Comparison of ticagrelor and thienopyridine P2Y12 binding characteristics and antithrombotic and bleeding effects in rat and dog models of thrombosis/hemostasis

Ticagrelor (AZD6140), the first reversibly binding oral P2Y₁₂ receptor antagonist, blocks adenosine diphosphate (ADP)-induced platelet aggregation via a mode of action distinct from that of thienopyridine antiplatelet agents. The latter must be metabolically activated and binds irreversibly to P2Y₁₂ for the life of the platelet, precluding restoration of hemostatic function without the generation of new platelets. In in vitro studies comparing binding characteristics of ticagrelor and compound 105, a chemical compound indistinguishable from the active metabolite of prasugrel, ticagrelor exhibited 1) an approximately 100-fold higher affinity for P2Y₁₂ and rapid achievement of equilibrium (vs no equilibrium reached with compound 105) as assessed by radioligand displacement in a receptor filtration binding assay, 2) 48-fold greater potency in a functional receptor assay using recombinant human P2Y₁₂, and 3) 63-fold greater potency in inhibiting ADP-induced aggregation in washed human platelets. In rat and dog models of thrombosis/hemostasis, there was greater separation between doses that provided antithrombotic effect and those that increased bleeding for ticagrelor compared with clopidogrel and compound 072, a chemical compound indistinguishable from the prasugrel parent compound. The ratio of dose resulting in 3-fold increase in bleeding time to dose resulting in 50% restoration of blood flow in rats was 9.7 for ticagrelor compared with 2.0 for clopidogrel and 1.4 for compound 072. Similar results were observed in dogs. Our findings suggest that reversibility of P2Y₁₂ binding with ticagrelor may account for the greater separation between antithrombotic effects and increased bleeding compared with the irreversible binding of clopidogrel and prasugrel.     

Dabigatran, rivaroxaban and apixaban versus enoxaparin for thomboprophylaxis after total knee or hip arthroplasty: pool-analysis of phase III randomized clinical trials

Objectives

To compare the main efficacy and safety endpoints of the pivotal randomised clinical trials (RCTs) on venous thromboembolism (VTE) prevention after total hip (THR) or knee (TKR) replacement with the new oral anticoagulants (NAs) versus enoxaparin.

Methods

A pool-analysis of 10 RCTs that included 32.144 randomised patients was performed. Efficacy outcomes were total VTE and all-cause mortality, major VTE, and proximal DVT. Safety outcomes were major bleeding, and clinically relevant (major or non-major) bleeding.

Results

Overall, a significant effect favouring NAs was found for the primary efficacy outcome (RR 0.71; 95%CI 0.56-0.90), major VTE (RR 0.59; 95%CI 0.41-0.84), and proximal DVT (RR 0.51; 95%CI 0.35-0.76). Compared to enoxaparin 40 mg QD, rivaroxaban showed superiority (RR 0.50; 95%CI 0.34-0.73), followed by apixaban (RR 0.63; 95%CI 0.36-1.01) and dabigatran (RR 1.02; 95%CI 0.86-1.20). There was significant heterogeneity among trials and subgroups analysed for these efficacy outcomes. Major bleeding (RR 1.04; 95% CI 0.74-1.46) and clinically relevant bleeding (RR 1.03; 95%CI 0.88-1.21) was similar with NAs or enoxaparin. Rivaroxaban showed a trend toward more major bleeding episodes than enoxaparin (RR 1.88; 95%CI 0.92-3.82) and apixaban showed the lowest clinically relevant bleeding risk (RR 0.81; 95%CI 0.64-1.01).

Conclusions

Overall, NAs showed more efficacy and same safety when compared to the recommended dose of enoxaparin after THR and TKR. There are little differences in efficacy and bleeding risk among NAs and the type of prophylaxis that should be analysed further.     

Apixaban versus enoxaparin in patients with total knee arthroplasty. A meta-analysis of randomised trials

It was the objective of this study to systematically compare the effects of apixaban versus enoxaparin in patients following total knee arthroplasty (TKA). A systematic search of Medline, EMBASE, Cochrane Central Register of Controlled Trials was conducted. Eligible studies were prospective, randomised control trials (RCT) of apixaban therapy, comparing with enoxaparin, in patients who have a high risk of venous thromboembolism (VTE) after TKA. Three RCTs involving 7,337 individuals were identified, of whom 4,057 were treated with apixaban 2.5 mg once daily, and 3280 were subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Meta-analysis demonstrated the odds ratio (OR) for the composite of major VTE (proximal deep-vein thrombosis and pulmonary embolism) for apixaban versus enoxaparin was 0.47 (95% confidence interval [CI]: 0.27 to 0.82, 0.6% vs. 1.2%) and 2.09 (95%CI: 0.99 to 4.45, 0.6% vs. 0.3%), respectively. All-cause mortality occurred in 0.2% of the apixaban group versus 0.09% of the enoxaparin group (OR=1.74; 95%CI, 0.51 to 5.95). With respect to safety outcomes, apixaban was associated with a lower major bleeding rate than enoxaparin (OR=0.55, 95%CI: 0.32 to 0.96). No significant differences were detected between two strategies in other endpoints of safety profile analysed: clinically relevant non-major bleeding, raised hepatic transaminase enzyme or bilirubin concentrations and arterial thromboembolic events. In conclusion, apixaban is non-inferior to subcutaneous enoxaparin when used for the same duration, with considerable advantage regarding safety profile of major bleeding after TKA.     

Relationship between CYP2C19*2, *3 gene polymorphism and the recurrence in ischemic stroke patients treated with clopidogrel in China: A meta-analysis

BackgroundThe relationship between CYP2C19 *2,*3 gene variants and the recurrence in ischemic stroke patients treated with clopidogrel is still controversial according to the available published literature. To evaluate correlations between CYP2C19 *2,*3 gene variants, metabolic typing according to *2, *3 SNPs (the polymorphism of rs4244285, rs4986893) and stroke recurrence, we performed this study through meta-analysis.MethodsLiteratures reporting the relationship between CYP2C19*2 and *3 polymorphism and the recurrence in ischemic stroke patients treated with clopidogrel were searched in CNKI, Wanfang Database, VIP, China Biomedical Database, PubMed and Cochrane Library from the establishment database to December 2020. Meta-analysis was performed with RevMan 5.3.ResultsA total of 9 articles with 10 trials involving 1333 ischemic stroke patients were included. The results of meta-analysis showed CYP2C19*2 GA/AA genotype had a higher risk of recurrent stroke than GG in patients with ischemic stroke treated with clopidogrel(P<0.05) (GA+AA vs. GG:OR=2.50, 95% CI:1.66～3.75;GA vs. GG:OR=2.16, 95% CI:1.41～3.31;AA vs. GG:OR=4.40, 95% CI:2.39～8.08; AA vs. GA:OR=2.15, 95% CI:1.20-3.84; allele A vs. G:OR=2.08, 95% CI:1.58-2.75). There was no significant difference in stroke recurrence risk between CYP2C19*3 GA vs. GG genotype (P=0.65)(OR=0.86,95% CI:0.44～1.67). Compared with extensive metabolizer (EM), patients with intermediate metabolizer (IM) and poor metaholizer (PM) of CYP2C19 had a higher risk of stroke recurrent after clopidogrel treatment (IM+PM vs. EM:OR=2.20, 95%CI:1.58～3.08, P<0.05; IM vs. EM:OR=2.06,95% CI: 1.45～2.91, P<0.05;PM vs. EM: OR=3.32,95% CI:1.98～5.56, P<0.05; PM vs. IM: OR=1.45,95% CI: 0.91～2.32,P=0.11).ConclusionAmong ischemic stroke patients taking clopidogrel, CYP2C19*2 gene mutation and CYP2C19 metabolizer were associated with stroke recurrence, CYP2C19*2 and *3 gene carriers were more likely to stroke recurrent than CYP2C19*1 gene carriers.     

坦度螺酮治疗癫痫伴焦虑、抑郁效果的系统评价

目的 系统评价坦度螺酮治疗癫痫伴焦虑、抑郁的临床效果及安全性。方法 计算机检索PubMed、Cochrane、Science Direct、Embase、维普、万方和中国知网等数据库，检索时间为从建库至 2018年8月，收集坦度螺酮治疗癫痫合并焦虑抑郁的随机对照试验，应用Rev Man 5.3软件进行Meta分析。结果 共纳入6个随机对照试验，包含462例。Meta分析结果显示:坦度螺酮显著降低汉密尔顿焦虑 量表评分（SMD=-1.01；95% CI:-1.91~-0.11；P=0.03），显著降低汉密尔顿抑郁量表评分（SMD=-1.57；95% CI:-2.42~-0.72；P=0.001），显著降低副反应发生率（OR=0.43；95% CI:0.22~0.82； P=0.01），显著增加有效率（OR=3.31；95% CI:1.97~5.56；P<0.001）。结论 坦度螺酮治疗癫痫伴焦虑抑郁具有显著的临床效果及较好的药物安全性。     

缺血性卒中患者因氯吡格雷低反应性改为高维持量及替格瑞洛后血小板抑制率变化

目的探讨用血栓弹力图评价符合双抗治疗的缺血性脑血管病患者,因氯吡格雷低反应性,改为高维持剂量及改服替格瑞洛后血小板抑制率的变化。方法选择符合双抗治疗的缺血性脑血管病患者联合应用抗血小板制剂(阿司匹林肠溶片100 mg/qd+氯吡格雷75 mg/qd)前及后7 d,用血栓弹力图检测患者的花生四烯酸(AA)和二磷酸腺苷(ADP)途径诱导的血小板抑制率,筛选出氯吡格雷低反应性者96例,随机分为3组,常规剂量组(氯吡格雷75 mg/qd,32例)、高维持量组(氯吡格雷150 mg/qd,32例)和替格瑞洛组(替格瑞洛90 mg/bid,32例),3组阿司匹林继续按原剂量服用。分组后3组按新方案治疗7 d,再次复查血栓弹力图。结果分组后高维持量组及替格瑞洛组ADP诱导的血小板抑制率较常规剂量组有显著性差异(P0.05),3组均未发生出血等严重不良事件,替格瑞洛组发生1例轻度呼吸困难。替格瑞洛组高于同一时间点高维持量组ADP途径诱导的血小板抑制率(P0.05)。结论针对常规剂量氯吡格雷的低反应性,替格瑞洛及双倍剂量的氯吡格雷均能有效降低血小板的高反应性,并且替格瑞洛的作用更为明显,且未增加出血等不良事件的发生。     

Aspirin platelet reactivity on platelet function and clinical outcome in minor stroke or transient ischemic attack

ObjectiveWhether aspirin platelet reactivity affects platelet function and clinical outcomes with different antiplatelet therapies in patients with mild stroke or transient ischemic attack (TIA) remains unclear. We conducted a subgroup analysis of the PRINCE trial.Materials and methodsPatients with mild stroke or TIA were randomized into aspirin+ticagrelor, or aspirin+clopidogrel groups; aspirin reaction units (ARU) were measured at the baseline and after 7 ± 2 days to assess response to treatment. High on-treatment platelet reactivity (HPR) was defined as ≥550 ARU (poor response to aspirin). The platelet functions of ticagrelor and clopidogrel were measured using the VerifyNow P2Y₁₂ assay for P2Y₁₂ reaction units (PRU); HPR to P2Y₁₂ was defined as >208 PRU (poor response to P2Y₁₂). Clinical outcomes included stroke and clinical vascular and bleeding events after 90 days.ResultsAmong 628 enrolled patients, 69 (11%) were poor aspirin responders. After 7 ± 2 days, the proportion of poor P2Y₁₂ responders for ticagrelor versus clopidogrel significantly reduced in poor (2.6% versus 27.4%) and good (14.3% versus 29.4%) aspirin responders. There were significant interactions between treatment groups, and between treatment groups and aspirin platelet reactivity for poor P2Y₁₂ responders (P = 0.01). After 90 ± 7 days, there were no significant interactions between treatment groups and aspirin platelet reactivity for new stroke risk (good aspirin responders: 5.5% versus 8.8%, hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.32 to 1.16; P = 0.13; poor aspirin responders: 8.6% versus 8.8%, HR: 0.97, 95% CI: 0.20–4.81; P = 0.97; P for interaction = 0.60). Major bleeding was less frequent in poor than good aspirin responders (ticagrelor/aspirin: 0.4%/0%; clopidogrel/aspirin: 1.4%/0%).ConclusionsIn patients with minor stroke or TIA, clopidogrel, and particularly ticagrelor, decreased platelet function in poor versus good aspirin responders. The poor platelet reactivity of aspirin could not sufficiently reduce the risk of recurrent stroke with ticagrelor or clopidogrel; however, HPR (poor aspirin response) may have a protective effect on clinically relevant major bleeding.     

The Effect of Locally Administered Fibrinolytic Drugs Following Aneurysmal Subarachnoid Hemorrhage : A Meta-Analysis with Eight Randomized Controlled Studies

ObjectiveRapid dissolution of blood clots reduces vasospasm and hydrocephalus after subarachnoid hemorrhage (SAH), and locally administered fibrinolytic drugs (LAFDs) could facilitate the dissolution. However, the efficacy of LAFDs remains controversial. The aim of this meta-analysis was to determine the efficacy of LAFDs for vasospasm and hydrocephalus and in clinical outcomes. MethodsFrom PubMed, EMBASE, and Cochrane database, data were extracted by two authors. Meta-analysis was performed using a random effect model. Inclusion criteria were patients who had LAFDs with urokinase-type or recombinant tissue-plasminogen activator after SAH in comparison with medically untreated patients with fibrinolytic drugs. We only included randomized controlled trials (RCTs) in this analysis. The outcomes of interest were vasospasm, hydrocephalus, mortality, and 90-day unfavorable functional outcome. ResultsData from eight RCTs with 550 patients were included. Pooled-analysis revealed that the LAFDs were significantly associated with lower rates of vasospasm (LAFDs group vs. control group, 26.5% vs. 39.2%; odds ratio [OR], 0.48; 95% confidence interval [CI], 0.32–0.73); hydrocephalus (LAFDs group vs. control group, 26.0% vs. 31.6%; OR, 0.54; 95% CI, 0.32–0.91); and mortality (LAFDs group vs. control group, 10.5% vs. 15.7%; OR, 0.58; 95% CI, 0.34–0.99). The proportion of 90-day unfavorable outcomes was lower in the LAFDs group (LAFDs group vs. control group, 32.7% vs. 43.5%; OR, 0.55; 95% CI, 0.37–0.80). ConclusionThis meta-analysis with eight RCTs indicated that LAFDs were significantly associated with lower rates of vasospasm and hydrocephalus after SAH. Thus, LAFDs could consequently reduce mortality and improve clinical outcome after SAH.     

脑室外引流后穿刺道出血的危险因素分析

目的探讨脑室外引流后穿刺道出血的危险因素,为预防和早期诊治脑室外引流后穿刺道出血提供理论依据。 方法回顾性分析阜阳市肿瘤医院神经外科自2018年1月至2021年5月收治的脑室外引流手术患者114例,根据其有无穿刺道出血分为出血组（28例）及未出血组（86例）。比较2组患者的基线资料,并将单因素分析中有统计学意义的因素纳入多因素Logistic回归分析,探究脑室外引流后穿刺道出血的独立危险因素。 结果单因素分析结果显示,出血组患者年龄、脑卒中史、术前抗血小板药物、术前抗凝药物穿刺次数高于未出血组,同期颅脑手术率低于未出血组,差异均有统计学意义（P<0.05）。多因素Logistic回归分析结果显示,术前抗血小板药物（OR=7.205,95%CI：2.243~23.144）、穿刺次数（OR=2.473,95%CI：1.315~4.650）是脑室外引流后穿刺道出血的独立危险因素,而同期颅脑手术（OR=0.163,95%CI：0.038~0.702）是脑室外引流后穿刺道出血的独立保护因素。 结论术前抗血小板药物和穿刺次数是脑室外引流后穿刺道出血的独立危险因素,同期颅脑手术是脑室外引流后穿刺道出血的独立保护因素,临床中应注意积极预防、早期干预。     

Clopidogrel in addition to aspirin reduces in-hospital major cardiac and cerebrovascular events in unselected patients with acute ST segment elevation myocardial

We sought to assess the effect of clopidogrel on in-hospital events in unselected patients with acute ST elevation myocardial infarction (STEMI). In a retrospective analysis of consecutive patients enrolled in the Acute Coronary Syndromes (ACOS) registry with acute STEMI we compared outcomes of either adjunctive therapy with aspirin alone or aspirin plus clopidogrel within 24 hours after admission.A total of 7,559 patients were included in this analysis, of whom 3,541 were treated with aspirin alone, and 4,018 with dual antiplatelet therapy.The multivariable analysis with adjustment for baseline characteristics and treatments showed that the rate of in-hospital MACCE (death, non-fatal reinfarction, non-fatal stroke) was significantly lower in the aspirin plus clopidogrel group,compared to the aspirin alone group in the entire cohort and all three reperfusion strategy groups (entire group odds ratio 0.60, 95% CI 0.49-0.72 , no reperfusion OR 0.69,95% CI 0.51-0.94,fibrinolysis OR 0.62,95% CI 0.44-0.88, primary PCI OR 0.54, 95% CI 0.39-0.74).There was a significant increase in major bleeding complications with clopidogrel (7.1% vs. 3.4%, p<0.001). In clinical practice early adjunctive therapy with clopidogrel in addition to aspirin in patients with STEMI is associated with a significant reduction of in-hospital MACCE regardless of the initial reperfusion strategy.This advantage was associated with an increase in major bleeding complications.     

氯吡格雷联合阿司匹林治疗对轻型卒中与短暂性脑缺血发作患者功能预后的影响：CHANCE与POINT试验联合分析

目的 评价氯吡格雷联合阿司匹林双抗治疗对轻型缺血性卒中与TIA患者功能预后的影响。 方法 提取CHANCE和POINT试验所有的个体数据。这两项试验中,所有纳入患者在症状发作12 h （POINT）或24 h（CHANCE）以内随机接受氯吡格雷联用阿司匹林或单用阿司匹林治疗。结局指标为3个 月时功能预后不良（mRS≥2）,三等级定义卒中复发[致残性或致死性卒中复发（mRS≥2）、非致残性 卒中复发（mRS 0或1）、无卒中复发]。 结果 共10 013例患者纳入分析,其中来自CHANCE试验5132例（51.3%）,来自POINT试验4881例 （48.7%）;氯吡格雷联用阿司匹林组4995例（49.9%）,单用阿司匹林组5018例（50.1%）。氯吡格雷联 用阿司匹林组3个月时功能预后不良的患者比例低于单用阿司匹林组（11.6% vs 12.6%,校正OR 0.82, 95%CI 0.72～0.94,P =0.005）。氯吡格雷联用阿司匹林组致残性或致死性卒中复发（4.6% vs 6.1%, 校正OR 0.73,95%CI 0.61～0.87,P <0.001）、非致残性卒中复发（1.9% vs 3.0%,校正OR 0.62,95%CI 0.47～0.80,P <0.001）和卒中复发的整体致残性（校正cOR 0.70,95%CI 0.60～0.81,P <0.001）低于单 用阿司匹林组。 结论 与单用阿司匹林治疗相比,氯吡格雷联用阿司匹林治疗可进一步改善轻型缺血性卒中和TIA 患者3个月时功能预后,减少致残性卒中复发。     

缺血性卒中/TIA患者抗栓药物的使用及影响因素分析：中国七城市门诊连续病例的横断面调查

目的 评估中国缺血性卒中(IS)或短暂性脑缺血发作（TIA）患者应用抗血栓药物（包括抗血小板药物和抗凝药物）的现况，并分析其影响因素。方法 采用横断面研究方法，调查2006年7月1日至8月15日期间，中国主要城市二、三级医院神经内科门诊连续IS或TIA患者近期的抗血栓药物使用情况。22家医院参加调查，总计2384例卒中患者连续入选；有3家不符合中心入选标准被除外，最后19家医院的资料被采用，总计有2283例卒中患者的数据纳入分析中。结果 2283例卒中患者中，使用阿司匹林者占71.9％，使用阿司匹林+氯吡格雷占4.2％，使用氯吡格雷者占7.3％，各种抗血小板药物合计例数占75.6％。伴心房颤动的81例卒中患者中，使用华发林者占17.3％。医疗保险[比值比（OR）1.473，95%可信区间（CI）1.088～1.994]、公费医疗（OR 1.632，95%CI 1.029～2.589）、月均收入≥500元以上（OR 2.136，95%CI 1.508～3.026）、高血压（OR 1.463，95%CI 1.159～1.847）和脂代谢紊乱（OR 1.499，95%CI 1.187～1.893）是卒中患者接受抗血小板药物的促进因素。患者年龄≥75岁（OR 0.701，95%CI 0.498～0.988）及改良的Rankin评分4～5分（OR 0.684，95%CI 0.486～0.965）是用药的阻碍因素。结论 中国大城市二、三级医院IS和TIA患者的抗血栓治疗现状不容乐观，各类抗血栓药物应用的比例较低，为改善以上状况，亟待探索有效的改进模式，缩短临床实践与指南间的差距。     

Ticagrelor, but not clopidogrel and prasugrel, prevents ADP-induced vascular smooth muscle cell contraction: a placebo-controlled study in rats

Introduction

Off-target effects of novel antiplatelet agents due to their potential clinical benefits are currently an area of intensive investigation. We aimed to compare the effects of different P2Y₁₂ antagonists on the reactivity of vascular smooth muscle cells.

Materials and methods

Wistar rats (n = 30) were pretreated with an investigated drug or placebo. Clopidogrel (50 mg/kg, n = 7), prasugrel (10 mg/kg, n = 7), ticagrelor (10 mg/kg, n = 7) or placebo (n = 9) were administered orally 12 and 2 hours before experiments. Constrictions of rat tail arteries induced with a stable analogue of adenosine diphosphate (2-MeS-ADP), phenylephrine and arginine vasopressin were measured as an increase in perfusion pressure. Effects of ticagrelor were assessed in the presence of ticagrelor (1 μM/L) added to the perfusion solution as this drug reversibly inhibits the P2Y₁₂ receptor.

Results

Pretreatment with clopidogrel and prasugrel did not inhibit 2-MeS-ADP-induced contraction while ticagrelor did. Experiments employing endothelium-deprived arteries provided similar results. Clopidogrel and prasugrel did not influence concentration-response curves in the presence of neither phenylephrine nor arginine vasopressin. The curves obtained for both vasopressors in the presence of ticagrelor and 2-MeS-ADP were shifted to the right with a significant reduction in the maximal response.

Conclusions

Oral administration of ticagrelor, in contrast to clopidogrel and prasugrel, prevents adenosine diphosphate-induced contraction of vascular smooth muscle cells in a rat model. Both the clinical significance and detailed mechanism of our findings warrant further investigation.     

抗血小板药预防脑卒中的应用进展

以阿司匹林为代表的抗血小板药已被证实在对脑卒中预防有确实的疗效。阿司匹林、氯吡格雷等抗血小板药物作为脑卒中预防的基础用药,其疗效确切并已经列入相关脑卒中预防指南。替卡格雷、西洛他唑、三氟柳、沙格雷酯等新型抗血小板药物在部分地区的临床试验中也已经取得了令人满意的脑卒中预防结果。但是多年来,阿司匹林的最佳预防剂量仍在商榷中,在患者应用抗血小板药物的过程中,存在一定比例的出血并发症。当两种抗血小板药物合用更可能导致出血并发症的发生比例增高。寻求抗血小板药的疗效及出血并发症间的平衡点,促进抗血小板药物的进步与发展。文中就抗血小板药物在预防脑卒中的应用进展作介绍。     

微信干预对社区精神分裂症患者服药依从性、精神病性症状及复发率影响的Meta分析

目的系统评价微信干预对社区精神分裂症患者服药依从性、精神病性症状及复发率的影响。方法计算机检索PubMed、Cochrane Library、CBM、中国知网、万方和维普数据库,搜集有关微信干预对社区精神分裂症患者影响的随机对照研究,检索时限均为2011年1月1日-2020年11月1日。由2名研究者独立筛选文献、提取数据并评价纳入研究的偏倚风险后,采用Stata 12.0进行Meta分析。结果共检索到381篇文献,最终纳入10项随机对照研究,共1251例患者,其中微信干预组641例,常规健康教育组610例。Meta分析结果显示,相对于常规健康教育组,微信干预组服药依从性(OR=3.05,95%CI:1.98~4.69,P<0.01)更高,PANSS评分(SMD=-1.05,95%CI:-1.46~-0.64,P<0.01)和复发率(OR=0.34,95%CI:0.24~0.48,P<0.01)更低。结论基于微信平台的互动干预方式可能有助于提高社区精神分裂症患者服药依从性、改善精神病性症状和降低复发率。     

Resistance to anti-platelet agents

In the last few years, the concept of resistance to antiplatelet agents has been largely emphasized in the medical literature, although its definition is still uncertain. The real prevalence of resistance to aspirin appears to be rather low. In contrast, resistance to clopidogrel (a P2Y12 inhibitor), which is mostly due to inefficient metabolism of the pro-drug clopidogrel to its active metabolite, is a rather frequent condition, which is associated with lower clinical efficacy of the drug. The proposed solution to the problem of clopidogrel resistance, based on monitoring the pharmacological response with platelet function tests, is cumbersome, not effective in all treated patients and not practicable yet, because the most appropriate laboratory test has not yet been identified. The use of new P2Y12 inhibitors, such as prasugrel and ticagrelor, which adequately inhibit P2Y12-dependent platelet function in the vast majority of treated subjects, appears the best solution to the problem of clopidogrel resistance.     

替格瑞洛与西洛他唑对氯吡格雷抵抗的急性缺血性脑卒中患者的疗效及安全性比较

目的 探讨替格瑞洛与西洛他唑对氯吡格雷抵抗的急性缺血性脑卒中(AIS)患者的疗效及安全性的影响。方法 将80例对氯吡格雷抵抗(血小板聚集率>50%)AIS患者按照数字表法随机分为替格瑞洛组(入组40例,完成37例)和西洛他唑组(入组40例,完成39例); 在AIS常规治疗的基础上替格瑞洛组将氯吡格雷换用替格瑞洛治疗(90 mg/次,2次/d); 西洛他唑组将氯吡格雷换用西洛他唑治疗(100 mg/次,2次/d)。于改变治疗方案前及改变治疗方案后1、3、6、12个月分别检测血小板聚集率(PIR),观察2组治疗12个月内的缺血事件、出血事件及药物的不良反应。结果 改变治疗方案后12个月替格瑞洛组总有效率显著高于西洛他唑组(z=-2.086,P=0.037)。替格瑞洛组缺血事件发生率低于西洛他唑组(χ²=4.057,P=0.034); 替格瑞洛组的出血事件发生率高于西洛他唑组(χ²=4.501,P=0.034); 替格瑞洛组的呼吸困难发生率高于西洛他唑组(χ²=4.505,P=0.034); 替格瑞洛组的其他不良反应发生率高于西洛他唑组(χ²=4.021,P=0.045)。改变治疗方案后1、3、6、12个月替格瑞洛组患者的PAR低于西洛他唑组(F=15.320,P=0.000)。结论 对氯吡格雷抵抗的AIS患者,替格瑞洛比西洛他唑的血小板抑制作用更强,缺血事件发生率更低,但出血事件、呼吸困难及其他不良反应的发生率更高,因此对于血栓风险较高、出血风险较低的患者,建议换用替格瑞洛; 对于血栓风险较低、出血风险较高的患者,建议换用西洛他唑。     

Bilateral vs. unilateral repetitive transcranial magnetic stimulation in treating major depression: A meta-analysis of randomized controlled trials

Previous studies have demonstrated inconsistent findings regarding the efficacy of bilateral vs. unilateral repetitive transcranial magnetic stimulation (rTMS) in treating major depressive disorder (MDD). Therefore, this meta-analysis was conducted to compare the efficacy of these two rTMS modalities. Data were obtained from seven randomized controlled trials (RCTs) consisting of 509 subjects. Bilateral and unilateral rTMS displayed comparable efficacy in treating MDD with a pooled odds ratios of 1.06 (95% confidence interval (CI)=0.58–1.91) for response rates and 1.05 (95% CI=0.52–2.11) for remission rates. Subgroup analysis found that bilateral rTMS was equally effective in comparison with both left and right unilateral rTMS. No significant differences in drop-out rates were found. No publication bias was detected. In conclusion, the pooled examination demonstrated that bilateral rTMS displays comparable anti-depressant efficacy and acceptability to unilateral rTMS in treating MDD. These findings suggest that simultaneous rTMS of the right and left dorsolateral prefrontal cortices in MDD patients does not provide marginal benefits in terms of efficacy or acceptability. As the number of RCTs included here was limited, further large-scale multi-center RCTs are required to validate our conclusions.     

High platelet reactivity and clinical outcome - fact and fiction

In patients suffering from acute coronary syndromes or undergoing percutaneous coronary intervention, oral antiplatelet treatment is routinely administered with the primary aim of inhibiting platelet-mediated thrombus formation and subsequent abrupt vessel occlusion. Simultaneous inhibition of blood platelet cyclooxygenase-1 by aspirin and of the P2Y12 receptor by clopidogrel or prasugrel is currently recommended in this setting. Inter-individual response variability to aspirin and especially to clopidogrel is the subject of much debate as evidence has grown over the years linking an attenuated response to treatment with the occurrence of ischaemic events. Consequently, the clinical entity of high (on-treatment) platelet reactivity (HPR) was born and subsequently characterised in numerous studies over the last decade. Until recently, alternative treatment options were limited in patients exhibiting HPR. At present the antiplatelet therapy landscape is changing with the advent of prasugrel and ticagrelor as alternative and more potent treatment options. Different tests for monitoring platelet function are available and are being increasingly employed in research projects and clinical routine. These tests may prove useful for achieving optimal platelet inhibition for the individual patient, and several centres now incorporate such testing in day-to-day practice. Widespread adoption of this practice and incorporation into clinical guidelines awaits the results of ongoing trials in which treatment is changed based on platelet function monitoring. This review aims to summarise available facts and fiction in relation to platelet function testing and reactivity with a particular focus on P2Y12 receptor inhibition in patients undergoing coronary stent placement.     

Comparison of two preventive dual antiplatelet regimens for unruptured intracranial aneurysm embolization with flow diverter/disrupter: A matched-cohort study comparing clopidogrel with ticagrelor

PurposeStandard dual antiplatelet therapy (DAPT) for complex aneurysms treated with flow diversion and flow disruption is acetylsalicylic acid (ASA) plus clopidogrel. However, clopidogrel resistance frequently occurs and can lead to thromboembolic events. Ticagrelor is an alternative not requiring platelet inhibition testing. We compared two DAPT regimens (ASA with clopidogrel or ticagrelor) on morbi-mortality, safety and efficacy of unruptured aneurysm embolization with flow diverter/disrupter.Materials and methodsThis retrospective analysis of a 1:1 matched cohort compares patients treated with ASA + clopidogrel (March 2013–December 2015) vs. ASA + ticagrelor (January 2016–March 2017). No platelet inhibition testing was conducted. Patients matched for age (±10 years), type of treatment and aneurysm sac size ( ± 2 mm). Primary outcome measures were morbidity and mortality at 1-month; secondary outcomes were thromboembolic and hemorrhagic complications [on angiography and magnetic resonance imaging (MRI)] and groin complications. Outcomes were compared using bivariate analyses.ResultsNinety patients fulfilled inclusion criteria, of which 80 remained after matching (40 per group). There was no statistical difference in 1-month morbidity between the ticagrelor and clopidogrel groups (2.5% vs. 10%, P = 0.36) and no deaths reported. We observed no significant differences between ticagrelor and clopidogrel groups in terms of angiographic thromboembolic complications (5% vs. 12.5%, P = 0.43), territorial infarction on DWI (2.5% vs. 7.5%, P = 0.61), angiographic (0% vs. 0%, P = 1) and MRI (5% vs 5%, P = 1) hemorrhagic complications, new microbleeds (57.5% vs. 40%, P = 0.12) and groin puncture complications (2.5% vs. 0%, P = 1). At three months, there was no delayed territorial infarction or hemorrhage in either group.ConclusionsTicagrelor is safe and effective in replacing clopidogrel as DAPT for unruptured aneurysms.