达比加群酯对非瓣膜性房颤导管消融围术期抗凝疗效和安全性的 Meta 分析

目的：系统评价达比加群酯对非瓣膜性房颤导管消融围术期的抗凝疗效和安全性。方法计算机检索 PubMed、EMbase、The Cochrane Library（2016年第2期）、CMB、知网、万方和维普数据库,搜集有关房颤导管消融围术期使用达比加群酯和华法林抗凝治疗的随机对照及非随机对照的研究文献,由两位评价员独立筛选文献、提取资料和评价纳入研究的偏倚风险后,采用 RevMan 5．3软件进行 Meta 分析。结果最终纳入23个研究、共7673例患者。Meta 分析结果显示：达比加群酯组脑卒中或短暂性脑缺血发生率与华法林组无明显区别[OR ＝1．0,95％CI：0．60～1．68,P ＝0．99],大出血事件发生率无明显区别[OR ＝0．79,95％CI：0．52～1．19, P ＝0．25],小出血事件发生率显著降低[OR ＝0．71,95％CI：0．57～0．87,P ＝0．001]。结论达比加群酯在房颤导管消融围术期抗凝疗效及大出血并发症的发生率上与华法林无明显区别,小出血并发症的发生率较华法林降低。     

达比加群酯与低分子肝素预防髋关节置换术后下肢深静脉血栓的作用比较

目的 比较达比加群酯与低分子肝素预防髋关节置换术后并发下肢深静脉血栓（DVT）的疗效与安全性的差异。方法 选择2014年1月至2015年10月在宣城中心医院住院的单髋或双髋关节置换术患者73例,随机分为基础治疗组（对照组）24例,达比加群酯组（DE组）25例,低分子肝素组（LMWH组）24例。置换后行双下肢彩色多普勒检查评估DVT形成情况,并观察比较各组患者治疗前后血小板计数,凝血酶元时间（PT）变化情况及安全性。结果 DE组和LMWH预防DVT效果优于对照组（P<0.05）,而DE组和LMWH组患者在预防DVT发生上差异无统计学意义（P>0.05）。DE组和LMWH组在治疗期间均无严重出血。结论 达比加群酯与低分子肝素均具有较好的预防髋关节置换后DVT的发生,达比加群酯疗效及安全性与低分子肝素作用相当。     

达比加群酯的合成

4-甲胺基-3-硝基苯甲酸与3-(吡啶-2-基氨基)丙酸乙酯在羰基二咪唑的作用下反应形成3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,经锌粉还原得到3-[(3-氨基-4-甲胺基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,随后与N-(4-氰基苯基)甘氨酸在羰基二咪唑以及醋酸作用下一锅制得3-[[2-[(4-氰基苯胺基)甲基]-1-甲基-1H-苯并咪唑-5-羰基](吡啶-2-基)氨基]丙酸乙酯,再进行成脒化反应以及酰化反应后即可制得达比加群酯,总收率约48％.     

达比加群酯降解杂质的合成

目的 为了更好的控制甲磺酸达比加群酯的质量,合成达比加群酯的5个降解杂质。方法 以N-[2-[[(4-氰基苯基)氨基]甲基]-1甲基-1H-5-苯并咪唑]羰基]-N-2-吡啶基-β-氨基丙酸乙酯为原料,经过成脒反应、酰胺反应、水解反应制备了杂质A~E。结果 所得产物经¹H-NMR,LC-MS和¹³C-NMR初步确证了结构,收率≥65%。结论 该合成路线反应条件温和,产品纯度高。     

新型口服抗凝药与心房颤动的抗凝治疗

心房颤动(房颤)是临床最常见的心律失常,增加脑卒中的发病率和死亡率。抗凝治疗是预防房颤合并脑卒中的有效手段。目前能够长期服用的口服抗凝药物只有华法林,但华法林存在个体差异、复杂的药物和药物及药物和食物之间的相互作用,需要定期抗凝监测和频繁调整剂量,具有局限性。研发新型口服抗凝药成为新的热点,活化凝血因子X抑制剂和凝血酶抑制剂在房颤抗凝领域的研究进展迅速,已经取得了明确的循证医学证据。现将这一领域的研究进展做一综述。     

Investigational drugs for the treatment of acute myocardial infarction: focus on antiplatelet and anticoagulant agents

Background: Advances in our understanding of the complex pathophysiologic mechanisms responsible for high-risk atherosclerotic plaque rupture resulting in acute myocardial infarction (AMI) have led to the development of numerous antiplatelet and anticoagulant agents for treatment of AMI.

Areas covered: We review various antithrombotic drugs which were recently investigated for the treatment of AMI. A MEDLINE search for relevant articles on newer antiplatelet agents and anticoagulants drugs for the treatment of AMI was performed, and important original investigations were reviewed. We also briefly discuss agents that completed evaluation and were recently recommended by expert guidelines.

Expert opinion: The antiplatelet agents cangrelor and vorapaxar and the anticoagulant rivaroxaban, have shown promise for the reduction of ischemic events when administered during, and in the acute phase following AMI. However, these agents have not been compared with more potent P2Y₁₂ inhibitors, prasugrel, and ticagrelor. Finding an optimum combination of these agents to achieve an appropriate risk (bleeding) – benefit (reduction in ischemic events) balance is challenging. Further evaluation of agents that show promise is important for enhancing our armamentarium of pharmacologic agents for the successful treatment of AMI.     

Dabigatran Reversal With Idarucizumab Preceding Thrombolysis in an Octogenarian Patient with Chronic Kidney Disease and Acute Stroke: A Case Report

Background and PurposeReversing the effect of dabigatran among patients with atrial fibrillation is important to normalize coagulation profile among patients who develop serious hemorrhage from any source. However, such intervention always has the potential to cause a prothrombotic state. Among patients suspected of ischemic stroke, Idarucizumab, may be administered preceding thrombolysis. This is a considerable option when given during the critical phase of revascularization.MethodsWe report the case of an 84-year old, male, banker, known hypertensive with chronic renal disease. He has non valvular atrial fibrillation receiving Dabigatran at 75 mg twice daily and presented with symptoms of right-sided weakness, right hemisensory loss, facial asymmetry, and slurring of speech equating to National Institute of Health Stroke Scale (NIHSS) of 5. After coming into the hospital for a suspected stroke, 3 hours and 25 minutes after symptoms, complete reversal of Dabigatran with Idarucizumab was administered and intravenous thrombolysis was initiated 271 minutes post ictus. There was immediate improvement of the right upper extremity weakness and dysarthria 30 minutes post infusion. At 13 days post ictus, the patient was discharged with minimal right central facial palsy and right arm drift (NIHSS 2). Brain CT scan post revascularization did not reveal any hemorrhage and anticoagulant Apixaban 2.5 mg twice daily was started and maintained thereafter. Brain Magnetic Resonance Angiogram (MRA) showed complete recanalization of the left proximal MCA after 52 days.ConclusionOur case showed the effectiveness and safety of giving Idarucizumab followed by thrombolysis in Dabigatran-treated atrial fibrillation with ischemic stroke. Based on this case, the procedure can be performed in an elderly population with chronic kidney disease when administered close to the limit of threshold for thrombolysis.     

阿司匹林 氯吡格雷联合达比加群酯治疗冠心病合并房颤行PCI术患者临床疗效及血流变指标变化对照研究

目的探讨阿司匹林、氯吡格雷联合达比加群酯胶囊治疗冠心病合并房颤行经皮冠状动脉介入术患者的临床效果及对血流变指标的影响.方法将98例行经皮冠状动脉介入术的冠心病台并房颤患者根据治疗方案不同分为观察组与对照组,每组49例,两组行经皮冠状动脉介入术后均口服阿司匹林、氯吡格雷治疗,观察组在上述治疗基础上加用进比加群酯胶囊治疗,观察6个月.治疗前后采用血流变分析仪检测两组血液流变学指标变化,指标包括全血比黏度、纤维蛋白原、血浆比黏度;比较两组栓塞事件发生率及再出血发生率,结果治疗6个月后,两组全血比黏度、纤维蛋白原、血浆比黏度水平均较治疗前显著下降(P<0.05或0.01),观察组均显著低于对照组(P<0.01);观察组栓塞事件发生率(4.1%)显著低于对照组(18.4%)(P<0.05),再出血发生率(18.4%)与对照组(14.3%)比较差异无统计学意义(P>0.05).结论冠心病合并房颤患者行经皮冠状动脉介入术后在阿司匹林及氯吡格雷治疗基础上予以达比加群酯胶囊治疗,能有效改善患者的血液流变学状况,减少血栓形成,不增加出血风险,安全性高.