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Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

To establish reperfusion within the infarct-related coronary artery, acute myocardial infarction is often treated with a combination of fibrinolytic agents, heparin, and aspirin. Despite this therapy, reperfusion is unsuccessful in some patients and reocclusion occurs in others. The addition of the antiplatelet agent clopidogrel to the regimen substantially improved the rate of reperfusion without a significant increase in bleeding complications. The results of this study should prompt rethinking of the protocol for reperfusion therapy in patients with acute myocardial infarction. Despite therapy with fibrinolytic agents, reperfusion is unsuccessful in some patients and reocclusion occurs in others. The addition of clopidogrel to the regimen substantially improved the rate of reperfusion without a significant increase in bleeding complications. The benefit of fibrinolytic therapy for myocardial infarction with ST-segment elevation is limited by inadequate reperfusion or reocclusion of the infarct-related artery in a sizable proportion of patients. Initial reperfusion fails to occur in approximately 20 percent of patients 1 – 3 and is associated with a doubling of mortality rates. 4 The artery becomes reoccluded in an additional 5 to 8 percent of patients during their index hospitalization, and this event is associated with an increase in mortality rates by a factor of nearly three. 5 Platelet activation and aggregation play a key role in initiating and propagating coronary-artery thrombosis. In the Second . . .

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 P2Y 12 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%; E AUC50 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.

Background and Objectives: Ticagrelor, the first reversibly binding oral P2Y 12 receptor antagonist, improves outcomes in patients with acute coronary syndromes (ACS) compared with clopidogrel. In the ONSET-OFFSET study (parallel group trial) and the RESPOND study (crossover trial), the pharmacodynamic effects of ticagrelor were compared with clopidogrel in patients with coronary artery disease (CAD). We now report the pharmacokinetic analyses of ticagrelor, and the exposure-inhibition of platelet aggregation (IPA) relationships from these studies. Patients and Methods: Patients were treated with ticagrelor (180 mg loading dose, 90 mg twice daily maintenance dose) or clopidogrel (600 mg loading dose, 75 mg once daily maintenance dose) in addition to aspirin (acetylsalicylic acid) [75–100 mg once daily]. Ticagrelor administration was for 6 weeks in ONSET-OFFSET. In RESPOND, ticagrelor was given for 14 days before or after 2 weeks of clopidogrel in patients classified as clopidogrel responders or non-responders. Pharmacokinetics and IPA were evaluated following the loading and last maintenance doses. Exposure-IPA relationships were evaluated using a sigmoid maximum effect (E max ) model. Outcome Measures: The outcome measures were ticagrelor and AR-C124910XX (active metabolite) pharmacokinetics and exposure-IPA relationships in both trials, including the effect of prior clopidogrel exposure, and effects in clopidogrel responders and non-responders in RESPOND. Results: In ONSET-OFFSET, maximum (peak) plasma concentration (C max ), time to C max (t max ) and area under the plasma concentration-time curve from time 0 to 8 hours (AUC 8 ) for ticagrelor were 733 ng/mL, 2.0 hours and 4130 ng · h/mL, respectively; and for AR-C124910XX were 210 ng/mL, 2.1 hours and 1325 ng · h/mL, respectively. E max estimates were IPA > 97%. Trough plasma ticagrelor (305 ng/mL) and AR-C124910XX (121 ng/mL) concentrations were 5.2 and 7.7 times higher than respective concentration producing 50% of maximum effect (EC 50 ) estimates. In RESPOND, ticagrelor mean C max and AUC 8 following 2-week dosing were comparable between clopidogrel responders (724 ng/mL and 3983 ng · h/mL, respectively) and non-responders (764 ng/mL and 3986 ng · h/mL, respectively). Pharmacokinetics of ticagrelor were unaffected by prior clopidogrel dosing. E max estimates were IPA > 96% for both responders and non-responders. Trough plasma concentrations were sufficient to achieve high IPA. Conclusions: Ticagrelor pharmacokinetics in stable CAD patients were comparable to previous findings in stable atherosclerotic and ACS patients, and were not affected by prior clopidogrel exposure or clopidogrel responsiveness. Ticagrelor effectively inhibited platelet aggregation, and trough plasma concentrations of ticagrelor and AR-C124910XX were sufficient to result in high IPA in stable CAD patients.

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.

Prasugrel is more effective than clopidogrel in reducing platelet aggregation in acute coronary syndromes. Data available on prasugrel reloading in clopidogrel treated patients with high residual platelet reactivity (HRPR) i.e. poor responders, is limited. To determine the effects of prasugrel loading on platelet function in patients on clopidogrel and high platelet reactivity undergoing percutaneous coronary intervention for acute coronary syndrome (ACS). Patients with ACS on clopidogrel who were scheduled for PCI found to have a platelet reactivity ≥40 AUC with the Multiplate Analyzer, i.e. \"poor responders\" were randomised to prasugrel (60 mg loading and 10 mg maintenance dose) or clopidogrel (600 mg reloading and 150 mg maintenance dose). The primary outcome measure was proportion of patients with platelet reactivity <40 AUC 4 hours after loading with study medication, and also at one hour (secondary outcome). 44 patients were enrolled and the study was terminated early as clopidogrel use decreased sharply due to introduction of newer P2Y12 inhibitors. At 4 hours after study medication 100% of patients treated with prasugrel compared to 91% of those treated with clopidogrel had platelet reactivity <40 AUC (p = 0.49), while at 1 hour the proportions were 95% and 64% respectively (p = 0.02). Mean platelet reactivity at 4 and 1 hours after study medication in prasugrel and clopidogrel groups respectively were 12 versus 22 (p = 0.005) and 19 versus 34 (p = 0.01) respectively. Routine platelet function testing identifies patients with high residual platelet reactivity (\"poor responders\") on clopidogrel. A strategy of prasugrel rather than clopidogrel reloading results in earlier and more sustained suppression of platelet reactivity. Future trials need to identify if this translates into clinical benefit. ClinicalTrials.gov NCT01339026.

Background: Clopidogrel, a potent antiplatelet agent, reduces the risk for thrombotic events in patients with atherothrombotic diseases. Clopidogrel is marketed primarily as a bisulfate salt. A different salt preparation of clopidogrel, clopidogrel besylate, has been developed and might provide an additional treatment option for patients. Objective: The aim of this study was to compare the pharmacokinetic, pharmacodynamic, and tolerability profiles of clopidogrel besylate with those of clopidogrel bisulfate to determine bioequivalence for the purposes of marketing approval. Methods: A randomized, open-label, 2-period, single- and multiple-dose, comparative crossover study was conducted in healthy Korean male subjects. The subjects received either clopidogrel bisulfate or clopidogrel besylate as a single 300-mg oral loading dose (day 1) followed by a 75-mg/d (once daily) maintenance dose on days 2 to 6. After a 15-day washout period, subjects were administered the alternative salt preparation according to the same protocol. The plasma concentrations of clopidogrel and its primary metabolite (SR26334) were assessed using high-performance liquid chromatography/tandem mass spectrometry after administration of the loading dose. The platelet aggregation response to 10-μmol/L adenosine diphos-phate was measured using turbidometric aggregometry during the single- and multiple-dosing periods and at steady state (day 6). Tolerability was monitored using physical examination, including vital sign measurements, and laboratory analysis. Results: Forty-four subjects were enrolled and completed the study (mean [SD] age, 24.3 [2.7] years; weight, 70.0 [8.2] kg). The mean values for Cmax, Tmax, and AUC0−t with clopidogrel (parent drug) of clopidogrel besylate (5.2 ng/mL, 0.9 hour, and 10.1 ng/mL/h, respectively) were similar to those with clopidogrel bisulfate (5.4 ng/mL, 0.9 hour, and 10.3 ng/mL/h). The mean values for Cmax, AUC0−t, and AUC0−∞ with the SR26334 of clopidogrel besylate (10.9 μg/mL, 38.8 μg/mL/h, and 43.0 μg/mL/h, respectively) were not significantly different from those with the SR26334 of clopidogrel bisulfate (11.9 μg/mL, 40.6 μg/mL/h, and 43.8 μg/mL/h). The mean values for maximal antiplatelet effect (Emax) and area under the time-effect curve (AUEC) with the 2 clopidogrel salt preparations were as follows: clopidogrel besylate, 58.8 h · % and 4299.1 h · % inhibition, respectively; and clopidogrel bisulfate, 61.7 h · % and 4406.9 h · % inhibition; these differences were not statistically significant. The 90% CIs for the ratios of the log-transformed Cmax, AUC, Emax, and AUEC values were within the predetermined bioequivalence range of 80% to 125%. Three adverse events (6.8%) were reported during the study and included abdominal discomfort (1 subject [2.3%] in the group that received clopidogrel bisulfate), easy fatigability (1 subject [2.3%] immediately before administration of loading dose of clopidogrel besylate), and thrombocytopenia (1 subject [2.3%] in the group receiving the clopidogrel bisulfate). All adverse events were transient and mild. Conclusions: In these healthy Korean male subjects, the differences in the pharmacokinetic and pharmacodynamic properties between the 2 clopidogrel salt preparations did not reach statistical significance and met the regulatory requirements for bioequivalence. Both preparations were well tolerated.

High on-treatment platelet reactivity (HTPR) is accompanied by an increased risk of adverse outcomes. Direct comparison of the antiplatelet effects between ticagrelor and high-dose clopidogrel has not yet been reported in acute myocardial infarction (AMI) or coronary artery in-stent restenosis (ISR) patients with HTPR. Consecutive patients with AMI or coronary artery ISR treated with standard-dose clopidogrel (75 mg/day) were screened with the VerifyNow assay, defining HTPR as P2Y12 reaction units (PRUs) >208. Of the 102 screened patients, 48 (47.06%) patients with HTPR were randomly assigned to either ticagrelor (180 mg/90 mg twice daily) or high-dose clopidogrel (150 mg/day) for 24 hours. Baseline characteristics and mean PRUs were similar in both groups. After 24 hours, ticagrelor was associated with a significantly lower platelet reactivity than high-dose clopidogrel (44.38 ± 40.26  vs. 212.58 ± 52.34 PRU, P  < 0.05). No patient receiving ticagrelor exhibited HTPR, whereas 15 (62.50%) patients after treatment with high-dose clopidogrel remained HTPR ( P  < 0.05). During the follow-up (mean, 138.42 ± 53.59 days), no patient exhibited a major bleeding event in either treatment group. In conclusion, in patients with AMI or coronary artery ISR exhibiting HTPR after standard clopidogrel treatment, ticagrelor is significantly more effective compared with high-dose clopidogrel in overcoming HTPR.

An increasing hemoglobin A1c (HbA1c) level portends an adverse cardiovascular prognosis; however, the association between glycemic control, platelet reactivity, and outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is unknown. We sought to investigate whether HbA1c levels are associated with high platelet reactivity (HPR) in patients loaded with clopidogrel and aspirin, thereby constituting an argument for intensified antiplatelet therapy in patients with poor glycemic control. In the prospective, multicenter Assessment of Dual Antiplatelet Therapy With Drug Eluting Stents registry, HbA1c levels were measured as clinically indicated in 1,145 of 8,582 patients, stratified by HbA1c <6.5% (n = 551, 48.12%), 6.5% to 8.5% (n = 423, 36.9%), and >8.5% (n = 171, 14.9%). HPR on clopidogrel and aspirin was defined after PCI as P2Y12 reaction units (PRU) >208 and aspirin reaction units >550, respectively. HPR on clopidogrel was frequent (48.3%), whereas HPR on aspirin was not (3.9%). Patients with HbA1c >8.5% were younger, more likely non-Caucasian, had a greater body mass index, and more insulin-treated diabetes and acute coronary syndromes. Proportions of PRU >208 (42.5%, 50.2%, and 62.3%, p <0.001) and rates of definite or probable stent thrombosis (ST; 0.9%, 2.7%, and 4.2%, p = 0.02) increased progressively with HbA1c groups. Clinically relevant bleeding was greatest in the intermediate HbA1c group (8.2% vs 13.1% vs 9.5%, p = 0.04). In adjusted models that included PRU, high HbA1c levels (>8.5) remained associated with ST (hazard ratio 3.92, 95% CI 1.29 to 12.66, p = 0.02) and cardiac death (hazard ratio 4.24, 95% CI 1.41 to 12.70) but not bleeding at 2-year follow-up. There was no association between aspirin reaction units >550 and HbA1c levels. In conclusion, in this large-scale study, HbA1c and HPR were positively associated, but the clinical effect on adverse outcome was driven by poor glycemic control, which predicted ST and cardiac death after PCI regardless of PRU levels, warranting efforts to improve glycemic control after DES implantation in patients with diabetes mellitus.

ABSTRACT Objective: Clopidogrel is an oral thienopyridine antiplatelet agent indicated for the treatment of atherothrombotic events in patients with acute coronary syndrome (ACS). Prasugrel, a novel oral thienopyridine, is under investigation for the reduction of atherothrombotic events in patients with ACS undergoing percutaneous coronary intervention. Prasugrel's solubility decreases with increasing pH, suggesting that concomitantly-administered medications that increase gastric pH may lower the rate and/or extent of prasugrel absorption. This study evaluated the influence of ranitidine coadministration on the pharmacokinetics and pharmacodynamics of the respective active metabolite of prasugrel and clopidogrel. Research design and methods: In this open-label, two-period, two-treatment, crossover study, 47 healthy male subjects were randomized to one of two study arms, receiving either prasugrel (60-mg loading dose [LD], 10-mg maintenance dose [MD] for 7 days; n = 23) or clopidogrel (600-mg LD, 75-mg MD for 7 days; n = 24). In one treatment period, subjects received prasugrel or clopidogrel alone, and in the alternate period received the same thienopyridine with ranitidine (150 mg twice daily, starting 1 day before the LD). Pharmacokinetic parameter estimates (AUC0−t last, Cmax, and tmax) and inhibition of platelet aggregation (IPA) by light transmission aggregometry were assessed at multiple time points after the LD and final MD. Results: Ranitidine had no clinically significant effect on the area under the plasma-concentration-time curve (AUC) and did not affect the time to Cmax (tmax) for active metabolites of either prasugrel or clopidogrel. It reduced the geometric mean maximum concentrations of active metabolite (Cmax) after a prasugrel and clopidogrel LD by 14% and 10%, respectively, but these differences were not statistically significant. When coadministered with a 60-mg prasugrel LD, ranitidine did not affect the time to, or magnitude of, peak IPA, but did result in a modest reduction at 0.5 h from 67.4 to 55.1% (p < 0.001). Ranitidine did not affect prasugrel IPA during MD. For clopidogrel, IPA was not affected by ranitidine. Prasugrel and clopidogrel were both well-tolerated, with/without ranitidine. Conclusions: Results from this study suggest that there is no significant drug–drug interaction between oral ranitidine therapy and concomitantly-administered prasugrel or clopidogrel.