Herbert Noack

A comparison of dabigatran etexilate with warfarin in patients with mechanical heart valves: THE Randomized, phase II study to evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart valve replacement (RE-ALIGN).

BACKGROUND Vitamin K antagonists are the only oral anticoagulants approved for long-term treatment of patients with a cardiac valve replacement. OBJECTIVE This study aims to test a new dosing regimen for dabigatran etexilate in patients with a mechanical bileaflet valve. METHODS Patients aged ≥ 18 years and ≤ 75 years, either undergoing implantation of a mechanical bileaflet valve (aortic or mitral or both) during the current hospital stay or having undergone implantation a mitral bileaflet valve >3 months before randomization, will be randomized between dabigatran etexilate or warfarin (in a ratio of 2:1) in an open-label design. Initial doses of dabigatran will be based on the estimated creatinine clearance, and the doses will be adjusted based on measuring trough dabigatran plasma levels to achieve levels ≥ 50 ng/mL at steady state. Doses will range between 150 mg twice a day and 300 mg twice a day. Warfarin management and target international normalized ratio will be according to current practice guidelines at the discretion of the treating physicians. The plan is to treat 270 patients with dabigatran etexilate for a total study population of approximately 405 patients. Clinical efficacy and safety outcomes will be analyzed in an exploratory manner. CONCLUSIONS RE-ALIGN is the first study to test an alternative to warfarin in patients with mechanical heart valves. A definitive phase III study will be planned based on the results of this study.

Treatments for stroke prevention in atrial fibrillation: A network meta-analysis and indirect comparisons versus dabigatran etexilate

Patients with atrial fibrillation at moderate to high risk of stroke are not always anticoagulated despite a lack of contraindications to vitamin K antagonists (VKAs) like warfarin. These patients are treated with aspirin, aspirin-clopidogrel combination therapy or even receive no thromboprophylaxis. The oral direct thrombin inhibitor, dabigatran etexilate 150 mg BID and 110 mg BID, might represent an alternative for these patients; however, no head-to-head clinical trial data exist versus these alternative treatments. A network meta-analysis (NMA) was performed to indirectly compare dabigatran etexilate with antiplatelets and placebo. Compared with placebo, dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke (ischaemic and haemorrhagic) by 75% (relative risk [RR] 0.25; 95% confidence interval [CI] 0.12-0.51), ischaemic stroke by 77% (RR 0.23; 95% CI 0.14-0.38), systemic embolism by 83% (RR 0.17; 95% CI 0.05-0.50) and mortality by 36% (RR 0.64; 95% CI 0.45-0.91). Dabigatran etexilate 150 mg BID was estimated to significantly reduce the risk of any stroke compared with aspirin monotherapy by 63% (RR 0.37; 95% CI 0.20-0.69) and aspirin plus clopidogrel by 61% (RR 0.39; 95% CI 0.21-0.72). Trends toward reduced risk with both dabigatran etexilate regimens were found for most clinical outcomes. Relative risk estimates of dabigatran etexilate versus adjusted-dose VKAs within the NMA were consistent with results from the head-to-head randomised trial of these two strategies. Indirect evidence suggests treatment with dabigatran etexilate offers benefit for the prevention of stroke, systemic embolism and mortality over antiplatelets and placebo. There was no indication of increased intracranial or extracranial haemorrhage with dabigatran etexilate compared to antiplatelet agents.

Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Substudy of the RE-LY trial.

In patients with atrial fibrillation (AF) who require interruption of dabigatran or warfarin for an elective surgery/procedure, the risks and benefits of perioperative bridging anticoagulation is uncertain.We accessed the database from RE-LY, a randomised trial comparing dabigatran with warfarin for stroke prevention in AF, to assess the potential benefits and risks of bridging. In patients who had a first interruption of dabigatran or warfarin for an elective surgery/procedure, we compared the risk for major bleeding (MB), stroke or systemic embolism (SSE) and any thromboembolism (TE) in patients who were bridged or not bridged during the period of seven days before until 30 days after surgery/procedure. We used multivariable Cox regression to adjust for potential confounders.Bridging was used more during warfarin interruption than dabigatran interruption (27.5 % vs 15.4 %; p< 0.001). With dabigatran interruption, bridged patients had more MB (6.5 % vs 1.8 %, p< 0.001) than those not bridged but bridged and not bridged groups did not differ for any TE (1.2 % vs 0.6 %, p=0.16) and SSE (0.5 % vs 0.3 %, p=0.46). With warfarin interruption, bridged patients had more MB (6.8 % vs 1.6 %, p< 0.001) and any TE (1.8 % vs 0.3 %, p=0.007) than those not bridged but bridged and not bridged groups did not differ for SSE (0.5 % vs 0.2 %, p=0.321). In conclusion, in patients who interrupted dabigatran or warfarin for a surgery/ procedure in the RE-LY trial, use of bridging anticoagulation appeared to increase the risk for major bleeding irrespective of dabigatran or warfarin interruption.

Major bleeding in patients with atrial fibrillation receiving vitamin K antagonists: a systematic review of randomized and observational studies

Aims Clinical trials have shown that anticoagulation with vitamin K antagonists (VKAs), e.g. warfarin, decreases the risk of stroke in patients with atrial fibrillation (AF); however, increased bleeding risk is one of the safety concerns. The primary objective was to conduct a systematic review of the published literature, assessing the risk of major bleeding and mortality in patients with AF treated with VKAs. Methods and results Online searches of MEDLINE, EMBASE, BIOSIS, and the Cochrane Library were performed to a pre-specified protocol from 1960 to March 2012 for randomized controlled trials (RCTs) and from January 1990 to March 2012 for observational studies. A total of 47 studies (16 RCTs and 31 observational studies) were included. Cumulative follow-up was 61 563 patient-years for RCTs and 484 241 patient-years for observational studies. The overall median incidence of major bleeding was 2.1 per 100 patient-years (range, 0.9–3.4 per 100 patient-years) for RCTs and 2.0 per 100 patient-years (range, 0.2–7.6 per 100 patient-years) for observational studies. With study year as a proxy for changing management patterns, some evidence of bleeding rates and/or their reporting increasing over time was noted. Mortality rates from observational studies were inadequately reported to allow comparison with those from RCT data. Conclusion The median rate of major bleeding in observational studies and RCTs is similar. The larger heterogeneity in bleeding rates observed in a real-life setting could reflect a high variability in standard of care of patients on VKAs and/or methodological differences between observational studies and/or variability in data sources.

Efficacy and safety of dabigatran compared to warfarin in patients with paroxysmal, persistent, and permanent atrial fibrillation : results from the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) study

To the Editor: Dabigatran etexilate 150 mg twice daily (bid) is more effective than warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) with no increase in major bleeding ([1][1]). Dabigatran etexilate 110 mg bid reduces major bleeding compared to

Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism in patients aged over 75 years or with moderate renal impairment undergoing total knee or hip replacement.

Oral dabigatran etexilate is indicated for the prevention of venous thromboembolism (VTE) in patients undergoing total knee replacement or total hip replacement. We investigated the cost-effectiveness of the 150 mg once daily (od) dose recommended for patients aged over 75 or with moderate renal impairment, from a United Kingdom National Health Service perspective. Dabigatran etexilate was compared with subcutaneous enoxaparin 40 mg od, using a decision model. Risks for VTE and bleeding were derived from subgroup analyses of the phase III trials. Dabigatran etexilate was less costly than enoxaparin; cost savings varied from pound62 to pound274 (base-case analyses) and were primarily due to differences in administration costs. Results were robust across a range of sensitivity analyses. Dabigatran etexilate 150 mg od is cost saving compared with enoxaparin 40 mg od in patients aged over 75years and in patients with moderate renal impairment, with comparable efficacy and safety.

Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy).

Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.Background: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. Methods: This is a post hoc analysis of the RE-LY trial. Results: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16–1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88–1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56–0.95 with VHD; HR, 0.84; 95% CI, 0.71–0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64–1.06) or without VHD (HR, 0.98; 95% CI, 0.83–1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37–0.93) and those without VHD (HR, 0.67; 95% CI, 0.52–0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65–1.45; and HR, 0.88; 95% CI, 0.70–1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. Conclusions: The presence of any VHD did not influence the comparison of dabigatran with warfarin. Clinical Trial Registration: URL: . Unique identifier: [NCT00262600][1]. # Clinical Perspective {#article-title-14} [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00262600&atom=%2Fcirculationaha%2F134%2F8%2F589.atom

Comparison of dabigatran versus warfarin in diabetic patients with atrial fibrillation: Results from the RE-LY trial

OBJECTIVE Diabetes mellitus (DM) is frequent among patients with atrial fibrillation (AF). The RE-LY trial permits evaluation of patient characteristics, outcomes and the effectiveness of dabigatran etexilate among diabetic individuals. METHODS Patient characteristics and outcomes were compared between diabetic and non-diabetic patients and the relative efficacy of each dose of dabigatran (150 mg bid and 110 mg bid) versus warfarin was evaluated. RESULTS Of 18,113 patients in RE-LY, 4221 patients (23.3%) had DM. Patients with DM were younger (70.9 vs. 71.7 years), more likely to have hypertension (86.6% vs. 76.5%), coronary artery disease (37.4% vs. 24.9%) and peripheral vascular disease (5.6% vs. 3.2%); (all p<0.01). Time in therapeutic range for warfarin-treated patients was 65% for diabetic versus 68% for non-diabetic patients (p<0.001). Regardless of assigned treatment, stroke or systemic embolism was more common among patients with DM (1.9% per year vs. 1.3% per year, p<0.001). DM was also associated with an increased risk of death (5.1% per year vs. 3.5% per year, p<0.001) and major bleeding (4.2% per year vs. 3.0% per year, p<0.001). The absolute reduction in stroke or systemic embolism with dabigatran compared to warfarin was greater among patients with DM than those without DM (dabigatran 110 mg: 0.59% per year vs. 0.05% per year; dabigatran 150 mg: 0.89% per year vs. 0.51% per year). CONCLUSIONS Compared to non-DM patients, AF patients with DM derive a greater absolute risk reduction in embolic events when treated with dabigatran. ClinicalTrials.gov Identifier: NCT00262600.

Thromboprophylaxis with dabigatran etexilate in patients over seventy-five years of age with moderate renal impairment undergoing or knee replacement

PURPOSE Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation. METHODS We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran. RESULTS Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin. CONCLUSION For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.

Assessing the impact of dabigatran and warfarin on health-related quality of life: Results from an RE-LY sub-study

BACKGROUND Anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent strokes. Vitamin K antagonists, such as warfarin, are associated with numerous practical limitations--frequent anticoagulation monitoring, lifestyle and dietary restrictions--that complicate patient management and may impact health-related quality of life (HRQoL). This study derived HRQoL estimates for AF patients receiving warfarin or dabigatran etexilate (dabigatran), a new oral anticoagulant not requiring anticoagulation monitoring, during one year of stable treatment, i.e. in the absence of outcome events, such as strokes or major bleedings. METHODS Changes in HRQoL over time and between treatments were assessed using the EQ-5D (utility and Visual Analogue Scale (VAS) scores) at baseline, 3 and 12 months in a sub-group of 1435 patients participating in the RE-LY trial. RE-LY was a phase III study that compared the safety and efficacy of warfarin, dabigatran 150 mg bid and dabigatran 110 mg bid for stroke prevention in patients with AF. RESULTS Utilities ranged from 0.805 (dabigatran 150 mg bid) to 0.811 (dabigatran 110 mg bid) at baseline, and did not change over the one year observation period. No differences between the dabigatran groups and warfarin were statistically significant except for the dabigatran 150 mg bid group at 3 months. Similarly, none of the within-group or between-group differences in VAS scores were statistically significant. CONCLUSIONS Over the course of one year, all anticoagulated patients without outcome events (e.g. strokes or major bleedings) had stable HRQoL. Scores between dabigatran and warfarin were comparable, which was unexpected given the known complexities of warfarin treatment.