Antiplatelet Therapy and Cardiac Surgery: Review of Recent Evidence and Clinical Implications

Since the publication of the 2009 Canadian Cardiovascular Society position paper on antiplatelet therapy and cardiac surgery, new antiplatelet strategies with either double-dose clopidogrel or with new and more potent agents (prasugrel and ticagrelor) have become accepted practice. For the patient requiring coronary artery bypass surgery who has recently received either double-dose clopidogrel or one of the new P2Y12 platelet inhibitors, increased perioperative bleeding can be anticipated. For patients who are stable and can wait, surgery should be delayed for 5 days after the last dose of clopidogrel (standard or double-dose), and for 7 days after the last dose of prasugrel. Patients who have received ticagrelor should wait 5 days after the last dose before surgery, although it is likely that surgery can be safely performed 3 days after discontinuing ticagrelor. For patients who require emergency surgery despite recently receiving double-dose clopidogrel, prasugrel, or ticagrelor, the measures to limit perioperative bleeding discussed in the 2009 Canadian Cardiovascular Society position paper remain applicable, but have not yet been rigourously tested. Recent studies have suggested the value of preoperative in vitro platelet aggregometry to determine perioperative bleeding risk.     

抗血小板治疗的最新进展

大量临床研究已证实抗血小板药物：阿司匹林、噻吩吡啶类药物、血小板膜糖蛋白受体桔抗剂、西洛他唑等在预防和治疗心脑血管疾病以及外周动脉血管病变中具有十分重要的作用。洞悉药物的作用机理、应用现状、进展和存在的争议,对于更好地运用该类药物具有十分重要的作用。现就相关内容进行简要综述。     

Duration of Dual Antiplatelet Therapy in Coronary Artery Disease: a Review Article

Dual antiplatelet therapy (DAPT) following an acute coronary syndrome or after placement of a coronary artery stent is superior to aspirin alone for prevention of atherothrombotic events but carries an increased bleeding risk. DAPT should be continued for at least 12 months based on current guidelines. Recent randomized trials demonstrate reduced ischemic events including myocardial infarction (MI), stroke, and death with continued DAPT for up to 30 months or longer, particularly in the post-MI population. However, this clinical benefit is accompanied by an increased risk of bleeding. Additional trials show mixed safety and efficacy with duration of DAPT of less than 12 months. The current data emphasizes the need to individualize DAPT duration at the patient level to balance the clinical benefits of a reduced risk of cardiovascular ischemic events with the greater risk of clinically significant bleeding. Patients at an increased risk of ischemic events and a lower risk of bleeding should be strongly considered for prolonged DAPT beyond the 1 year currently recommended in the practice guidelines.     

Antiplatelet Therapy: Targeting the TxA2 Pathway

The thromboxane (Tx) A₂ pathway is a major contributor to the amplification of the initial platelet activation process. TxA₂ mediates its effect through the thromboxane prostanoid (TP) receptor that is expressed not only in platelets, but also in endothelial cells, macrophages, and monocytes, and thus contributes to the development of atherosclerotic lesions. The TxA₂ pathway is therefore a major target in the treatment of cardiovascular disease. Aspirin—the most widely used antiplatelet drug—is very effective at inhibiting platelet-derived TxA₂ synthesis. However, aspirin’s effects can be overcome by several other soluble agonists such as isoprostanes, which are aspirin-insensitive ligands of the TP receptor that are preferentially produced in diabetes mellitus. Other drugs, with either inhibitory effects on Tx synthase or antagonist effects on TP, have been developed with the hope of providing a better, more complete inhibition of the TxA₂ pathway.     

Optimal Duration of Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention: An Umbrella Review

BackgroundThe optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention with stenting requires consideration of patient characteristics, and decision makers require a comprehensive overview of the evidence.MethodsWe performed an umbrella review of systematic reviews (SRs) of randomized controlled trials of extended DAPT (> 12 months) compared with DAPT for 6 to 12 months after percutaneous coronary intervention with stenting. Outcomes of interest were death, myocardial infarction (MI), stroke, stent thrombosis, major adverse cardiac and cerebrovascular events, bleeding, and urgent revascularization. We aimed to assess the evidence of benefits and harms among clinically important subgroups (eg, elderly patients, those with diabetes, prior MI, acute coronary syndrome). We assessed the quality of the included reviews by use of A Measurement Tool to Assess Systematic Reviews (AMSTAR).ResultsSixteen SRs involving 8 randomized controlled trials were included. Most scored 7 or more points on the AMSTAR checklist. There was no significant difference in outcomes with extended DAPT compared with 6 months of DAPT in most SRs, with the exception of an increased risk of major bleeding. Compared with 12 months, extended DAPT may reduce the risk of MI and stent thrombosis; however, the findings were not consistent across all reviews. There have been conflicting reports of an increased risk of death with extended DAPT. Few SRs assessed outcomes among patient subgroups.ConclusionsExtended DAPT may reduce the risk of MI and stent thrombosis but increase the risk of major bleeding and death. Whether the effects of extended DAPT are consistent across patient subgroups is unclear, and future SRs should address this knowledge gap.     

Single vs Dual Antiplatelet Therapy Following Transcatheter Aortic Valve Implantation: A Systematic Review

There is wide variability in prescribing of antiplatelet regimens following transcatheter aortic valve implantation (TAVI). The objective of this review was to evaluate published and unpublished reports regarding the efficacy and safety of dual antiplatelet therapy (DAPT) compared with a single antiplatelet agent in patients undergoing TAVI. We searched MEDLINE, CENTRAL, Embase, and unpublished sources of literature from inception to December 2014 using terms synonymous with TAVI and DAPT. We included randomized controlled trials (RCTs) and cohort or case‐control studies that compared DAPT with a single antiplatelet agent post‐TAVI. Four articles met the inclusion criteria (2 RCTs, 2 cohort studies), of which all were deemed to be at high risk of bias, for a total of 662 patients. Compared with a single antiplatelet agent, DAPT did not significantly reduce all‐cause mortality (risk ratio: 1.22, 95% confidence interval: 0.72‐2.09, I² = 0%). Due to selective outcome reporting and variable follow‐up, other outcomes of interest could not be meta‐analyzed; however, evaluation of individual studies demonstrated no significant reduction in thrombotic events with DAPT and a similar or higher risk of bleeding. Current evidence, though limited by low methodological quality, suggests a lack of benefit and potential harm with DAPT compared with a single antiplatelet agent in patients post‐TAVI. Therefore, clinicians should evaluate the use of DAPT in patients post‐TAVI on a case‐by‐case basis until more robust evidence is available to guide practice.     

Antiplatelet Therapy in Interventional Cardiology: I. Newer Oral Antiplatelet Agents

Journal of Thrombosis and Thrombolysis -     

Combined Antiplatelet Therapy in Atrial Fibrillation:

Atrial fibrillation (AF), the most commonly encountered cardiac rhythm disorder, affects approximately 1% of the general population and is associated with serious complications, most notably ischemic stroke. AF-associated stroke occurs at an annual rate of 4.5%. Anticoagulation therapy with warfarin has been demonstrated in randomized controlled trials to reduce the risk for AF-related stroke by two thirds, but warfarin therapy is markedly underused in clinical practice because of its narrow therapeutic window and its implications on quality of life. This article reviews the present knowledge and potential future research avenues for the role of antiplatelet therapy in AF as an alternative to anticoagulation with warfarin for prevention of AF-associated stroke. Antiplatelet therapy recently has been shown to be protective against thrombotic events related to blood stasis. There is ample evidence from experimental and clinical studies that a combination of different antiplatelet agents may increase antithrombotic efficacy compared to monotherapy. Accordingly, a series of randomized controlled trials (ACTIVE [Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events]) has been designed to vigorously examine the role of combined antithrombotic therapy for prevention of vascular events, including stroke in high-risk AF patients. The ACTIVE program began patient enrollment in spring 2003. (J Cardiovasc Electrophysiol, Vol. 14, pp. S60-S63, September 2003, Suppl.)     

下肢动脉硬化闭塞腔内治疗前行抗凝及抗血小板治疗对临床预后的影响

目的　探讨术前行低分子肝素抗凝及阿司匹林抗血小板对下肢动脉硬化闭塞介入治疗患者无复流现象及疗效的影响。方法　选择126例126条肢体行介入治疗的下肢动脉硬化闭塞患者将其随机分成三组：阿司匹林组（44例）：术前3天口服阿司匹林　100　mg　qd;低分子肝素组（40例）：术前3天皮下注射低分子肝素4100　U　q12h;对照组（42例）：完善相关检查后即行手术。分别于入院时、术前、术后0　h、术后24　h测定血浆凝血酶调节蛋白（PTM）、可溶性纤维蛋白单体复合物（sFMC）、血小板α-颗粒膜糖蛋白140（　GMP-140）、D-二聚体（DD）及血浆黏度测定,术前及术后第3天测踝臂指数（ABI）,比较两组内不同时间点各项指标的变化及两组间的差异。同时记录三组术后发生患肢无复流、急性动脉血栓形成或栓塞、穿刺部位出血或血肿的例数。结果　①对照组sFMC、GMP-140、DD和血浆黏度在术后0　h显著升高（P<0.05或0.01）并达峰值,术后24　h较术后0　h有所下降,但仍明显高于术前（P<0.05或0.01）。②与对照组比较,两治疗组术前sFMC、GMP-140、DD和血浆黏度显著降低（P<0.05）。③两治疗组sFMC和血浆黏度在术后0　h、术后24　h与术前比较无明显升高（P>0.05）,而DD有显著增高（P<0.01）,但与对照组同一时间点比较升高的幅度明显降低（P<0.01）。低分子肝素组术后0　h、术后24　h　GMP-140、DD较阿司匹林组明显增高（P<0.05）。④两治疗组术后ABI与对照组同时间点比较升高幅度明显增加（P<0.05）。⑤三组患者PTM术后同术前均无明显变化（P>0.05）。⑥阿司匹林组术后发生患肢无复流及急性动脉血栓形成或栓塞率明显低于低分子肝素组及对照组（P<0.05）,三组穿刺部位出血或血肿并发症的发生率无差异。结论　动脉硬化闭塞介入治疗前行抗血小板或抗凝治疗明显降低血栓前状态,有效降低无复流及急性动脉血栓形成率,同时不增加出血并发症的发生率,抗血小板优于抗凝。     

Considerations Regarding Antiplatelet Therapy in the Elderly

Adults over the age of 65 years represent more than half of the patients living with heart disease in the United States. However, the majority of the large, multi-center, randomized clinical trials that have led to the creation of the guidelines for antiplatelet therapy have enrolled only a small number of elderly patients. This article reviews the published data on antiplatelet therapy for coronary artery and cerebrovascular disease, focusing on elderly patients. We found evidence to support the use of aspirin for both primary and secondary prevention of ischemic heart disease, and of aspirin and clopidogrel in the setting of acute coronary syndromes and for stroke prevention in patients with atrial fibrillation not on anticoagulation. Further studies are needed to characterize the benefits and risks in the elderly of prasugrel, ticagrelor and the glycoprotein IIb/IIIa inhibitors.     

奥美拉唑和泮托拉唑对氯吡格雷抗血小板效应的影响

目的:探讨在中国人群中奥美拉唑、泮托拉唑是否降低氯吡格雷的抗血小板效应.方法:接受择期冠状动脉介入治疗或药物治疗的急性冠状动脉综合征患者在常规氯吡格雷、阿司匹林治疗基础上,将患者随机分为奥美拉唑组(奥美拉唑40 mg/d,n=30)和泮托拉唑组(泮托拉唑40 mg/d,n=30),分别于治疗前及治疗后7天抽血测定血管扩张刺激磷蛋白(VASP)磷酸化水平计算血小板反应性指数(PRI)及二磷酸腺苷诱导的血小板聚集率(ADP-Ag),并观察30天的主要心血管事件.结果:两组一般资料比较差异无统计学意义(P>0.05);奥美拉唑组治疗后第7天与治疗前相比血小板聚集率及血小板反应性指数数值均显著下降,差异有统计学意义(P<0.05～0.01);泮托拉唑组治疗后第7天与治疗前相比血小板聚集率数值显著下降,差异有统计学意义(P<0.01),但血小板反应性指数与治疗前相比差异无统计学意义(P>0.05).两组组间治疗后第7天和治疗前血小板聚集率及血小板反应性指数比较差异均无统计学意义(P>0.05);两组的30天主要不良心血管事件差异无统计学意义(P>0.05).结论:奥美拉唑对双联抗血小板治疗效应无明显影响,但泮托拉唑可能具有抑制氯吡格雷的抗血小板治疗实验室效应.     

Clinical Considerations with the Use of Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention

Despite the proven benefits of using antiplatelet therapy in patients undergoing percutaneous coronary intervention (PCI), a number of key questions remain to be answered. In recent years, clopidogrel dosing strategies among such patients have evolved considerably, with newer approaches involving loading doses prior to PCI and increases in the time interval and loading dosage in an effort to overcome variable responsiveness/hyporesponsiveness to platelet inhibition. Further, the role of glycoprotein (GP) IIb/IIIa antagonists in elective stenting continues to be defined, with recent evidence suggesting that most appropriate use of these agents is in high‐risk patients with elevated troponin levels. There appears to be a relationship between the use of GP IIb/IIIa antagonists with clopidogrel loading and attenuation of early inflammatory and cardiac marker release. Strategies to minimize the chance of late stent thrombosis in patients who receive drug‐eluting stents (DES) are also under intense investigation. Among some patients receiving sirolimus and paclitaxel DES, current standard long‐term antiplatelet strategies may be insufficient. Patient nonadherence to treatment and premature discontinuation and underutilization of antiplatelet therapies by physicians remain important clinical problems with potentially dire consequences. Copyright © 2008 Wiley Periodicals, Inc.     

主动脉球囊反搏最新临床研究回顾

主动脉球囊反搏（IABP）已在临床使用数十年,但一直缺乏相关的随机临床试验证据,既往相关的研究多为非随机试验及观察性研究。在最近几年内,IABP相关的多中心随机临床实验结果相继发表,然而研究结果却与普遍理解的IABP应有的生理方面获益不相符。在急性心肌梗死合并心源性休克、ST段抬高性心肌梗死不伴休克及高危经皮冠状动脉介入治疗中,使用IABP辅助均未达到实验预期的结果。但在这些研究中使用IABP有长期获益的趋势,且实验结果提示对于部分患者,选择使用IABP可以得到临床获益且得到较好的血流动力学支持。表明对于IABP的进一步评估和临床研究应该以患者为中心制定个性化治疗方案,且使用应达到最大的生理获益。现就最近几年IABP相关的随机临床实验予以综述。     

Personalized Therapy of Hypertension: the Past and the Future

During the past 20 years, the studies on genetics or pharmacogenomics of primary hypertension provided interesting results supporting the role of genetics, but no actionable finding ready to be translated into personalized medicine. Two types of approaches have been applied: a “hypothesis-driven” approach on the candidate genes, coding for proteins involved in the biochemical machinery underlying the regulation of BP, and an “unbiased hypothesis-free” approach with GWAS, based on the randomness principles of frequentist statistics. During the past 10–15 years, the application of the latter has overtaken the application of the former leading to an enlargement of the number of previously unknown candidate loci or genes but without any actionable result for the therapy of hypertension. In the present review, we summarize the results of our hypothesis-driven approach based on studies carried out in rats with genetic hypertension and in humans with essential hypertension at the pre-hypertensive and early hypertensive stages. These studies led to the identification of mutant adducin and endogenous ouabain as candidate genetic-molecular mechanisms in both species. Rostafuroxin has been developed for its ability to selectively correct Na⁺ pump abnormalities sustained by the two abovementioned mechanisms and to selectively reduce BP in rats and in humans carrying the gene variants underlying the mutant adducin and endogenous ouabain (EO) effects. A clinical trial is ongoing to substantiate these findings. Future studies should apply both the candidate gene and GWAS approaches to fully exploit the potential of genetics in optimizing the personalized therapy.     

Prasugrel: A Novel Thienopyridine Antiplatelet Agent. A Review of Preclinical and Clinical Studies and the Mechanistic Basis for Its Distinct Antiplatelet Profile

Prasugrel (CS‐747, LY640315) is a novel member of the thienopyridine class of oral antiplatelet agents that includes ticlopidine and clopidogrel. Like other thienopyridines, prasugrel is a prodrug that is inactive in vitro. Prasugrel's distinct chemical structure permits efficient conversion to its active metabolite with a less rigorous dependence on specific cytochrome P‐450 enzymes. Prasugrel is rapidly converted in vivo to an active metabolite (R‐138727) that binds specifically and irreversibly to the platelet P2Y₁₂ purinergic receptor inhibiting ADP‐mediated platelet activation and aggregation. Preclinical studies indicated that prasugrel is approximately 10‐ and 100‐fold more potent at inhibiting ex vivo platelet aggregation and in vivo thrombus formation than clopidogrel and ticlopidine, respectively. Early clinical data in healthy subjects confirmed the greater platelet inhibition and consistency with prasugrel compared to clopidogrel. While the active metabolites of prasugrel and clopidogrel resulted in similar levels of platelet inhibition in vitro, the amount of each active metabolite generated in vivo was quite different—prasugrel (60 mg) resulting in an approximately 12‐fold greater exposure to its active metabolite compared with clopidogrel (300 mg). This observation provides a mechanistic basis for the faster, greater, and more consistent inhibition of platelet aggregation observed with prasugrel. Clinical studies in patients with cardiovascular disease confirmed the potent antiplatelet effect of prasugrel compared with clopidogrel. Collectively, these phase 1/1b studies and a phase 2 study (JUMBO‐TIMI 26) aided in dose selection for the recently completed phase 3 trial (TRITON‐TIMI 38) in patients with acute coronary syndrome undergoing percutaneous coronary intervention.