Management of Dabigatran‐Associated Bleeding with Two Doses of Idarucizumab Plus Hemodialysis

Vitamin K antagonists have been a mainstay of treatment for patients requiring anticoagulation for atrial fibrillation, but direct oral anticoagulants, such as dabigatran, have become increasingly prescribed. Compared with warfarin, dabigatran has a significantly lower risk of life‐threatening bleeding; however, bleeding events can still occur, supporting the need for effective reversal strategies. Idarucizumab was recently approved by the U.S. Food and Drug Administration to reverse the anticoagulant effects of dabigatran when life‐threatening bleeding occurs or an urgent need for an invasive medical procedure exists. Before idarucizumab's approval, reversal strategies included hemodialysis, coagulation factor replacement, and, in the setting of acute ingestion, activated charcoal. We describe the case of a 58‐year‐old, obese woman with a history of atrial fibrillation who developed acute kidney injury while taking dabigatran 150 mg twice/day, resulting in coagulopathy. Despite receiving idarucizumab 5 g and hemodialysis, there was a rebound increase in prothrombin time (PT) and activated partial thromboplastin time (aPTT) values, prompting administration of an additional 5‐g dose of idarucizumab and continued hemodialysis, with subsequent PT and aPTT values remaining within their appropriate ranges. To our knowledge, this is the first case report to describe the successful use of repeat dosing of idarucizumab with hemodialysis to reverse the anticoagulant effects of dabigatran. Although two doses of idarucizumab were given to our patient, this dosing regimen is not the current standard of practice. Administration of idarucizumab and the use of additional reversal strategies should involve an assessment of each individual patient's severity of bleeding and subsequent risk of thrombosis. Due to the recent availability of idarucizumab and varying success with alternative reversal strategies, additional knowledge is needed for the optimal reversal of anticoagulation from dabigatran.     

Real World Outcomes Associated with Idarucizumab: Population-Based Retrospective Cohort Study

Idarucizumab reverses the anticoagulant effect of dabigatran, but few comparative studies have reported on clinical outcomes with idarucizumab. Our objective was to determine the effect of idarucizumab on clinical outcomes. We conducted a retrospective cohort study in a nationally representative sample of hospitals in the United States. The study population included adults ≥ 18 years who were hospitalized for dabigatran-associated major bleeding between January 1, 2015 and December 31, 2017. We compared idarucizumab-exposed patients to the unexposed group. Our primary outcome of interest was in-hospital mortality. We included 266 exposed and 1345 non-exposed participants across 271 hospitals. Among participants with gastrointestinal bleeding, there was no statistically significant difference in the odds of in-hospital mortality [9/153 (5.9%) vs 37/1124 (3.3%); adjusted odds ratio = 1.39, 95% confidence interval 0.51–3.45] between the idarucizumab-exposed and non-exposed groups. Among participants with intracranial bleeding, there was an excess of in-hospital mortality [13/112 (11.6%) vs 6/217 (2.8%)] associated with idarucizumab exposure, but limitations include sparse data and the inability to rule out residual confounding or confounding by disease severity. Among a large nationally representative sample of adult patients with dabigatran-associated major bleeding in the United States, we found no difference in in-hospital mortality among patients with gastrointestinal bleeding associated with idarucizumab exposure. An excess risk of in-hospital mortality associated with idarucizumab exposure among participants with intracranial bleeding deserves further exploration.     

逆转达比加群酯抗凝活性的研究进展和处理建议

达比加群酯是一种直接抑制凝血酶的新型口服抗凝药,具有较好的抗凝疗效和安全性,出血是其最常见的不良反应,发生率略低于或类似于华法林和依诺肝素。当服用达比加群酯的患者发生大出血,或者需进行手术或侵入性处理时,常须紧急逆转其抗凝活性。目前尚未研发出达比加群酯特异性解药,临床上应根据患者的出血部位和严重程度,进行综合治疗。监测凝血酶凝固时间（TT）和蛇静脉酶凝结时间（ECT）等指标有助于判断逆转达比加群酯活性的疗效。     

The discovery of dabigatran etexilate for the treatment of venous thrombosis

ABSTRACT

Introduction: Venous thromboembolism (VTE) can be life-threatening and requires anticoagulant treatment; for many years, vitamin K antagonists, e.g. warfarin, were the only oral anticoagulants available for long-term treatment. Although highly effective, they have many limitations including a slow onset, a multitude of drug–drug and drug–food interactions, and a narrow therapeutic range. These limitations spurred the search for non-vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran etexilate.

Areas covered: The authors illustrate the progression of preclinical and clinical studies leading to the development of dabigatran, the only approved NOAC to act by direct thrombin inhibition. They focus on molecule discovery, animal models of thrombosis, clinical trials and post-launch activities in VTE treatment.

Expert opinion: Dabigatran demonstrated comparable efficacy to the highly effective warfarin, and a more favourable safety profile in trials of VTE treatment. A favourable anticoagulant safety profile in addition to efficacy is essential for VTE treatment. Availability of the dabigatran-specific reversal agent, idarucizumab, provides a means of rapidly reversing the anticoagulant effect if required. Future investigations into the optimal duration of VTE treatment and an evaluation of the impact of idarucizumab, in real-world studies, could provide valuable information to help optimise treatment for selected patients.     

Positive Outcome After Intentional Overdose of Dabigatran

Introduction

Dabigatran (Pradaxa?), an orally active direct thrombin inhibitor, was approved by the United States Food and Drug Administration for the prevention of stroke in patients with atrial fibrillation in October 2010. Life-threatening consequences from dabigatran therapy include hemorrhage and bleeding complications, but they typically occur after renal impairment. We describe the first case report of intentional, acute overdose with dabigatran.

Case Report

A 57-year-old woman with a medical history of depression and atrial fibrillation presented to the emergency department after ingesting 11.25 g of dabigatran in a suicide attempt. Despite an ecchymosis indicative of prior trauma, there was no evidence of acute bleeding. After receiving gastric lavage and activated charcoal therapy in the emergency department, she was admitted to the ICU. On presentation, dabigatran blood levels measured 970 ng/mL and thrombin clot times measured above the testable limits (>120 s) until 52 h post-arrival. The remainder of her clinical course was uncomplicated, and the patient was transferred to an inpatient psychiatric unit for depression follow-up.

Discussion

This case shows the clinical course of a patient with an acute, massive dabigatran overdose with no significant clinical consequences. Currently, there is no ideal method to monitor anticoagulation levels; there is no pharmacologic reversal method, and hemodialysis is an undesirable treatment option.     

An update on the pharmaceutical management of thrombosis

Introduction: Anticoagulants such as heparins and vitamin K antagonists (VKA) are effective for thrombosis prevention and treatment, but are associated with the risk of bleeding and other limitations, spurring the search for improved drugs.

Areas covered: to evaluate the newer anticoagulants, focusing on those tested in phase III clinical trials such as direct oral anticoagulants (DOACs), antisense oligonucleotides (ASO) and warfarin analogues. DOACs such as dabigatran, rivaroxaban, apixaban and edoxaban are licensed for stroke prevention in atrial fibrillation and treatment of venous thromboembolism, dabigatran, rivaroxaban and apixaban for postoperative thromboprophylaxis in patients undergoing elective hip or knee arthroplasty and rivaroxaban for secondary prevention of acute coronary syndromes. ASO interfering with Factor XI hepatic synthesis were effective and safe for thromboprophylaxis in elective knee arthroplasty.

Expert opinion: DOACs have overcome some limitations of anticoagulants such as VKA, but are still associated with a risk of bleeding and they lack both standardized and widely available tests measuring their anticoagulant effect and a reversal agent, except for idarucizumab, specific for dabigatran, in case of major or life threatening bleeding or emergency surgery. Agents targeting Factor XI and possibly Factor XII may be ideal anticoagulants, as they can prevent thrombosis with low bleeding risk.     

Dabigatran Etexilate

The need for safe, effective, and easily administered and monitored antithrombotic treatments that do not have the issues common to warfarin treatment has led to the development of new anticoagulant drugs. Dabigatran etexilate (Pradaxa®, Pradax?) is a prodrug of the direct thrombin inhibitor dabigatran, a direct, reversible, potent inhibitor of thrombin. Dabigatran does not interact with food, and is associated with very few known drug interactions. Dabigatran etexilate, at dosages of 110 and 150 mg twice daily, was shown to be noninferior to warfarin with regard to the incidence of stroke or systemic embolism in a large, randomized, partially blinded, multicenter study in a wide spectrum of patients with atrial fibrillation. Moreover, the higher dosage was associated with significantly greater efficacy than warfarin in this regard. These results were supported by secondary endpoints and subgroup analyses. In general, dabigatran etexilate is well tolerated, although it is associated with a higher rate of dyspepsia than warfarin. Major bleeding was as common in recipients of the higher dosage as, and less common in recipients of the lower dosage of dabigatran etexilate than, that in recipients of warfarin, and intracranial bleeding, life-threatening major bleeding, and total bleeding were less common in recipients of either dabigatran etexilate dosage than in warfarin recipients. However, the higher dosage of dabigatran etexilate was associated with a higher rate of gastrointestinal bleeding than warfarin. The incidence of hepatotoxicity did not significantly differ across treatment groups. In conclusion, dabigatran etexilate 150 mg twice daily is more effective than warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and generally well tolerated, particularly with regard to bleeding endpoints compared with warfarin. It requires more frequent administration than warfarin, but provides multiple improvements to various issues associated with warfarin administration. Direct comparisons with other new anticoagulant drugs would be beneficial, as would further investigation into the effects in different patient populations, long-term effects, and the gastrointestinal bleeding and dyspepsia observed with dabigatran etexilate treatment. Dabigatran etexilate is a promising new option for the prevention of stroke and systemic embolism in patients with atrial fibrillation.     

Idarucizumab for Reversal of Dabigatran Prior to Acute Surgery: A Schematic Approach Based on a Case Report

Dabigatran, an oral direct thrombin inhibitor, is frequently used in treatment of venous thromboembolism and prevention of stroke in non‐valvular atrial fibrillation. Recently, idarucizumab, a monoclonal antibody fragment that reverses the dabigatran effect, was introduced to the market to be used in case of life‐threatening bleeding or acute surgery/invasive procedures. Whether usage should be guided by measurement of plasma dabigatran and/or other coagulation parameters is, however, still uncertain. We here describe the use of idarucizumab prior to acute surgery in a patient on dabigatran and acetylsalicylic acid. In this case, the decision to use idarucizumab was based on the clinical manifestations and other routine coagulation parameters, as the plasma dabigatran concentration was not available prior to administration. Due to challenges with the plasma dabigatran analysis and taking the safety of idarucizumab into consideration, it could be questioned whether a dabigatran measurement in general is necessary in this setting. Based on this case, we suggest a scheduled approach when considering requesting a plasma dabigatran measurement prior to administration of idarucizumab.     

Reversing the Effect of Oral Anticoagulant Drugs: Established and Newer Options

The vitamin K antagonists (VKAs) have been the standard (and only) oral anticoagulants used for the long-term treatment or prevention of venous thromboembolism or stroke in patients with atrial fibrillation. The coagulopathy induced by VKAs can be reversed with vitamin K, and in urgent situations, the vitamin K-dependent coagulation factors can be replaced by transfusion. In the last decade, a new class of oral anticoagulants has been developed, direct oral anticoagulants that bind to a specific coagulation factor and neutralize it. These compounds were shown to be effective and safe compared with the VKAs and were licensed for specific indications, but without a specific reversal agent. The absence of a reversal agent is a barrier to more widespread use of these agents. Currently, for the management of major life-threatening bleeding with the direct oral anticoagulants, most authorities recommend the use of four factor prothrombin complex concentrates. There are now three reversal agents in development and poised to enter the market. Idarucizumab is a specific antidote targeted to reverse the direct thrombin inhibitor, dabigatran, which was recently approved for use in the USA. Andexanet alfa is an antidote targeted to reverse the oral direct factor Xa inhibitors as well as the indirect inhibitor enoxaparin. Ciraparantag is an antidote targeted to reverse the direct thrombin and factor Xa inhibitors as well as the indirect inhibitor enoxaparin.     

Enhanced Elimination of Dabigatran Through Extracorporeal Methods

Several pharmacokinetic studies have suggested that dabigatran possesses a number of ideal properties for expedited removal via extracorporeal methods. However, this practice has not been prospectively evaluated in patients with life-threatening bleeding or requiring emergency surgery secondary to dabigatran-associated coagulopathy. The purpose of this literature review is to evaluate the published evidence surrounding extracorporeal removal of dabigatran in the setting of emergency surgery or life-threatening bleeding. A query of MEDLINE, Web of Science, International Pharmaceutical Abstracts, and Google Scholar using the terms dabigatran, dabigatran etexilate, hemodialysis, renal replacement therapy, hemorrhage, and atrial fibrillation was used to retrieve relevant literature. Furthermore, a manual search of the references of the identified literature was performed to capture additional data. Current evidence suggests that extracorporeal removal of dabigatran may play a role in the setting of life-threatening bleeding and emergent surgery. Conflicting evidence exists with regard to the potential for redistribution based on serum dabigatran concentrations. In addition, a number of practicalities must be considered before incorporating this technique in the clinical setting. Extracorporeal removal of dabigatran may be a treatment modality in selected patients who require emergency reversal.     

Hemopericardium in a patient treated with dabigatran etexilate

Dabigatran etexilate is a new oral anticoagulant used for the prevention of systemic thromboembolism in patients with atrial fibrillation. Acute bleeding episodes are known to occur with dabigatran etexilate therapy; however, only a few case reports in the literature describe such events. We describe a 70-year-old man treated with dabigatran etexilate for newly diagnosed, nonvalvular atrial fibrillation who developed a large hemopericardium that appeared to be temporally related to dabigatran etexilate administration. One month after starting the drug, an incidental finding of a small pericardial effusion was found on echocardiography. One month later, the patient came to his pulmonologist's office complaining of shortness of breath; a large pericardial effusion was found on a noncontrast computed tomographic scan, and the patient was admitted to the hospital. Laboratory monitoring of his coagulation status was limited due to the lack of assays available to directly monitor the therapeutic effects of dabigatran. The internal laboratory was able to perform a dilute thrombin time (DTT) test as part of a quality improvement project aiming to validate an assay for monitoring patients receiving dabigatran therapy. A DTT was therefore performed in conjunction with routine coagulation assays to evaluate the patient's coagulation status. After pericardiocentesis, the patient recovered without incident and was discharged without anticoagulant therapy. Although the Naranjo adverse reaction probability scale only indicated a possible relationship (score of 1) between the patient's development of hemopericardium and dabigatran etexilate therapy, investigation into the patient's clinical course, comorbidities, and laboratory results led us to conclude that dabigatran etexilate was responsible for the hemopericardium. To our knowledge, this report is the first to describe a case of potentially life-threatening pericardial bleeding that was temporally related to starting dabigatran etexilate therapy. Although we found that the DTT was a viable method of monitoring coagulation status in a patient receiving dabigatran etexilate therapy, the assay lacks approval by the United States Food and Drug Administration, which limits its clinical utility and widespread use at this time. Clinicians should be aware of the potential for life-threatening bleeding with use of this agent and the difficulty associated with monitoring and reversing this therapy in the setting of acute bleeding.     

Newer oral anticoagulants: A review of laboratory monitoring options and reversal agents in the hemorrhagic patient

Purpose Available evidence on laboratory monitoring of coagulation assays and reversal strategies for the management of hemorrhagic events associated with the newer anticoagulants is reviewed. Summary While there are no published studies with dabigatran and prothrombinase-induced clotting time (PiCT) and no chromogenic assays available to measure the anticoagulant effects, thrombin time and activated partial thromboplastin time (aPTT ) may be used to detect the presence of dabigatran. Although ecarin clotting time is sensitive to elevated concentrations of dabigatran, only a small fraction of institutions have access to this assay. Rivaroxaban and apixaban prolong prothrombin time, dilute prothrombin time, aPTT, Heptest results, and PiCT to varying degrees, having the most- pronounced effects at higher concentrations. In contrast, the chromogenic antifactor Xa assay proved to be sensitive to lower amounts of rivaroxaban and apixaban with less variability. Despite the expectations with these newer anticoagulants, the associated risk of bleeding is significant, and there are insufficient data depicting treatment options in emergency situations. Until four-factor prothrombin complex concentrates (PCCs) become available in the United States, the obtainable options are activated PCC, three-factor PCCs, and recombinant factor VIIa. Conclusion Although there is currently no gold standard of measurement for any of the newer anticoagulants, the published literature enables practitioners to evaluate the efficacy and sensitivity of a majority of these assays. Prohemostatic agents can be used in instances of severe, life-threatening hemorrhagic complications.     

Spotlight on dabigatran etexilate in the prevention of stroke and systemic embolism in patients with atrial fibrillation

The need for safe, effective and easily administered and monitored antithrombotic treatments that do not have the issues common to warfarin treatment has led to the development of new anticoagulant drugs. Dabigatran etexilate (Pradaxa?, Pradax?) is a prodrug of the direct thrombin inhibitor dabigatran, a direct, reversible, potent inhibitor of thrombin. Dabigatran does not interact with food, and is associated with very few known drug interactions. Dabigatran etexilate, at dosages of 110 and 150 mg twice daily, was shown to be noninferior to warfarin with regard to the incidence of stroke or systemic embolism in a large, randomized, partially blinded, multicentre study in a wide spectrum of patients with atrial fibrillation. Moreover, the higher dosage was associated with significantly greater efficacy than warfarin in this regard. These results were supported by secondary endpoints and subgroup analyses. In general, dabigatran etexilate is well tolerated, although it is associated with a higher rate of dyspepsia than warfarin. Major bleeding was as common in recipients of the higher dosage as, and less common in recipients of the lower dosage of dabigatran etexilate than, that in recipients of warfarin, and intracranial bleeding, life-threatening major bleeding and total bleeding were less common in recipients of either dabigatran etexilate dosage than in warfarin recipients. However, the higher dosage of dabigatran etexilate was associated with a higher rate of gastrointestinal bleeding than warfarin was. The incidence of hepatotoxicity did not significantly differ across treatment groups. In conclusion, dabigatran etexilate 150 mg twice daily is more effective than warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and is generally well tolerated, particularly with regard to bleeding endpoints compared with warfarin. It requires more frequent administration than warfarin, but provides multiple improvements to various issues associated with warfarin administration. Direct comparisons with other new anticoagulant drugs would be beneficial, as would further investigation into the effects in different patient populations, long-term effects, and the gastrointestinal bleeding and dyspepsia observed with dabigatran etexilate treatment. Dabigatran etexilate is a promising new option for the prevention of stroke and systemic embolism in patients with atrial fibrillation.     

Clinical Experience of Life-Threatening Dabigatran-Related Bleeding at a Large,Tertiary Care,Academic Medical Center: a Case Series

Introduction

Dabigatran, an oral direct thrombin inhibitor, is FDA approved for the prevention of stroke in patients with nonvalvular atrial fibrillation. No agent exists for the reversal of dabigatran-related major bleeding. Prothrombin complex concentrate (PCC) has been studied in reversal but was not shown to affect the surrogate markers of bleeding such as the thrombin time, ecarin clotting time, or activated partial thromboplastin time (aPTT). Recombinant factor VIIa (rFVIIa) may provide benefit in patients with life-threatening or major bleeding; however, it has not been studied in dabigatran-related bleeding. PCC and rFVIIa are agents utilized at our institution for major bleeding in patients receiving anticoagulant therapy. Due to the high cost and thrombogenic risk of both rVIIa and PCC and lack of a clear reversal strategy, we reviewed the management of all reported cases of dabigatran-related bleeding.

Methods

This was a retrospective chart review of patients admitted to UMass Memorial Medical Center with a bleeding event and also receiving dabigatran therapy.

Results

Eleven patients on dabigatran admitted for bleeding were identified. Seven were admitted for an intracranial hemorrhage (ICH) and four for a gastrointestinal hemorrhage (GIH). The baseline characteristics are as follows: mean age was 74.55 years (range, 63–89), and seven were male. Admission mean hemoglobin was 11.88 g/dl (range, 6.1–18), mean international normalized ratio (INR) was 2.2 (range, 1.1–7.1), and mean aPTT was 42.21 s (range, 36–81.4). Interventions received included fresh frozen plasma (n = 6), platelets (n = 3), packed red blood cells (n = 4), rFVIIa (n = 2), intravenous fluids (n = 10), surgical intervention (n = 3), and dialysis (n = 2). No patients received PCC. Four patients survived in the ICH group, and four patients survived in the GIH group.

Conclusion

Reversal strategies for dabigatran-related bleeding events at our institution are highly variable. Intracranial hemorrhage in patients on dabigatran was associated with 43 % mortality. Patients with severe dabigatran-related bleeding may benefit from a standardized approach to treatment.     

Dabigatran: Review of Pharmacology and Management of Bleeding Complications of This Novel Oral Anticoagulant

Dabigatran (Pradaxa) is a competitive direct thrombin inhibitor approved by the US FDA for prevention of embolic stroke in patients with nonvalvular atrial fibrillation. Dabigatran has a pharmacokinetic profile that produces predictable anticoagulation responses, does not undergo CYP 450 metabolism, has few drug-drug and drug-food interactions, and does not require frequent laboratory monitoring of clotting parameters. Clinicians are rapidly prescribing this agent as a replacement for warfarin therapy. However, no therapeutic agent has been accepted to reliably reverse the hemorrhagic complications of dabigatran. As of yet, there is no solid evidence to guide management of bleeding complications; management should start with local control of bleeding when possible and transfusion of pRBCs if needed. Transfusion of FFP would not be expected to help control bleeding. Limited and mixed data exist for transfusion of factor VIIa and prothrombin complex concentrates; these therapies should be considered as well as dialysis, which will increase elimination in patients with life-threatening or closed-space bleeding due to dabigatran. We present an article that reviews the pharmacokinetics, clinical trial literature, and consensus guidelines regarding this novel oral anticoagulant.     

达比加群酯相关肾损伤的定性系统评价

目的：探讨达比加群酯相关肾损伤的临床特点及其防治,为安全用药提供参考。方法：检索PubMed、Ovid、Web of Science、Embase、Springer-link、Wiley Oline Library、CNKI、万方数据库和维普数据库,收集达比加群酯相关肾损伤的文献,检索时限均为建库截至2019年1月,提取相关数据进行分析。结果：初筛相关文献156篇,最终纳入符合标准的文献14篇,均来自国外期刊。14篇文献包括达比加群酯相关肾损伤患者14例,其中男9例,女5例;年龄59~89岁,中位年龄为80岁;临床表现主要为出血,其中以血尿为主;在达比加群酯相关肾损伤治疗后,4例肾功能恢复,4例肾功能改善,3例肾功能未恢复,3例肾功能恶化。结论：达比加群酯可能导致肾损伤,在肾损伤相关疾病的基础上也可能导致达比加群酯毒性增加,在出现危及生命的出血的紧急情况下血液透析不一定能达到很好疗效,可使用达比加群酯逆转剂——依达赛珠单抗（idarucizumab）解毒。临床在使用时,应权衡药物使用的利弊,以及时应对不良反应的防治、发生及处理。     

凝血酶时间比值对非瓣膜性房颤患者服用达比加群酯后出血风险预测研究

目的 寻找新的抗凝参数以监测非瓣膜性房颤患者服用达比加群酯后的出血风险。方法 本研究为回顾性队列研究,以2018年11月—2019年10月接受达比加群酯110 mgbid治疗的非瓣膜性房颤患者为研究对象。通过比较长期使用组和初次使用组,出血组和未出血组间的临床统计学数据,筛选最佳监测指标。使用Logistic回归分析确定出血的相关影响因素,绘制ROC曲线并寻找最佳临界值以预测出血事件。结果 本研究共纳入了487例患者,在长期使用组中,出血事件的发生率为14.1%(35/249)。所有患者均进行了6项常规凝血功能检测,包括凝血酶时间/凝血酶时间比,活化部分凝血酶原时间/活化部分凝血酶原时间比,凝血酶原时间/国际标准化比值。通过Logistic回归分析确定凝血酶时间(thrombintime,TT)比值是与出血事件相关的唯一独立变量。使用TT比值区分患者有无发生出血,临界值为16.25,灵敏度为31.4%,特异性为94.0%,曲线下面积为0.65。结论 研究表明TT比值>16.25是出血的独立危险因素,可用于评估接受达比加群酯治疗的非瓣膜性房颤患者的出血风险。     

Long-term outcome in patients with non-valvular atrial fibrillation on dabigatran: a prospective cohort study

ABSTRACT

Introduction: Most studies on thromboembolic and bleeding risk in patients with non-valvular atrial fibrillation (NVAF) exposed to non-vitamin K oral anticoagulants stem from interrogation of insurance databases.

Areas covered: We studied 742 consecutive patients with NVAF who started treatment with dabigatran in three hospitals in Italy. Average follow-up was 1.80 years.

Mean age was 76.2 years. CHA₂DS₂VASc score was 0–1 in 37 (5%), 2 in 97 (13%) and ≥ 3 in 604 (82%) patients. NVAF was permanent in 349 (48%). Overall, 76% of patients remained on treatment over the entire follow-up period. Among 180 patients who discontinued permanently, the most frequent reasons were dyspepsia (33.9%), bleeding (17.8%), and renal worsening (12.1%). About 48% and 74% of permanent discontinuations occurred during the first 6 and 12 months of treatment, respectively. Rates of major events (per 100 patient-years) were 0.75 for stroke, 0.31 for myocardial infarction, 1.50 for all-cause death, and 1.80 for major bleedings. The rate of intracranial bleedings was 0.45 and that of major gastrointestinal bleedings was 0.75.

Expert opinion: This prospective cohort study confirms the low incidence of stroke, major bleeding and intracranial bleeding, and a 76% persistence with treatment, in patients with NVAF treated with dabigatran over about 2 years.     

Effectiveness and safety of direct oral anticoagulants in atrial fibrillation patients switched from vitamin K antagonists: A systematic review and meta‐analysis

A substantial proportion of atrial fibrillation patients initiating direct oral anticoagulants (DOAC) are vitamin K antagonists (VKA)‐experienced, for example switchers from VKA to DOAC. With this study, we aimed to summarize available evidence on the effectiveness and safety of DOAC vs VKA in real‐life VKA‐experienced atrial fibrillation patients. We searched EMBASE, MEDLINE and Cochrane Library systematically for English‐language studies indexed any time before October 2018. We included studies of VKA‐experienced atrial fibrillation patients initiating DOAC therapy, with continued VKA therapy as comparator. Outcomes included arterial thromboembolism and bleeding. When appropriate, meta‐analysis was performed by calculating pooled, weighted and adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Eight cohort studies comparing VKA‐experienced DOAC (dabigatran or rivaroxaban) users with continued VKA users were included. When comparing DOAC to VKA, an increased risk of ischaemic stroke and myocardial infarction was found for dabigatran (pooled aHR of 1.61 [95% CI 1.19‐2.19, I² = 65%] and 1.29 [95% CI 1.10‐1.52, I² = 0%], respectively), but not for rivaroxaban. The use of dabigatran in VKA‐experienced users was associated with an increased risk of gastrointestinal bleeding (pooled aHR 1.63 [95% CI 1.36‐1.94, I² = 30%]), but a decreased risk of intracranial bleeding (pooled aHR 0.45 [95% CI 0.32‐0.64, I² = 0%]). In conclusion, the use of dabigatran in prior VKA users in clinical practice was associated with a slightly increased risk of arterial thromboembolism and gastrointestinal bleeding, but a decreased risk of intracranial bleeding. Importantly, observational studies of real‐life VKA‐experienced oral anticoagulant users may be confounded by the reason for switching.