Management of antiplatelet therapy inpatients at risk for coronary StentThrombosis undergoing non-cardiac surgery

Percutaneous coronary interventions (PCIs) have become the most commonly performed coronary revascularization procedures. At the same time, there is an increased likelihood that patients with intracoronary stents will need to undergo surgery. Two serious consequences emerge from this situation: (i) stent thrombosis in relation to discontinuation of antiplatelet therapy, and (ii) major bleeding in relation to continuation of antiplatelet therapy. The best solution to overcome the risks resulting from surgery performed in patients after stent implantation is to postpone the operation until after re-endothelialization of the vessel surface is completed. Expert recommendations advise that patients can be sent for non-cardiac surgery 3 months after bare-metal stent PCI and 12 months after drug-eluting stent PCI, with continuation of aspirin therapy. Difficult decisions regarding antiplatelet management arise when a patient that is still receiving dual antiplatelet therapy with aspirin and a thienopyridine has to undergo surgery that cannot be postponed. Discussions between the treating cardiologist, the surgeon and the anaesthesiologist about this situation are recommended in order to achieve a reasonable expert consensus.     

The safety and efficacy of aspirin and clopidogrel as a combination treatment in patients with coronary heart disease

The use of aspirin and clopidogrel in combination has become part of the standard clinical care of patients with coronary artery disease. The use of this combination provides significant benefits compared with the use of aspirin alone in patients with acute coronary syndromes, and in patients treated with percutaneous coronary intervention with stent placement (both bare metal and drug-eluting stents). Clinical trials have demonstrated significant efficacy of this dual therapy; however, there is the potential for significant bleeding complications from the synergistic antiplatelet effects. In total, it appears that when there is vessel injury (mechanical from perctutaneous coronary intervention or a ruptured plaque), dual antiplatelet therapy with aspirin and clopidogrel results in improved outcomes, albeit with a small but significant inherent risk of increased bleeding.     

新一代药物洗脱支架依维莫司药物洗脱支架临床循证研究

经皮冠状动脉介入（percutaneous coronary intervention,PCI）自20世纪70年代末应用临床以来,已成为治疗冠心病主要手段之一。第一代药物洗脱支架（drug-eluting stent,DES）如雷帕霉素洗脱支架（Cypher）和紫杉醇洗脱支架Taxus）的循证医学证据表明其与金属裸支架比较,能进一步改善PCI的早期疗效,并减少再狭窄的风险。第一代DES在停止双重抗血小板治疗后出现的潜在的支架晚期血栓形成,是第一代DES最大的安全性问题。新一代DES依维莫司药物涂层支架（Xience V）具有优越的抗再狭窄疗效以及长期安全性。本文就依维莫司药物涂层支架（Xience V）的临床循证研究作一介绍。     

西洛他唑治疗经皮冠脉内介入术后对阿司匹林致上消化道出血患者的随访研究

目的观察经皮冠脉内介入术(percutaneous coronary intervention,PCI)后使用西洛他唑对阿司匹林致上消化道出血患者的外周血血小板聚集率、PGE2及心血管事件发生率的影响。方法 64例确诊冠心病并行PCI术后的患者,服用阿司匹林和氯吡格雷双重抗血小板治疗出现阿司匹林相关上消化道出血,其中32例患者改用西洛他唑加氯吡格雷,而另外32例患者出血治疗后继续原抗血小板治疗方案,随访比较两组患者血小板聚集率、PGE2及心血管事件发生率。结果平均随访(0.9±0.1)年,两组患者血小板聚集率均明显下降,西洛他唑组的血小板聚集率显著低于阿司匹林组(P<0.05),外周血PGE2的浓度高于阿司匹林组(P<0.05),但两组患者临床不良事件发生率差异无统计意义。结论对PCI术后上消化道出血患者,应用西洛他唑替代阿司匹林,联用氯吡格雷进行抗血小板治疗,经过短期的临床观察,其血小板聚集率优于阿司匹林,升高外周血PGE2的浓度,且安全性与阿司匹林相当,可用于预防上消化道出血的复发。     

An update on clinical and pharmacological aspects of drug-eluting stents

The introduction of stents to clinical practice was the major breakthrough in the field of percutaneous coronary intervention. The introduction of stents was associated with two serious complications, the first was increase in subacute thrombosis within the first 30 days of stent implantation later controlled with the use of high pressure inflation and dual antiplatelet therapy, the second was the phenomenon of in-stent restenosis that was primarily caused by smooth muscle proliferation. While coronary stenting eliminates elastic recoil, it is unable to inhibit excessive neointimal formation. Stents were associated with an increase of neointimal formation compared to balloon angioplasty as a result of excessive injury to the vessel wall and the inflammatory process from interaction of metal with vessel wall. Local delivery of the potential agents for inhibition of neointimal formation to the site of the lesion was considered the desired approach. Several compounds have been tested for stent coating, primarily with the aim of the inhibition of SMC proliferation. Recently, new stents have emerged which are loaded with anti-inflammatory, anti-migratory, anti-proliferative or pro-healing drugs. In this review article the results of clinical studies investigating drug-eluting stents are discussed from pharmacological and clinical points of view, reviewing the current literature and the future prospective.     

Stent-based delivery of antisense oligodeoxynucleotides targeted to the PDGF A-chain decreases in-stent restenosis of the coronary artery

BACKGROUND: Although the use of drug-eluting stents (DESs) has been shown to limit neointima hyperplasia, currently available DESs may adversely affect reendothelialization, possibly precipitating cardiac events. We evaluated the effect of an antisense oligodeoxynucleotide (ODN) targeted to the platelet-derived growth factor (PDGF) A-chain on in-stent restenosis in pig coronary artery. METHODS: A bare metal stent coated with phosphorothioate-linked antisense ODN or nonsense ODN, or a bare metal stent without ODN (control), was implanted in the mid segment of the left anterior descending artery (LAD). Twenty-eight days after implantation, angiography and intravascular ultrasound (IVUS) were performed, the LAD was removed, and stenosis was evaluated pathologically. RESULTS: Volumetric stenosis ratios were 64 +/- 11.9, 44 +/- 3.4, and 26 +/- 3.8% in coronary arteries implanted with control, nonsense ODN-coated, and antisense ODN-coated stents, respectively. In angioscopic findings, the lumen surface was smooth in the stented segments in all groups. Struts of antisense ODN-coated stents were observed embedded in the neointima, whereas embedding was not observed in nonsense ODN-coated stents or control stents, indicating a decrease in hyperplasia in response to antisense ODN treatment. Pathologic findings showed 77 +/- 5.8, 68 +/- 12.2, and 38 +/- 5.3% stenosis in coronary arteries implanted with control stents, nonsense ODN-coated stents, and antisense ODN-coated stents, respectively. A continuous lining of endothelial cells was observed along the lumen of coronary arteries implanted with antisense ODN-coated stents. CONCLUSIONS: Stent-based delivery of an antisense ODN targeted to the PDGF A-chain effectively inhibits neointima formation after stent implantation in pig coronary artery by suppressing VSMC hyperplasia and preserving endothelialization. Antisense-ODNs may provide a therapy for in-stent restenosis of the coronary artery.     

杂交技术在治疗冠心病多支病变中的应用

目的探讨胸骨下段小切口非体外循环下冠状动脉旁路移植术联合经皮冠状动脉支架植入术(杂交技术)在治疗冠心病多支病变中的临床价值。方法 21例冠心病患者中,两支冠脉血管病变4例,三支冠脉血管病变17例;均采用杂交技术进行心肌再血管化。采用胸骨下段小切口,在非体外循环下行左乳内动脉至前降支吻合;其余狭窄冠脉血管行药物涂层支架植入。结果 21例患者共植入支架38个,平均每例心肌再血管化2.6支,手术均成功,无围术期心肌梗死及手术死亡。患者术后平均ICU观察时间为26.2h,术后平均住院时间9d。随访2-16个月,所有患者均无心绞痛症状发作。结论杂交技术治疗冠心病多支病变近、中期疗效确切。     

Potential Interaction between Clopidogrel and Proton Pump Inhibitors

Clopidogrel is widely used in patients with acute coronary syndromes and following percutaneous coronary intervention with stent implantation. The antiplatelet action of clopidogrel is felt to be of critical importance for the reduction of abrupt thrombotic occlusion of stents, particularly with drug-eluting devices. When clopidogrel is used alone or in combination with aspirin (acetylsalicylic acid), the benefits of antiplatelet therapy must be weighed against the potential for serious bleeding, particularly gastrointestinal (GI) bleeds. To minimize the risk of GI injury, proton pump inhibitors (PPIs) are considered the drugs of choice. However, a growing body of evidence suggests that PPIs may adversely interact with clopidogrel, diminishing the antiplatelet effect. Although the current evidence remains controversial, the potential for increased risk of thrombotic complications warrants cautious use of this drug combination until further research can determine the extent of this interaction and whether it is a drug-class effect.     

Emerging antiplatelet therapy for coronary artery disease and acute coronary syndrome

Antiplatelet therapy is used widely with proven benefit for the prevention of further ischemic cardiac complications in patients with known coronary artery disease (CAD) and a history of acute coronary syndrome (ACS). The limitations of conventional antiplatelet therapy with aspirin, clopidogrel, or prasugrel, as well as the fact that rates of recurrent ischemic events still remain high with use of these agents, underscore the need to investigate alternate agents that may further reduce event rates while limiting bleeding risk. The selection of antiplatelet therapy is further influenced by the following: ticagrelor was approved in July 2011 by the United States Food and Drug Administration (FDA), and clopidogrel is slated to become available as a generic productin 2012. We provide an overview of emerging agents for the treatment of CAD and ACS, including the reversible P2Y(12) antagonists ticagrelor, cangrelor, and elinogrel, and a new class of oral protease-activated receptor-1 (PAR-1) inhibitors, vorapaxar and atopaxar.The recently approved P2Y(12) antagonists prasugrel and ticagrelor demonstrate enhanced ability to prevent adverse cardiac outcomes. However, this comes at a cost of a potential increased risk of bleeding. New adverse effects have also emerged, including dyspnea for all of the reversible P2Y(12) antagonists (ticagrelor, cangrelor, and elinogrel) and ventricular pauses for ticagrelor. In addition, the newer P2Y(12) antagonists have a faster onset and offset. Two of these agents, cangrelor and elinogrel, are available as intravenous formulations, which may provide additional benefits in patients who undergo coronary artery bypass graft (CABG) surgery. Trials with the PAR-1 inhibitors have also shown trends toward reductions in cardiac events, but not without the possibility of increased bleeding. More than ever, as the arsenal of antiplatelet therapy expands, health care providers need to understand the pharmacologic and pharmacodynamic differences between conventional and emerging antiplatelet therapies for patients with ACS and CAD. Health care providers must also carefully assess patient-specific factors such as risk of thrombosis, concomitant disease states, age, drug adherence, and aspirin dose, and plan for those patients who will be undergoing CABG when selecting antiplatelet therapy in order to optimally balance bleeding and thrombosis risk.     

Stent thrombosis and duration of dual antiplatelet therapy

Stent thrombosis (ST) is a rare complication following coronary stenting; however given the associated serious consequences, in particular death and myocardial infarction, it remains a source of considerable concern for cardiologists. Although no differences have been found between drug-eluting stents (DES) and bare-metal stents (BMS) in terms of early ST, some studies have reported adverse outcomes associated with DES as compared to BMS at long-term follow-up. Delayed endothelial coverage of the stent struts, inflammation and local hypersensitivity due to the interaction between the drug and polymer coating have been characterized to be typical for DES compared to BMS and may prolong the window of vulnerability to ST. Consequently the recommended duration of dual antiplatelet therapy (DAT) was longer with DES than with BMS. Results from studies investigating the optimal duration of DAT remain inconclusive and the current recommendation seems to be that patients undergoing DES implantation should have DAT for at least 6-12 months. Our treatment strategy requires more detailed analysis and should improve as we understand more about the impact of the newer generation DES and variability in antiplatelet therapy response, in addition to the effects of novel therapeutic agents and the availability of more data on the optimum duration of DAT.     

Oral antiplatelet therapy and percutaneous coronary intervention

The benefit of oral antiplatelet therapy following percutaneous coronary intervention (PCI) with intracoronary stent implantation is well established. Combined aspirin with clopidogrel or ticlopidine therapy is superior to aspirin alone in reducing thrombotic events after stent placement. Clopidogrel is the drug of choice, given that its efficacy is comparable to ticlopidine and it has a superior safety profile. Despite dual antiplatelet therapy, patients remain at risk of recurrent vascular events. Optimal timing, duration and dosage of antiplatelet therapy remain controversial. Recent evidence suggests additional benefit with clopidogrel pretreatment, high clopidogrel loading dose and long-term dual antiplatelet therapy post-PCI in high-risk patients.     

植入药物洗脱支架后短期与长期双联抗血小板疗效比较的Meta分析

目的 评价短期（3～6个月）与长期（12个月）双联抗血小板治疗对冠状动脉药物洗脱支架植入后的临床效果。方法 研究病例包括稳定性心绞痛、急性冠脉综合征、无症状心肌缺血,均为原位血管病变。临床观察终点为：全因死亡、心源性死亡、心肌梗死、卒中、支架内血栓形成、靶病变再血管化治疗、严重出血、净不良临床事件（net adverse clinical event）。通过检索Pubmed、中国生物医学文献等中、英文数据库及手工检索,对符合条件的随机对照研究经质量评估、数据提取,进行Meta分析。结果 共计纳入12项随机对照研究。Detsky评分均大于5分。共计25 949个病例,随访率97.9%。两组在全因死亡（OR=0.86,95%CI 0.71～1.05,P=0.14）、心源性死亡（OR=0.94,95% CI 0.70～1.25,P=0.67）、支架血栓形成（OR=1.36,95%CI 0.94～1.98,P=0.11）、卒中（OR=1.01,95%CI 0.71～1.42,P=0.98）、靶病变再血管化（OR=0.121,95%CI 0.94～1.55,P=0.14）及净不良临床事件（OR=0.98,95%CI 0.83～1.14,P=0.75）均无明显差别;短期组随访期间心肌梗死发生率高于长期组（OR=1.27,95%CI 1.02～1.59,P=0.04）,长期组严重出血的比例明显增加（OR=0.69,95%CI 0.50～0.95,P=0.02）。亚洲人群研究结果：长期治疗组全因死亡高于短期组（OR=0.72,95%CI 0.53～0.97,P=0.03）,两组严重出血无明显差别。结论 依据限定的临床观察终点,短期双联抗血小板疗效不劣于长期组;7项亚组人群研究,长期组全因死亡率高,不排除与样本量偏少产生的偏移及（或）人群的个体差异有关,结果还有待进一步验证。此结果可作为临床工作警示,依据患者出血风险及冠状动脉病变结果个体化调整双联抗血小板周期。     

Sirolimus-eluting coronary stent.

PURPOSE: The mechanism of action and pharmacokinetics of sirolimus when used as part of a drug-eluting stent (DES) and the efficacy and cost of using DESs versus bare-metal stents are discussed. SUMMARY: The use of balloon angioplasty with or without coronary artery stenting is limited by the phenomenon of in-stent restenosis (ISR). Until very recently, most efforts to overcome ISR had been ineffective. The search to prevent or reduce the frequency of ISR has led to the recent development of novel coronary artery stents designed to deliver a drug that acts locally. The first DES was approved by FDA in April 2003. This stent releases sirolimus, an agent that inhibits vascular smooth-muscle-cell proliferation. To date, four major clinical trials have demonstrated the sirolimus-eluting stent to be safe and effective in preventing restenosis in de novo coronary artery lesions. CONCLUSION: The sirolimus-eluting coronary stent is associated with less ISR than non-drug-containing stents, but further investigation is needed to determine its exact place in the treatment of coronary artery occlusion.     

Triple antithrombotic therapy in patients with atrial fibrillation who have undergone percutaneous coronary intervention with stent implantation

Purpose The efficacy and safety of triple antithrombotic therapy in patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) with stent implantation are reviewed. Summary A systematic literature search of PubMed, EMBASE, and International Pharmaceutical Abstracts identified a total of 10 cohort studies and one meta-analysis investigating triple antithrombotic therapy in this patient population. With respect to efficacy, evidence from nonrandomized studies supports the superiority of triple antithrombotic therapy over dual antiplatelet therapy at preventing major adverse cardiac events and all-cause mortality. With respect to safety, the heterogeneous methodology and definitions for bleeding in the studies do not allow for easy interpretation and quantification of bleeding risk. There appears to be qualitative consistency that the rate of bleeding is higher with triple antithrombotic therapy compared with dual antiplatelet therapy. The meta-analysis, as well as a recent large registry data cohort study, demonstrated a twofold increase in the risk of major bleeding with triple antithrombotic therapy. Conclusion The heterogeneous methodology of the available studies does not allow for conclusive interpretation and quantification of the efficacy and safety of triple antithrombotic therapy in patients with AF undergoing PCI with stent implantation compared with dual antiplatelet therapy. Evidence from small cohort studies support the benefit of triple antithrombotic therapy at reducing major adverse cardiac events and all-cause mortality with higher rates of bleeding.     

Drug-eluting stents for acute myocardial infarction

This is a review of the literature comparing the efficacy and safety of drug-eluting stents (DES) versus bare-metal stents (BMS) in patients with acute myocardial infarction (MI). The present article reviews whether DES are beneficial in the setting of primary percutaneous coronary intervention (PCI), and this has been the subject of many recent publications and debate among clinicians. To the best of our knowledge there are limited registries and randomized trials about DES for acute MI in the English literature. Bare-metal stents have a higher incidence of instent restenosis whereas DES might have a slightly higher late thrombosis risk. With the current data DES might still have an advantage over BMS in the treatment of ST-segment elevation MI (STEMI) patients with the vastly improved target vessel revascularization rates. Despite the lack of well-designed head-to-head long-term prospective clinical trials, DES may not be effective in patients who are on short-term dual antiplatelet therapy owing to an increased risk of late stent thrombosis. In conclusion, DES use in STEMI patients continuing long-term dual antiplatelet therapy is safe and effective.     

新型抗血小板药坎格瑞洛的国外研究现状

新型抗血小板药物坎格瑞洛是首个速效、静脉使用的抗血小板药物,可逆性地与P2Y12受体结合,发挥抗血小板作用,与传统的抗血小板药物氯吡格雷相比,其起效迅速、半衰期短,已广泛应用于需要进行冠脉介入治疗(PCI)的急性冠脉综合征(ACS)患者和心源性休克患者中.CHAMPION试验以患者死亡、心肌梗死和心肌缺血导致的血管重建...     

新型P2Y12受体抑制剂替格瑞洛临床研究进展

抗血小板药物是急性冠脉综合征（Acute Coronary Syndrome,ACS）治疗的基石,对防治心肌缺血和介入并发症是有益的。目前治疗ACS和经皮冠状动脉介入治疗（percutaneous coronary intervention,PCI）指南推荐使用的口服抗血小板药物包括氯吡格雷、替格瑞洛、普拉格雷联合阿司匹林双重抗血小板治疗预防复发性缺血事件。本文对新型P2Y12受体抑制剂替格瑞洛的药代动力学和药效学特点以及在ACS患者中的循证医学证据作一介绍。     

不同冠心病患者药物涂层支架置入术后双抗血小板疗程的Meta分析

目的：系统评价不同冠心病患者药物涂层支架置入术后双抗血小板疗程的有效性和安全性。方法：检索MEDLINE、EMBASE和Cochrane Library数据库,获得冠心病患者药物涂层支架置入术后不同疗程双抗血小板治疗的随机对照试验,采用RevMan 5.2软件分别对性别、年龄、冠心病类型、是否合并糖尿病及置入不同药物涂层支架患者短疗程相对长疗程双抗血小板治疗的有效性和安全性进行Meta分析。结果：共检索到文献4 322篇,最终纳入9个随机对照试验,共30 244例患者。Meta分析显示非老年患者[RR 1.42,95%CI（1.20~1.70）]、置入紫杉醇[RR 1.70,95%CI（1.26~2.29）]和西罗莫司药物涂层支架[RR 1.71,95%CI（1.07~2.74）]的患者短疗程相对长疗程可增加未合并出血的主要复合终点发生率,而不同性别、老年患者、冠心病类型、是否合并糖尿病及置入依维莫司和佐他莫司药物涂层支架的患者短疗程相对长疗程双抗血小板治疗的主要复合终点发生率无显著性差异。结论：临床在为冠心病患者制定药物涂层支架置入术后双抗血小板疗程时应结合患者个体情况进行综合评估,对于非老年患者、置入紫杉醇和西罗莫司药物涂层支架的患者可在指南推荐的基础上适当延长双抗血小板疗程。     

Prasugrel during primary percutaneous coronary intervention: evidence from clinical data

Primary percutaneous coronary intervention (PCI) encompassing stent implantation is a mainstay in the management of acute ST-elevation myocardial infarction (STEMI). Despite refinements in techniques and devices, peri- and post-procedural antithrombotic therapy remains pivotal to prevent early and late thrombotic events, without unduly increasing bleeding risk. Concomitant dual antiplatelet therapy with aspirin and clopidogrel has been considered until recently the standard of care in terms of oral antiplatelet agents. However, most recently a novel and more potent thienopyridine, prasugrel, has been tested in randomized trials including patients with STEMI, and subsequently approved for clinical practice in Europe and North America. Despite its potent antithrombotic effect, prasugrel also carries a statistically significant increase in the risk of bleeding, especially in the elderly, those with low body weight, and previous stroke or transient ischemic attack. Thus, the use of prasugrel, as well as that of clopidogrel or ticagrelor, should best be individualized to maximize clinical benefits and minimize hazards.     

药物洗脱支架置入对糖尿病并发冠心病患者不良心血管事件的影响

目的评价药物洗脱支架置人对糖尿病并发冠心病患者不良事件的影响。方法对600例行药物洗脱支架植入术的患者进行随访,其中糖尿病患者147例。通过随访术后主要不良心血管事件（包括死亡,非致死性心肌梗死,再次靶病变血运重建和再次靶血管血运重建）和支架内再狭窄的发生率评价药物洗脱支架在糖尿病患者中的疗效。结果糖尿病患者和非糖尿病患者术后的主要不良心血管事件（7．9％与4．9％,P=0．344）和支架内再狭窄（6．0％与4．9％,P=0．540）发生率之间差异元统计学意义。糖尿病患者植入Cypher和TAXUS支架后主要不良心血管事件（7．9％与4．9％,P=0．344）和支架内再狭窄（1．4％与1．9％,P=1．000）发生率之间差异无统计学意义。结论糖尿病患者使用药物洗脱支架是安全有效的,且Cypher和TAXUS两种支架在糖尿病患者中疗效差异无统计学意义。