Acute Stroke Management in Patients Taking Dabigatran

Dabigatran etexilate is emerging as an alternative for vitamin K antagonists, but evidence‐based guidelines for management of intracerebral hemorrhage and acute ischemic stroke in patients taking this drug are nonexistent. This review summarizes current knowledge on key pharmacological features and the assessment of dabigatran activity. Pragmatic approaches are provided for individualized decision taking with regard to hemostatic therapy and reperfusion strategies in acute stroke patients.     

Direct inhibitors of thrombin, hirudin, bivalirudin, and dabigatran etexilate

Thrombin inhibition is an important objective in the prevention and treatment of thrombosis. A new molecule, dabigatran etexilate or Pradaxa(?), has been recently licensed for thromboprophylaxis in major orthopedic surgery in several countries but not in the USA. In contrast, the FDA has approved it for prevention in patients with non-valvular atrial fibrillation. This new orally active anticoagulant is being developed for the treatment of venous thromboembolism and acute coronary syndromes in patients with non-valvular atrial fibrillation. Dabigatran is a reversible inhibitor of free thrombin and clot-bound thrombin. An oral thrombin inhibitor melagatran is no longer available due to hepatic toxicity. Several other thrombin inhibitors are used via parenteral administration: lepirudine and desirudine, bivalirudine and argatroban. They are mostly given to patients with heparin-induced thrombocytopenia (HIT). Bivalirudine is used for acute coronary syndrome in patients undergoing percutaneous interventions. The main pharmacologic characteristics of thrombin inhibitor agents are presented focusing on dabigatran etexilate and including the main results of clinical trials.     

A new approach with anticoagulant development: tailoring anticoagulant therapy with dabigatran etexilate according to patient risk

Introduction: Although vulnerable patients, including the elderly and those with renal impairment or low body weight, are at greater risk of bleeding and/or venous thromboembolism following total hip or total knee replacement, there have been few clinical studies to determine the optimal dose of anticoagulants for this group.

Areas covered: For this paper the authors searched the literature for data on efficacy and bleeding rates with low-molecular-weight heparins and fondaparinux in routine clinical practice; and on the effects of standard or reduced dosing with these anticoagulants or with the oral direct thrombin inhibitor dabigatran etexilate in vulnerable patient groups.

Expert opinion: Tailoring anticoagulation therapy according to the risk of individual patients is the best way to optimize the benefit/risk of thrombosis and bleeding, and is recommended on treatment guidelines. Specific recommendations for dose reduction have been made for fondaparinux in renal impairment. The availability of two approved doses of dabigatran etexilate for thromboprophylaxis following orthopedic surgery allows the dose to be tailored to the individual patient's characteristics, based on the age and renal function of the patient, as recommended by the European Medicines Agency, in order to maintain efficacy while decreasing bleeding risk.     

The hidden costs of anticoagulation in hospitalized patients with non-valvular atrial fibrillation

Introduction: Non-valvular atrial fibrillation (NVAF) and ischemic stroke are collectively associated with annual hospital costs of tens of billions of dollars in the USA. Oral anticoagulant (OAC) treatment with warfarin reduces the risk of stroke in patients with NVAF. Unfortunately, because of the complexity of warfarin therapy and potential for adverse events (AEs), many patients who might benefit go untreated or receive suboptimal therapy, increasing their stroke and/or bleeding risk.

Areas covered: This review explores current hospital costs and resource utilization for NVAF patients on warfarin therapy and the potential impact of newer OACs in this area.

Expert opinion: Many ischemic strokes could be prevented through wider use of OACs. Further, admissions due to anticoagulant-associated AEs could be reduced by optimizing OAC therapy. In the hospital, specialized anticoagulation services can decrease costs by improving the effectiveness of warfarin management, empowering patients through education and optimizing care transitions. With fewer interactions and no dose titration or monitoring required, the novel OACs (NOACs) have the potential to further decrease inpatient resource utilization and costs. It is important that, as data become available, inpatient costs are included in cost–benefit comparisons between warfarin and the NOACs.     

Oral anticoagulant use in addition to antiplatelet therapy for secondary prevention in acute coronary syndrome: current perspectives

Patients with acute coronary syndrome (ACS) are typically managed with long-term dual antiplatelet therapy of acetylsalicylic acid plus a P2Y₁₂ platelet receptor antagonist; however, although effective, the risk of another vascular event within 12 months remains at approximately 10%. Considerable efforts have been made to find improved therapeutic approaches to secondary prevention in ACS. The ATLAS ACS 2-TIMI 51 trial demonstrated that rivaroxaban (2.5 mg twice daily) significantly reduced recurrent vascular events, increased the risk of major bleeding but not the risk of fatal bleeding, and resulted in reduced rates of death from cardiovascular causes. These results formed the basis for approval in Europe of rivaroxaban (2.5 mg twice daily) in conjunction with standard antiplatelet therapy for the secondary prevention of ACS.     

The status and future directions of cardiac surgery

Oral anticoagulation is the mainstay of therapy for stroke prevention in patients with atrial fibrillation. Vitamin K antagonists such as warfarin reduce the risk of cardioembolic stroke by approximately two-thirds compared with no treatment, but are limited by their unpredictable anticoagulant effect and narrow therapeutic index. Warfarin therapy requires routine coagulation monitoring, which is inconvenient for patients and costly for the healthcare system. The limitations of the vitamin K agonists have spurred the development of new oral anticoagulants that selectively inhibit thrombin or factor Xa. The Randomized Evaluation of Long-Term Anticoagulation (RE-LY) trial of 18,113 patients with nonvalvular atrial fibrillation and at least one additional risk factor for stroke demonstrated that dabigatran etexilate given at a dose of 150 mg twice daily compared with warfarin, reduced the rate of stroke or systemic embolism by one-third with a similar rate of major bleeding, whereas dabigatran etexilate given at a dose of 110 mg twice daily compared with warfarin had a similar rate of stroke or systemic embolism and reduced the rate of major bleeding by one-fifth. Both doses of dabigatran etexilate reduced intracranial bleeding by approximately two-thirds compared with warfarin. Based on the results of the RE-LY trial, both the US FDA and Health Canada recently approved dabigatran etexilate for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.     

达比加群酯联合阿司匹林在非瓣膜性房颤治疗中的 应用效果及安全性评价

目的分析非瓣膜性心房颤动(房颤)患者使用达比加群酯联合阿司匹林进行治疗的临床疗效及安全性。方法120例非瓣膜性房颤患者,根据随机数字表法分为对照组和实验组,各60例。对照组患者采用常规抗凝治疗,实验组患者采用达比加群酯联合阿司匹林治疗。对比两组患者的治疗效果及不良反应发生情况。结果实验组患者的治疗总有效率为93.33%(56/60),高于对照组的73.33%(44/60),差异具有统计学意义(P<0.05)。实验组患者的不良反应发生率为23.33%(14/60),低于对照组的51.67%(31/60),差异具有统计学意义(P<0.05)。结论应用达比加群酯联合阿司匹林治疗非瓣膜性房颤可取得显著的疗效且安全性高,值得在临床上推广和应用。     

Reversing the anticoagulation effects of dabigatran

The standard of care for oral anticoagulation therapy has primarily been warfarin, which is limited by its indirect mechanism-of-action, variable kinetics, tolerability, and routine monitoring concerns. The direct-acting oral anticoagulants (DOACs) have predictable pharmacokinetics and pharmacodynamics, and improved safety and efficacy compared to warfarin for the prevention of stroke in patients with nonvalvular atrial fibrillation and prevention or management of venous thromboembolism.

Consequential bleeding is a concern with all anticoagulants. Vitamin K is not a rapid reversal agent for warfarin; rather it facilitates synthesis of new vitamin K-dependent clotting factors, which can take longer than 24 h. Other nonspecific agents, including recombinant activated factor VII, three- and four-factor prothrombin complex concentrates (PCC), and activated PCC or Factor Eight Inhibitor Bypassing Activity (FEIBA®), are options based on clinical need.

Specific agents to quickly reverse the effects of DOACs have been under development, and idarucizumab, a monoclonal antibody fragment that rapidly binds dabigatran, has been approved for clinical use in cases of dabigatran-related life-threatening bleeding, or if a dabigatran-treated patient needs emergency surgery or an invasive procedure. Idarucizumab specifically and rapidly reverses dabigatran-induced anticoagulation as measured by established coagulation assays. However, this does not guarantee complete hemostasis, especially if a patient has underlying comorbidities such as renal or liver disease, or has experienced recent trauma that requires urgent surgery. In these cases, concomitant supportive therapy and/or administration of concentrated clotting factors may be considered. Emerging data from ongoing trials and clinical experience will further inform providers regarding optimal approaches for anticoagulation reversal.