非瓣膜性房颤患者应用利伐沙班出血危险因素分析

摘要：目的:分析非瓣膜性房颤患者服用利伐沙班发生出血的危险因素。方法:收集2017年3～6月201例使用利伐沙班抗凝治疗的拟行射频消融术的非瓣膜性住院患者资料,记录患者年龄、性别、既往史,以及C反应蛋白、血糖、肝肾功能、心功能指标、合并疾病及联合用药等信息。采用单因素方差分析和多因素回归分析方法评估相关出血危险因素。结果:在所有纳入研究的患者中住院期间共有23例(11.4%)发生了出血,178例(88.6%)未发生出血,利伐沙班引起的出血发生率为11.4%(23/201)。研究发现合并冠心病与利伐沙班引起的出血事件有显著的相关性[P=0.001,OR=4.013,95%CI(1.634,9.859)],此外,联合应用阿司匹林[P=0.001,OR=5.111, 95%CI(1.961,13.319)]或氯吡格雷[P=0.001,OR=5.490,95%CI(2.150,14.017)],其出血风险会显著增加。合用氯吡格雷[P=0.029,OR=3.281, 95%CI(1.129,9.531)]和凝血酶原时间(PT)>13.0 s[P=0.034,OR=2.914,95%CI(1.082,7.851)]可显著增加利伐沙班相关的出血风险。结论:合并冠心病和联用抗血小板药物(阿司匹林、氯吡格雷)与利伐沙班引起的出血事件有显著的相关性。多因素回归分析发现,联用氯吡格雷和PT>13.0 s是非瓣膜性房颤患者应用利伐沙班发生出血的独立危险因素。     

基于CYP2C19基因多态性选择抗血小板药物对急性冠状动脉综合征或经皮冠状动脉介入治疗患者主要心血管事件和出血风险影响的Meta分析

摘要：目的:系统评价基于CYP2C19基因多态性选择抗血小板药物对急性冠状动脉综合征（ACS）或经皮冠状动脉介入治疗（PCI）患者主要心血管事件（MACE）和出血事件发生率的影响。方法:计算机检索PubMed、EMbase、The Cochrane Library、CNKI、WanFang Data和Clinicaltrials.gov数据库,搜集评估ACS或PCI患者基于CYP2C19基因指导用药和传统方法选择抗血小板药物治疗的研究,检索时限均为从建库至2022年2月21日。由两位评价员独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan 5.3软件进行Meta分析。结果:共纳入11篇文献,包括8 120例患者。Meta分析结果显示,与基于传统方法选择抗血小板药物治疗组比较,基因指导用药组能够明显降低MACE发生率[RR=0.66,95%CI（0.52,0.85）,P=0.001],尤其是显著降低死亡事件发生率[RR=0.73,95%CI（0.55,0.98）,P=0.04]、心肌梗死发生率[RR=0.56,95%CI（0.42,0.75）,P=0.000 1]、支架内血栓事件发生率[RR=0.49,95%CI（0.29,0.83）,P=0.008],但是两者靶向血管重建事件发生率[RR=0.88,95%CI（0.64,1.21）,P=0.43]以及卒中发生率[RR=0.60,95%CI（0.35,1.04）,P=0.07]差异无统计学意义。此外与按照传统方法选择抗血小板药物治疗组相比,基于CYP2C19基因多态性选择抗血小板药物组还能明显降低出血事件发生率[RR=0.83,95%CI（0.70,0.99）,P=0.04]。结论:基于CYP2C19基因多态性选择抗血小板药物能够显著降低ACS或PCI患者MACE发生率和出血风险。但上述结论仍需更高质量的多中心随机对照试验予以验证。     

冠心病患者个体化抗血小板治疗有效性和安全性的系统评价

目的:系统评价冠心病患者根据实验室检测结果进行个体化抗血小板治疗的有效性和安全性,为临床个体化抗血小板治疗提供参考。方法:计算机检索PubMed、Embase和Cochrane图书馆,检索时限为各数据库建库起至2018年2月,收集冠心病患者基于实验室检测结果进行个体化抗血小板治疗对比常规抗血小板治疗的随机对照试验(RCT),提取资料并按照Cochrane系统评价员手册5.2.0进行质量评价后,采用Rev Man 5.3统计软件对主要心血管不良事件、全因死亡、心血管死亡、心肌梗死、支架血栓、卒中、严重出血等指标的发生率进行Meta分析,并对不同种族、实验室检测方法和干预疗程进行亚组分析。结果:共纳入7项RCT,合计8 615例患者。Meta分析结果显示,与常规抗血小板治疗方案相比,基于实验室检测结果的个体化抗血小板治疗患者的主要心血管不良事件[RR=0.93,95%CI(0.74,1.16),P=0.51]、全因死亡[RR=0.89,95%CI(0.56,1.41),P=0.61]、心血管死亡[RR=0.68,95%CI(0.36,1.25),P=0.21]、心肌梗死[RR=1.03,95%CI(0.92,1.16),P=0.56]、支架血栓[RR=0.52,95%CI(0.22,1.24),P=0.14]、卒中[RR=1.03,95%CI(0.65,1.63),P=0.90]和严重出血[RR=0.78,95%CI(0.53,1.14),P=0.20]发生率均无显著性差异。亚组分析结果显示根据CYP2C19基因型进行个体化给药可显著降低主要心血管不良事件发生率[RR=0.29,95%CI(0.14,0.64),P=0.002]和全因死亡发生率[RR=0.11,95%CI(0.01,0.87),P=0.04],而干预疗程达6个月可显著降低全因死亡发生率[RR=0.11,95%CI(0.01,0.87),P=0.04],其余亚组分析中两组患者的各项指标比较,差异均无统计学意义。结论:与常规抗血小板治疗方案相比,对于冠心病患者基于实验室检测结果进行个体化抗血小板治疗并不能显著降低主要心血管不良事件和出血的发生风险。虽然亚组分析显示根据CYP2C19基因型进行个体化给药可显著减少主要心血管不良事件和心血管死亡的发生风险,但该结论尚需更多大样本、高质量研究证实。     

替格瑞洛和氯吡格雷治疗携带CYP2C19功能缺失等位基因的轻度缺血性卒中或短暂性脑缺血发作患者有效性和安全性的系统评价

目的 系统评价替格瑞洛和氯吡格雷治疗携带CYP2C19功能缺失等位基因的轻度缺血性卒中或短暂性脑缺血发作患者的有效性和安全性。方法 系统检索PubMed、Embase、the Cochrane Library、CNKI、万方数据库等数据库,检索时限均为从建库至2022年6月。由2名研究者独立筛选文献、提取资料并评价纳入研究的方法学质量,使用RevMan 5.3软件进行Meta分析。结果 共纳入2篇研究,7087例患者。与氯吡格雷比较,替格瑞洛降低携带CYP2C19 LOF等位基因的轻度缺血性卒中或短暂性脑缺血发作患者卒中[RR=0.78,95%CI（0.66-0.93）,I2=0%,P=0.007]和血管事件发生率[RR=0.78,95%CI（0.66-0.91）,I2=0%,P=0.002]。替格瑞洛-阿司匹林组任何出血[HR=2.18,95%CI（1.66-2.85）]和小出血[HR=2.41,95%CI（1.81-3.20）]发生率高于氯吡格雷-阿司匹林组,且替格瑞洛-阿司匹林组呼吸困难（1.2% vs 0.2%,P<0.001）和心律失常（1.7% vs 0.8%,P=0.001）发生率比氯吡格雷-阿司匹林组更常见;两组严重出血发生率差异无统计学意义。结论 与氯吡格雷比较,替格瑞洛降低携带CYP2C19 LOF等位基因的轻度缺血性卒中或TIA患者卒中和血管事件发生率,且不增加严重出血风险;但替格瑞洛组小出血、呼吸困难和心律失常发生率高。     

CYP2C19*17基因对氯吡格雷临床疗效影响的Meta分析

目的:系统评价CYP2C19*17基因对氯吡格雷临床疗效的影响。方法:分别对EMBase、PubMed、Cochrane图书馆、中国生物医学文献数据库(CBM)以及中国期刊网数据库(CNKI)等进行文献检索,用ReviewsManager5.1系统进行数据分析。结果:共纳入5篇文献,包含6项研究,合计29499例患者。Meta分析结果显示,CYP2C19*17携带者在使用氯吡格雷后,心血管事件发生率显著低于非携带者[RR=0.82,95%CI(0.73,0.93),P=0.001];出血事件发生率高于非携带者[RR=1.20,95%CI(1.01,1.42),P=0.03]。结论:在使用氯吡格雷的心血管疾病患者中,与CYP2C19*17非携带者比较,心血管事件发生率在CYP2C19*17携带者中较低,而出血性事件的发生率则较高。因此,CYP2C19*17携带者在使用氯吡格雷时应谨防出血性事件的发生,基因检测有助于完善个体化合理用药。     

阿司匹林在动脉硬化性心脑血管疾病中的应用调查研究

<正>大量的循证医学证明,在心血管高危患者中抗血小板药物阿司匹林长期治疗能够使严重心血管联合终点事件发生率降低约1/9,其中致死性心肌梗死的危险减低1/3,非致死性卒中的危险减低1/4,血管事件病死率减低1/6,在无动脉硬化性心脑病史的患者中,阿司匹林治疗能够使血管事件的总发生率下降15%,心肌梗死和冠心病死亡的危险性总体降低23%,其中有血管病史的患者降低31%,有糖尿病史的患     

PCI 术后三联与双联抗凝策略疗效比较的 Meta 分析

目的 比较双联 （阿司匹林、 氯吡格雷） 与三联 （阿司匹林、 氯吡格雷、 华法林） 抗血小板聚集方案治疗同时 有应用口服抗凝药物（OAC）及双联抗血小板聚集药物（DAPT）指征患者的疗效与安全性。方法 检索 PubMed、 Cochrane、 Embase 数据库, 收集 1966 年 1 月—2016 年 4 月发表的有 OAC 及 DAPT 应用指征的患者抗凝药物使用的 疗效和安全性比较的研究, 同时辅以手检纳入文献的参考文献。对文献进行筛选、 质量评价与资料提取, 采用 RevMan 5.1 软件进行 Meta 分析, 主要终点事件为全因死亡率, 次要终点事件包括缺血性卒中、 主要出血事件、 心肌 梗死以及支架内血栓形成。结果 共纳入 16 项研究, 共 7 083 例患者（三联 3 330 例, 双联 3 753 例）, 中位随访期 1.6 年, 平均年龄 73.2 岁。Meta 分析显示： 三联抗凝与双联抗凝策略相比, 全因死亡率[OR（95%CI） =0.94（0.79～ 1.13）, P=0.54]、 心肌梗死发生率[OR（95%CI） =1.21（0.92～1.59）, P=0.16]、 支架内血栓事件发生率[OR（95%CI） =1.02 （0.55～1.90）, P=0.94]差异均无统计学意义, 相对于采取双联抗凝策略的患者, 应用三联抗凝策略能降低缺血性卒中 风险[OR（95%CI） =0.44（0.30～0.63）, P＜0.001], 增加主要出血事件风险[OR（95%CI） =1.31（1.07～1.61）, P=0.008]。 结论 针对同时具有应用 OAC 及 DAPT 指征的患者, 使用三联抗凝策略在降低卒中风险的同时会增加出血的风险。     

基于Meta分析的基因检测指导对个体化抗血小板治疗有效性和安全性研究

摘要：目的:系统评价基因检测指导的个体化抗血小板治疗与常规治疗比较在急性冠状动脉综合征（ACS）或接受经皮冠状动脉介入治疗（PCI）患者中的有效性和安全性。方法:计算机检索PubMed、Cochrane Library、Embase、Web of Science、CNKI、 WanFang Data、SinoMed数据库及中国临床试验注册中心（ChiCTR）,搜集有关ACS或行PCI术的患者基因检测指导的个体化抗血小板治疗与常规抗血小板治疗比较的随机对照试验（RCT）,检索时限均为从建库至2021年5月10日。由两位评价员独立筛选文献、提取资料并评价纳入研究的偏倚风险后,采用RevMan 5.3软件进行Meta分析。结果:共纳入5个RCT,累计6 329例患者。Meta分析结果显示,与常规抗血小板治疗相比,基因检测指导的个体化抗血小板治疗可降低心肌梗死发生率[RR=0.57,95%CI（0.42,0.78）,P<0.01]和支架内血栓形成发生率[RR=0.45,95%CI（0.25,0.80）,P<0.01],两组的主要不良心血管事件（MACE）发生率[RR=0.73,95%CI（0.50,1.07）,P=0.11]、全因死亡发生率[RR=0.82,95%CI（0.41,1.63）,P=0.57]、任意出血发生率[RR=0.84,95%CI（0.58,1.23）,P=0.37]、心血管死亡率[RR=0.78,95%CI（0.54,1.13）,P=0.19]和卒中发生率[RR=0.70,95%CI（0.38,1.27）,P=0.23]差异均无统计学意义;在安全性方面,两组大出血发生率差异无统计学意义[RR=0.88,95%CI（0.64,1.23）,P=0.46],但基因指导治疗组可降低小出血发生率[RR=0.74,95%CI（0.59,0.94）,P=0.01]。结论:基因检测指导的个体化抗血小板治疗相比于常规治疗虽未明显降低患者MACE、全因死亡、心血管死亡、卒中和任意出血、大出血等风险,但在降低患者心肌梗死、支架内血栓、小出血风险方面更有优势。基因检测指导的个体化抗血小板治疗方案可能更适合高危冠心病患者。     

经导管主动脉瓣置换术后双联抗血小板用药时间对术后并发症疗效和安全性影响的Meta分析

目的:系统评价经导管主动脉瓣置换术(TAVI)后双联抗血小板用药时间对术后并发症疗效和安全性的影响,为TAVI术后抗血小板治疗方案的制订提供循证参考。方法:计算机检索Cochrane临床对照试验注册中心、PubMed、Embase、Web of Science、万方数据以及中国期刊全文数据库,检索时限均为建库起至2019年2月,收集双联抗血小板用药时间对TAVI术后并发症疗效(全因死亡率及脑卒中事件发生率)和安全性(大出血事件发生率)影响的随机对照试验(RCT)和观察性研究。对符合纳入标准的临床研究进行资料提取后,采用Cochrane偏倚风险评价工具5.1.0(RCT)或纽卡斯尔-渥太华量表(观察性研究)进行质量评价,采用Rev Man 5.3及Stata 14.0统计软件进行Meta分析,并针对各结局及不同用药时间进行Meta回归分析。结果:共纳入3项RCT、10项观察性研究,合计2 868例患者。Meta分析结果显示,用药后1个月和6个月的全因死亡率分别为0.05[95%CI(0.03,0.07),P<0.001]、0.07[95%CI(0.05,0.08),P<0.001];用药后1个月、3个月、6个月的大出血事件发生率分别为0.14[95%CI(0.08,0.19),P<0.001]、0.11[95%CI(0.03,0.19),P=0.007]、0.13 [95%CI(0.05,0.22),P=0.002];用药后1个月的脑卒中事件发生率为0.04[95%CI(0.03,0.05),P<0.001]。Meta回归分析结果显示,用药后6个月内的全因死亡率[回归系数=0.005 7,95%CI(-0.001 6,0.013 0),P=0.116]、大出血事件发生率[回归系数=-0.000 5,95%CI(-0.022 4,0.021 4),P=0.959]、脑卒中事件发生率[回归系数=0.001 4,95%CI(-0.003 8,0.006 5),P=0.570]与双联抗血小板治疗方案的用药时间均无相关性。结论:延长双联抗血小板治疗方案的用药时间对增加TAVI术后并发症的治疗效果无明显影响,对安全性也无明显影响。     

免疫调节药物治疗多发性骨髓瘤发生深静脉血栓风险的系统评价和Meta分析

目的:系统评价免疫调节药物(IMiDs)治疗多发性骨髓瘤(MM)发生深静脉血栓(DVT)的风险,为临床安全用药提供参考。方法:计算机检索自建库起至2018年12月31日PubMed、Web of Science、Cochrane图书馆、中国期刊全文数据库、万方数据、中文科技期刊数据库、www.ClinicalTrials.gov中有关IMiDs治疗MM患者发生DVT风险的随机对照试验(RCT)。使用Stata 12.0统计软件对DVT发生率和相对危险度(RR)进行Meta分析,使用GRADE系统对所得证据进行评估分级。结果:共纳入11项RCT,合计3 365例患者(其涉及3种药)。Meta分析结果显示,使用IMiDs治疗MM时DVT的发生率为7.3%[95%CI(4.5%,10.2%)]。与常规化疗相比,IMiDs治疗MM发生DVT的风险更高[RR=3.57,95%CI(2.42,5.27),P<0.01]。不同治疗阶段的亚组分析显示,IMiDs治疗诱导阶段MM患者后,DVT发生的风险较常规化疗方案增加386%[RR=4.86,95%CI(2.85,8.30),P<0.01],该证据级别为中等;与常规化疗方案相比,IMiDs在维持阶段[RR=2.40,95%CI(0.70,8.27),P=0.16]和复发阶段[RR=2.01,95%CI(0.74,5.46),P=0.17]治疗MM患者DVT发生风险无显著性差异。沙利度胺、来那度胺致DVT发生率分别为11%[95%CI(9%,13%)]、3%[95%CI(2%,4%)]。结论:现有证据表明,IMiDs在MM治疗发生DVT的风险较高,临床用药需关注。     

Primary and secondary stroke prevention with antiplatelet drugs

Aspirin is not effective in the primary prevention of stroke. Patients with TIA or ischemic stroke carry a risk of recurrent stroke between 5 and 20% per year. In patients with TIA or ischemic stroke of noncardiac origin antiplatelet drugs are able to decrease the risk of stroke by 11-15% and the risk of stroke, MI and vascular death by 15-22%. Aspirin is the most widely used drug. It is affordable and effective. Low doses of 50-325 mg aspirin are as effective as high doses and cause less gastrointestinal side effects. Severe bleeding complications are dose-dependent. The combination of aspirin with slow release dipyridamole is superior to aspirin alone for stroke prevention. Clopidgrel is superior to aspirin in patients at high risk of recurrence. The combination of aspirin plus clopidogrel is not more effective than clopidogrel alone but carries a higher bleeding risk. None of the antiplatelet agents is able to reduce mortality.     

Antiplatelet therapy in cerebrovascular disorders

Antiplatelet treatment is a mainstay in acute and long-term secondary stroke prevention. Aspirin is still most widely used worldwide, however, there is increasing evidence from small randomised trials that dual antiplatelet therapy combining aspirin with dipyridamole or clopidogrel might be more effective in the acute and early chronic post-ischemic phase (i.e. first 90 days). Both clopidogrel and the combination of aspirin and extended-release dipyridamole are recommended by current guidelines in long-term secondary stroke prevention in patients who are at high risk for a recurrent ischemic stroke, since they are more effective compared with aspirin monotherapy.Antiplatelet agents are the therapy of choice in patients with ischemic stroke due to intracranial stenosis and patent foramen ovale. In contrast, oral anticoagulation is clearly superior to single or double antiplatelet therapy in patients with cardioembolic stroke, mainly caused by atrial fibrillation.Concerning newer antiplatelet agents, only cilostazol appears to be a promising therapeutic option in patients with ischemic stroke in the near future, but so far, only studies in Asian stroke patients have been performed.     

Combination antiplatelet agents for secondary prevention of ischemic stroke

Stroke is a leading cause of death and the primary cause of serious, long-term disability in the United States. Joint guidelines from the American Heart Association (AHA) and American Stroke Association (ASA), as well as recent guidelines from the Eighth American College of Chest Physicians (ACCP) Conference on Antithrombotic and Antiplatelet Therapy, recommend aspirin, clopidogrel, or extended-release dipyridamole plus aspirin as acceptable first-line options for secondary prevention of ischemic events in patients with a history of ischemic stroke or transient ischemic attack (TIA). The ACCP strongly recommends the combination of extended-release dipyridamole plus aspirin over aspirin monotherapy (highest level of evidence) and suggests clopidogrel monotherapy over aspirin monotherapy (lower level of evidence). The AHA-ASA guidelines suggest that either extended-release dipyridamole plus aspirin or clopidogrel monotherapy should be used over aspirin monotherapy. Both guidelines recommend avoiding the combination of clopidogrel and aspirin for most patients with previous stroke or TIA. Results from recent trials evaluating combination antiplatelet therapy have been published that enhance the AHA-ASA recommendations and provide the foundation for the updated ACCP guideline. To identify pertinent combination antiplatelet trials, a MEDLINE search of the literature from 1967-2007 was performed. Two trials were identified--the European-Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) and Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA). The ESPRIT compared aspirin monotherapy with the combination of aspirin plus extended-release dipyridamole for prevention of secondary ischemic events in patients with a history of TIA or minor stroke. The CHARISMA trial compared aspirin plus clopidogrel with aspirin alone in a population at high risk for atherothrombotic events using the composite outcome of myocardial infarction, stroke, and death from cardiovascular causes. Data from ESPRIT add to evidence that the combination of aspirin plus extended-release dipyridamole is superior to aspirin alone. The findings of the CHARISMA trial reinforce recommendations from both AHA-ASA and ACCP that the combination of aspirin and clopidogrel be reserved for special populations requiring this antiplatelet combination (e.g., those who have had coronary artery stenting).     

Antithrombotic drugs for secondary stroke prophylaxis

Stroke is the third most common cause of adult mortality in the United States. Antithrombotic agents form the mainstay of stroke prevention. Aspirin produces a modest reduction in the risk of second stroke and is widely recommended for initial therapy. The thienopyridines ticlopidine and clopidogrel are alternatives for secondary prevention in patients who do not respond to or cannot take aspirin. They are no more effective than aspirin and have been associated with thrombotic thrombocytopenic purpura. The combination of aspirin and extended-release dipyridamole has several mechanisms of action and an additive effect on reducing stroke risk compared with either agent alone. A 2-fold increase in risk reduction and favorable safety profile suggest that the combination can serve as first-line prophylaxis against a second stroke.     

Adverse effects and drug interactions of antithrombotic agents used in prevention of ischaemic stroke

Stroke is the third most common cause of death in the US. Primary prevention of stroke can be achieved by control of risk factors including hypertension, diabetes mellitus, elevated cholesterol levels and smoking. Approximately one-third of all ischaemic strokes occur in patients with a history of stroke or transient ischaemic attack (TIA). The mainstay of secondary prevention of ischaemic stroke is the addition of medical therapy with antithrombotic agents to control the risk factors for stroke. Antithrombotic therapy is associated with significant medical complications, particularly bleeding.Low-dose aspirin (acetylsalicylic acid) has been shown to be as effective as high-dose aspirin in the prevention of stroke, with fewer adverse bleeding events. Aspirin has been shown to be as effective as warfarin in the prevention of noncardioembolic ischaemic stroke, with significantly fewer bleeding complications. Ticlopidine may be more effective in preventing stroke than aspirin, but is associated with unacceptable haematological complications. Clopidogrel may have some benefit over aspirin in preventing myocardial infarction, but has not been shown to be superior to aspirin in the prevention of stroke. The combination of clopidogrel and aspirin may be more effective than aspirin alone in acute coronary syndromes, but the incidence of adverse bleeding is significantly higher. Furthermore, the combination of aspirin with clopidogrel has not been shown to be more effective for prevention of recurrent stroke than clopidogrel alone, while the rate of bleeding complications was significantly higher with combination therapy. The combination of aspirin and extended-release dipyridamole has been demonstrated to be more effective than aspirin alone, with the same rate of adverse bleeding complications as low-dose aspirin. When selecting the appropriate antithrombotic agent for secondary prevention of stroke, the adverse event profile of the drug must be taken into account when assessing the overall efficacy of the treatment plan.     

Dipyridamole/aspirin combination in secondary stroke prevention: effects on absolute myocardial blood flow and coronary vascular resistance

OBJECTIVE: In the European Stroke Prevention Study (ESPS 2), oral administration of a fixed combination of 200 mg extended-release dipyridamole and 25 mg aspirin (twice daily) after ischemic stroke or transient ischemic attack, significantly reduced the risk of stroke compared to placebo as well as compared to aspirin or dipyridamole alone. However, the i.v. application of dipyridamole over 4 - 6 min is known to increase myocardial blood flow up to 6-fold, and thereby potentially provoke ischemic wall motion abnormalities in patients with coronary artery disease. We therefore assessed the cardiac side effects of the dipyridamole/aspirin combination on absolute myocardial blood flow (MBF) and coronary vascular resistance (CVR). METHODS: MBF and CVR were measured using 150-water positron emission tomography in 24 patients after stroke or transient ischemic attack, before and 6.7 +/- 1.9 days after starting the dipyridamole/aspirin combination (Aggrenox) therapy. RESULTS: Resting MBF increased by 39% (max. 112%), from 0.92 +/- 0.13 (ml x g(-1) x min(-1)) at baseline to 1.28 +/- 0.27 (ml x g(-1) x min(-1)) under ongoing dipyridamole/aspirin combination therapy (p < 0.0005). CVR consecutively decreased from 105.3 +/- 16.9 to 74.1 +/- 16.5 (mmHg x ml(-1) x g x min) (p < 0.0005). The relative increase in MBF correlated negatively with the body surface area. No correlation was found between relative MBF increase and duration of dipyridamole/aspirin combination therapy (range 4 - 10 days). CONCLUSIONS: Orally administered dipyridamole/aspirin combination therapy in secondary stroke prevention increases MBF and decreases CVR significantly. These cardiac side effects of the dipyridamole/aspirin combination should be taken into account in stroke patients with proven or suspected coronary artery disease, particularly in combination with a small body surface area.     

Prevention of ischaemic stroke--antiplatelets

Aspirin is the treatment of first choice for long-term secondary prevention of vascular events in patients with confirmed non-cardioembolic ischaemic stroke or TIA. However, there is no good evidence that it is of benefit in primary stroke prevention. If aspirin is contra-indicated, dipyridamole monotherapy is a relatively cheap, but slightly less effective, alternative. Aspirin and dipyridamole have an additive effect in secondary stroke prevention, but there is a high incidence of side effects and subsequent discontinuation of treatment with combination therapy. It is reasonable to consider clopidogrel for secondary prevention of vascular events in patients with ischaemic stroke who are intolerant of aspirin or dipyridamole, or who have a history of ischaemic heart disease. However, its cost is considerable. Over the next decade, oral antiplatelet agents directed against specific platelet receptors, or a combination of antiplatelet drugs inhibiting different aspects of platelet function, may improve secondary prevention of stroke.     

Clinical pharmacokinetics of antiplatelet agents used in the secondary prevention of stroke

Stroke is one of the leading causes of death and debilitation. Several million stroke survivors are alive throughout the world today. Prevention of recurrent stroke is of major importance to stroke survivors. Several pharmacological agents are currently available for use in secondary stroke prevention.Clopidogrel, the combination of immediate-release aspirin and extended-release dipyridamole and aspirin alone are the most widely recommended agents for use in the secondary prevention of strokes. Clopidogrel has shown superiority over aspirin in the combined endpoints of stroke, death and myocardial infarction. The immediate-release aspirin/extended-release dipyridamole combination has shown superiority to aspirin alone in the secondary prevention of stroke.Dipyridamole has been studied as an antiplatelet agent for several decades. Early trials to prove its efficacy compared with aspirin were not favourable, and patients often experienced many adverse effects. Researchers began developing an extended-release formulation in an effort to maintain therapeutic blood concentrations with less frequent daily administration and better adverse effect profile. Pharmacokinetic analysis of this new product showed it to have a more consistent and reproducible absorption compared with immediate-release dipyridamole. The rate of absorption of extended-release dipyridamole is considerably slower than that of immediate-release dipyridamole, while similar plasma concentrations are maintained to optimise antiplatelet efficacy. This allows extended-release dipyridamole to be administered twice daily rather than four times daily.A large-scale randomised trial was conducted with extended-release dipyridamole 200mg in combination with immediate-release aspirin 25mg given twice daily. The combination product showed a greater efficacy at preventing a recurring stroke then either agent administered alone. Indirect comparisons with clopidogrel show that the combination of immediate-release aspirin/extended-release dipyridamole may be more effective than clopidogrel at preventing a recurring stroke.     

Antiplatelet therapy in peripheral arterial disease

Antiplatelet therapy significantly reduces the incidence of vascular death, nonfatal myocardial infarction, and nonfatal stroke in patients with peripheral arterial disease (PAD) and intermittent claudication, in patients undergoing peripheral grafting, in patients undergoing peripheral angioplasty, and in patients with carotid disease. Aspirin, aspirin plus dipyridamole, ticlodipine, and clopidogrel have been shown to be efficacious in the treatment of PAD. Data from the Clopidogrel versus Aspirin in Patients at Risk for Ischaemic Events (CAPRIE) trial demonstrated in 11,592 patients with PAD that patients randomized to clopidogrel 75 mg daily had a 24% significant (p=0.0028) reduction in vascular death, nonfatal myocardial infarction, and nonfatal stroke than patients randomized to aspirin 325 mg daily. These data favor the use of clopidogrel in patients with PAD.     

Antiplatelet therapy for the prevention of recurrent stroke and other serious vascular events: a review of the clinical trial data and guidelines

ABSTRACT

Background: One strategy of reducing the burden of stroke is the prevention of recurrent stroke, following an initial ischaemic stroke or transient ischaemic attack (TIA) of arterial origin, by means of antiplatelet therapy.

Scope: This review article surveys and discusses the current clinical trial data and guidelines for the use of antiplatelet therapy in the prevention of recurrent stroke/TIA of arterial origin (not stroke due to atrial fibrillation). Based on the latest available evidence, a new antiplatelet treatment algorithm for the long-term treatment of patients following atherothromboembolic ischaemic stroke or TIA is proposed.

Findings: Meta-analyses of randomised clinical trials in patients with TIA and ischaemic stroke of arterial origin indicate that, compared with control, the relative risk reduction (RRR) for recurrent stroke and other serious vascular events is 13% (95% confidence interval [CI] 6% to 19%) with aspirin, 13% (4% to 21%; p = 0.046) with dipyridamole and 34% (24% to 43%) with the combination of aspirin and dipyridamole. Compared with aspirin, the relative risk of recurrent stroke and other serious vascular events is reduced by 7.3% (95% CI –5.7% to 18.7%) with clopidogrel and 18% (9% to 26%; p = 0.0003) with the combination of aspirin and dipyridamole. The combination of aspirin and clopidogrel is not significantly more effective in preventing serious vascular events than clopidogrel alone (RRR 6.4%; –4.6% to 16.3%) in the long-term treatment of patients with previous ischaemic stroke and TIA, mainly because of a cumulative excess of bleeding complications. The relative risks and benefits of long-term treatment with clopidogrel and the combination of aspirin and dipyridamole are being compared in an ongoing large clinical trial (PRoFESS). Current Australian therapeutic guidelines for antiplatelet therapy among patients with TIA and ischaemic stroke of arterial origin have incorporated important new findings from recently published clinical trials and recommend aspirin or the combination of dipyridamole plus aspirin as the preferred long-term antiplatelet therapy.

Conclusion: Whilst awaiting the results of the PRoFESS trial, the combination of dipyridamole plus aspirin is the preferred antiplatelet regimen to reduce the risk of recurrent vascular events among patients with TIA and ischaemic stroke of arterial origin.