DABIGATRAN (PRADAXA®)















RE-LY Study - Dabigatran vs Warfarin in Atrial Fibrillation, NEJM (2009) [PubMed abstract]
  • The RE-LY study enrolled 18,113 patients with atrial fibrillation and other risk factors for stroke
Main inclusion criteria
  • A fib and any one of the following: previous stroke or TIA, EF < 40%, NYHA class II - IV heart failure, age ≥ 75 years or age 65 - 74 with diabetes, hypertension, or coronary artery disease
Main exclusion criteria
  • Severe heart valve disorder
  • Stroke within 6 months
  • High risk for bleeding
  • CrCl < 30 ml/min
Baseline characteristics
  • Average age 72 years
  • Average CHADS2 score - 2.1
  • Prior stroke or TIA - 20%
  • A fib type: Persistent - 32% | Paroxysmal - 33% | Permanent - 35%
Randomized treatment groups
  • Group 1 (6015 patients) - Dabigatran 110 mg twice a day
  • Group 2 (6076 patients) - Dabigatran 150 mg twice a day
  • Group 3 (6022 patients) - Warfarin (target INR 2.0 - 3.0)
  • Warfarin therapy was open-label. Dabigatran was open-label but dose was blinded.
  • Concomitant aspirin (< 100 mg/day) and other antiplatelet drugs were permitted
Primary outcome: Stroke or systemic embolism
Results

Duration: Median of 2 years
Outcome Dab 110 Dab 150 Warfarin Comparisons
Primary outcome (%/year) 1.53% 1.11% 1.69% 1 vs 3 p=0.34 | 2 vs 3 p<0.001 | 1 vs 2 p=0.005
Stroke (%/year) 1.44% 1.01% 1.57% 1 vs 3 p=0.41 | 2 vs 3 p<0.001 | 1 vs 2 p=0.003
Overall mortality (%/year) 3.75% 3.64% 4.13% 1 vs 3 p=0.13 | 2 vs 3 p=0.051 | 1 vs 2 p=0.66
Hemorrhagic stroke (%/year) 0.12% 0.10% 0.38% 1 vs 3 p<0.001 | 2 vs 3 p<0.001 | 1 vs 2 p=0.67
Major bleeding (%/year) 2.71% 3.11% 3.36% 1 vs 3 p=0.003 | 2 vs 3 p=0.31 | 1 vs 2 p=0.052
Dyspepsia 11.8% 11.3% 5.8% 1 and 2 vs 3 p<0.001
Drug discontinuation 20.7% 21.2% 16.6% 1 and 2 vs 3 p<0.001
  • In the warfarin group, the INR was in the therapeutic range 64% of the time

Findings: In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. Dabigatran administered at a dose of 150 mg, as compared with warfarin, was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage





RE-COVER Study - Dabigatran vs Warfarin for VTE, NEJM (2009) [PubMed abstract]
  • The RE-COVER study enrolled 2539 patients with acute venous thromboembolism (DVT or PE)
Main inclusion criteria
  • Acute, symptomatic, objectively verified proximal DVT or PE
Main exclusion criteria
  • Duration of symptoms > 14 days
  • Hemodynamic instability
  • High risk for bleeding
  • CrCl < 30 ml/min
Baseline characteristics
  • Average age 55 years
  • Previous VTE - 26%
  • Active cancer - 4.7%
  • Qualifying event: DVT - 69% | PE - 21% | Both - 9.6%
Randomized treatment groups
  • Group 1 (1274 patients) - Dabigatran 150 mg twice a day for 6 months
  • Group 2 (1265 patients) - Warfarin (target INR 2.0 - 3.0) for 6 months
  • All patients were given parenteral anticoagulation for at least 5 days
  • Warfarin was started at randomization and parenteral anticoagulation was continued until the INR was at least 2.0
  • Dabigatran was started when parenteral anticoagulation was stopped. The first dose was given within 2 hours of the time that the next dose of parenteral therapy would have been due.
  • Parenteral anticoagulation was given for an average of 10 days in both groups
Primary outcome: Composite of symptomatic venous thromboembolism or death associated with venous thromboembolism in the 6 months after random assignment
Results

Duration: 6 months
Outcome Dabigatran Warfarin Comparisons
Primary outcome 2.4% 2.1% HR 1.10, 95%CI [0.65 - 1.84]
Symptomatic DVT 1.3% 1.4% HR 0.87, 95%CI [0.44 - 1.71]
Symptomatic nonfatal PE 1.0% 0.6% HR 1.85, 95%CI [0.74 - 4.64]
Overall mortality 1.6% 1.7% HR 0.98, 95%CI [0.53 - 1.79]
Major bleeding 1.6% 1.9% HR 0.82, 95%CI [0.45 - 1.48]
Major or clinically relevant nonmajor bleeding 5.6% 8.8% HR 0.63, 95%CI [0.47 - 0.84]
Early drug discontinuation 16% 14.5% N/A
  • In subgroup analysis, there was no significant difference between treatments in patients who presented with a DVT or a PE
  • In the warfarin group, the INR was in the therapeutic range 60% of the time [7]

Findings: 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





RE-MEDY Study - Dabigatran vs Warfarin for Extended Therapy in VTE, NEJM (2013) [PubMed abstract]
  • The RE-MEDY study enrolled 2856 patients who had been treated for 3 - 12 months with anticoagulation for a VTE
Main inclusion criteria
  • Symptomatic, objectively confirmed DVT or PE that had been treated for 3 - 12 months with approved anticoagulation
  • Increased risk for recurrent VTE based on site investigator's assessment
Main exclusion criteria
  • Interruption of anticoagulant therapy for ≥ 2 weeks during the initial 3 - 6 months
  • High risk for bleeding
  • CrCl < 30 ml/min
  • Significant liver disease
Baseline characteristics
  • Average age 55 years
  • Active cancer - 4%
  • Known thrombophilia - 18%
  • Qualifying event: DVT - 65% | PE - 23% | Both - 12%
Randomized treatment groups
  • Group 1 (1430 patients) - Dabigatran 150 mg twice a day
  • Group 2 (1426 patients) - Warfarin (target INR 2 - 3)
  • Average treatment before study enrollment was 199 days
Primary outcome: Composite of recurrent symptomatic and objectively verified venous thromboembolism or death associated with venous thromboembolism
Results

Duration: Average of 473 days
Outcome Dabigatran Warfarin Comparisons
Primary outcome 1.8% 1.3% HR 1.44, 95%CI [0.78 - 2.64]
Symptomatic DVT 1.2% 0.9% HR 1.32, 95%CI [0.64 - 2.71], p=0.46
Symptomatic nonfatal PE 0.7% 0.4% HR 2.04, 95%CI [0.70 - 5.98], p=0.19
Overall mortality 1.2% 1.3% HR 0.90, 95%CI [0.47 - 1.72], p=0.74
Major bleeding 0.9% 1.8% HR 0.52, 95%CI [0.27 - 1.02], p=0.06
Major or clinically relevant bleeding 5.6% 10.2% HR 0.54, 95%CI [0.41 - 0.71], p<0.001
Acute coronary syndrome 0.9% 0.2% p=0.02

Findings: Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo




RE-NOVATE Study - Dabigatran vs Enoxaparin for VTE Prophylaxis after Hip surgery, Lancet (2007) [PubMed abstract]
  • The RE-NOVATE study enrolled 3494 patients undergoing total hip replacement
Main inclusion criteria
  • Scheduled to undergo unilateral total hip replacement
Main exclusion criteria
  • Bleeding disorder
  • History of acute intracranial disease or hemorrhagic stroke
  • GI bleed or ulcer disease within 6 months
  • Use of long-acting NSAIDs
  • Significant liver disease
  • CrCl < 30 ml/min
Baseline characteristics
  • Average age 64 years
  • History of VTE - 3%
  • Average duration of surgery - 86 minutes
  • Median duration of hospital stay - 9 days
Randomized treatment groups
  • Group 1 (1146 patients) - Dabigatran 220 mg once daily for 28 - 35 days
  • Group 2 (1163 patients) - Dabigatran 150 mg once daily for 28 - 35 days
  • Group 3 (1154 patients) - Enoxaparin 40 mg subq daily for 28 - 35 days
  • Enoxaparin was started the evening before surgery
  • Dabigatran was started 1 - 4 hours after surgery. First dose was halved.
  • Compression stockings were permitted, but intermittent pneumatic compression devices were not.
Primary outcome: Composite of symptomatic thromboembolism (DVT and PE), thromboembolism detected on venography performed within 24 hours of last dose, and death from any cause
Results

Duration: Median of 33 days
Outcome Dab 220 Dab 150 Enoxaparin Comparisons
Primary outcome 6% 8.6% 6.7% 1 vs 3 p>0.05 | 2 vs 3 p>0.05
Major bleeding 2% 1.3% 1.6% 1 vs 3, p=0.44, 2 vs 3, p=0.60
Asymptomatic DVT 4.6% 7.2% 6.3% N/A
Symptomatic PE 0.4% 0.1% 0.3% N/A
Overall mortality 0.3% 0.3% 0% N/A
  • Dabigatran was started an average of 3.4 hours after surgery and continued for a median of 33 days after surgery
  • About 24% of randomized patients were not included in the final efficacy analysis, primarily because they did not undergo proper venography at study end

Findings: 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























Recommended dosing in adults
Nonvalvular atrial fibrillation
  • CrCl > 30 ml/min: 150 mg twice a day
  • CrCl 15 - 30 ml/min: 75 mg twice a day
  • CrCl < 15 ml/min: dosing recommendation cannot be provided
  • May take without regard to food. Swallow capsule whole with full glass of water.
Treatment of DVT and PE
  • Dabigatran should be started after 5 - 10 days of parenteral anticoagulation
  • CrCl > 30 ml/min: 150 mg twice a day
  • CrCl ≤ 30 ml/min: dosing recommendation cannot be provided
  • May take without regard to food. Swallow capsule whole with full glass of water.
Prevention of recurrent DVT and PE
  • CrCl > 30 ml/min: 150 mg twice a day
  • CrCl ≤ 30 ml/min: dosing recommendation cannot be provided
  • May take without regard to food. Swallow capsule whole with full glass of water.
VTE prophylaxis after hip replacement
  • CrCl > 30 ml/min: 110 mg 1 - 4 hours after surgery and after hemostasis has been achieved, then 220 mg once daily for 28 - 35 days
  • CrCl ≤ 30 ml/min: dosing recommendation cannot be provided
  • If dabigatran is not started on the day of surgery, initial dose should be 220 mg
  • May take without regard to food. Swallow capsule whole with full glass of water.




  • Reference [5]
Dabigatran Dosing in Pediatric Patients (8 - 17 years)
Actual Weight Dose # of capsules
24.2 lbs (11 kg) to less than 35.2 lbs (16 kg) 75 mg twice daily one 75 mg capsule twice daily
35.2 lbs (16 kg) to less than 57.2 lbs (26 kg) 110 mg twice daily one 110 mg capsule twice daily
57.2 lbs (26 kg) to less than 90.2 lbs (41 kg) 150 mg twice daily one 150 mg capsule twice daily
or
two 75 mg capsules twice daily
90.2 lbs (41 kg) to less than 134.2 lbs (61 kg) 185 mg twice daily one 110 mg capsule plus one 75 mg capsule twice daily
134.2 lbs (61 kg) to less than 178.2 lbs (81 kg) 220 mg twice daily two 110 mg capsule twice daily
≥ 178.2 lbs (81 kg) 260 mg twice daily one 150 mg capsule plus one 110 mg capsule twice daily
or
one 110 mg capsule plus two 75 mg capsules twice daily