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- Dyspnoea management in acute coronary syndrome patients treated with ticagrelor. [REVIEW]
- Eur Heart J Acute Cardiovasc Care 2014 Sep 29.
The occurrence of dyspnoea in acute coronary syndrome (ACS) patients has always been considered a challenging diagnostic and therapeutic clinical scenario. P2Y12 platelet receptor inhibitors (i.e., clopidogrel, prasugrel and ticagrelor) are currently the cornerstone of treatment of ACS patients. Thus, in the last few years, the potential association between ACS and dyspnoea has also become more challenging with the increasing use of ticagrelor in these patients due to its beneficial effects on ischaemic event prevention and mortality, since ticagrelor can induce dyspnoea as a side effect. The present article is intended to review the current literature regarding dyspnoea occurrence in ACS patients, especially those treated with ticagrelor, and to propose ticagrelor-associated dyspnoea management recommendations based on current knowledge.
Dual antiplatelet therapy with low-dose acetylsalicylic acid (ASA) and an inhibitor of the P2Y12 adenosine diphosphate (ADP) receptor is the standard treatment for patients presenting with acute coronary syndrome (ACS) or undergoing elective coronary interventions according to the current guidelines published by the European Society of Cardiology (ESC). New generation P2Y12 inhibitors, such as prasugrel and ticagrelor exert stronger and more consistent inhibition of the P2Y12 receptor. In clinical studies enrolling patients with ACS these drugs decreased the incidence of ischemic events compared to the standard therapy with clopidogrel and ASA; however, this beneficial effect was associated with an increase in bleeding events. Alternative therapeutic approaches via addition of drugs with different modes of action showed an overall reduction of ischemic events but also failed to uncouple this beneficial effect from an increased bleeding risk.
- Does clopidogrel with aspirin after acute minor stroke or transient ischemic attack increase the risk of cerebral hemorrhage? [Journal Article]
- Chin Med J (Engl) 2014 Sep; 127(18):3352-3.
- Incidence of Intracranial Hemorrhage and Outcomes After Ground-level Falls in Geriatric Trauma Patients Taking Preinjury Anticoagulants and Antiplatelet Agents. [JOURNAL ARTICLE]
- Am Surg 2014 Oct; 80(10):975-978.
Antiplatelet and anticoagulant medication increases the risk of intracranial hemorrhage (ICH) after a fall in geriatric patients. We sought to determine whether there were differences in ICH rates and outcomes based on type of anticoagulant or antiplatelet agent after a ground-level fall (GLF). Our institutional trauma registry was used to identify patients 65 years old or older after a GLF while taking warfarin, clopidogrel, or aspirin over a 2-year period. Rates and types of ICH and patient outcomes were evaluated. Of 562 patients who met inclusion and exclusion criteria, 218 (38.8%) were on warfarin, 95 (16.9%) were on clopidogrel, and 249 (44.3%) were on aspirin. Overall ICH frequency was 15 per cent with no difference in ICH rate, type of ICH, need for craniotomy, mortality, or intensive care unit or hospital length of stay between groups. Patients with ICH were more likely to present with abnormal Glasgow Coma Score, history of hypertension, and/or loss of consciousness.
- Comparison of a solid SMEDDS and solid dispersion for enhanced stability and bioavailability of clopidogrel napadisilate. [JOURNAL ARTICLE]
- Carbohydr Polym 2014 Dec 19.:365-374.
The intention of this study was to compare the physicochemical properties, stability and bioavailability of a clopidogrel napadisilate (CN)-loaded solid dispersion (SD) and solid self-microemulsifying drug delivery system (solid SMEDDS). SD was prepared by a surface attached method using different ratios of Cremophor RH60 (surfactant) and HPMC (polymer), optimized based on their drug solubility. Liquid SMEDDS was composed of oil (peceol), a surfactant (Cremophor RH60) and a co-surfactant (Transcutol HP). A pseudo-ternary phase diagram was constructed to identify the emulsifying domain, and the optimized liquid SMEDDS was spray dried with an inert solid carrier (silicon dioxide), producing the solid SMEDDS. The physicochemical properties, solubility, dissolution, stability and pharmacokinetics were assessed and compared to clopidogrel napadisilate (CN) and bisulfate (CB) powders. In solid SMEDDS, liquid SMEDDS was absorbed or coated inside the pores of silicon dioxide. In SD, hydrophilic polymer and surfactants were adhered onto drug surface. The drug was in crystalline and molecularly dispersed form in SD and solid SMEDDS, respectively. Solid SMEDDS and SD greatly increased the solubility of CN but gave lower drug solubility compared to CB powder. These preparations significantly improved the dissolution of CN, but the latter more increased than the former. Stability under accelerated condition showed that they were more stable compared to CB powder, and SD was more stable than solid SMEDDS. They significantly increased the oral bioavailability of CN powder. Furthermore, SD showed significantly improved oral bioavailability compared to solid SMEDDS and CB powder. Thus, SD with excellent stability and bioavailability is recommended as an alternative for the clopidogrel-based oral formulation.
- Does baseline hematocrit influence the assays of on-treatment platelet reactivity to clopidogrel? [Journal Article]
- Am Heart J 2014 Oct; 168(4):545-51.
High on-treatment platelet reactivity (HTPR) has been shown to be associated with adverse cardiac events in patients undergoing percutaneous coronary intervention, but the effect of baseline hematologic parameters upon platelet reactivity remains controversial.The present study aims to evaluate the impact of hematocrit on 2 different assay methods used to assess on-treatment platelet reactivity to clopidogrel.We tested clopidogrel on-treatment platelet reactivity in 466 consecutive patients using VerifyNow P2Y12 (VN) and light transmission aggregometry (LTA) with adenosine diphosphate (ADP) 5 and 20 μM assays 6 to 24 hours after percutaneous coronary intervention. Patients were categorized into 4 groups according to baseline hematocrit. One-year major adverse cardiac events, including death, nonfatal myocardial infarction, and definite stent thrombosis, were collected.Lower hematocrit was associated with higher P2Y12 reaction unit (PRU) and a higher rate of HTPR (P < .001) as measured by VN assay. No differences were seen among the 4 groups in platelet reactivity measured by LTA using ADP 5 μM (P = .23) and ADP 20 μM (P = .21). In a multivariable logistic regression model, baseline hematocrit was independently associated with PRU ≥208 (odds ratio [OR] 0.92, 95% CI 0.86-0.97, P = .005) but had no correlation with LTA ADP 5 μM ≥46% (OR 1.0, 95% CI 0.95-1.06, P = .88) or LTA ADP 20 μM ≥59% (OR 1.03, 95% CI 0.97-1.09, P = .39). In a logistic regression model, the addition of VN assay results, hematocrit, and interaction between the hematocrit and assay results had shown a significant influence on the area under curve for prediction of 1-year major adverse cardiac events compared with baseline clinical variables only for PRU (0.63 vs 0.76, P = .006) but not with LTA (0.64 vs 0.74, P = .13).Baseline hematocrit has a differential influence on results of the ex vivo platelet functional assays. Lower baseline hematocrit was independently associated with HTPR by VN but not LTA. This may affect the interpretation of platelet function testing in patients with significant anemia.
- Saphenous Vein Graft Failure after Coronary Artery Bypass Surgery: Insights from PREVENT IV. [JOURNAL ARTICLE]
- Circulation 2014 Sep 26.
-Coronary artery bypass grafting (CABG) success is limited by vein graft failure (VGF). Understanding factors associated with VGF may improve patient outcomes.-We examined 1828 participants in the PREVENT IV trial undergoing protocol-mandated follow-up angiography 12-18 months post-CABG or earlier clinically-driven angiography. Outcomes included patient- and graft-level angiographic VGF (≥75% stenosis or occlusion). Variables were selected using Fast False Selection Rate methodology. We examined relationships between variables and VGF in patient- and graft-level models using logistic regression without and with generalized estimating equations. At 12-18 months post-CABG, 782 of 1828 (42.8%) patients had VGF, and 1096 of 4343 (25.2%) vein grafts had failed. Demographic and clinical characteristics were similar between patients with and without VGF, though VGF patients had longer surgical times, worse target artery quality, longer graft length, and more frequently underwent endoscopic vein harvesting. After multivariable adjustment, longer surgical duration (odds ratio [OR] per 10-minute increase 1.05, 95% confidence interval [CI] 1.03-1.07), endoscopic vein harvesting (OR 1.41, 95% CI 1.16-1.71), poor target artery quality (OR 1.43, 95% CI 1.11-1.84), and postoperative use of clopidogrel or ticlopidine (OR 1.35, 95% CI 1.07-1.69) were associated with patient-level VGF. The predicted likelihood of VGF in the graft-level model ranged from 12.1-63.6%.-VGF is common and associated with a number of patient and surgical factors. These findings may help identify patients with risk factors for VGF and inform the development of interventions to reduce VGF. Clinical Trial Registration Information-ClinicalTrials.gov. Identifier: NCT00042081.
- CYP2C19 Genotype Has a Greater Effect on Adverse Cardiovascular Outcomes Following PCI and in Asian Populations Treated with Clopidogrel: A Meta-Analysis. [JOURNAL ARTICLE]
- Circ Cardiovasc Genet 2014 Sep 25.
-The degree to which cytochrome P450 (CYP) 2C19 genotype influences the effectiveness of clopidogrel remains uncertain due to considerable heterogeneity in results between studies and potential publication bias. Clopidogrel indication and ethnic population have been proposed to influence the effect of CYP2C19 genotype.-A systematic review was undertaken up to 14 November 2013. Meta-analysis of the CYP2C19 genotype effect was stratified by the predominant clopidogrel indication (percutaneous coronary intervention [PCI] vs non PCI) and ethnic population (Caucasian vs Asian) of each primary study. The primary analysis was restricted to studies with 500 or more participants which comprised 24 studies and a total of 36,076 participants. The association between carriage of at least one CYP2C19 loss-of-function (LoF) allele and major cardiovascular outcomes differed significantly (p<0.001) between studies of Caucasians not undergoing PCI (RR 0.99 [95% confidence interval 0.84 to 1.17], n=7043), Caucasians undergoing PCI (RR 1.20 [1.10 to 1.31], n=19,016), and Asians undergoing PCI (RR 1.91 [1.61 to 2.27], n=10,017). Similar differences were identified in secondary analyses of two CYP2C19 LoF alleles, stent thrombosis outcomes, and studies with 200 or more participants. Minimal heterogeneity was apparent between studies of Asian populations.-The reported association between CYP2C19 LoF allele carriage and major cardiovascular outcomes differs based on the ethnic population of the study and to a lesser extent, the clopidogrel indication. This is potentially of major importance given that over 50% of Asians carry one or more CYP2C19 LoF alleles.
- Effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel in rats. [JOURNAL ARTICLE]
- Biopharm Drug Dispos 2014 Sep 25.
Erigeron breviscapus (Vant.) Hand-Mazz, a traditional Chinese medicine, is often co-prescribed with clopidogrel for the treatment of ischemic vascular diseases. Scutellarin is the representative bioactive flavonoid isolated from this herb. The aim of this study was to explore the effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel. The in vitro studies using rat liver microsomes showed that scutellarin significantly inhibited the metabolism of clopidogrel. The IC50 value was 2.1 μM. Ten male rats were employed to investigate the effect of scutellarin on the pharmacokinetics of clopidogrel in vivo. After pretreatment with scutellarin, there were significant increase in the AUC0-∞ (from 0.9 ± 0.4 to 1.7 ± 0.6 ng/mL h; P < 0.05) and Cmax (from 0.4 ± 0.1 to 0.9 ± 0.1 ng/mL; P < 0.05) of clopidogrel. The pharmacokinetic data for clopidogrel active metabolite showed significant decrease in AUC0-∞ (18.2 ± 5.6 to 11.4 ± 3.7 ng/mL h; P < 0.05) and Cmax (from 8.2 ± 1.2 to 4.3 ± 0.3 ng/mL; P < 0.05) after pretreatment with scutellarin. Collectively, the metabolism and pharmacokinetics of clopidogrel were significantly affected by scutellarin. This study indicated that potential herb-drug interaction between scutellarin and clopidogrel should be taken into consideration in clinical use. This article is protected by copyright. All rights reserved.