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

Objective To assess the cost-effectiveness of dabigatran etexilate, a new oral anticoagulant, versus warfarin and other alternatives for the prevention of stroke and systemic embolism in UK patients with atrial fibrillation (AF). Methods A Markov model estimated the cost-effectiveness of dabigatran etexilate versus warfarin, aspirin or no therapy. Two patient cohorts with AF (starting age of <80 and ≥80 years) were considered separately, in line with the UK labelled indication. Modelled outcomes over a lifetime horizon included clinical events, quality-adjusted life years (QALYs), total costs and incremental cost-effectiveness ratios (ICERs). Results Patients treated with dabigatran etexilate experienced fewer ischaemic strokes (3.74 dabigatran etexilate vs 3.97 warfarin) and fewer combined intracranial haemorrhages and haemorrhagic strokes (0.43 dabigatran etexilate vs 0.99 warfarin) per 100 patient-years. Larger differences were observed comparing dabigatran etexilate with aspirin or no therapy. For patients initiating treatment at ages <80 and ≥80 years, the ICERs for dabigatran etexilate were £4831 and £7090/QALY gained versus warfarin with a probability of cost-effectiveness at £20 000/QALY gained of 98% and 63%, respectively. For the patient cohort starting treatment at ages <80 years, the ICER versus aspirin was £3457/QALY gained and dabigatran etexilate was dominant (ie, was less costly and more effective) compared with no therapy. These results were robust in sensitivity analyses. Conclusions This economic evaluation suggests that the use of dabigatran etexilate as a first-line treatment for the prevention of stroke and systemic embolism is likely to be cost-effective in eligible UK patients with AF

No influence of dabigatran anticoagulation on hemorrhagic transformation in an experimental model of ischemic stroke

Background: Dabigatran etexilate (DE) is a new oral direct thrombin inhibitor. Clinical trials point towards a favourable risk-to-benefit profile of DE compared to warfarin. In this study, we evaluated whether hemorrhagic transformation (HT) occurs after experimental stroke under DE treatment as we have shown for warfarin. Methods: 44 male C57BL/6 mice were pretreated orally with 37.5 mg/kg DE, 75 mg/kg DE or saline and diluted thrombin time (dTT) and DE plasma concentrations were monitored. Ischemic stroke was induced by transient middle cerebral artery occlusion (tMCAO) for 1 h or 3 h. We assessed functional outcome and HT blood volume 24 h and 72 h after tMCAO. Results: After 1 h tMCAO, HT blood volume did not differ significantly between mice pretreated with DE 37.5 mg/kg and controls (1.5±0.5 µl vs. 1.8±0.5 µl, p>0.05). After 3 h tMCAO, DE-anticoagulated mice did also not show an increase in HT, neither at the dose of 37.5 mg/kg equivalent to anticoagulant treatment in the therapeutic range (1.3±0.9 µl vs. control 2.3±0.5 µl, p>0.05) nor at 75 mg/kg, clearly representing supratherapeutic anticoagulation (1.8±0.8 µl, p>0.05). Furthermore, no significant increase in HT under continued anticoagulation with DE 75 mg/kg could be found at 72 h after tMCAO for 1 h (1.7±0.9 µl vs. control 1.6±0.4 µl, p>0.05). Conclusion: Our experimental data suggest that DE does not significantly increase hemorrhagic transformation after transient focal cerebral ischemia in mice. From a translational viewpoint, this indicates that a continuation of DE anticoagulation in case of an ischemic stroke might be safe, but clearly, clinical data on this question are warranted

Bleeding with direct oral anticoagulants vs warfarin: clinical experience.

The risk of bleeding in the setting of anticoagulant therapy continues to be re-evaluated following the introduction of a new generation of direct oral anticoagulants (DOACs). Interruption of DOAC therapy and supportive care may be sufficient for the management of patients who present with mild or moderate bleeding, but in those with life-threatening bleeding, a specific reversal agent is desirable. We review the phase 3 clinical studies of dabigatran, rivaroxaban, apixaban, and edoxaban in patients with nonvalvular atrial fibrillation, in the context of bleeding risk and management

How we treat bleeding associated with direct oral anticoagulants

Direct oral anticoagulants are at least as effective as vitamin K antagonists for the prevention and treatment of thromboembolism. Unfortunately, differently from vitamin K antagonists, they have the great drawback of lacking specific antidotes in the case of bleeding or emergency situations such as trauma, stroke requiring thrombolysis, and urgent surgery. The progressive development of antidotes for these new drugs, which, it is hoped, will become available in the near future, will allow better and safer management of the rapid reversal of their anticoagulant effect

Reversal of the Anticoagulation Effects of Dabigatran Etexilate by Idarucizumab in Three Patients Needing Urgent Surgical Intervention and One Case of Intravenous Thrombolysis in Ischaemic Stroke

Objective: To describe the benefits of reversal of the anticoagulation effects of dabigatran etexilate in patients requiring urgent surgery or thrombolysis for ischaemic stroke. Materials and methods: Four patients, treated with dabigatran etexilate and presenting with cholecystitis, tibial fracture, lower limb ischaemia and ischaemic stroke, respectively. Results: Administration of idarucizumab normalized bleeding parameters and provided safe conditions for surgery and, in one case, successful thrombolysis of an ischaemic stroke. Conclusion: The introduction of an effective reversal agent for dabigatran etexilate allows physicians perform surgery under conditions of normal coagulation and permits thrombolysis in patients with ischaemic stroke despite being treated with dabigatran etexilate

Warfarin versus dabigatran etexilate: an assessment of efficacy and safety in patients with atrial fibrillation

dabigatran etexilate, warfarin, oral anticoagulation, atrial fibrillation, efficacy, safety.Introduction Oral anticoagulation is the mainstay for stroke and thromboembolic events prevention in patients with atrial fibrillation (AF). Given limitations of warfarin therapy non-vitamin K oral anticoagulants have been developed, including direct thrombin inhibitors (i.e. dabigatran etexilate). Dabigatran etexilate has been tested thoroughly in terms of efficacy and safety in clinical trials and studies, involving 'real world' cohorts. In this review currently available evidence in patients with non-valvular AF is discussed. Areas covered The pharmacology, efficacy and safety, and current aspects of use of dabigatran etexilate in patients with non-valvular AF are reviewed in comparative manner to warfarin both for chronic anticoagulation and in different clinical settings. Expert opinion Dabigatran etexilate appeared to have several pharmacokinetic and pharmacodynamic advantages over warfarin as well as a favourable efficacy and safety profile being at least non-inferior and often superior to warfarin in patients with non-valvular AF. The latter was shown in the clinical trials, meta-analyses and studies with 'real world' data. Currently ongoing trials will expand the body of evidence on warfarin and will aid decision-making in currently controversial areas. Important limitations of dabigatran etexilate include contraindications for its use in patients with prosthetic heart valves and end-stage chronic kidney disease

Evidence supporting idarucizumab for the reversal of dabigatran.

Idarucizumab is a monoclonal antibody fragment specifically targeted to dabigatran. It has demonstrated prompt and durable reversal of the anticoagulant effects of dabigatran in animal studies and phase 1 studies of young, elderly, and renally impaired volunteers. Although elective invasive procedures and most bleeding complications in dabigatran-treated patients can be managed by temporarily stopping dabigatran therapy and using supportive measures, there are rare clinical situations that require urgent reversal of the anticoagulant effect of dabigatran. The effectiveness and safety of 5 g of intravenous idarucizumab is being investigated in a prospective, open-label, single-cohort study in patients with serious bleeding or in those requiring an urgent procedure. In an interim analysis of the first 90 participants, idarucizumab rapidly and completely reversed the anticoagulant activity of dabigatran in 88%-98% of participants, and there were no safety concerns, with no deaths or serious adverse events being attributable to idarucizumab. Supported by these interim results, idarucizumab has been approved in the United States and the European Union for use when reversal of the anticoagulant effects of dabigatran is needed for emergency surgery/urgent procedures or in patients with life-threatening or uncontrolled bleeding. Clinical use of idarucizumab should follow the same processes as patient enrollment in this study, which is projected to be completed in 2016. The outcomes achieved with this specific reversal agent are likely to be of continued interest to treating physicians

Patient safety and estimation of renal function in patients prescribed new oral anticoagulants for stroke prevention in atrial fibrillation

OBJECTIVE: In clinical trials of dabigatran and rivaroxaban for stroke prevention in atrial fibrillation (AF), drug eligibility and dosing were determined using the Cockcroft-Gault equation to estimate creatine clearance as a measure of renal function. This cross-sectional study aimed to compare whether using estimated glomerular filtration rate (eGFR) by the widely available and widely used Modified Diet in Renal Disease (MDRD) equation would alter prescribing or dosing of the renally excreted new oral anticoagulants. PARTICIPANTS: Of 4712 patients with known AF within a general practitioner-registered population of 930 079 in east London, data were available enabling renal function to be calculated by both Cockcroft-Gault and MDRD methods in 4120 (87.4%). RESULTS: Of 4120 patients, 2706 were <80 years and 1414 were ≥80 years of age. Among those ≥80 years, 14.9% were ineligible for dabigatran according to Cockcroft-Gault equation but would have been judged eligible applying MDRD method. For those <80 years, 0.8% would have been incorrectly judged eligible for dabigatran and 5.3% would have received too high a dose. For rivaroxaban, 0.3% would have been incorrectly judged eligible for treatment and 13.5% would have received too high a dose. CONCLUSIONS: Were the MDRD-derived eGFR to be used instead of Cockcroft-Gault in prescribing these new agents, many elderly patients with AF would either incorrectly become eligible for them or would receive too high a dose. Safety has not been established using the MDRD equation, a concern since the risk of major bleeding would be increased in patients with unsuspected renal impairment. Given the potentially widespread use of these agents, particularly in primary care, regulatory authorities and drug companies should alert UK doctors of the need to use the Cockcroft-Gault formula to calculate eligibility for and dosing of the new oral anticoagulants in elderly patients with AF and not rely on the MDRD-derived eGFR