Novel anticoagulants for stroke prevention in atrial fibrillation and chronic kidney disease

Atrial fibrillation (AF) is about three-times more prevalent in patients with chronic kidney disease and the prevalence of AF increases with the degree of renal impairment. Clinical studies have shown increased risk of stroke, bleeding and death in patients with chronic kidney disease and AF. Despite, this increased risk, anticoagulation is underutilized due to increased bleeding risk in this population. Recently direct thrombin inhibitors and factor Xa inhibitors have been shown to be more efficacious in stroke prevention with reduced bleeding than warfarin. As the usage of these novel anticoagulants increases it is important to understand the data available in regard to these high risk patients.     

Advances in anticoagulation: focus on dabigatran, an oral direct thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor with a rapid onset. Patients on dabigatran do not require coagulation monitoring. Recent prospective randomized trials have shown the efficacy of dabigatran for the prevention of venous thromboembolism after knee or hip arthroplasty and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Because dabigatran is cleared principally by the kidneys, dosage adjustments are required in the setting of renal dysfunction. There currently is no reversal agent for dabigatran although hemodialysis can facilitate its rapid removal in life-threatening circumstances. The management of severe bleeding associated with dabigatran also may include the administration of a procoagulant, such as recombinant activated factor VII. Based on recent guidelines, regional anesthesia should be used cautiously in patients taking this novel oral thrombin inhibitor.     

新型抗凝药Dabigatran或将成为华法林替代品用于治疗静脉血栓栓塞

在过去的60年里,维生素K拮抗剂华法林一直作为抗凝剂用于多种适应证,包括静脉血栓栓塞（VTE）。但有专家称,华法林可能是市场上最具危险性的药物之一。该药不仅疗效具有很大的个体差异,且可与其他许多药物和食物产生不良的相互作用,用药者需每2～3周作1次血液检查,以确保用药安全。虽经数十年的研究,目前尚无合适的华法林替代品上市,在欧盟获准上市用于VTE的口服直接凝血酶抑制剂ximelagatran（Exanta）却因发现可致肝损伤而备受冷落。     

Dabigatran etexilate for venous thromboembolism: a safety evaluation

Introduction: Recently, new oral anticoagulants (NOACs) have become available to treat thromboembolic disorders. The efficacy and safety of these agents have been thoroughly tested in various clinical trials. In this article, we discuss the evidence for the safety and efficacy of dabigatran in the prevention and treatment of venous thromboembolism (VTE).

Areas covered: We discuss the pharmacology of dabigatran and compare it to that of warfarin and two of the other popular NOACs, rivaroxaban and apixaban. The indications for and evidence behind dabigatran in the prevention of VTE are presented, as well as the trials examining its potential use for the treatment and extended treatment of VTE. We conclude by considering the safety aspects of the drug.

Expert opinion: For most patients the overall net clinical benefit would seem to be in favour of dabigatran. Both efficacy and safety have been proven in the setting of robust randomised controlled trials. ‘Real world’ registry data as well as long-term trial follow-up will add further critical information. Long-term experience might be one of the few advantages warfarin still has over dabigatran in patients who are eligible for both.     

Insights from the dabigatran versus warfarin in patients with atrial fibrillation (RE-LY) trial

Oral anticoagulants such as warfarin have been used widely for the treatment of venous thromboembolism and stroke prevention in atrial fibrillation (AF) patients. Warfarin has significant limitations and also requires frequent monitoring. Thus, there is an unmet need, with the quest for alternative oral anticoagulants with stable pharmacokinetics and pharmacodynamics that do not need monitoring. The paper under evaluation provides us with up-to-date information on the safety and efficacy of a new oral anticoagulant, dabigatran, compared with warfarin for stroke prevention in AF patients.     

Treating arrhythmias: an expert opinion

Introduction: Significant progress has recently been made in the pharmacological treatment of arrhythmias. This concerns mainly atrial fibrillation, which affects millions of patients.

Areas covered: This review covers recent, clinically relevant developments in arrhythmia treatment, especially with regard to novel agents for the management of atrial fibrillation: dronedarone for rhythm control, vernakalant for pharmacological conversion, and advances in antithrombotic treatment. The field of pharmacological treatment of ventricular arrhythmias is also briefly discussed. Relevant papers were identified by an extensive Pubmed search using appropriate keywords.

Expert opinion: Dronedarone has been proposed as one of the first-choice antiarrhythmic drugs for almost all categories of patients with atrial fibrillation. However, its effectiveness in prevention of arrhythmia recurrences is less than that of amiodarone. Administration to patients with severe heart failure is associated with increased mortality and should be avoided. There are also very recent reports over rare but severe cases of hepatic injury in patients treated with dronedarone, including two cases of acute liver failure leading to liver transplant. Intravenous vernakalant is effective for the rapid pharmacological conversion of atrial fibrillation. Dabigatran, an oral direct thrombin inhibitor, has been shown to be effective in stroke reduction without increase in bleeding rates; additionally, no monitoring of antithrombotic effectiveness is needed. Rivaroxaban, an oral direct factor Xa inhibitor, has also shown promising results. These developments in the pharmacological treatment of arrhythmia will presumably affect clinical decision making.     

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.     

New anticoagulants for the prevention of stroke in atrial fibrillation

Oral anticoagulation in atrial fibrillation is obligatory to lower the risk of spontaneous cerebrovascular and systemic thromboembolism. For this purpose, vitamin K antagonists (coumarins) have been recommended as the most effective drugs for a long time. However, problems with the practical use of these agents, e.g. the need for frequent and regular coagulation controls, the inter‐individual differences in maintaining a stable therapeutic range, as well as drug or food interactions, have led to the search and investigation of alternative compounds characterized by a more simple use (e.g. without regular controls of therapeutic levels), high efficacy, as well as low risk of bleeding. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban and apixaban have recently been investigated to prove whether they fulfill the high expectancy of an ideal anticoagulant with respect to a more favorable efficacy/safety profile and without the need for coagulation controls, thereby improving quality of life. Dabigatran (RE‐LY) achieved an impressive reduction in stroke and non‐central nervous system (non‐CNS) embolism (110 mg: 1.5%/year; 150 mg: 1.1%/year) in contrast to warfarin (1.7%/year; P = 0.34 and P < 0.001) with a favorable action on bleeding hazards. The results of rivaroxaban which were obtained in the ROCKET AF study (on treatment analysis: stroke and non‐CNS embolism: 1.7%/year vs. 2.15%/year with warfarin; P = 0.015; primary safety endpoint major and minor bleeding: 14.91 vs. 14.52%; P = 0.442) point in the same direction. And finally, compared to aspirin, apixaban reduced the combined primary efficacy endpoint by 52% with comparable rates of bleeding (AVERROES). This review gives a summary of the current knowledge about these agents and their potential future importance.