Dabigatran (Pradaxa)


Indications

Systemic Embolism Prevention in Nonvalvular Atrial Fibrillation (see Atrial Fibrillation)

Clinical Efficacy-General

  • FDA Approved in October, 2012 for Stroke Prevention in Non-Valvular Atrial Fibrillation: however, dabigatran was available for longer and for other indications in other countries
  • PETRO Trial (Am J Cardiol, 2007) [MEDLINE]: RCT of blinded dabigatran 50/150/300 mg BID (with/without ASA) vs open-label coumadin (n = 502) x 12 wks
    • Thromboembolic Episodes Were Limited to the 50 mg Dabigatran Group
  • RE-LY Trial (NEJM, 2009) [MEDLINE]: randomized, non-blinded, non-inferiority trial in patients with non-valvular atrial fibrillation, comparing dabigatran to coumadin -> primary endpoints: stroke, systemic embolism
    • Dabigatran 110 mg BID was Similar to Coumadin for the Prevention of Thromboembolism and Stroke with Lower Rates of Bleeding
    • Dabigatran 150 mg BID was Superior to Coumadin for the Prevention of Thromboembolism and Stroke with Similar Rates of Major Bleeding
  • Stroke Prevention During Atrial Fibrillation Cardioversion (Circulation, 2011) [MEDLINE]
    • Dabigatran was Comparable to Coumadin, in Terms of 30-Day Risk of Stroke and Bleeding
  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Novel Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin: risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]
    • Novel Oral Anticoagulants are a Viable Option for Patients Requiring Long-Term Anticoagulation, Although the Treatment Benefits Compared with Coumadin are Small and Vary Depending on the Control Achieved by Coumadin Treatment
  • Systematic Review and Meta-Analysis of Bleeding Complications with DOAC’s in Atrial Fibrillation and Venous Thromboembolism (Blood. 2014) [MEDLINE]
    • DOAC’s were Associated with Less Major Bleeding Less Fatal Bleeding, Less Intracranial Bleeding, Less Clinically Relevant Bleeding, and Less Total Bleeding, as Compared to Coumadin
  • Systematic Review and Meta-Analysis of Mortality Outcomes of DOAC’s in Patients with Atrial Fibrillation and Venous Thromboembolism (J Thromb Haemost, 2015) [MEDLINE]
    • DOAC’s were Associated with a Lower Rate of Fatal Bleeding, Lower Case-Fatality Rate of Major Bleeding, Decreased Cardiovascular Mortality, and Decreased All-Cause Mortality, as Compared to Coumadin

Clinical Efficacy-Cost Effectiveness

  • Systematic Review of Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation (Rev Port Cardiol, 2015) [MEDLINE]
    • Novel Oral Anticoagulants are Cost-Effective for Stroke Prevention in Atrial Fibrillation, as Compared to Coumadin
  • Review of Cost-Effectiveness of Novel Oral Anticoagulants for Stroke Prevention in Non-Valvular Atrial Fibrillation (Curr Cardiol Rep, 2015) [MEDLINE]
    • Novel Oral Anticoagulants are Cost-Effective for Stroke Prevention in Atrial Fibrillation, as Compared to Coumadin

Venous Thromboembolism (see Deep Venous Thrombosis and Acute Pulmonary Embolism)

Clinical Efficacy

  • FDA Approved in April, 2014 for the Treatment of Venous Thromboembolism
  • RE-COVER Trial (NEJM, 2009) [MEDLINE]: randomized, double-blind, non-inferiority trial (n = 1274) in acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days, comparing dabigatran 150 mg BID with coumadin to INR 2-3
    • Dabigatran 150 mg BID is as Effective as Coumadin, has Safety Profile Similar to Coumadin, and Does Not Require INR Monitoring
  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Novel Oral Anticoagulants Decreased All-Cause Mortality, as Compared to Coumadin: risk ratio [RR], 0.88 [95% CI, 0.82 to 0.96]
    • Novel Oral Anticoagulants are a Viable Option for Patients Requiring Long-Term Anticoagulation, Although the Treatment Benefits Compared with Coumadin are Small and Vary Depending on the Control Achieved by Coumadin Treatment
  • RE-COVER II Trial (Circulation, 2014) [MEDLINE]: randomized, double-blind, double-dummy trial N = 2589) in acute venous thromboembolism treated with low-molecular-weight or unfractionated heparin for 5-11 days, comparing dabigatran 150 mg twice daily with coumadin (used pooled analysis of RE-COVER and RE-COVER II trial data(
    • Dabigatran Had Similar Effects on Recurrence of Venous Thromboembolism and a Lower Risk of Bleeding, as Compared to Coumadin
  • Cochrane Systematic Review and Meta-Analysis of DOAC’s (Dabigatran, Rivaroxaban, Apixaban, and Edoxaban) in the Treatment of Acute Symptomatic Venous Thromboembolism (J Thromb Haemost, 2014) [MEDLINE]
    • DOAC’s Have Comparable Efficacy to Coumadin and are Associated with a Significantly Lower Risk of Hemorrhagic Complications (Although the Number Needed to Treatment to Prevent One Major Bleed was Notably High at 149)
  • Systematic Review and Meta-Analysis of Bleeding Complications with DOAC’s in Atrial Fibrillation and Venous Thromboembolism (Blood. 2014) [MEDLINE]
    • DOAC’s were Associated with Less Major Bleeding Less Fatal Bleeding, Less Intracranial Bleeding, Less Clinically Relevant Bleeding, and Less Total Bleeding, as Compared to Coumadin
  • Systematic Review and Meta-Analysis of Mortality Outcomes of DOAC’s in Patients with Atrial Fibrillation and Venous Thromboembolism (J Thromb Haemost, 2015) [MEDLINE]
    • DOAC’s were Associated with a Lower Rate of Fatal Bleeding, Lower Case-Fatality Rate of Major Bleeding, Decreased Cardiovascular Mortality, and Decreased All-Cause Mortality, as Compared to Coumadin

Venous Thromboembolism Prophylaxis Post-Knee and Hip Replacement (see Deep Venous Thrombosis)

Clinical Efficacy


Pharmacology

Pharmacokinetics

Metabolism

Drug Interactions


Administration

PO Dosing

Hepatic Dose-Adjustment

Renal Dose-Adjustment

Venous Thromboembolism

Non-Valvular Atrial Fibrillation

Venous Thromboembolism Prophylaxis

Dose Adjustment for Obesity (2016 International Society of Thrombosis and Hemostasis Recommendations) (J Thromb Haemost, 2016) [MEDLINE]

Effect on Anticoagulation Tests

Conversion from/to Other Anticoagulants

Conversion from Dabigatran

Conversion to Dabigatran

Abrupt Discontinuation of Dabigatran


Periprocedural/Perioperative Management of Dabigatran Anticoagulation

Recommendations for Periprocedural/Perioperative Management of Dabigatran (American College of Chest Physicians Clinical Practice Guideline for the Perioperative Management of Antithrombotic Therapy) (Chest, 2022) [MEDLINE]


Reversal of Dabigatran Anticoagulation


Adverse Effects

Hemorrhagic Adverse Effects

General Comments

  • Reports of Fatal Hemorrhage: between 3/08-10/11, 260 fatal hemorrhages attributable to dabigatran have been reported

Post-Hip Replacement or Knee Replacement DVT Prophylaxis Trials

  • Incidence of Minor/Major Bleeding: no difference between dabigatran and enoxaparin

Atrial Fibrillation Trials

  • PETRO Trial (2007) [MEDLINE]
    • In 300 mg/day arm: 23% had bleeding events
    • Major bleeding was limited to patients in the ASA + dabigatran group
    • ASA significantly increased the bleeding risk above that of 300 mg/day dabigatran dose alone
  • RE-LY Trial (2009) [MEDLINE]
    • In 150 mg BID arm: fatal hemorrhage was lower (0.23% per year), as compared to coumadin (0.33% per year)
    • Life-threatening hemorrhage was higher with dabigatran 150 mg BID than with dabigatran 110 mg BID -> lower dose was not FDA-approved
    • RE-LY trial excluded patients with CrCl <30 (and only 19% of study subjects had CrCl 30-49)
  • Subgroup Analysis by Age from RE-LY Trial (Boehringer Ingelheim. Pradaxa (dabigatran etexilate): advisory committee briefing document. August 27, 2010)
    • Among the 39% (7,238 of 18,113) of patients >75 years, bleeding was increased among the patients treated with dabigatran (150 mg/day) (hazard ratio, 1.18 [95% confidence interval, 0.98-1.43])
    • This was not attributed solely to poor renal function, as shown by subanalysis of subjects >75 y/o with normal renal function, in whom dabigatran (150 mg/day) was still associated with increased bleeding (hazard ratio, 1.219 [95% confidence interval, 0.65-2.266])
  • Analysis of the (RE-LY) Trial (Circulation 2011 May 31;123(21):2363-72)
    • In patients with AF <75 y/o, both doses of dabigatran (110 BID or 150 BID) had lower risks of both intracranial and extracranial bleeding, as compared to coumadin
    • In patients with AF >75 y/o, intracranial bleeding risk is lower but extracranial bleeding risk is similar or higher with both doses of dabigatran (110 BID or 150 BID), as compared to coumadin -> in patients >75 y/o, RR was 1.18 for major bleeding with 150 BID
    • 2-fold higher risk of major bleeding in both dabigatran and coumadin patients with CrCl <50, as compared to CrCl >80
      • Renal failure is known to increase risk of coumadin-related bleeding, even though coumadin is not excreted renally
    • Interestingly, study did not find an interaction between incidence of major bleeding and CrCl -> suggests that age-related factors are more important as determinants of bleeding risk
    • Site of Bleeding: multiple with most common being “unreported site”, surgical bleeding, genito-urinary, intra-ocular, ENT, and intra-thoracic sites
  • Case Reports of Major Bleeding in Elderly Patients (2011) [MEDLINE]
    • One case of 84 y/o with fatal lower gastrointestinal hemorrhage and one case of 89 y/o with non-fatal epistaxis
    • Accompanying editorial cautions against use in elderly >75 y/o, particularly in the setting of renal failure

Venous Thrombembolism Trials

  • RE-COVER Trial (2009) [MEDLINE]
    • Study: randomized, double-blind, non-inferiority trial (n = 1274) in acute venous thromboembolism who were initially given parenteral anticoagulation therapy for a median of 9 days (range, 8-11 days), comparing dabigatran 150 mg BID with coumadin to INR 2-3
    • Main Findings: dabigatran 150 mg BID is as effective as coumadin, has a safety profile that is similar to that of coumadin, and does not require laboratory monitoring of INR
  • RE-COVER II Trial (2014) [MEDLINE]
    • Study: randomized, double-blind, double-dummy trial N = 2589) in acute venous thromboembolism treated with low-molecular-weight or unfractionated heparin for 5-11 days, comparing dabigatran 150 mg twice daily with coumadin
      • Used pooled analysis of RE-COVER and RE-COVER II trial data
    • Main Findings: dabigatran had similar effects on recurrence of venous thromboembolism and a lower risk of bleeding compared with warfarin for the treatment of acute venous thromboembolism

Comparative Rates of Hemorrhage Between Coumadin and Novel Oral Anticoagulants

  • Systematic Review of Novel Oral Anticoagulants, As Compared to Coumadin (Ann Intern Med, 2012) [MEDLINE]: included chronic non-valvular atrial fibrillation trials (RE-LY Trial (2009): dabigatran, ARISTOTLE Trial (2011): apixaban, ROCKET AF Trial (2011): rivaroxaban) and venous thromboembolism trials (EINSTEIN-DVT (2010): rivaroxaban, RE-COVER (2009): dabigatran, EINSTEIN-PE (2012): rivaroxaban)
    • Decreased Risk of Fatal Bleeding, as Compared to Coumadin (RR, 0.60 [CI, 0.46 to 0.77])
    • Decreased Risk of Major Bleeding, as Compared to Coumadin (RR, 0.80 [CI, 0.63 to 1.01])
    • Increased Risk of Gastrointestinal Bleeding, as Compared to Coumadin (RR, 1.30 [CI, 0.97 to 1.73])
    • Increased Risk of Discontinuation Due to Adverse Events, as Compared to Coumadin (RR, 1.23 [CI, 1.05 to 1.44])
    • Bleeding Risk for New Oral Anticoagulants May Be Higher in Patients >75 y/o or Those Receiving Coumadin Who Have Good Control
  • Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (Chest, 2016) [MEDLINE]
    • CrCl 50-80 mL/min: novel oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
    • CrCl <50 mL/min: novel oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
      • Apixaban had the lowest rate of major bleeding in this subgroup

Types of Hemorrhage

Other Adverse Effects

  • Ischemic Events Following Premature Discontinuation: US boxed warning


References

General

Indications

Atrial Fibrillation

Venous Thromboembolism

Administration

Administration in Specific Clinical Subsets of Patients