达比加群酯在非瓣膜性房颤患者中用药依从性分析

目的：调查达比加群酯在某三甲医院非瓣膜性房颤（non-valvular atrial fibrillation，NVAF）患者中的用药依从性，探讨影响依从性的因素，为制订提高达比加群酯依从性的有效措施提供依据。方法：医院信息系统（hospital information system，HIS）检索2016年2月-2018年1月使用达比加群酯的患者，筛选符合纳入标准的患者。统计随访患者3，6，9，12，18个月达比加群酯的覆盖天数比例（proportion of days covered，PDC），并计算PDC≥0.8的比例。使用SPSS17.0统计软件对影响药物依从性的因素进行统计分析。结果：随访3，6，9，12，18个月的PDC值≥0.8的患者比例分别为75.00%，59.50%，51.52%，49.57%，60.42%。结果显示糖尿病病史（χ²=8.316，P=0.004），既往抗凝药物使用史（χ²=8.764，P=0.003）、脑卒中/短暂性脑缺血发作（transient ischemic attack，TIA）史（χ²=6.304，P=0.012）与随访12个月的PDC≥0.8的患者比例显著相关。结论：患者的用药依从性随服药时间的延长而下降，1年后趋于稳定。有糖尿病病史、既往抗凝药使用史、脑卒中/TIA病史患者的长期依从性高于无既往史的患者。     

What is the Role of Reversal Agents in the Management of Emergency Department Patients with Dabigatran-Associated Hemorrhage?

Background

In 2010, the U.S. Food and Drug Administration (FDA) approved dabigatran as the first non-warfarin oral anticoagulant for use in the United States. At the time of FDA approval, there was no antidote or effective treatment for dabigatran-induced hemorrhage. In 2015, the FDA approved idarucizumab for the treatment of dabigatran-induced hemorrhage. The purpose of this clinical practice statement is to evaluate the role of select reversal agents in the management of patients with dabigatran-associated bleeding.

骨科大手术中的静脉血栓的预防:口服抗凝药的系统回顾和间接比较

目的:基于有效的循证证据,以低分子肝素为对照组,分析达比加群、阿哌沙班和利伐沙班在骨科大手术后预防静脉血栓的有效性与安全性。方法:在Pub Med和Embase中系统地检索随机对照试验以及参考文献中关键的文章,这些文章评价了以低分子肝素为对照组,达比加群、阿哌沙班和利伐沙班在进行了骨科大手术的病人中的作用。结果:评价的结果包括总静脉血栓(total VTE)、深静脉血栓(DVT)、肺栓塞(PE)、死亡和主要出血事件(major bleeding)。笔者独立地评价了每1篇文章的方法质量同时独立地提取了文献数据。在总静脉血栓预防方面,利伐沙班和阿哌沙班优于达比加群,分别为[RR=0.37,95%CI(0.23,0.60)]和[RR=0.58,95%CI(0.35,0.96)]。利伐沙班和阿哌沙班之间没有区别[RR=0.64,95%CI(0.33,1.25)]。利伐沙班与阿哌沙班相比增加了出血风险[RR=1.57,95%CI(1.20,2.07)],利伐沙班与达比加群相比增加了出血风险[RR=1.25,95%CI(0.93,1.70)]。阿哌沙班和达比加群在出血方面没有差别[RR=0.78,95%CI(0.58,1.07)]。结论:在接受骨科大手术病人之中,利伐沙班和阿哌沙班2种药物与达比加群相比,预防静脉血栓的效果更好,出血风险相似。利伐沙班与阿哌沙班相比,预防静脉血栓的效果相似,但是增加了出血的风险。     

Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE‐LY trial

Background

Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF.

Objectives

To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE‐LY trial.

Methods

HAS‐BLED, ORBIT, ATRIA and HEMORR₂HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated.

Results

There were 1182 (6.5%) major bleeding events during a median follow‐up of 2.0 years. For all the four schemes, high‐risk subgroups had higher risk of major bleeding (all P  < 0.001). The ORBIT score showed the best discrimination with c‐indices of 0.66, 0.66 and 0.62, respectively, for major, life‐threatening and intracranial bleeding, which were significantly better than for the HAS‐BLED score (difference in c‐indices: 0.050, 0.053 and 0.048, respectively, all P  < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P  = 0.0019), ATRIA (P  < 0.001) and HEMORR₂HAGES (P  < 0.001) scores. HAS‐BLED score showed a nonsignificant trend for interaction (P  = 0.0607).

Conclusions

Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

     

Direct Oral Anticoagulants: New Drugs and New Concepts

Direct oral anticoagulants (DOACs) are approved for multiple thromboembolic disorders and provide advantages over existing agents. As with all anticoagulants, management protocols for the eventuality of bleeding are important. Randomized phase III studies generally show that DOACs have a similar risk of clinically relevant bleeding compared with standard anticoagulants, with reductions in major bleeding in some cases. This may be particularly important in patients with atrial fibrillation, for whom the rate of intracranial hemorrhage was approximately halved with DOACs compared with warfarin. Conversely, the risk of gastrointestinal bleeding may be increased. Specific patient characteristics, such as renal impairment, comedications, and particular aspects of each drug, including the proportion eliminated by the kidneys, must be taken into account when assessing the risk of bleeding. Although routine coagulation monitoring of DOACs is not required, it may be useful under some circumstances. Of the traditional clotting assays, a sensitive and calibrated prothrombin time may be useful for detecting the presence or absence of clinically relevant factor Xa inhibitor concentrations (rivaroxaban or apixaban), but specific anti–factor Xa assays can measure drug levels quantitatively. For dabigatran, the results of an activated partial thromboplastin time test may exclude a clinically relevant pharmacodynamic effect, but a calibrated dilute thrombin time assay can be used for quantification of drug levels. In the event of mild or moderate bleeding, normal hemostatic support measures are recommended. For life-threatening bleeding, use of nonspecific prohemostatic agents may be considered, although clinical evidence is scarce. Specific antidotes are in development.     

Additive effect of dabigatran and high-dose aspirin in the development of haemorrhagic pleural effusion in a patient with tuberculous pleuritis

Tuberculous pleuritis can rarely cause haemorrhagic pleural effusion. Dabigatran etexilate can have an additive effect on increasing the risk of haemorrhage. Aspirin cannot cause major haemorrhage, but in the elderly it can cause gastrointestinal bleeding via ulceration of the gastrointestinal mucosa. We report here the case of a 77-year-old male who presented to the hospital with a 2-month history of progressive dyspnoea. He had been taking dabigatran etexilate (220 mg) and high-dose acetylsalicylic acid (aspirin; 300 mg) daily for chronic atrial fibrillation. A chest X-ray revealed a moderately sized right pleural effusion confirmed by a computed tomography scan, which also showed bronchiectasis of both lungs. Dabigatran was discontinued and aspirin was decreased to the minimal therapeutic dose of 100 mg before thoracentesis was performed. Lymphocyte-predominant (50%) haemorrhagic fluid of 500 ml was drained, positive for acid-fast bacilli smear and polymerase chain reaction of Mycobacterium tuberculosis. A chest tube was placed and an additional 1250 ml of haemorrhagic exudate drained out. We treated the patient with a routine regimen of antituberculous medication and the infection resolved without complications other than the bronchiectasis present before treatment. We think that the combination of dabigatran etexilate and high doses of aspirin increased the risk of pleural haemorrhage in this patient with tuberculous pleuritis.     

Newer oral anticoagulant agents: a new era in medicine

After a gap of almost 60 years following the development of warfarin, 2 new categories of oral anticoagulant agents have been approved for clinical use - the direct thrombin inhibitors and factor Xa inhibitors. These agents promise to be more convenient to administer with fixed dosing but still have equivalent efficacy and improved bleeding risk compared to warfarin. The clinical community is looking forward to the widespread usage of these agents but there is also some apprehension regarding bleeding risks, non-availability of specific reversal strategies and lack of specific monitoring parameters. This review article will attempt to educate the reader about three representative drugs from these classes: Dabigatran, Rivaroxaban and Apixaban. We will discuss the historical perspective to the development of these drugs, available research data and pharmacology of these agents. The best strategies for monitoring and reversal of these drugs in special situations will also be touched upon.