Janet Schnee

Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism

BACKGROUND The direct oral thrombin inhibitor dabigatran has a predictable anticoagulant effect and may be an alternative therapy to warfarin for patients who have acute venous thromboembolism. METHODS In a randomized, double-blind, noninferiority trial involving patients with acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (interquartile range, 8 to 11), we compared oral dabigatran, administered at a dose of 150 mg twice daily, with warfarin that was dose-adjusted to achieve an international normalized ratio of 2.0 to 3.0. The primary outcome was the 6-month incidence of recurrent symptomatic, objectively confirmed venous thromboembolism and related deaths. Safety end points included bleeding events, acute coronary syndromes, other adverse events, and results of liver-function tests. RESULTS A total of 30 of the 1274 patients randomly assigned to receive dabigatran (2.4%), as compared with 27 of the 1265 patients randomly assigned to warfarin (2.1%), had recurrent venous thromboembolism; the difference in risk was 0.4 percentage points (95% confidence interval [CI], -0.8 to 1.5; P<0.001 for the prespecified noninferiority margin). The hazard ratio with dabigatran was 1.10 (95% CI, 0.65 to 1.84). Major bleeding episodes occurred in 20 patients assigned to dabigatran (1.6%) and in 24 patients assigned to warfarin (1.9%) (hazard ratio with dabigatran, 0.82; 95% CI, 0.45 to 1.48), and episodes of any bleeding were observed in 205 patients assigned to dabigatran (16.1%) and 277 patients assigned to warfarin (21.9%; hazard ratio with dabigatran, 0.71; 95% CI, 0.59 to 0.85). The numbers of deaths, acute coronary syndromes, and abnormal liver-function tests were similar in the two groups. Adverse events leading to discontinuation of the study drug occurred in 9.0% of patients assigned to dabigatran and in 6.8% of patients assigned to warfarin (P=0.05). CONCLUSIONS For the treatment of acute venous thromboembolism, a fixed dose of dabigatran is as effective as warfarin, has a safety profile that is similar to that of warfarin, and does not require laboratory monitoring. (ClinicalTrials.gov number, NCT00291330.)

Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial

BACKGROUND After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. METHODS In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28-35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. FINDINGS Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference -0.7%, 95% CI -2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, -0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0.44 for 220 mg, p=0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. INTERPRETATION Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.

Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE‐MODEL randomized trial

Background: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. Methods: In this randomized, double‐blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once‐daily, starting with a half‐dose 1–4 h after surgery, or subcutaneous enoxaparin 40 mg once‐daily, starting the evening before surgery, for 6–10 days. Patients were followed up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. Results: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group vs. 36.4% (183 of 503) of the dabigatran etexilate 220‐mg group (absolute difference, −1.3%; 95% CI, −7.3 to 4.6) and 40.5% (213 of 526) of the 150‐mg group (2.8%; 95% CI,−3.1 to 8.7). Both doses were non‐inferior to enoxaparin on the basis of the prespecified non‐inferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% vs. 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow‐up. Conclusions: Dabigatran etexilate (220 mg or 150 mg) was at least as effective as enoxaparin and had a similar safety profile for prevention of VTE after total knee replacement surgery.

Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery.

Dabigatran, an oral once-daily unmonitored thrombin inhibitor, has been tested elsewhere using enoxaparin 40 mg once daily. We used the North American enoxaparin 30 mg BID regimen as the comparator. This was a double-blind, centrally randomized trial. Unilateral total knee arthroplasty patients were randomized to receive oral dabigatran etexilate 220 or 150 mg once daily, or enoxaparin 30 mg SC BID after surgery, blinded. Dosing stopped at contrast venography, 12 to 15 days after surgery. Among 1896 patients, dabigatran 220 and 110 mg showed inferior efficacy to enoxaparin (venous thromboembolism rates of 31% [P = .02 vs enoxaparin], 34% [P < .001 vs enoxaparin], and 25%, respectively). Bleeding rates were similar, and no drug-related hepatic illness was recognized. Dabigatran, effective compared to once-daily enoxaparin, showed inferior efficacy to the twice-daily North American enoxaparin regimen, probably because of the latters more intense and prolonged dosing.

Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II)

This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.

Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.

This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.

Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: A pooled analysis of three trials

BACKGROUND Three randomized, double-blind trials compared dabigatran, an oral direct thrombin inhibitor, with enoxaparin for the primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee arthroplasty. OBJECTIVES AND METHODS We conducted a pre-specified pooled analysis of these trials. 8,210 patients were randomized, of whom 8,135 were treated (evaluable for safety) with dabigatran 220 mg or 150 mg once-daily, or subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Efficacy analyses were based on the modified intention-to-treat population of 6,200 patients with an evaluable outcome. The common risk difference (RD) of treatment effect between each dabigatran dose and enoxaparin was estimated using fixed-effects models, and statistical heterogeneity was estimated using the I2 statistic. RESULTS The composite outcome of major VTE (proximal deep vein thrombosis and/or pulmonary embolism) and VTE-related mortality occurred in 3.3% of the enoxaparin group versus 3.0% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, 95% CI -1.3% to 0.9%, I2=37%) and 3.8% of the 150 mg group (RD vs. enoxaparin 0.5%, -0.6% to 1.6%, I2=0%). Major bleeding occurred in 1.4% of the enoxaparin group versus 1.4% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, -0.8% to 0.5%, I2=40%) and 1.1% of the 150 mg group (RD vs. enoxaparin -0.4%, -1.0% to 0.2%, I2=0%). CONCLUSIONS Oral dabigatran was as effective as subcutaneous enoxaparin in reducing the risk of major VTE and VTE-related mortality after hip or knee arthroplasty and has a similar bleeding profile.

A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system

Dabigatran is approved for stroke risk reduction in patients with nonvalvular atrial fibrillation (NVAF). Data from diverse clinical practice settings will help establish whether the risk:benefit ratio seen in clinical trials is comparable with routine clinical care. This study aimed to compare the safety and effectiveness of dabigatran and warfarin in clinical practice. We undertook a propensity score-matched (PSM) cohort study (N=12,793 per group; mean age 74) comparing treatment with dabigatran or warfarin in the US Department of Defense claims database, October 2009 to July 2013. Treatment-naïve patients with first prescription claim for dabigatran (either FDA-approved dose) or warfarin between October 2010 and July 2012 (index) and a diagnosis of NVAF during the 12 months before index date were included. Primary outcomes were stroke and major bleeding. Secondary outcomes included ischaemic and haemorrhagic stroke, major gastrointestinal (GI), urogenital or other bleeding, myocardial infarction (MI) and death. Time-to-event was investigated using Kaplan-Meier survival analyses. Outcomes comparisons were made utilising Cox-proportional hazards models of PSM groups. Dabigatran users experienced fewer strokes (adjusted hazard ratio [95 % confidence intervals] 0.73 [0.55-0.97]), major intracranial (0.49 [0.30-0.79]), urogenital (0.36 [0.18-0.74]) and other (0.38 [0.22-0.66]) bleeding, MI (0.65 [0.45-0.95]) and deaths (0.64 [0.55-0.74]) than the warfarin group. Major bleeding (0.87 [0.74-1.03]) and major GI bleeding (1.13 [0.94-1.37]) was similar between groups and major lower GI bleeding events were more frequent (1.30 [1.04-1.62]) with dabigatran. In conclusion, compared with warfarin, dabigatran treatment was associated with a lower risk of stroke and most outcomes measured, but increased incidence of major lower GI bleeding.

RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial

This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.

Characteristics of patients with non-valvular atrial fibrillation using dabigatran or warfarin in the US.

Abstract Objective: In order to understand characteristics of atrial fibrillation patients in the era of new oral anticoagulants (NOACs), this study explores differences in characteristics between patients treated with dabigatran etexilate (DE) and warfarin (W) that may be due to patient channeling in ‘real-world’ clinical practice. Research design and methods: Medco claims data were used to characterize 41,805 non-valvular atrial fibrillation (NVAF) patients from the US with a DE (N = 7055) or W (N = 34,750) prescription between February 2011 and April 2012. The first prescription for each treatment in this period defined the index date. The treatment groups were stratified by newly diagnosed or warfarin-experienced patients. Characteristics, comedications, and comorbidities in the 12 month period prior to index date were assessed. Results: Newly diagnosed patients initiating DE had overall lower use of comedications compared to W patients. In contrast, warfarin-experienced patients switching from W to DE showed higher use of antibiotics, beta blockers, gastrointestinal drugs and NSAIDs compared to patients remaining on W. Newly diagnosed NVAF patients initiating DE showed lower proportions for comorbidities such as myocardial infarction, congestive heart failure, and renal disease. This was also reflected in the Charlson comorbidity index (CCI) (mean DE 2.1 vs. W 3.0) and the CHA2DS2-VASc score (mean DE 3.4 vs. W 4.0). For warfarin-experienced NVAF patients, these differences were not seen. Interpretation of results is limited by the fact that administrative claims data are not gathered for scientific research. Underreporting of non-serious conditions might occur and life-style variables, laboratory values and over-the-counter medication were not available. Conclusions: As also seen for other newly marketed drugs, differences in baseline characteristics, comedication, and comorbidities were detected between DE and W in newly diagnosed patients, as well as in warfarin-experienced patients. This channeling may have significant impact on comparative outcome studies if not properly addressed in study design and analysis.