased with prasugrel (p=0.0033)., Interpretation: In patients with STEMI undergoing PCI, prasugrel is more effective than clopidogrel for prevention of ischaemic events, without an apparent excess in bleeding.

Background: Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 (CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel., Methods: Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography., Findings: Median clopidogrel exposure time was 1.07 years (IQR 0.28-3.0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio [HR] 3.69 [95% CI 1.69-8.05], p=0.0005), as did stent thrombosis (eight vs four events; HR 6.02 [1.81-20.04], p=0.0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3.00 [1.27-7.10], p=0.009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4.04 [1.81-9.02], p=0.0006)., Interpretation: The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction.

Objectives: We investigated whether maintenance therapy with clopidogrel 150 mg/day produces greater platelet inhibition than the standard 75-mg/day dose and whether the higher maintenance dose increases platelet inhibition in low responders to clopidogrel 75 mg/day., Background: Patients show interindividual variability in their platelet response to clopidogrel. Low responders could potentially obtain greater clinical benefit from greater doses of clopidogrel., Methods: One hundred fifty-three elective percutaneous coronary intervention patients were randomized to clopidogrel 150 mg/day (n = 58) or 75 mg/day (n = 95) for 4 weeks, with vasodilator-stimulated phosphoprotein assay-guided switching to clopidogrel 150 mg/day after 2 weeks in low responders (platelet reactivity index >or=69%). All patients received aspirin 75 mg/day., Results: After 2 weeks, clopidogrel 150 mg/day produced a significantly lower platelet reactivity index than clopidogrel 75 mg/day (43.9 +/- 17.3% vs. 58.6 +/- 17.7%; p < 0.0001). The proportion of low responders was significantly lower in patients randomized to clopidogrel 150 mg/day than in those randomized to clopidogrel 75 mg/day (8.6% vs. 33.7%; p = 0.0004). In the clopidogrel 75 mg/day group, 64.5% (20 of 31) of low responders became responders after switching to clopidogrel 150 mg/day for 2 weeks. No major bleeds occurred during the study; the incidence of minor bleeds was similar in each treatment group., Conclusions: In elective percutaneous coronary intervention patients, a 150-mg/day clopidogrel maintenance dose produces greater inhibition of platelet function than clopidogrel 75 mg/day. In low responders to clopidogrel 75 mg/day, switching to clopidogrel 150 mg/day overcomes low responsiveness in a majority of patients. These findings warrant further clinical evaluation. (VASP-02; EudraCT number: 2004-005230-40).

Background: Clopidogrel loading has mostly been studied in clopidogrel-naïve patients. Whether clopidogrel-treated patients readmitted for an acute coronary syndrome or percutaneous coronary intervention can benefit from a new load of clopidogrel and at what dose remain unknown. Our aim was to evaluate the impact of 3 different strategies of administration of a loading dose of 900 mg clopidogrel in patients already treated with a maintenance dose of 75 mg clopidogrel for at least 7 days on residual platelet aggregation., Methods and Results: Patients treated long term by clopidogrel 75 mg/d were assigned to receive a first loading dose of 300, 600, or 900 mg clopidogrel and 4 hours later a second loading dose of 600, 300, or 0 mg, respectively, to achieve a total loading dose of 900 mg in all patients. Platelet aggregation was evaluated at baseline, at 4 hours after the initial load (and before second load), and at 24 hours using light transmission aggregometry with 20 micromol ADP and the point-of-care assay VerifyNow P2Y(12). The primary objective of the study was to evaluate the inhibition (relative change) of residual platelet aggregation (percentage of IRPA) between 600- and 900-mg first loading at 4 hours. IRPA at 24 hours also was evaluated as a secondary objective, as well as the rate of suboptimal response at 4 hours defined as IRPA <10%. We included 166 consecutive patients with acute coronary syndromes (n=80, 48%) or stable coronary artery disease (n=86, 52%). Baseline characteristics were similar in the 3 dose groups. A significant stepwise increase was found in percentage IRPA assessed at 4 hours in patients initially assigned to 300 versus 600 versus 900 mg (30.7% versus 40.3% versus 64.0%, respectively; P=0.0024). The difference in percentage IRPA at 4 hours was not significant between 300 and 600 mg but was significant between 600 and 900 mg and between 300 and 900 mg. Percentage IRPA assessed at 24 hours when all patients had received 900 mg did not differ between the 3 loading regimens. The rates of suboptimal response (IRPA <10% at 4 hours) were 23.6%, 20.4%, and 5.3% with 300, 600, and 900 mg, respectively (P=0.02 for all)., Conclusions: In patients treated long term with 75 mg clopidogrel, a new loading dose of 900 mg improves IRPA and reduces poor and/or slow response to clopidogrel significantly more than that obtained with 300 or 600 mg.