Efficacy and safety of dabigatran versus warfarin from the RE-LY trial.

Background: Current data for atrial fibrillation (AF) and stroke are predominantly derived from North American and European patients. Although the burden of AF is high in Latin America (LA), little is known about current management of AF in the region. Methods: We aimed to assess the consistency of efficacy and safety outcomes associated with dabigatran etexilate (DE) versus warfarin in patients with AF in LA from the RE-LY (Randomised Evaluation of Long-Term Anticoagulant Therapy) trial. Data from 956 LA patients and 17 157 non-LA patients were included in this analysis. χ2 test and Cox proportional regression analysis were performed. The primary efficacy outcome included all strokes or systemic embolism (SE). Main safety outcome was major bleeding. Results: LA patients were more often female, had higher proportion of permanent AF and lower creatinine clearance, among other characteristics. Vitamin K antagonist use at randomisation and time in therapeutic range were lower in LA than in non-LA patients (44% vs 63%, p<0.001; and 61.3±22.6% vs 64.6±19.6%, p=0.015, respectively). Efficacy endpoints were 0.91% versus 1.68% for DE 150 mg twice daily versus warfarin, respectively. Stroke/SE risk was lower in LA patients treated with DE 150 mg twice daily compared with warfarin, although not significant (HR 0.54; 95% CI 0.18 to 1.62). The annual stroke/SE rates for DE 110 mg twice daily versus warfarin were 1.82 versus 1.68, also not significantly different (HR 1.09; CI 0.44 to 2.67). There were no treatment-by-region interactions for either dose of DE on efficacy and safety outcomes. Conclusion: Despite differences in the clinical profile and AF management, the efficacy and safety benefits of dabigatran over warfarin in LA patients relative to non-LA patients are consistent with those observed in the main RE-LY trial.

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.

Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation.

AIMS: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. METHODS AND RESULTS: The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). CONCLUSION: Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.

Effectiveness and outcome of management strategies for dabigatran- or warfarin-related major bleeding events.

BACKGROUND: Strategies used for the management of dabigatran-related major bleeding events (MBEs), and their effectiveness have not been systematically evaluated. METHODS: Reports on 1034 individuals experiencing 1121 MBEs (696 on dabigatran, and 425 on warfarin) in 5 phase III randomized controlled trials were assessed independently by two investigators. RESULTS: MBEs were managed either by drug discontinuation only (37%), or drug discontinuation with either transfusion of only red cell concentrates (38%), or plasma (23%). Few MBEs (2%) were treated with coagulation factor concentrates. The effectiveness of the management was assessed as good in significantly larger proportion of MBEs on dabigatran (91%) than on warfarin (84%, odds ratio [OR] 1.68; 95% confidence interval [CI], 1.14-2.49), which was consistent with the lower 30-day mortality (OR (OR 0.66; 95% CI, 0.44-1.00)). The effectiveness of bleeding management in non-traumatic bleeding was better in patients with dabigatran than with warfarin (OR 1.82; 95% CI, 1.18-2.79) but was similar in traumatic bleeding (OR 0.75; 95% CI, 0.25-2.30). The relative effectiveness of management of bleeding and 30-day mortality rates across other key subgroups of patients or sites of bleeding, the use of platelet inhibitors, age-, sex- and renal function subgroups, were comparable in MBEs on dabigatran or warfarin. CONCLUSION: Despite the unavailability of a specific antidote at the time of these studies, bleeding in patients receiving dabigatran was managed in the overwhelming majority of patients without coagulation factor concentrates, with comparable or superior effectiveness and lower 30-day mortality rates versus those who bleed while receiving warfarin.

Comparison of Characteristics and Outcomes of Dabigatran Versus Warfarin in Hypertensive Patients With Atrial Fibrillation (from the RE-LY Trial).

Hypertension is frequent in patients with atrial fibrillation (AF) and is an independent risk factor for stroke. The Randomized Evaluation of Long Term Anticoagulant TherapY (RE-LY) trial found dabigatran 110 mg (D110) and 150 mg twice daily (D150) noninferior or superior to warfarin for stroke reduction in patients with AF, with either a reduction (D110) or similar rates (D150) of major bleeding. Baseline characteristics and outcomes were compared in patients with and without hypertension. The quality of blood pressure control was also assessed. In RE-LY, 14,283 patients (78.9%) had hypertension. The mean blood pressure at baseline was 132.6 ± 17.6/77.7 ± 10.6 and 124.8 ± 16.7/74.6 ± 10.0 mm Hg for patients with and without hypertension, respectively. More patients with hypertension were diabetic (25.6% vs 14.8%, p <0.001), women (38.6% vs 28.3%, p <0.001), and had greater CHADS2 (2.3 vs 1.4, p <0.001) and CHA2DS2-VASc scores (3.8 vs 2.8, p <0.001). Mean blood pressure in all treatment arms in hypertensive patients was similar (130 ± 18/76 ± 11 mm Hg) during the trial. The efficacy and safety of D110 and D150 compared to warfarin were similar (p = nonsignificant) in hypertensive (stroke/systemic embolism rate of 1.47%, 1.20%, and 1.81% and major bleed rate of 2.89%, 3.70%, and 3.69% in the D110, D150, and W, respectively) and normotensive patients (stroke/systemic embolism rate of 1.79%, 0.78%, and 1.36% and major bleed rate of 2.84%, 2.37%, and 3.03% per year in the D110, D150, and W, respectively). Hypertensive patients had more major bleeds (3.39% vs 2.76%; p = 0.007). Intracranial bleeds were similar (0.47% vs 0.31%; p = 0.12). In conclusion, patients with hypertension in RE-LY were more likely female, diabetic, with a greater CHADS2 and CHA2DS2-VASc scores. Blood pressure control in RE-LY was excellent. The benefits of dabigatran over warfarin, including a substantial reduction of intracranial hemorrhage, were similar in both hypertensive and non-hypertensive patients.

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.

Critical appraisal of network meta-analyses evaluating the efficacy and safety of new oral anticoagulants in atrial fibrillation stroke prevention trials.

OBJECTIVES: To critically appraise published network meta-analyses (NMAs) evaluating the efficacy or safety of the new oral anticogulants (NOACs) dabigatran, rivaroxaban, and apixaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). METHODS: A systematic literature review was performed to identify the relevant NMAs using MEDLINE, EMBASE, Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. The synthesis studies were evaluated using the "Questionnaire to assess the relevance and credibility of the NMA." RESULTS: Eleven NMAs evaluating NOACs among adults with nonvalvular AF were identified. Most NMAs included three large phase III randomized controlled trials, comparing NOACs to adjusted-dose warfarin (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], and Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]). The main differences identified related to potential treatment effect modifiers regarding the mean time spent in therapeutic range (TTR) in the warfarin arm, the risk of stroke or systemic embolism across the trials (mean CHADS2 score: C = congestive heart failure, H = hypertension, A = older than age 75 years, D = diabetes mellitus, S2 = prior stroke or history of transient ischemic attack) or primary versus secondary prevention, and type of populations used in the analysis. Kansal et al. [Kansal AR, Sharma M, Bradley-Kennedy C, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada: comparative efficacy and cost-effectiveness. Thromb Haemost 2012;108:672-82] appropriately adjusted the ROCKET-AF TTR to match the RE-LY population on the basis of individual patient data. Meta-regressions are not expected to minimize confounding bias given limited data, whereas subgroup analyses had some impact on the point estimates for the treatment comparisons. CONCLUSIONS: Results of the synthesis studies were generally comparable and suggested that the NOACs had similar efficacy, although some differences were identified depending on the outcome. The extent to which differences in the distribution of TTR, CHADS2 score, or primary versus secondary prevention biased the results remains unclear.

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.

Comparison of the cost-effectiveness of new oral anticoagulants for the prevention of stroke and systemic embolism in atrial fibrillation in a UK setting.

PURPOSE: Three new oral anticoagulants (NOACs) have recently become available in the United Kingdom as an alternative to warfarin in the prevention of stroke and systemic embolism in atrial fibrillation. This study examines the relative cost-effectiveness of dabigatran (BID dosing of 150 mg or 110 mg based on patient age), rivaroxaban, and apixaban from a UK payer perspective. METHODS: A previously published model that follows up patients through treatment of atrial fibrillation during a lifetime was adapted to allow comparison of the 3 NOACs and warfarin. Acute thromboembolic and bleeding events, as well as long-term consequences of stroke, intracranial hemorrhage, and acute myocardial infarction, were tracked. Relative efficacy was calculated from a formal indirect treatment comparison using data from the 3 key trials (Randomized Evaluation of Long-Term Anticoagulation Therapy, Rivaroxaban Once-daily oral direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation, and Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) of the NOACs. Data from the rivaroxaban trial were adjusted for the difference in international normalized ratio control among warfarin patients versus the other 2 trials. Model outputs included total costs, event rates, and quality-adjusted life-years. FINDINGS: Among the patients taking NOACs, those taking dabigatran had the highest total QALYs (7.68 QALYs), followed by apixaban (7.63 QALYs) and rivaroxaban (7.47 QALYs). Patients taking dabigatran had the lowest total lifetime costs (£23,342), followed by apixaban (£24,014) and rivaroxaban (£25,220). The differences between dabigatran and apixaban were modest but consistent in sensitivity analyses, with the directionality only changing at the limits of the CIs for the relative risks of ischemic stroke or intracranial hemorrhage or when assuming that both treatment discontinuation and post-event disability rates differ by drug. IMPLICATIONS: Dabigatran was found to be economically dominant over rivaroxaban and apixaban in the UK setting. These economic findings are based on relative clinical efficacy from an indirect treatment comparison and would benefit from any data of direct comparisons of the NOACs in the future.

Anticoagulant-related gastrointestinal bleeding--could this facilitate early detection of benign or malignant gastrointestinal lesions?

INTRODUCTION: The higher incidence of gastrointestinal (GI) bleeding with the non-vitamin K oral anticoagulants (NOACs) may be related to pre-existing malignancies; diagnostic measures triggered by these bleedings could lead to early detection of these malignancies. METHODS: We retrieved the preferred terms on GI bleeding and GI cancer reported as adverse events (AEs) from phase III studies in patients with atrial fibrillation for each NOAC on ClinicalTrials.gov . We also analyzed the RE-LY trial database. RESULTS: From ClinicalTrials.gov , AE-GI bleeding incidence was: dabigatran 110 mg b.i.d. (D110: 1.42% versus 1.37%), dabigatran 150 mg b.i.d. (D150: 1.93% versus 1.37%), rivaroxaban (3.52% versus 2.68%), and apixaban (1.93% versus 1.59%), compared with warfarin, respectively. The incidence of AE-GI cancer was similar between the NOACs (D110 [0.79%], D150 [0.61%], rivaroxaban [0.83%], and apixaban [0.69%]), but numerically higher compared with warfarin (0.37%; 0.73%; 0.57%, respectively). In the RE-LY database, the same pattern was seen for dabigatran, with an association between GI bleeding and GI cancer diagnosis. CONCLUSION: Anticoagulant-related GI bleeding may represent the unmasking of pre-existing malignancies leading to increased detection of GI cancer. This may be especially in the first month of treatment and could explain the numerically higher numbers of GI malignancies observed with NOACs.

Efficacy and cost-effectiveness of dabigatran etexilate versus warfarin in atrial fibrillation in different age subgroups.

This study aims to estimate the cost-effectiveness of dabigatran 150 mg twice daily versus warfarin for stroke and systemic embolism risk reduction in patients with nonvalvular atrial fibrillation initiating treatment before age 75 (<75), at or after age 75 (≥ 75), and the overall population (All) from a US Medicare payer perspective. Clinical event rates by age cohort with dabigatran or warfarin for safety-on-treatment and intent-to-treat populations were estimated from Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY). An economic model was adapted using these data to evaluate the impact of starting age on clinical and economic outcomes. Costs were obtained from Medicare payment schedules and utilities from publications. Model outputs included event rates, costs, quality-adjusted life-years, and incremental cost-effectiveness ratios. The RE-LY analysis shows that the <75 cohort has lower rates of all events than the ≥ 75 cohort; versus warfarin, dabigatran performed better in main efficacy and safety in all age cohorts with the exception of extracranial hemorrhage in the ≥ 75 cohort. The clinical event costs avoided per patient for dabigatran were $1,100, $135, and $713 for cohorts <75, ≥ 75, and All, respectively. Extrapolating over a lifetime horizon, the model found that dabigatran resulted in lower rates of stroke and intracranial hemorrhage and higher rates for extracranial hemorrhage versus warfarin for all age cohorts. Lifetime quality-adjusted life-years and costs were higher for dabigatran than warfarin, resulting in incremental cost-effectiveness ratios of $52,773, $65,946, and $56,131 for cohorts <75, ≥ 75, and All, respectively. In conclusion, dabigatran was cost-effective versus warfarin in US patients with atrial fibrillation regardless of age of treatment initiation.

Twice- or once-daily dosing of novel oral anticoagulants for stroke prevention: a fixed-effects meta-analysis with predefined heterogeneity quality criteria.

BACKGROUND: A number of novel oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) are in clinical use for various indications. The dosing regimens differ between twice-daily and once-daily dosing for the prevention of stroke in patients with atrial fibrillation. With the availability of the results from four phase 3 studies (>70,000 patients), we explored whether twice-daily or once-daily dosing provides better risk-benefit balance among novel oral anticoagulants. METHODS: We conducted a strict, stepwise, fixed-effects meta-analysis with predefined heterogeneity quality criteria to generate the most appropriate common estimates for twice-daily (BID) or once-daily (QD) dosing regimens. An indirect comparison of these dosing regimens with fixed-effects meta-analysis common estimates (where available), or individual compound results, was done respectively. RESULTS: Comparing indirectly BID vs QD dosing regimens resulted in hazard ratios (HR [95% confidence interval]) for stroke and systemic embolism of 0.75 (0.58-0.96) for dabigatran 150 mg BID, and 0.91 (0.73-1.13) for apixaban BID vs the QD dosing regimen. For ischemic stroke, the HR of BID vs QD was 0.85 (0.69-1.05). For intracranial hemorrhage, BID vs rivaroxaban QD was 0.57 (0.37-0.88) and, vs edoxaban QD, 0.81 (0.54-1.22). Due to heterogeneity, common estimates for major bleeding QD or BID were not justified, therefore indirect comparison of regimens were not possible. All non-vitamin K antagonist oral anticoagulants reduced all-cause mortality vs warfarin with a HR of 0.90 (0.86-0.96) without differences between regimen. CONCLUSIONS: Based on the available phase 3 study evidence, the twice-daily dosing regimen of non-vitamin K antagonist oral anticoagulants appears to offer a more balanced risk-benefit profile with respect to stroke prevention and intracranial hemorrhage.

Patient outcomes using the European label for dabigatran. A post-hoc analysis from the RE-LY database.

In the RE-LY trial dabigatran 150 mg twice daily (D150) showed significantly fewer strokes, and 110 mg (D110) significantly fewer major bleeding events (MBE) compared to well-controlled warfarin in patients with atrial fibrillation (AF). The European (EU) label currently recommends the use of D150 in AF patients who are aged < 80 years without an increased risk for bleeding (e.g. HAS-BLED score <3) and not on concomitant verapamil. In other patients, D110 is recommended. In this post-hoc analysis of the RE-LY dataset, we simulated how dabigatran (n=6,004) would compare to well-controlled warfarin (n=6,022) used according to the EU label. "EU label simulated dabigatran treatment" was associated with significant reductions in stroke and systemic embolism (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.60-0.91), haemorrhagic stroke (HR 0.22; 95%CI 0.11-0.44), death (HR 0.86; 95%CI 0.75-0.98), and vascular death (HR 0.80; 95%CI 0.68-0.95) compared to warfarin. Dabigatran was also associated with less major bleeding (HR 0.85; 95%CI 0.73-0.98), life-threatening bleeding (HR 0.72; 95%CI 0.58-0.91), intracranial haemorrhage (HR 0.28; 95%CI 0.17-0.45), and "any bleeds" (HR 0.86; 95%CI 0.81-0.92), but not gastrointestinal major bleeding (HR 1.23; 95%CI 0.96-1.59). The net clinical benefit was significantly better for dabigatran compared to warfarin. In conclusion, this post-hoc simulation of dabigatran usage based on RE-LY trial dataset indicates that "EU label simulated dabigatran treatment" may be associated with superior efficacy and safety compared to warfarin, and are in support of the EU label and the 2012 European Society of Cardiology AF guideline recommendations. Thus, adherence to European label/guideline use results in a clinically relevant benefit for dabigatran over warfarin, for both efficacy and safety.

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.

Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: a pooled analysis.

INTRODUCTION: Three pivotal phase 3 trials have demonstrated that oral dabigatran etexilate showed similar safety and efficacy to enoxaparin 40 mg once daily (qd) for venous thromboembolism (VTE) prevention in patients undergoing total knee or hip replacement. Obesity is an established independent risk factor for VTE. METHODS: A post-hoc pooled analysis of the three trials was performed to evaluate the safety and efficacy of dabigatran 220 mg qd versus enoxaparin 40 mg qd in patients with a normal body mass index (BMI) of >20-25 kg/m(2), pre-obese patients (BMI >25-30 kg/m(2)) and obese patients (BMI >30 kg/m(2)). The primary efficacy endpoint was major VTE and VTE-related mortality; safety endpoints included major, clinically relevant, or any bleeding events. RESULTS: The mean BMIs for patients in the dabigatran and enoxaparin arms from all three trials, separately, were between 27.5 and 29.9 kg/m(2). Of the participants, 1417 (24.9%) had a normal BMI, 2373 (41.7%) were pre-obese and 1826 (32.1%) obese. In patients with normal BMI, the rates of the primary efficacy endpoint were significantly lower in the dabigatran than in the enoxaparin group (2.1% versus 4.3%; OR 0.48; 95% CI 0.24-0.97, P=0.037). No significant difference between dabigatran and enoxaparin in the primary efficacy endpoint was observed in the other subgroups. Bleeding rates were also similar between treatments for BMI subgroups. CONCLUSIONS: Dabigatran is an effective thromboprophylactic therapy for normal, pre-obese and obese patients, and outcomes in patients with a BMI >25 kg/m(2) do not differ from the overall population.

Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials.

BACKGROUND: There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin. METHODS: Three previously reported trials compared 220 mg and 150 mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n = 8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events. RESULTS: General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03-1.90; p = 0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin. CONCLUSIONS: Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.

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.

Dabigatran etexilate and concomitant use of non-steroidal anti-inflammatory drugs or acetylsalicylic acid in patients undergoing total hip and total knee arthroplasty: no increased risk of bleeding.

Patients undergoing total hip or knee arthroplasty should receive anticoagulant therapy because of the high risk of venous thromboembolism. However, many are already taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA) that can have antihaemostatic effects. We assessed the bleeding risk in patients treated with thromboprophylactic dabigatran etexilate, with and without concomitant NSAID or ASA. A post-hoc analysis was undertaken of the pooled data from trials comparing dabigatran etexilate (220 mg and 150 mg once daily) and enoxaparin. Major bleeding event (MBE) rates were determined and odds ratios (ORs) generated for patients who received study treatment plus NSAID (half-life ≤12 hours) or ASA (≤160 mg/day) versus study treatment alone. Relative risks were calculated for comparisons between treatments. Overall, 4,405/8,135 patients (54.1%) received concomitant NSAID and 386/8,135 (4.7%) received ASA.ORs for the comparison with/without concomitant NSAID were 1.05 (95% confidence interval [CI] 0.55-2.01) for 220 mg dabigatran etexilate; 1.19 (0.55-2.55) for 150 mg; and 1.32 (0.67-2.57) for enoxaparin. ORs for the comparison with/without ASA were 1.14 (0.26-5.03); 1.64 (0.36-7.49); and 2.57 (0.83-7.94), respectively. For both NSAIDs and ASA there was no significant difference in bleeding between patients with and without concomitant therapy in any treatment arm. Patients concomitantly taking NSAIDs or ASA have a similar risk of MBE to those taking dabigatran etexilate alone. No significant differences in MBE were detected between dabigatran etexilate and enoxaparin within co-medication subgroups, suggesting that no increased major bleeding risk exists when dabigatran etexilate is administered with NSAID or ASA.

Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip replacement surgery [corrected].

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.