- Impact of chronic kidney disease on platelet inhibition of clopidogrel and prasugrel in Japanese patients. [JOURNAL ARTICLE]
- J Cardiol 2016 Aug 23.
The impact of chronic kidney disease (CKD) on the antiplatelet effect of clopidogrel and low-dose (3.75mg) prasugrel in Japanese patients is largely unknown.A total of 53 consecutive Japanese patients with stable coronary artery disease who received aspirin and clopidogrel were enrolled, and categorized by estimated glomerular filtration rate (eGFR): CKD group (n=15, eGFR<60ml/min/1.73m(2)) and non-CKD group (n=38, eGFR≥60ml/min/1.73m(2)). Clopidogrel was switched to 3.75mg prasugrel. Platelet reactivity measurement using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA, USA) was performed at baseline (on clopidogrel) and day 14 (on prasugrel).The VerifyNow P2Y12 reaction units (PRU) during clopidogrel therapy was significantly higher in the CKD group than that in the non-CKD group (185.2±51.1 PRU vs. 224.3±57.0 PRU, p=0.02), whereas, the PRU with the prasugrel therapy in the CKD group and non-CKD group were not significantly different (149.9±51.1 PRU vs. 165.3±61.8 PRU, p=0.36). The PRU was significantly lower with the prasugrel therapy compared to that with the clopidogrel therapy both in the CKD group and in the non-CKD group.Antiplatelet effect of clopidogrel but not prasugrel is attenuated in patients with CKD. Prasugrel achieves a consistently lower platelet reactivity compared with clopidogrel regardless of the presence of mild to moderate CKD.
- Associations of P2Y12R Gene Polymorphisms with Susceptibility to Coronary Heart Disease and Clinical Efficacy of Antiplatelet Treatment with Clopidogrel. [JOURNAL ARTICLE]
- Cardiovasc Ther 2016 Aug 27.
To investigate the correlations of three P2Y12 receptor (P2Y12R) gene polymorphisms (rs7428575 T>G, rs2046934 C>T and rs3732759 A>G) with susceptibility to coronary artery disease (CHD) and clinical efficacy of clopidogrel treatment for CHD.From May 2014 to May 2015, 178 CHD patients (the case group) and 182 healthy controls (the control group) were selected from our hospital. The platelet-rich plasma (PRP) turbidimetry was used to measure the rate of adenosine diphosphate (ADP)-induced platelet aggregation before and after clopidogrel treatment. Clopidogrel-sensitive was defined as a 10% or greater decrease in the rate of platelet aggregation after 10 days of clopidogrel treatment, while clopidogrel-resistant was defined as a less than 10% decrease. Genotyping was performed by denaturing high-performance liquid chromatography (DHPLC). A haplotype analysis of P2Y12R gene polymorphisms was performed by using SHEsis software.There were significantly differences in genotype and allele frequencies of rs2046934 C>T and rs3732759 A>G between the case and control groups (all P < 0.05). Haplotypes GTA and TTA were negatively associated with CHD risk (both P < 0.05), but haplotype TCA was positively associated with CHD risk (P = 0.005). CHD patients in the clopidogrel-sensitive group had higher frequencies of TT genotype of rs2046934 C>T and lower frequencies of GG genotype of rs3732759 A>G than those in the clopidogrel-resistant group (both P < 0.05).P2Y12R gene rs2046934 C>T and rs3732759 A>G polymorphisms might be associated with the risk of CHD and the efficacy of clopidogrel treatment for CHD. This article is protected by copyright. All rights reserved.
- Prasugrel versus clopidogrel in acute coronary syndromes treated with PCI: Effects on clinical outcome according to culprit artery location. [JOURNAL ARTICLE]
- Int J Cardiol 2016 Aug 13.:632-638.
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.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.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).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.
- Design and Rationale of the RE-DUAL PCI Trial: A Prospective, Randomized, Phase 3b Study Comparing the Safety and Efficacy of Dual Antithrombotic Therapy With Dabigatran Etexilate Versus Warfarin Triple Therapy in Patients With Nonvalvular Atrial Fibrillation Who Have Undergone Percutaneous Coronary Intervention With Stenting. [JOURNAL ARTICLE]
- Clin Cardiol 2016 Aug 26.
Antithrombotic management of patients with atrial fibrillation (AF) undergoing coronary stenting is complicated by the need for anticoagulant therapy for stroke prevention and dual antiplatelet therapy for prevention of stent thrombosis and coronary events. Triple antithrombotic therapy, typically comprising warfarin, aspirin, and clopidogrel, is associated with a high risk of bleeding. A modest-sized trial of oral anticoagulation with warfarin and clopidogrel without aspirin showed improvements in both bleeding and thrombotic events compared with triple therapy, but large trials are lacking. The RE-DUAL PCI trial (NCT 02164864) is a phase 3b, a strategy of prospective, randomized, open-label, blinded-endpoint trial. The main objective is to evaluate dual antithrombotic therapy with dabigatran etexilate (110 or 150 mg twice daily) and a P2Y12 inhibtor (either clopidogrel or ticagrelor) compared with triple antithrombotic therapy with warfarin, a P2Y12 inhibtor (either clopidogrel or ticagrelor, and low-dose aspirin (for 1 or 3 months, depending on stent type) in nonvalvular AF patients who have undergone percutaneous coronary intervention with stenting. The primary endpoint is time to first International Society of Thrombosis and Hemostasis major bleeding event or clinically relevant nonmajor bleeding event. Secondary endpoints are the composite of all cause death or thrombotic events (myocardial infarction, or stroke/systemic embolism) and unplanned revascularization; death or thrombotic events; individual outcome events; death, myocardial infarction, or stroke; and unplanned revascularization. A hierarchical procedure for multiple testing will be used. The plan is to randomize ∼ 2500 patients at approximately 550 centers worldwide to try to identify new treatment strategies for this patient population.
- Pharmacodynamic effects of a new fixed-dose clopidogrel-aspirin combination compared with separate administration of clopidogrel and aspirin in patients treated with coronary stents: The ACCEL-COMBO trial. [JOURNAL ARTICLE]
- Platelets 2016 Aug 25.:1-7.
Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is a widely prescribed regimen to prevent ischemic events in patients undergoing percutaneous coronary intervention (PCI). A fixed-dose combination (FDC) capsule (HCP0911) has been developed to provide dosing convenience and improve adherence. We compared the antiplatelet effects of single daily dose HCP0911 with separate treatment with daily 75 mg clopidogrel plus 100 mg aspirin. This was a randomized, open-label, two-period, crossover, non-inferiority study conducted in stented patients who had been treated for at least 6 months with clopidogrel and aspirin. Thirty patients were randomly assigned to receive either daily 75 mg clopidogrel plus 100 mg aspirin treatment or HCP0911 for 2 weeks and then were crossed over to the other treatment for 2 weeks. Pharmacodynamic effects were measured with VerifyNow, light transmittance aggregometry (LTA), and thromboelastography (TEG(®)). The primary endpoint was P2Y12 Reaction Units (PRU) measured by VerifyNow. PRUs during treatment with HCP0911 were not inferior to those during separate treatment (202 ± 52 vs. 207 ± 60 PRU; mean difference, -5 PRU; 90% confidence interval of difference, -23 to 13 PRU; P for non-inferiority = 0.015 for predetermined limit). "BASE" and Aspirin Reaction Units by VerifyNow did not differ between the two treatments. During each treatment, there were no differences in maximal and final platelet aggregations by LTA (all P values ≥0.822) and TEG(®) measurements. In conclusion, in stented patients, the antiplatelet effect of a fixed-dose clopidogrel-aspirin combination, HCP0911, was not inferior to separate administration of clopidogrel and aspirin.
- A Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study. [JOURNAL ARTICLE]
- Circulation 2016 Aug 24.
-Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic (PD) profiles of these drugs in DM patients remains poorly explored and represented the aim of this study.-In this prospective, randomized, double-blind, double-dummy, cross-over PD study, aspirin-treated DM patients (n=50) with coronary artery disease (CAD) were randomized to receive prasugrel [60mg loading dose (LD)/10mg maintenance dose (MD) qd] or ticagrelor (180mg LD/90mg MD bid) for 1 week. PD assessments were conducted using 4 different assays, including VerifyNow P2Y12, VASP, light transmittance aggregometry and Multiplate, which allowed to explore ADP- and non-ADP-induced (arachidonic acid-, collagen-, thrombin receptor activating peptide-induced) platelet signaling pathways. The acute (baseline, 30 min and 2 h post-LD) and maintenance (1-week) effects of therapy were assessed. The primary end-point of the study was the comparison of P2Y12 reaction units (PRU) determined by VerifyNow P2Y12 at 1-week between prasugrel and ticagrelor.-ADP- and non-ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and MD. PRU defined by VerifyNow were similar between prasugrel and ticagrelor at 30 min and 2 h post-LD. At 1-week PRU was significantly lower with ticagrelor compared with prasugrel (52 [32-72] vs 83 [63-103]; LSM difference: -31; 95% CI: -57 to -4; p=0.022; primary endpoint). PD assessments measured by VASP, light transmittance aggregometry and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1-week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points.-In DM patients with CAD, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity compared to prasugrel in the acute and chronic phases of treatment, while the inhibition of measures of non-ADP-induced platelet reactivity were not significantly different between the two agents Clinical Trial Registration-URL: http://www.clinicaltrials.gov Unique identifier: NCT01852214.
- Directed evolution of mandelate racemase by a novel high-throughput screening method. [JOURNAL ARTICLE]
- Appl Microbiol Biotechnol 2016 Aug 24.
Optically pure methyl (R)-o-chloromandelate and (R)-acetyl-o-mandelic acid are key intermediates for the synthesis of (S)-clopidogrel, which could be prepared with 100 % theoretical yield by sequential hydrolysis and racemization. At the moment, efficient sequential hydrolysis and racemization are hindered by the low catalytic activity of mandelate racemase (MR) toward (S)-o-chloromandelic acid ((S)-2-CMA). In the present work, we proposed to improve the catalytic performance of MR toward (S)-2-CMA by directed evolution and developed an enantioselective oxidation system for high-throughput screening (HTS) of MR libraries. Based on this HTS method, a triple mutant V22I/V29I/Y54F (MRDE1) with 3.5-fold greater relative activity as compared to the native MR was obtained. Kinetic analysis indicated that the enhanced catalytic efficiency mainly arose from the elevated k cat. Further insight into the source of improved catalytic activity was gained by molecular simulations, finding that substrate binding and product release were possibly made easier by decreased steric bulk and increased hydrophobicity of substrate binding sites. In addition, the substrate (S)-2-CMA in the enzyme-substrate complex of MRDE1 seemed to have a lower binding free energy comparing with the complex of wild-type MR. The HTS method developed in this work and the successful directed evolution of MR based on this method provide an example for racemase engineering and may inspire directed evolution of other racemases toward enhanced catalytic performance on non-natural substrates.
- Identifying clinically-relevant sources of variability: the clopidogrel challenge. [JOURNAL ARTICLE]
- Clin Pharmacol Ther 2016 Aug 24.
High interindividual variability in clinical outcomes following clopidogrel's standard dosing regimen continues to be a challenge even two decades after its approval. CYP2C19 polymorphisms, obesity, older age, diabetes and drug-drug interactions have been identified as risk factors for adverse events and treatment failure. We conducted a mechanism-based pharmacokinetic/pharmacodynamic analysis, where we integrated knowledge on in vitro enzyme kinetic, physiological, genetic, and demographic information to characterize changes in platelet reactivity from baseline following clopidogrel antiplatelet therapy. When considering the combined impact of these covariates, our analysis results indicate that higher maintenance doses are required for CYP2C19 IMs and PMs compared to EMs and that respective maintenance doses have to be further increased for obese subjects for each of these CYP2C19 phenotypes. In addition, interindividual differences in the fraction absorbed and the CES1 activity were identified as sources of interindividual differences in clopidogrel's active metabolite concentrations and, thus, platelet reactivity. This article is protected by copyright. All rights reserved.
- Plasma miR-142 accounting for the missing heritability of CYP3A4/5 functionality is associated with pharmacokinetics of clopidogrel. [JOURNAL ARTICLE]
- Pharmacogenomics 2016 Aug 24.
To investigate whether plasma miRNAs targeting CYP3A4/5 have an impact on the variance of pharmacokinetics of clopidogrel.The contribution of 13 miRNAs to the CYP3A4/5 gene expression and activity was investigated in 55 liver tissues. The association between plasma miRNAs targeting CYP3A4/5 mRNA and clopidogrel pharmacokinetics was analyzed in 31 patients with coronary heart disease who received 300 mg loading dose of clopidogrel.Among 13 miRNAs, miR-142 was accounting for 12.2% (p = 0.002) CYP3A4 mRNA variance and 9.4% (p = 0.005) CYP3A5 mRNA variance, respectively. Plasma miR-142 was negatively associated with H4 Cmax (r = -0.5269; p = 0.0040) and associated with H4 AUC0-4h (r = -0.4986; p = 0.0069) after 300 mg loading dose of clopidogrel in coronary heart disease patients.miR-142 could account for a part of missing heritability of CYP3A4/5 functionality related to clopidogrel activation.
- Dacron Graft Intussusception Technique for Treatment of Type A Aortic Dissections: Technical Notes and Preliminary Results. [Journal Article]
- Braz J Cardiovasc Surg 2016 Apr; 31(2):115-9.
Optimal surgical management for acute type A aortic dissection (AAAD) remains unclear. The in-hospital mortality rate is still high (15%), and the intraoperative bleeding is an independent risk factor for hospital mortality.The aim of our study was describe a new method for aortic anastomosis in the repair of AAAD and report the hospital mortality and bleeding complications.Between January 2008 and November 2014, 24 patients, 16 male, median age 62 years, underwent surgical treatment of AAAD. The surgical technique consisted of intussusception of a Dacron tube in the dissected aorta, which is anastomosed with a first line of 2-0 polyester everting mattress suture and a second line of 3-0 polypropylene running suture placed at the outermost side. Open distal anastomosis was performed with bilateral selective antegrade cerebral perfusion in 13 (54.1%) patients.Cardiopulmonary bypass and aortic clamping time ranged from 75 to 135 min (mean=85 min) and 60 to 100 min (mean=67 min), respectively. The systemic circulatory arrest ranged from 29 to 60 min (mean=44.5 min). One (4.1%) patient required reoperation for bleeding, due to the use of preoperative clopidogrel. The postoperative bleeding was 382-1270 ml (mean=654 ml). We used an average of 4.2 units of red blood cells/patient. There were two (8.3%) hospital deaths, one due to intraoperative bleeding and another due to mesenteric ischemia. The average length of stay in the intensive care unit and hospital was 44 hours and 6.7 days, respectively.This new method for surgical correction of AAAD was reproducible and resulted in satisfactory clinical outcomes.