Direct Acting Oral Anticoagulants (DOACs)

Effective Date: January 18, 2023

Recommendations and Topics

• Scope
• Key Recommendations
• Definition
• Pharmacological Properties
• Therapeutic Indications
• Initiating a DOAC
• Ongoing Management
• Resources
• Appendices

This guideline provides recommendations on the use of direct acting oral anticoagulants (DOACs) in adults aged >19 years for the following indications:

• prevention of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF);
• treatment of hemodynamically stable venous thromboembolism (VTE); and,
• prevention of arterial vascular events in patients with stable coronary artery disease with or without peripheral artery disease.

How to make the decision to use a DOAC (instead of another anticoagulant), periprocedural management, and emergency reversal are all outside the scope of this guideline. Refer to BC Guidelines: Warfarin and BC Guidelines: Oral Anticoagulants: Elective Interruption & Emergency Reversal for more information on these topics.

• DOACs are considered first-line therapy for:
  • prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) for whom anticoagulation is indicated; and
  • treatment of hemodynamically stable venous thromboembolism (VTE).
• Do not use DOACs (instead of warfarin) for anticoagulation in mechanical heart valves, AF with moderate to severe mitral stenosis, and other very high-risk thrombotic indications.
• Confirm appropriate dosing as this varies widely across different indications. Dose adjustments may be indicated for renal impairment, age, weight, and drug-drug interactions. Refer to Table 2: DOAC dosing and therapeutic considerations based on indication and Appendix A: DOAC Drug Interactions for more information.
• Check renal function for all patients and liver function in patients with known hepatic dysfunction prior to initiating a DOAC. Monitor one or both periodically, based on clinical status.
• DOACs do not require routine laboratory monitoring. International normalized ratio (INR) and activated partial thromboplastin clotting time (aPTT) values do not reflect anticoagulant level or activity and should not be used to detect or exclude the presence of a DOAC.
• Check for potential drug-drug interactions and consider alternative therapy if a significant interaction is present.

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DOACs are a class of drugs with potent anticoagulant effects. DOACs work by inhibiting key activated clotting factors in the coagulation cascade. There are four DOACs currently available in Canada: three activated factor X (FXa) inhibitors (apixaban, edoxaban, and rivaroxaban) and one direct thrombin inhibitor (dabigatran).

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Pharmacological Properties

While DOACs have similar properties, their safety and suitability for individual patients differ based on each drug’s pharmacological profile.^1,2 As a class, DOACs have relatively predictable pharmacokinetic and pharmacodynamic properties, including:

• Rapid onset of action, reaching therapeutic effect in less than 4 hours.
• Half-lives that are highly dependent on renal and/or liver function.

DOACs have fewer food and drug interactions as compared to warfarin.³ However there are many drugs that should not be used concomitantly with DOACs. Refer to Table 2: DOAC dosing and therapeutic considerations based on indication and Appendix A: DOAC Drug Interactions for more information on therapeutic considerations and drug-drug interactions.

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Therapeutic Indications

DOACs are approved in three major clinical settings where oral anticoagulation is commonly used, but are not preferred over warfarin for certain patient populations and are contraindicated for others (see the Initiating a DOAC section below for more information). Refer to Table 2: DOAC dosing and therapeutic considerations based on indication for more detail on DOAC dosing and therapeutic considerations based on indication and the Resources section for information on the Rapid Access to Consultative Expertise (RACE) program.

DOACs for Non-valvular Atrial Fibrillation (NVAF)

DOACs are considered first line treatment for most patients with NVAF (strong recommendation, high-quality evidence),^4,5 based on direct comparison with warfarin in robust clinical trials investigating the prevention of stroke and systemic embolism in patients with NVAF.^6–9 As a class, DOACs have been shown to be superior or non-inferior to warfarin in terms of efficacy,^10,11 with reduced risk of stroke, intracranial bleeding, and all-cause mortality.¹⁰ DOACs also have comparable or better safety profiles, with no difference in major bleeding and a lower risk of intracranial bleeding.¹⁰ DOACs also offer important practical benefits for patients and providers (e.g., ease of administration, fewer dietary interactions, reduced monitoring requirements).

DOACs for Venous Thromboembolism (VTE)

DOACs are considered first line treatment for acute VTE and prevention of recurrent VTE in most patients because of their overall safety profile and convenience when compared to warfarin.^12–14 However, there is no difference in all-cause mortality, recurrent thrombosis or major bleeding between the use of DOACs and warfarin for VTE.¹⁴ Anticoagulant therapy for acute VTE is recommended for at least three months.¹⁵ Extended DOAC use in select patients (e.g., unprovoked index event or ongoing risk factors) beyond six months can reduce VTE recurrence and/or death when compared to a placebo,¹⁶ but it is associated with a higher risk of non-major clinically important bleeding.¹⁶

DOACs for Coronary Artery Disease (CAD) and Peripheral Artery Disease (PAD)

A very low dose of rivaroxaban (2.5 mg twice daily) combined with low-dose ASA once daily reduces the risk of cardiovascular death, stroke or myocardial infarction in patients with stable CAD and/or PAD.^17,18 Recent data show that this combination is also effective in reducing major adverse limb and cardiovascular thrombotic events after endovascular intervention in patients with PAD; these outcomes include limb ischemia, amputation, myocardial infarction, ischemic stroke, and death.¹⁹ However, the combination of very low dose rivaroxaban and low-dose ASA (dual pathway inhibition) is associated with an increased risk of major bleeding (primarily in the gastrointestinal tract) when compared to ASA alone, although no significant increase in fatal/ critical bleeding has been observed.^17,20

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Initiating a DOAC

Clinical Assessment

Before initiating a DOAC, ensure that the patient does not have a contraindication where warfarin or low molecular weight heparin (LMWH) is recommended instead. Refer to Table 1: Absolute contraindications for DOACs for more information on DOAC contraindications and BC Guidelines: Warfarin for more general warfarin information. Of note, DOACs are not contraindicated in frail elderly populations; a risk-benefit analysis favours anticoagulation for patients with NVAF in this population.²¹

Dosage

The table below is not an exhaustive list of all contraindications, precautions, and drug interactions. Consult a drug interaction checker or pharmacist, as needed. Refer to the Resources section for Child-Pugh Score and Cockcroft-Gault calculators.

Table 2: DOAC dosing and therapeutic considerations based on indication

^{Abbreviation: BID = twice daily; caps = capsules; CrCl = creatinine clearance; kg = kilogram; LMWH = low molecular weight heparin; µmol/L = micromoles per litre; mg = milligrams; mL/min = milliliters per minute; P-gp = P-glycoprotein; tabs = tablets; ­ = increase; ¯ = decrease.
Footnotes:}

1. ^{PharmaCare coverage as of January 2023 (subject to revision). Limited Coverage: Requires Special Authority to be eligible for reimbursement*. Non-benefit: Not eligible for reimbursement. *Reimbursement is subject to the rules of a patient’s PharmaCare plan, including any deductibles. In all cases, coverage is subject to drug price limits set by PharmaCare. See: www.health.gov.bc.ca/pharmacare/plans/index.html and www.health.gov.bc.ca/pharmacare/policy.html for further information. See the Special Authority Drug List for the Special Authorization Form for dabigatran;}
2. ^{Drugs costs are the BC retail cost rounded up to the nearest $5 of the generic, when available from mckesson.ca. Current as of January 2023 and does not include retail markups or pharmacy fees;}
3. ^{Lexicomp Drug Interactions. Accessed online May 5, 2022 from https://www.uptodate.com/drug-interactions/;}
4. ^{HIV Drug Interactions. University of Liverpool. Accessed online May 5, 2022 from https://www.hiv-druginteractions.org/checker}

Switching Between Warfarin and a DOAC

There is no need to switch to a DOAC for patients, especially frail elderly, who are currently and successfully anticoagulated with warfarin. Changes in anticoagulant therapy are associated with a transient increased risk of stroke and systemic embolism.²⁷ However, switching may be indicated for patients who are frequently outside the therapeutic INR range or those who cannot adhere to regular laboratory monitoring.²⁸ Refer to Appendix B: Switching Between Warfarin and DOAC for recommended approaches to switching between anticoagulant therapies.

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Bleeding Complications

Bleeding is a common adverse event for all anticoagulant drugs.^32,33 The risk of bleeding is influenced by the concomitant use of certain medications, patient co-morbidities, and lifestyle. Refer to Table 3: Risk factors for bleeding complications on anticoagulation therapy or risk factors for bleeding complications on anticoagulation therapy.

Table 3: Risk for bleeding complications on anticoagulation therapy^34-36

^{Abbreviations: ASA = acetylsalicylic acid; INR = international normalized ratio; mmHg = millimetres of mercury, mL = millilitre; NSAIDs = nonsteroidal anti-inflammatory drugs.
Adapted from: Warfarin Reversal Position Statement, Australasian Society of Thrombosis & Haematosis37}

When a patient on a DOAC is bleeding, the decision to continue, temporarily interrupt or permanently stop the DOAC depends on the severity of the bleeding event, the likelihood the event can be stopped with minimal intervention, and the risk of recurrence. It is most important to determine and address the cause of bleeding while considering the patient’s individual risk-benefit profile with regards to risk of thrombosis with DOAC discontinuation versus risk to patient with ongoing bleeding. Specialist consultation is recommended if the risk of thrombosis is uncertain or if specialty involvement is required to mitigate bleeding (e.g., RACE consult line).

Overall, DOACs do not usually require reversal because of their short half-life.³⁸ However, emergency reversal may be indicated for life-threatening bleeding situations or when urgent interventions are required.³⁸ Dabigatran is currently the only DOAC with a dedicated reversal agent. Refer to BC Guidelines Oral Anticoagulants: Elective Interruption and Emergency Reversal, Canadian Cardiology Society NVAF guidelines, and Thrombosis Canada for more information on bleeding management. In general:

• For most minor bleeding events (e.g., minor lesions, simple tooth extraction) DOACs can be continued with the application of local measures. Prolonged pressure may be required.
• For moderate bleeding that is challenging to control, consider brief DOAC interruption (e.g.,1-2 days). Because DOACs have a short duration of action, prolonged interruption increases the risk of thrombosis substantially.
• For potentially life-threatening bleeding (e.g., severe GI bleeding, intracranial bleeding) or bleeding into a critical site (e.g., joint), the DOAC should be stopped immediately, and the patient should seek care at the closest emergency department.

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References

1. Gong IY, Kim RB. Importance of Pharmacokinetic Profile and Variability as Determinants of Dose and Response to Dabigatran, Rivaroxaban, and Apixaban. Can J Cardiol. 2013;29(7):S24-S33. doi:10.1016/j.cjca.2013.04.002
2. Scaglione F. New Oral Anticoagulants: Comparative Pharmacology with Vitamin K Antagonists. Clin Pharmacokinet. 2013;52(2):69-82. doi:10.1007/s40262-012-0030-9
3. Zhu J, Alexander GC, Nazarian S, Segal JB, Wu AW. Trends and Variation in Oral Anticoagulant Choice in Patients with Atrial Fibrillation, 2010-2017. Pharmacother J Hum Pharmacol Drug Ther. 2018;38(9):907-920. doi:10.1002/phar.2158
4. Andrade JG, Aguilar M, Atzema C, et al. The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation. Can J Cardiol. 2020;36(12):1847-1948. doi:10.1016/j.cjca.2020.09.001
5. López-López JA, Sterne JAC, Thom HHZ, et al. Oral anticoagulants for prevention of stroke in atrial fibrillation: systematic review, network meta-analysis, and cost effectiveness analysis. BMJ. Published online November 28, 2017:j5058. doi:10.1136/bmj.j5058
6. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907
7. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638
8. Granger CB, Alexander JH, McMurray JJV, et al. Apixaban Versus Warfarin in Patients With Atrial fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039
9. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561
10. Carnicelli AP, Hong H, Connolly SJ, et al. Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation: Patient-Level Network Meta-Analyses of Randomized Clinical Trials With Interaction Testing by Age and Sex. Circulation. 2022;145(4):242-255. doi:10.1161/CIRCULATIONAHA.121.056355
11. Makam RCP, Hoaglin DC, McManus DD, et al. Efficacy and safety of direct oral anticoagulants approved for cardiovascular indications: Systematic review and meta-analysis. Pizzi C, ed. PLOS ONE. 2018;13(5):e0197583. doi:10.1371/journal.pone.0197583
12. Cohen AT, Bauersachs R. Rivaroxaban and the EINSTEIN clinical trial programme. Blood Coagul Fibrinolysis. 2019;30(3):85-95. doi:10.1097/MBC.0000000000000800
13. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
14. Gómez-Outes A, Terleira-Fernández AI, Lecumberri R, Suárez-Gea ML, Vargas-Castrillón E. Direct oral anticoagulants in the treatment of acute venous thromboembolism: A systematic review and meta-analysis. Thromb Res. 2014;134(4):774-782. doi:10.1016/j.thromres.2014.06.020
15. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease. Chest. 2016;149(2):315-352. doi:10.1016/j.chest.2015.11.026
16. Ebraheem M, Alzahrani I, Crowther M, Rochwerg B, Almakadi M. Extended DOAC therapy in patients with VTE and potential risk of recurrence: A systematic review and meta‐analysis. J Thromb Haemost. 2020;18(9):2308-2317. doi:10.1111/jth.14949
17. Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017;377(14):1319-1330. doi:10.1056/NEJMoa1709118
18. Rivaroxaban (Xarelto). Thrombosis Canada; 2021. https://thrombosiscanada.ca/clinicalguides/#
19. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in Peripheral Artery Disease after Revascularization. N Engl J Med. 2020;382(21):1994-2004. doi:10.1056/NEJMoa2000052
20. Koutsoumpelis A, Argyriou C, Tasopoulou KM, Georgakarakos EI, Georgiadis GS. Novel Oral Anticoagulants in Peripheral Artery Disease: Current Evidence. Curr Pharm Des. 2019;24(38):4511-4515. doi:10.2174/1381612825666181226151959
21. Seelig J, Pisters R, Hemels M, Huisman MV, ten Cate H, Alings M. When to withhold oral anticoagulation in atrial fibrillation – an overview of frequent clinical discussion topics. Vasc Health Risk Manag. 2019;Volume 15:399-408. doi:10.2147/VHRM.S187656
22. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus Warfarin in Patients with Mechanical Heart Valves. N Engl J Med. 2013;369(13):1206-1214. doi:10.1056/NEJMoa1300615
23. Woller SC, Stevens SM, Kaplan D, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv. 2022;6(6):1661-1670. doi:10.1182/bloodadvances.2021005808
24. Covert K, Branam DL. Direct-acting oral anticoagulant use at extremes of body weight: Literature review and recommendations. Am J Health Syst Pharm. 2020;77(11):865-876. doi:10.1093/ajhp/zxaa059
25. Chan YH, Chao TF, Lee HF, et al. Different Renal Function Equations and Dosing of Direct Oral Anticoagulants in Atrial Fibrillation. JACC Asia. 2022;2(1):46-58. doi:10.1016/j.jacasi.2021.11.006
26. Conway SE, Hwang AY, Ponte CD, Gums JG. Laboratory and Clinical Monitoring of Direct Acting Oral Anticoagulants: What Clinicians Need to Know. Pharmacother J Hum Pharmacol Drug Ther. 2017;37(2):236-248. doi:10.1002/phar.1884
27. Joosten LPT, Van Doorn S, Van De Ven PM, et al. Safety of Switching from a Vitamin K Antagonist to a Non-Vitamin K Antagonist Oral Anticoagulant in Frail Older Patients with Atrial Fibrillation: Results of the FRAIL-AF Randomized Controlled Trial. Circulation. Published online August 27, 2023:CIRCULATIONAHA.123.066485. doi:10.1161/CIRCULATIONAHA.123.066485
28. Piran S, Robinson M, Kruja E, Schulman S. Reasons for Switching from Warfarin to a Direct Oral Anticoagulant: A Retrospective Study. Blood. 2018;132(Supplement 1):5060-5060. doi:10.1182/blood-2018-99-116974
29. DOACs: Coagulation Testing. Thrombosis Canada; 2021. https://thrombosiscanada.ca/clinicalguides/#
30. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. doi:10.1016/j.jacc.2019.01.011
31. Elhosseiny S, Al Moussawi H, Chalhoub JM, Lafferty J, Deeb L. Direct Oral Anticoagulants in Cirrhotic Patients: Current Evidence and Clinical Observations. Can J Gastroenterol Hepatol. 2019;2019:4383269. doi:10.1155/2019/4383269
32. Vazquez S, Rondina MT. Direct oral anticoagulants (DOACs). Vasc Med. 2015;20(6):3. doi:10.1177/1358863X15600256
33. Gladstone DJ, Geerts WH, Douketis J, Ivers N, Healey JS, Leblanc K. How to Monitor Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation: A Practice Tool Endorsed by Thrombosis Canada, the Canadian Stroke Consortium, the Canadian Cardiovascular Pharmacists Network, and the Canadian Cardiovascular Society. Ann Intern Med. 2015;163(5):382-385. doi:10.7326/M15-0143
34. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G. Pharmacology and Management of the Vitamin K Antagonists. Chest. 2008;133(6):160S-198S. doi:10.1378/chest.08-0670
35. Schulman S, Beyth RJ, Kearon C, Levine M N. Hemorrhagic complications of anticoagulant and thrombolytic treatment. Am Coll Chest Physicians Evid-Based Clin Pract Guidel 8th Ed. 2008;133(6):257S-298S.
36. Maddali S, Biring T, Kopecky S, et al. Health Care Guideline: Antithrombotic Therapy Supplement. Institute for Clinical Systems Improvement; 2013. Accessed May 3, 2022. https://vdocuments.site/health-care-guideline-antithrombotic-therapy-supplement-2013-05-30-health-care.html
37. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EM. Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. 2004;181(9):6.
38. Chan N, Sobieraj-Teague M, Eikelboom JW. Direct oral anticoagulants: evidence and unresolved issues. The Lancet. 2020;396(10264):1767-1776. doi:10.1016/S0140-6736(20)32439-9

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Abbreviations

aPTT           Activated partial thromboplastin clotting time
CBC            Complete blood count
CrCl            Creatinine clearance
DOAC         Direct acting oral anticoagulant
eGFR          estimated glomerular filtration rate
HIV              Human immunodeficiency virus
LMWH         Low molecular weight heparin
NVAF           Non-valvular atrial fibrillation
VTE             Venous thromboembolism

Resources

Additional Resources

• Health Data Coalition: An online, physician-led data sharing platform that can assist you in assessing your own practice in areas such as chronic disease management or medication prescribing.
• General Practice Services Committee:
  • Practice Support Program: Offers focused, accredited training sessions for BC physicians to help improve practice efficiency and support enhanced care.
  • Chronic Disease Management and Complex Care Incentives: Compensates for the time and skill needed to work with patients with complex conditions or specific chronic diseases.
• QuitNow Smoking Cessation Program: Provides one-on-one coaching support and valuable resources in multiple languages. Phone: 1-877-455-2233 or Email: quitnow@bc.lung.ca
• Smokers’ Helpline: 1-866-366-3667
• Public Health Agency of Canada: Provides resources to help patients make wise choices about healthy living, including increasing physical activity and eating well.
• US Centre for Disease Control
• British Columbia Centre of Disease Control (BCCDC)

Appendices

• Appendix A: DOAC Drug Interactions (PDF, 1.3MB)
• Appendix B: Switching Between Anticoagulant Therapies (PDF, 599KB)

Associated Documents

• BC Pharmacare: Special Authority Request Form 5391 –Dabigatran for Atrial Fibrillation
• Contributors List (PDF, 163KB)

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This guideline is based on scientific evidence current as of the Effective Date.

This guideline was developed by the Guidelines and Protocols Advisory Committee, approved by the British Columbia Medical Association, and adopted by the Medical Services Commission. 

For more information about how BC Guidelines are developed, refer to the GPAC Handbook available at BCGuidelines.ca: GPAC Handbook.

 

THE GUIDELINES AND PROTOCOLS ADVISORY COMMITTEE 

The principles of the Guidelines and Protocols Advisory Committee are to: encourage appropriate responses to common medical situations recommend actions that are sufficient and efficient, neither excessive nor deficient permit exceptions when justified by clinical circumstances. Contact Information Guidelines and Protocols Advisory Committee PO Box 9642 STN PROV GOVT Victoria BC V8W 9P1 E-mail: hlth.guidelines@gov.bc.ca Web site: www.BCGuidelines.ca Disclaimer The Clinical Practice Guidelines (the “Guidelines”) have been developed by the Guidelines and Protocols Advisory Committee on behalf of the Medical Services Commission. The Guidelines are intended to give an understanding of a clinical problem, and outline one or more preferred approaches to the investigation and management of the problem. The Guidelines are not intended as a substitute for the advice or professional judgment of a health care professional, nor are they intended to be the only approach to the management of clinical problem. We cannot respond to patients or patient advocates requesting advice on issues related to medical conditions. If you need medical advice, please contact a health care professional.