Dabigatran (Pradaxa)

Indications

Systemic Embolism Prevention in Nonvalvular Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])

  • FDA Approval: Oct, 2010 for non-valvular atrial fibrillation (but was available for longer and for other indications in other countries)
  • PETRO Trial (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 (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 (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 receiving long-term anticoagulation, although the treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment

Venous Thromboembolism-Deep Venous Thrombosis (DVT)/Acute Pulmonary Embolism (PE) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]] and Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])

  • FDA Approval: April, 2014 for treatment of venous thromboembolism
  • RE-COVER Trial (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 receiving long-term anticoagulation, although the treatment benefits compared with warfarin are small and vary depending on the control achieved by warfarin treatment
  • 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

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

  • Systematic Review Comparing Novel Oral and Other Anticoagulants (Fondaparinux, Dabigatran, Rivaroxaban, Apixaban) to Enoxaparin Used as Venous Thromboembolism Prophylaxis After Major Orthopedic Surgery (Ann Vasc Surg, 2013) [MEDLINE]
    • Novel Anticoagulants Can Be Considered as Alternatives to Enoxaparin, Depending on Their Individual Clinical Characteristics and Cost-Effectiveness
    • Primary Efficacy (Any DVT, Non-Fatal PE, or All-Cause Mortality) Favored Fondaparinux and Rivaroxaban Over Enoxaparin
    • Compared to Enoxaparin, the Bleeding Risk was Similar for All Agents, Except Fondaparinux (Which Manifested a Significantly Higher Any-Bleeding Risk) and Apixaban (Which Manifested a Lower Any-Bleeding Risk)
  • Pooled Analysis of Three Trials Comparing Dabigatran with Enoxaparin in DVT Prophylaxis After Total Hip Arthroplasty (Thromb J, 2015) [MEDLINE]
    • Extended Dabigatran Prophylaxis (200 mg qday) was as Effective as Enoxaparin 40 mg qday in Decreasing the Risk of Venous Thromboembolism and All-Cause Mortality, with Similar Bleeding Risks
    • Clinical Outcome of Major Venous Thromboembolism and Venous Thromboembolism-Related Death was Significantly Decreased with Dabigatran, as Compared to Enoxaparin

Pharmacology

Pharmacokinetics

  • Orally Administered Dabigatran Etexilate is a Prodrugpeak effect occurs in 2-3 hrs
  • Elimination Half-Life: 12-17 hrs

Metabolism

  • Renal: 85% of dabigatran is eliminated by kidney -> renal failure increases drug levels

Drug Interactions

  • Amiodarone: increases dabigatran levels

Administration

PO Dosing

  • Non-Valvular Atrial Fibrillation: 150 mg BID
  • Deep Venous Thrombosis (DVT) Prophylaxis for Hip Replacement: 200 mg qday x 28-35 days
  • Deep Venous Thrombosis (DVT) Prophylaxis for Knee Replacement: 220 mg qday x 10 days
  • Venous Thrombembolism: 150 mg BID
    • Note: edoxaban/dabigatran require initial parenteral (heparin, etc) anticoagulation for the treatment of venous thromboembolism (see Edoxaban, [[Edoxaban]])

Hepatic Dose-Adjustment

  • None Required

Renal Dose-Adjustment

Venous Thromboembolism

  • CrCl >30 mL/min (US Package Labeling): no dose adjustment (unless CrCl is <50 ml/min and is receiving P-gp inhibitors, then avoid use)
  • CrCl ≤30 mL/min (US Package Labeling): no dose adjustment specified in manufacturer labeling (although this patient group was excluded from the clinical trials)
    • CrCl ≤30 mL/min (Per ACCP Recommendations): avoid use
  • End-Stage Renal Disease Requiring Hemodialysis (US Package Labeling): no dose adjustment provided in manufacturer labeling (although this patient group was excluded from the clinical trials), probably should avoid use

Non-Valvular Atrial Fibrillation

  • CrCl >50 mL/min (US Package Labeling): no dose adjustment
    • CrCl 50-80 mL/min: use with caution due to risk for increased dabigatran exposure (area under the curve may be increased 1.5x higher than normal)
  • CrCl 30-50 mL/min (US Package Labeling): no dose adjustment (unless patient is receiving concomitant dronedarone/ketoconazole, then decrease to 75 mg PO BID
    • Use with caution due to risk for increased dabigatran exposure (area under the curve may be increased 3x higher than normal), especially if patient is older
  • CrCl 15-30 mL/min (US Package Labeling): 75 mg PO BID (unless patient is receiving P-gp inhibitors, then avoid use)
    • Note: patients with CrCl <30 mL/min were excluded from the RE-LY trial
    • CrCl ≤30 mL/min (Per ACCP Recommendations): avoid use
  • End-Stage Renal Disease Requiring Hemodialysis (US Package Labeling): avoid use
    • Hemodialysis Removes Approximately 57% Over 4 hrs

Venous Thromboembolism Prophylaxis

  • CrCl >30 mL/min (US Package Labeling): no dose adjustment (unless CrCl is <50 ml/min and is receiving P-gp inhibitors, then avoid use)
  • CrCl ≤30 mL/min (US Package Labeling): no dose adjustment specified in manufacturer labeling (although this patient group was excluded from the clinical trials)
    • CrCl ≤30 mL/min (Per ACCP Recommendations): avoid use
  • End-Stage Renal Disease Requiring Hemodialysis (US Package Labeling): no dose adjustment specified in manufacturer labeling (although this patient group was excluded from the clinical trials), probably should avoid use

Effect on Anticoagulation Tests

  • Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time, [[Prothrombin Time]]): no effect-prolonged
  • Partial Thromboplastin Time (PTT) (see Partial Thromboplastin Time, [[Partial Thromboplastin Time]]): prolonged
  • Thrombin Time (TT) (see Thrombin Time, [[Thrombin Time]]): prolonged (note that this is unique among the novel oral anticoagulants, as dabigatran is a direct thrombin inhibitor)
  • Anti-Factor Xa Activity (see Anti-Factor Xa Activity, [[Anti-Factor Xa Activity]]): no effect

Conversion from/to Other Anticoagulants

Conversion from Dabigatran

  • Conversion From Dabigatran -> Unfractionated Heparin Drip/Low Molecular Weight Heparin Drip (and Ultimately, Coumadin: wait 12 hrs (for CrCl ≥30 mL/min) or 24 hrs (CrCl <30 mL/min) after last dose of dabigatran before starting unfractionated heparin drip or low molecular weight heparin
    • Note: with regard to eventual conversion to coumadin, the INR in first 2 days after discontinuing dabigatran may be inaccurate (reflecting a residual dabigatran effect)

Conversion to Dabigatran

  • Conversion From Coumadin -> Dabigatran: discontinue coumadin and start dabigatran when INR <2
  • Conversion From Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) or Fondaparinux -> Dabigatran: start dabigatran approximately 2 hrs prior to next scheduled dose of subcutaneous agent
  • Conversion From Unfractionated Heparin Drip/Argatroban Drip -> Dabigatran: start dabigatran as soon as drip is stopped

Abrupt Discontinuation of Dabigatran

  • Premature Discontinuation of Dabigatran Can Increase the Risk of Ischemic Events: for this reason, if dabigatran is discontinued for any reason other than hemorrhage or completion of course of therapy, consideration of coverage with an alternative anticoagulant should be considered

Management of Dabigatran Anticoagulation for Procedures

  • Invasive/Surgical Procedures
    • CrCl at least 50 mL/min: discontinue dabigatran 1-2 days before procedure
    • CrCl <50 mL/min: discontinue dabigatran 3-5 days before procedure
  • Major Surgery/Neuraxial Procedures
    • CrCl at least 50 mL/min: discontinue dabigatran 3 days before procedure
    • CrCl <50 mL/min: discontinue dabigatran >3 days before procedure

Reversal of Anticoagulation

  • Activated Charcoal (see Activated Charcoal, [[Activated Charcoal]])
    • Clinical Efficacy: early administration of activated charcoal might reduce the absorption of dabigatran (Thromb Haemost, 2010) [MEDLINE]
  • Fresh Frozen Plasma (see Fresh Frozen Plasma, [[Fresh Frozen Plasma]])
    • Clinical Efficacy: although the product insert suggests that fresh frozen plasma may be effective, it is only recommended to treat an elevated PTT that may result due to a dilutional coagulopathy that might occur during resuscitation
  • Hemodialysis (see Hemodialysis, [[Hemodialysis]])
    • Clinical Efficacy: removes 62% of circulating dabigatran within 2 hrs and 68% within 4 hrs (Thromb Haemost, 2010) [MEDLINE]
  • Idarucizumab (Praxbind) (see Idarucizumab, [[Idarucizumab]])
    • Clinical Efficacy: specific reversal agent for dabigatran
  • Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor, [[Prothrombin Complex Concentrate-4 Factor]])
    • Clinical Efficacy: in vitro studies and animal Models suggest that this may bypass the anticoagulant effects of high dabigatran concentrations (Thromb Haemost, 2010) [MEDLINE]
  • Recombinant Factor VIIa (see Factor VIIa, [[Factor VIIa]])
    • Clinical Efficacy: in vitro studies and animal Models suggest that this may bypass the anticoagulant effects of high dabigatran concentrations (Thromb Haemost, 2010) [MEDLINE]

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

  • Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. J Thromb Haemost 2004 Sep; 2 (9): 1573-80
  • A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005 Jan; 3 (1): 103-11
  • Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007 Sep 15; 370 (9591): 949-56
  • PETRO Trial : Dabigatran With or Without Concomitant Aspirin Compared With Warfarin Alone in Patients With Nonvalvular Atrial Fibrillation. American Journal of Cardiology, Volume 100, Issue 9 , Pages 1419-1426, 1 November 2007 [MEDLINE]
  • Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007 Nov; 5 (11): 2178-85
  • The RE-MOBILIZE writing committee. The oral thrombin inhibitor dabigatran etexilate vs the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. Epub 2008 Apr 14
  • Dabigatran etexilate. Drugs. 2008;68(12):1699-709
  • Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokin 2009;48(1):1-22 [MEDLINE]
  • The RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–1151 [MEDLINE]
  • Rationale and design of RE-LY: randomized evaluation of long-term anticoagulant therapy, warfarin, compared with dabigatran. Am Heart J. 2009;157:805–810
  • RE-COVER Trial: Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52. doi: 10.1056/NEJMoa0906598 [MEDLINE]
  • Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116-1127 [MEDLINE]
  • Boehringer Ingelheim. Pradaxa (dabigatran etexilate): advisory committee briefing document. August 27, 2010. http://www.fda.gov/downloads /AdvisoryCommittees/CommitteesMeetingMaterials/Drugs /CardiovascularandRenalDrugsAdvisoryCommittee/UCM247244.pdf
  • Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011 Jan 18;123(2):131-6 [MEDLINE]
  • Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011 May 31;123(21):2363-72
  • The use of dabigatran in elderly patients. Arch Intern Med. 2011 Jul 25;171(14):1285-6 [MEDLINE]
  • New anticoagulant drugs among elderly patients is caution necessary?: Comment on “The use of dabigatran in elderly patients”. Arch Intern Med. 2011 Jul 25;171(14):1287-8
  • Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost. 2011;105:371-378
  • Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res. 2011;127:457-465
  • Falsely elevated point-of-care INR values in dabigatran-treated patients. Heartwire. July 7, 2011. http://www.theheart.org/article/1251461.do
  • Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011;123:1436-1450 [MEDLINE]
  • New oral antithrombotics: focus on dabigatran, an oral, reversible direct thrombin inhibitor for the prevention and treatment of venous and arterial thromboembolic disorders. Vasc Heal Risk Manage 2012;8:45-57 [MEDLINE]
  • Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med. 2012;50:1601-1605
  • The new oral anticoagulants and the future of haemostasis laboratory testing. Biochem Med (Zagreb). 2012;22:329-341
  • Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother. 2012;46:1627-1636
  • Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med. 2012 Dec 4;157(11):796-807 [MEDLINE]
  • Systematic review of randomized controlled trials of new anticoagulants for venous thromboembolism prophylaxis in major orthopedic surgeries, compared with enoxaparin. Ann Vasc Surg. 2013 Apr;27(3):355-69. doi: 10.1016/j.avsg.2012.06.010. Epub 2013 Jan 23 [MEDLINE]
  • New oral anticoagulants in the treatment of pulmonary embolism: efficacy, bleeding risk, and monitoring. Thrombosis 2013;2013:973710. doi: 10.1155/2013/973710 [MEDLINE]
  • RE-COVER II Trial: Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014 Feb 18;129(7):764-72. doi: 10.1161/CIRCULATIONAHA.113.004450. Epub 2013 Dec 16 [MEDLINE]
  • Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials. Thromb J. 2015 Nov 17;13:36. doi: 10.1186/s12959-015-0067-8. eCollection 2015 [MEDLINE]
  • Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest. 2016,(): doi:10.1016/j.chest.2015.12.029 [MEDLINE]