Effective Date: January 18, 2023
Revised Date: January 4, 2024
This guideline provides recommendations on the use of direct oral anticoagulants (DOACs) in adults aged >19 years for the following indications:
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 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).
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:
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.
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 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 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
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
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
Absolute Contraindication | Alternative Recommendation |
---|---|
Mechanical heart valve | Warfarin22 |
Atrial fibrillation with moderate to severe mitral stenosis | Warfarin4 |
Pregnancy | LMWH, especially during first trimester |
Breastfeeding | LMWH or warfarin |
Triple positive antiphospholipid syndrome23 | Refer to specialist for alternative management |
Severe thrombocytopenia (platelet count < 50 x 109/L) | Refer to specialist for alternative management |
Clinically significant drug-drug interactions | Refer to Table 2: DOAC dosing and therapeutic considerations based on indication and Appendix A: DOAC Drug Interactions |
Abbreviations: LVMWH = low molecular weight heparin.
Specialty consultation is also recommended for certain patients where the evidence is weak or for patients at increased risk of adverse outcomes, including but not limited to:
Consult with your local pharmacist regarding potential drug-drug interactions that may reduce DOAC efficacy or increase a patient’s risk of bleeding. Consider alternative therapy if any significant interaction is present. Of note, polypharmacy in elderly patients may increase risks of adverse outcomes from drug-drug interactions. Refer to Table 2: DOAC dosing and therapeutic considerations based on indication for more details on DOAC dosing and therapeutic considerations and Appendix A: DOAC Drug Interactions for more information on drug interactions.
Complete blood count (CBC) and Creatinine Clearance (CrCl) must be checked for all patients prior to initiating a DOAC. The CrCl (calculated using Cockcroft-Gault formula) should be used to determine DOAC dosage according to the patient’s age, weight, and serum creatinine.25 Do not use the estimated glomerular filtration rate (eGFR) provided by laboratory reports as this can lead to inappropriate DOAC dosing in a significant proportion of patients. Liver function should also be checked in those with known hepatic dysfunction (e.g., cirrhosis, hepatitis) before starting a DOAC.
Patient education is an important component of drug initiation. Given that DOAC half-lives are relatively short (~12 hours), missing 1-2 doses can lead to subtherapeutic coverage and thus increased risk of stroke or recurrent thrombosis. Twice-daily DOACs (e.g., apixaban) may be more appropriate than once-daily DOACs (e.g., rivaroxaban) for patients for whom adherence is a concern.26
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
Abbreviations: 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:
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.
Reassess patients within 1-2 months of DOAC initiation to assess adherence, review potential adverse events (e.g., gastrointestinal upset, excessive bruising, bleeding), and assess bleed risk. Frequency of follow-up thereafter is individualized based on clinical factors:4,29
At follow-up, confirm ongoing indication for DOAC use, review current medications for drug-drug interactions, assess patient’s relative risks of bleeding and/or thromboembolism, and address any adverse events. Periodically educate patients regarding the importance of medication adherence and early identification of adverse events, including signs of stroke and recurrent thrombosis.
Poor renal function is a risk factor for bleeding and thus all patients on a DOAC should be tested at least once every 6-12 months.29,30 More frequent renal function testing may be indicated for certain patients (e.g., elderly patients with borderline renal function).29
Since all DOACs are partially metabolized by the liver31 and liver impairment can increase the risk of bleeding, liver function monitoring should be considered every 6-12 months for patients who have known hepatic dysfunction.26
Unlike warfarin, DOACs do not require routine laboratory monitoring of the anticoagulant effect. Classic coagulation tests like INR and partial thromboplastin time (PTT) are not helpful for assessing anticoagulant activity because results may be normal or abnormal, and prolongation of these clotting times do not reflect the degree of anticoagulant activity present.26 Consult a specialist if measuring the anticoagulant effect of a DOAC is being considered under special circumstances (e.g. after bariatric surgery). Refer to the Resources section below for information on the RACE line.
DOACs can interfere with special coagulation tests. Do not perform thrombophilia testing while a patient is taking a DOAC.
If special coagulation tests are being considered, contact a specialist. Refer to the Resources section below for information on the RACE line.
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.
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:
aPTT Activated partial thromboplastin clotting time
CBC Complete blood count
CrCl Creatinine clearance
DOAC Direct oral anticoagulant
eGFR estimated glomerular filtration rate
HIV Human immunodeficiency virus
LMWH Low molecular weight heparin
NVAF Non-valvular atrial fibrillation
VTE Venous thromboembolism
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:
Contact InformationGuidelines and Protocols Advisory Committee E-mail: hlth.guidelines@gov.bc.ca Web site: www.BCGuidelines.ca DisclaimerThe 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. |
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