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
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
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
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
Dose Adjustment for Obesity (2016 International Society of Thrombosis and Hemostasis Recommendations) (J Thromb Haemost, 2016) [MEDLINE]
BMI ≤40 kg/m2 and Weight <120 kg: standard dosing is recommended for both venous thromboembolism and atrial fibrillation
BMI >40 kg/m2 or Weight >120 kg: direct oral anticoagulants are not recommended (due to limited clinical data and possibility that patient may be underdosed)
If Direct Oral Anticoagulants are Used in this Patient Group, Drug-Specific Peak and Trough Levels (Anti-Factor Xa for Apixaban/Edoxaban/Rivaroxaban, Ecarin Time or Dilute Thrombin Time with Appropriate Calibrators for Dabigatran, or Mass Spectrometry for Any of the Agents) Should Be Measured: if levels fall below the expected range, change to coumadin is recommended (rather than dose adjustment of the direct oral anticoagulant)
Effect on Anticoagulation Tests
Prothrombin Time (PT)/International Normalized Ratio (INR) (see Prothrombin Time): no effect-prolonged
Thrombin Time (TT) (see Thrombin Time): prolonged (note that this is unique among the novel oral anticoagulants, as dabigatran is a direct thrombin inhibitor)
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
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]
In Patients Receiving Dabigatran Who Require an Elective Procedure/Surgery, Stop Dabigatran 1-4 Days Before the Procedure/Surgery (as Opposed to Continuing Dabigatran (Conditional Recommendation, Very Low Certainty of Evidence)
The Total Duration of Periprocedural/Perioperative Dabigatran Interruption Will Depend on the Bleeding Risk Associated with the Procedure/Surgery and the Patient’s Renal Function
Low-Moderate Bleeding Risk (with CrCl ≥50 mL/min): 1 day off dabigatran prior to procedure/surgery
Low-Moderate Bleeding Risk (with CrCl <50 mL/min): 2 days off dabigatran prior to procedure/surgery
High Bleeding Risk (with (with CrCl ≥50 mL/min): 2 days off dabigatran prior to procedure/surgery
High Bleeding Risk (with CrCl <50 mL/min): 4 days off dabigatran prior to procedure/surgery
This Management May Be Applied Irrespective of Whether Patients are Receiving Dabigatran for Atrial Fibrillation or Venous Thromboembolism
In Patients Receiving DOAC Who Require an Elective Procedure/Surgery, Perioperative Heparin Bridging is Not Recommended (Conditional Recommendation, Very Low Certainty of Evidence)
The Rapid Offset and Rapid Onset of Action of DOAC’s Obviates the Need for Heparin Bridging with Short-Acting Anticoagulants Such as Unfractionated Heparin or Low Molecular Weight Heparin in a Periprocedural/Perioperative Setting
In Patients Who Had DOAC Interruption for an Elective Procedure/Surgery, Resume DOAC >24 hrs After the Procedure/Surgery (as Opposed to Resuming Dabigatran within 24 hrs (Conditional Recommendation, Very Low Certainty of Evidence)
The Resumption of Postprocedure/Postoperative DOAC Will Depend on the Bleeding Risk Associated with the Procedure/Surgery
Low-Moderate Bleeding Risk: resume DOAC at least 24 hrs after procedure/surgery
High Bleeding Risk: resume DOAC 48-72 hours after procedure/surgery
DOAC’s Have a Rapid Onset of Action, with a Peak Effect Occurring 1-3 hrs After Intake, Thereby Requiring Cautious Administration After a Procedure/Surgery
In Patients Who Had DOAC Interruption for an Elective Procedure/Surgery, Routine DOAC Coagulation Function Testing is Not Recommended to Guide Periprocedural/Perioperative DOAC Management (Conditional Recommendation, Very Low Certainty of Evidence)
DOAC Level Testing May Be Considered, on a Case-by-Case Basis, in Non-Elective Periprocedural/Perioperative Clinical Situations
For Example, in Patients Who Require an Urgent/Emergency Prodedure/Surgery in Whom DOAC Level Testing May Inform the Need for Active DOAC Reversal with Administration of Blood Products or DOAC-Specific Reversal Agents
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
Clinical Efficacy: in vitro studies and animal Models suggest that this may bypass the anticoagulant effects of high dabigatran concentrations (Thromb Haemost, 2010) [MEDLINE]
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
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
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
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
Ischemic Events Following Premature Discontinuation: US boxed warning
References
General
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]
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]
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. https://www.theheart.org/article/1251461.do
Dabigatran etexilate: a new oral thrombin inhibitor. Circulation 2011;123:1436-1450 [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
Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. 2013 Apr;35(3):391-8. doi: 10.1007/s11239-013-0885-0 [MEDLINE]
Perioperative Management of Antithrombotic Therapy: An American College of Chest Physicians Clinical Practice Guideline. Chest. 2022 Aug 11;S0012-3692(22)01359-9. doi: 10.1016/j.chest.2022.07.025 [MEDLINE]
Indications
Atrial Fibrillation
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]
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
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
Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation. 2012;126:2381–2391 [MEDLINE]
Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e531S-75S. doi: 10.1378/chest.11-2304 [MEDLINE]
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]
Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955–962 [MEDLINE]
The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014 Oct 9;124(15):2450-8. doi: 10.1182/blood-2014-07-590323. Epub 2014 Aug 22 [MEDLINE]
Systematic review of cost-effectiveness analyses of novel oral anticoagulants for stroke prevention in atrial fibrillation. Rev Port Cardiol. 2015 Mar;34(3):179-91. doi: 10.1016/j.repc.2014.08.008. Epub 2015 Feb 27 [MEDLINE]
Cost-effectiveness of novel oral anticoagulants for stroke prevention in non-valvular atrial fibrillation. Curr Cardiol Rep. 2015;17:61 [MEDLINE]
Venous Thromboembolism
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
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
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]
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]
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]
Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2014;12(3):320-8. doi: 10.1111/jth.12485 [MEDLINE]
The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014 Oct 9;124(15):2450-8. doi: 10.1182/blood-2014-07-590323. Epub 2014 Aug 22 [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]
Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost. 2015 Nov;13(11):2012-20. doi: 10.1111/jth.13139. Epub 2015 Oct 5 [MEDLINE]
Administration
Administration in Specific Clinical Subsets of Patients
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
Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016 Jun;14(6):1308-13. doi: 10.1111/jth.13323. Epub 2016 Apr 27 [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]
