Systemic Embolism Prevention in Non-Valvular Atrial Fibrillation (see Atrial Fibrillation)
Clinical Efficacy
FDA Approved in January, 2015 for Stroke Prevention in Non-Valvular Atrial Fibrillation
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
FDA Approved in January, 2015 for the Treatment of Venous Thromboembolism
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
PO (Venous Thromboembolism): 5-10 days of parenteral anticoagulation, then 60 mg PO qday
Note: edoxaban/dabigatran require initial parenteral (heparin, etc) anticoagulation for the treatment of venous thromboembolism (see Dabigatran)
PO (Non-Valvular Atrial Fibrillation): 5-10 days of parenteral anticoagulation, then 60 mg PO qday
Note: edoxaban/dabigatran require initial parenteral (heparin, etc) anticoagulation for the treatment of venous thromboembolism (see Dabigatran)
Dose Adjustment
Hepatic
Mild Impairment (Child-Pugh Class A); no dose adjustment
Moderate-Severe Impairment (Child-Pugh Class B-C): avoid use
Renal
Venous Thromboembolism
CrCl ≥51 mL/min: No dosage adjustment recommended.
CrCl 15-50 mL/min: 30 mg PO qay
CrCl 30-50 mL/min (Beers Criteria for Patients ≥65 y/o): 30 mg PO qay
CrCl <30 mL/min (Beers Criteria for Patients ≥65 y/o): avoid use
CrCl <15 mL/min: avoid use
Hemodialysis: total edoxaban exposure is decreased by <7% during a 4-hour dialysis session
Non-Valvular Atrial Fibrillation
CrCl >95 mL/min: boxed warning regarding use in patients with atrial fibrillation -> avoid use
CrCl 51-95 mL/min: no dose adjustment
CrCl 15-50 mL/min: 30 mg PO qday
CrCl 30-50 mL/min (Beers Criteria for Patients ≥65 y/o): 30 mg PO qay
CrCl <30 mL/min (Beers Criteria for Patients ≥65 y/o): avoid use
CrCl <15 mL/min: avoid use
Hemodialysis: total edoxaban exposure is decreased by <7% during a 4-hour dialysis session
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): xxx
Conversion to Parenteral Anticoagulant: discontinue edoxaban and start the parenteral anticoagulant (unfractionated heparin drip/low molecular weight heparin) at the time the next dose of edoxaban would have been taken
Conversion to Edoxaban
Conversion from Unfractionated Heparin Drip: discontinue heparin drip and initiate edoxaban 4 hrs later
Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin): discontinue low molecular weight heparin and initiate edoxaban at the time of the next scheduled administration of low molecular weight heparin
Abrupt Discontinuation of Edoxaban
Premature Discontinuation of Edoxaban Can Increase the Risk of Ischemic Events: for this reason, if edoxaban 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 Edoxaban Anticoagulation
Recommendations for Periprocedural/Perioperative Management of Edoxaban (American College of Chest Physicians Clinical Practice Guideline for the Perioperative Management of Antithrombotic Therapy) (Chest, 2022) [MEDLINE]
In Patients Receiving Edoxaban Who Require an Elective Procedure/Surgery, Stop Edoxaban 1-2 Days Before the Procedure/Surgery (as Opposed to Continuing Edoxaban (Conditional Recommendation, Very Low Certainty of Evidence)
The Total Duration of Periprocedural/Perioperative Edoxaban Interruption Will Depend on the Bleeding Risk Associated with the Procedure/Surgery
Low-Moderate Bleeding Risk: 1 day off edoxaban prior to procedure/surgery
High Bleeding Risk: 2 days off edoxaban prior to procedure/surgery
This Management May Be Applied Irrespective of Whether Patients are Receiving Edoxaban 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 Edoxaban 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
Prothrombin Complex Concentrate-4 Factor is Suggested for Edoxaban-Associated Hemorrhage
Administration: 50 units/kg IV
Adverse Effects
Hemorrhagic Adverse Effects
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: boxed warnings
References
General
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
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]
New oral anticoagulants in the treatment of pulmonary embolism: efficacy, bleeding risk, and monitoring. Thrombosis 2013;2013:973710. doi: 10.1155/2013/973710 [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]
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
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]
Reversal of Edoxaban Anticoagulation
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]
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]
Adverse Effects
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]
