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April Issue - Novel Oral Anticoagulants - Stroke Prevention in Atrial Fibrillation

Novel oral anticoagulants for stroke prevention in atrial fibrillation: what does the family physician need to know?

Alan Bell, MD, CCFP

Alan Bell is a family physician and clinical researcher in Toronto, Ontario, Canada. He is Assistant Professor at the Department of Family and Community Medicine at the University of Toronto and practices at the Humber River Regional Hospital. Dr Bell has received the Canadian College of Family Physicians Award of Excellence and is the Past Chair of the Canadian Cardiovascular Society Antiplatelet Guideline Committee. He also serves on the Executive Council of Thrombosis Canada, the Canadian Stroke Network Professional Development Committee, and is a peer reviewer for the Canadian Medical Association Journal. Dr Bell has an ongoing commitment to continuing medical education and has published and presented worldwide.

Welcome to the April 2015 edition of the Thrombosis Adviser newsletter.

Dear Ladies and Gentlemen,

The novel oral anticoagulants (OACs), comprising the direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitors apixaban, rivaroxaban and (currently in the US and Japan only) edoxaban, provide a therapeutic alternative to vitamin K antagonist (VKA) anticoagulants for patients with non-valvular atrial fibrillation (AF) who are at risk of stroke or systemic embolism. Family and general practitioners (GPs) are very familiar with VKAs such as warfarin and international normalized ratio (INR) monitoring required for patients taking them, but they may be less experienced with the novel OACs. However, GPs are often the first point of contact for patients with AF, and they need to understand the appropriate use of the novel OACs. Furthermore, primary care physicians need to provide optimal follow-up for these patients when novel OAC treatment has been initiated elsewhere.

Non-valvular atrial fibrillation – who should receive anticoagulation?

Major international guidelines on stroke prevention in patients with non-valvular AF broadly concur on which patients should receive anticoagulant treatment. The European, American and Canadian recommendations all state that patients with non-valvular AF and at least one other risk factor for stroke (such as older age, diabetes or hypertension) should receive long-term anticoagulation with a VKA or novel OAC. Stroke risk should be determined using the CHADS2 or the increasingly preferred CHA2DS2-VASc risk scores. Importantly, the latest guidelines no longer advocate the use of acetylsalicylic acid (ASA, aspirin) for patients at moderate to high risk of stroke. Patients with AF but without additional stroke risk factors (CHADS2 or CHA2DS2-VASc = 0) should not receive anticoagulation.

Why are novel oral anticoagulants increasingly preferred to warfarin for stroke prevention in patients with atrial fibrillation?

When well controlled, warfarin is effective for the prevention of stroke and systemic embolism, offering an approximately 64% risk reduction compared with placebo. Unfortunately, good control is difficult to achieve in many patients. This is due to many factors, including the multiple food and drug interactions that compromise the anticoagulant effect of warfarin; patients often find it difficult to comply with the associated dietary requirements or may have prescriptions for interacting drugs. Although regular INR monitoring and dose adjustment can compensate for some of these issues, the need for monthly (or more frequent) blood tests is a burden on patients, healthcare providers and healthcare systems.

By contrast, novel OACs have predictable pharmacological properties that allow them to be taken at fixed doses once or twice daily without the need for routine coagulation monitoring. They exhibit fewer interactions with common medications and have a shorter half-life than warfarin, which is potentially useful or even vital if bleeding occurs. In randomized phase III clinical studies in patients with AF, all four novel OACs were non-inferior or superior to warfarin for the prevention of stroke and systemic embolism, consistently reduced the risk of intracranial haemorrhage and, in some cases, led to significant reductions in all-cause mortality and dangerous critical site bleeding. The benefit–risk profile of the novel OACs was consistent relative to warfarin irrespective of age, gender and stroke risk factors, meaning that these drugs are suitable for a broad patient population.

Who can receive a novel oral anticoagulant – and who shouldn’t?

The majority of patients with AF who are indicated for anticoagulation are eligible to receive novel OACs. In particular, patients who prefer not to have to undergo regular INR monitoring, those for whom INR control is difficult, patients requiring medications that interact with VKAs and patients who have had an ischaemic stroke or bleeding episode while receiving VKA therapy may be good candidates for a novel OAC. Patient preference is also key, and it is important that GPs understand and clearly explain the differences between novel OACs and warfarin, particularly if a patient has received warfarin before. Equally, patients and physicians should consider whether they prefer once- (rivaroxaban, edoxaban) or twice-daily (dabigatran, apixaban) dosing for stroke prevention in AF, which may be driven by their own choice and whether they are receiving other once/twice-daily medications that can be conveniently taken at the same time.

Rivaroxaban, apixaban, dabigatran and edoxaban are all partially eliminated by the kidney; therefore, renal function affects the decision to adjust the dosage or avoid these agents completely. Regulatory agency recommendations for use and dosage based on creatinine clearance (CrCl) differ by region, and local prescribing information should always be consulted. In general, novel OACs should never be used if CrCl is <15 ml/min and, in some regions, they are contraindicated when CrCl is <30 ml/min.

GPs should be aware of how to calculate CrCl and the importance of monitoring renal function at follow-up visits (especially in the elderly or those with chronic kidney disease). Most patients should have their CrCl checked every 6–12 months. The lack of routine coagulation monitoring with novel OACs does not remove the necessity for follow-up, but the frequency of visits can be tailored to the needs of the individual patient.

Novel OACs are also contraindicated in pregnancy and in patients with active or very high risk of bleeding, and they should not be taken in combination with other anticoagulants (unless required to switch between anticoagulants). Antiplatelet agents including ASA should only be co-administered when there is a clear indication to do so, and non-steroidal anti-inflammatory drugs avoided whenever possible. For the direct Factor Xa inhibitors, co-medications that are strong inhibitors of both the cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) elimination pathways in the liver are contraindicated – common drugs falling into this category are the HIV protease inhibitors (e.g. ritonavir) and azole antimycotics. Notably, dabigatran elimination is only dependent on P-gp and not CYP3A4.

What support is available for general practitioners?

In the November 2014 issue of Canadian Family Physician, my colleagues and I published an open-access two-part guide to the novel OACs for GPs, comparing the options and answering some of the most frequently asked questions. Various online tools are also available to assist GPs in the management of patients with AF who are receiving novel OACs or warfarin. The non-profit organization Thrombosis Canada ( has a comprehensive range of clinical guides and calculators for determining, among other things, stroke risk score, bleeding risk and CrCl, and provides information to guide decisions – for example, periprocedural management when a patient requires a minor or major invasive procedure – and dosing of novel OACs. It should be noted, however, that these tools have been constructed using the Canadian stroke prevention guidelines, and physicians in other countries and regions may need to follow their own local guidance in some or all aspects of care.

Yours sincerely,

Alan Bell,
Toronto, ON, Canada

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