新型口服抗凝血剂达比加群酯的研究进展

华法林是大多数国家长期抗凝的主要药物之一。华法林虽然可以口服给药,但其治疗范围狭窄,必须严格掌握治疗指征。此外华法林与其他药物相互作用大,个体差异较大,治疗期间需严密观察病情,并依据国际标准化比率随时调整用量。在近几年中许多新的抗凝血剂已经开发出来。达比加群酯是一种新型口服的直接凝血酶抑制剂。本研究综述了达比加群酯的临床研究进展及潜在适应证,为该药物的临床应用提供依据。     

Monitoring anticoagulant therapy with new oral agents

Thromboembolic disease is a major leading cause of mortality and morbidity in industrialized countries. Currently, the management of these patients is challenging due to the availability of new drugs with proven efficacy and security compared to traditional oral vitamin K antagonists. These compounds are characterized by a predictable pharmacokinetic profile for which blood monitoring is not routinely needed. Nevertheless, some data have suggested inter-patient variability in the anticoagulant effect of these drugs, raising concerns about their effectiveness and safety. Although mass-spectrometry is the gold standard to determine drug plasma concentrations, this method is not widely available in every-day practice and some coagulation assays are commonly used to determine the anticoagulant effect of these drugs. The present review aims to summarize the current knowledge regarding the clinical question of how and when to monitor patients with new anticoagulant oral agents.     

Oral Anticoagulant Use After Bariatric Surgery: A Literature Review and Clinical Guidance

Bariatric surgery may alter the absorption, distribution, metabolism, or elimination (disposition) of orally administered drugs via changes to the gastrointestinal tract anatomy, body weight, and adipose tissue composition. As some patients who have undergone bariatric surgery will need therapeutic anticoagulation for various indications, appropriate knowledge is needed regarding anticoagulant drug disposition and resulting efficacy and safety in this population. We review general considerations about oral drug disposition in patients after bariatric surgery, as well as existing literature on oral anticoagulation after bariatric surgery. Overall, available evidence on therapeutic anticoagulation is very limited, and individual drug studies are necessary to learn how to safely and effectively use the direct oral anticoagulants. Given the sparsity of currently available data, it appears most prudent to use warfarin with international normalized ratio monitoring, and not direct oral anticoagulants, when full-dose anticoagulation is needed after bariatric surgery.     

达比加群酯治疗高龄女性非瓣膜性心房纤颤的安全性和有效性分析

目的探讨达比加群酯抗凝治疗高龄女性患者非瓣膜性心房纤颤(房颤)的疗效及安全性。方法选取解放军210医院2014年9月至2015年4月收治的非瓣膜性房颤高龄老年女性(年龄≥80岁)患者9例,给予达比加群酯110 mg,每日2次,观察其抗凝疗效及药物安全性。结果本组9例患者均获得6个月随访。末次随访时,9例患者均无新发脑梗死,无脑出血。药物不良反应方面,2例(22.2%)消化不良,1例(11.1%)上腹痛,患者为空腹服药,纠正为餐后服药后上腹痛缓解;2例(22.2%)皮下瘀斑,1例(11.1%)牙龈出血。无严重出血事件,血红蛋白、血小板、肝功能、肾功能无变化。结论达比加群酯抗凝治疗高龄老年女性患者非瓣膜性房颤安全、有效。     

心房颤动合并冠心病冠状动脉介入治疗术后达比加群酯 抗凝治疗的有效性及安全性研究

目的 研究达比加群酯(dabigatran etexilate)在心房颤动(房颤)合并冠心病冠状动脉介入治疗(PCI)术后抗凝治疗中的有效性及安全性。方法 选取2015年3月至2016年3月安徽医科大学第二附属医院收治的房颤合并冠心病冠状动脉介入治疗病人90例,采用随机数字表法分为观察组和对照组,每组45例。观察组每天两次口服达比加群酯110 mg;对照组予以华法林治疗,调节国际标准化比值(INR)至2.0~3.0之间;同时两组均予以阿司匹林100 mg/d。观察随访12个月,比较两组病人实验室指标变化、新发急性心肌梗死、急性脑梗死、非中枢神经系统栓塞、出血事件及不良反应的发生率。结果 观察组中栓塞事件发生率(8.9%)与对照组(17.8%)相比差异无统计学意义(χ²=1.538,P=0.215);达比加群酯在降低与血栓形成有关的实验室指标上较华法林更优,同时观察组出血事件发生率低于对照组(χ²=4.406,P=0.036);两组在不良反应事件发生率上均差异无统计学意义(P>0.05)。结论 达比加群酯在房颤合并冠心病PCI术后病人抗凝治疗中与华法林的疗效相似,且达比加群酯的安全性更高,是此类病人抗凝治疗的理想选择。     

Cost-effectiveness of dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation in Taiwan

Background

Economic evaluation of dabigatran, a new anti-antithrombotic agent, is done mostly in Western countries. It remains to be seen whether dabigatran will be cost effective in a practice environment where warfarin is significantly underused and the costs of both warfarin and international normalized ration INR monitoring are cheap.

Methods

We performed a cost-effectiveness analysis with a Markov model to evaluate the value of dabigatran to prevent stroke and systemic embolism in patients with atrial fibrillation (AF) in Taiwan. Dabigatran was given through sequential dosing, where patients < 80 years old received 150 mg of dabigatran twice a day and the dosage was reduced to 110 mgs for patients ≥ 80 years old. Dabigatran was compared with warfarin under two scenarios: the “real-world adjusted-dose warfarin” assuming all AF patients eligible for warfarin were given the medication and maintained at the INR observed in routine clinical practice in Taiwan, and the “real-world prescribing behaviour” similar to the treatment with antithrombotics in real-world practice in Taiwan, where eligible patients could receive warfarin, aspirin, or no treatment.

Results

The percentage of AF patients who received warfarin, aspirin or no treatment in Taiwan was 16%, 62% and 22%, respectively. The event rates of ischemic stroke per 100 patient-years were 4.5, 8.0, and 6.0 for sequential dabigatran, real-world prescribing behaviour and real-world warfarin use, respectively. The incremental cost-effectiveness ratio was $280 US per quality-adjusted-year (QALY) in the real-world prescribing scenario and $10,551 US/QALY in real-word warfarin use.

Conclusions

Dabigatran was highly cost-effective in a clinical practice setting where warfarin has been significantly underused.     

Direct oral anticoagulants in the treatment of acute venous thromboembolism: A systematic review and meta-analysis

Introduction

Acute venous thromboembolism (VTE) is a common disease associated to significant morbidity and mortality.

Materials and methods

We systematically reviewed and meta-analysed clinical outcomes with direct oral anticoagulants (DOAC: dabigatran, rivaroxaban, apixaban or edoxaban) for treatment of acute VTE. We used MEDLINE and CENTRAL, clinical trials registers, conference proceedings, and websites of regulatory agencies to identify randomised clinical trials of DOAC compared with conventional treatment [parenteral anticoagulant followed by a vitamin K antagonist (VKA)] for acute VTE. Two investigators independently extracted data. Relative risk of recurrent VTE, bleeding events, deaths and a net clinical endpoint (composite of recurrent VTE, major bleeding, and death) were estimated using a random effect meta-analysis (RevMan software).

Results

Six trials including 27,127 patients were selected. The risk of recurrent VTE was similar with the DOAC and standard treatment (relative risk 0.91, 95% confidence interval 0.79 to 1.06). The DOAC reduced the risk of major bleeding in comparison with standard treatment (0.62, 0.45 to 0.85) (absolute risk difference, − 0.6%; 95% confidence interval − 1.0% to − 0.3%), but there was heterogeneity across trials in the relative risk of bleeding. No between treatment differences were found in the relative risk of all-cause mortality (0.98, 0.84 to 1.14). The DOAC and conventional treatment differed on the net clinical endpoint (0.85, 0.75 to 0.97). Subgroup analyses in relevant subgroups (index pulmonary embolism, heparin lead-in, age, gender, renal function, presence of cancer), as well as sensitivity analyses, were consistent with the main analysis.

Conclusions

The DOAC seem as effective as, and probably safer than standard treatment of acute VTE. The relative efficacy and safety of the DOAC was consistent across a wide range of patients.     

Measurement of dabigatran: previously demonstrated Hemoclot® Thrombin Inhibitor assay reagent instability on Sysmex CS-2100i is no longer an issue

The Hemoclot^® Thrombin Inhibitor (HTI) assay has been recommended for measurement of dabigatran concentrations in specific clinical situations. Traditionally, reagents for biochemical assays are prepared from instructions found in the package insert. For the HTI reagents the manufacturer recommends incubating the reagents much longer than indicated in the package insert. These recommendations are added to the application sheets designed for different analyzers. Many clinicians and laboratory personnel may be unaware of the discrepancy between the two instructions, resulting in incorrect handling of the reagents. The aim of this study was to investigate the effect of the two different preparation methods on reagent stability and test results. For the standard concentration range, reagent stability on Sysmex CS-2100i was only two hours instead of the eight hours indicated by the producer when following package insert instructions (incubation time: 15?min). Stability was increased to five hours when following the application sheet (incubation time: 60?min). Two years later, the study was repeated using samples of patients treated with dabigatran etexilate. This time, reagent stability was at least six hours. Since the reagent composition was unchanged, the increased stability could be due to changed logistics by the supplier, with stock and transfer closer by. Previously demonstrated HTI reagent instability is no longer an issue at our laboratory. The reliability of results of clinical studies in which the assay has been used is potentially compromised.