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July Issue - Novel oral anticoagulants for stroke prevention in atrial fibrillation: what to do about challenging patients

Alan Bell, MD, CCFP

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 July 2015 edition of the Thrombosis Adviser newsletter.

Dear Ladies and Gentlemen,

Patients with atrial fibrillation (AF) commonly have other chronic or short-term conditions or factors that complicate their treatment. Anticoagulant therapy for the prevention of AF-related stroke is particularly challenging when patients are taking co-medications because of the many drug–drug interactions with vitamin K antagonists (VKAs) such as warfarin. This can leave patients poorly protected against ischaemic events or at increased risk of bleeding. Drug–drug interactions are less of an issue with the novel oral anticoagulants (OACs), which have fewer interactions with commonly used medications. These drugs have shown similar efficacy to warfarin with a consistent safety profile across a broad range of patient populations by age, sex and number of stroke risk factors. Nevertheless, it is important that general practitioners (GPs) – who often manage these patients on a day-to-day basis – are aware of the most common patient groups that require closer follow-up and/or dose adjustments when they are receiving treatment with rivaroxaban, apixaban or dabigatran (edoxaban is now also available in the United States and Japan).

Renal impairment*

Renal impairment is a major issue for GPs, particularly considering that patients with AF tend to be elderly and may have age-related declining kidney function. All novel OACs are to some extent eliminated by the kidneys. A reduced dose of rivaroxaban (15 mg once daily rather than the normal 20 mg once daily) is approved for patients with AF plus moderate renal impairment (creatinine clearance [CrCl] 30–49 ml/min), based on data from the randomized phase III ROCKET AF study. Dose reductions for other novel OACs are more complex and depend on other patient factors, including age and body weight (see table). Patients with severe renal impairment (CrCl 15–29 ml/min) were not included in the phase III studies, but some novel OACs can be used with caution in these patients in certain territories (physicians should refer to the specific prescribing information for their country/region). The exception is dabigatran, which cannot be used in patients with severe renal impairment because approximately 80–85% of the dose is cleared through the kidneys. Patients with renal failure (CrCl <15 ml/min) should not receive novel OACs – these patients may be more suited to VKAs, which are much less reliant on renal elimination (although dose adjustment may still be needed).

Patients with normal kidney function or mild dysfunction (CrCl 50–80 ml/min) do not require dose adjustment with rivaroxaban, apixaban or dabigatran. According to the US Prescribing Information, edoxaban should not be used in patients with CrCl >95 ml/min because of reduced efficacy in clinical studies, probably because of more rapid elimination.

Clinicians should regularly assess the renal function of elderly patients if they are receiving a novel OAC, using the Cockcroft–Gault equation.

Drug Approved dose regimens in patients with atrial fibrillation according to renal function and other factors*
  Normal dose Adjusted dose

(patients in whom this dose should be used)
Dose in severe renal impairment (CrCl 15–29 ml/min)† Renal failure (CrCl <15 ml/min)
a href="" target="_blank">Dabigatran 150 mg bid 110 mg bid

(if patient is ≥80 years old or receiving verapamil; also consider reduced dose for patients aged 375 years with ≥1 risk factor for bleeding, e.g. CrCl 30–49 ml/min)
Contraindicated in Europe and Canada Contraindicated
Rivaroxaban 20 mg od

(CrCl ≥50 ml/min)
15 mg od

(CrCl 30–49 ml/min)
15 mg od in territories where approved for these patients Not recommended
Apixaban 5 mg bid 2.5 mg bid

(if patient has ≥2 of: sCr ≥133 µmol/l; aged ≥80 years; weight ≤60 kg)
2.5 mg bid in territories where approved for these patients Not recommended
Edoxaban 60 mg od
(CrCl 50–95 ml/min)
30 mg od
(CrCl 30–49 ml/min)
30 mg od Not recommended

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*Based on European and Canadian Prescribing Information; variations may exist elsewhere.

To be used with caution, and not approved in all countries/territories in patients with severe renal impairment – refer to specific Prescribing Information.

Approved in the United States and Japan only. Information shown is from US Prescribing Information.

bid, twice daily; CrCl, creatinine clearance; od, once daily; sCr, serum creatinine.

Hepatic impairment*

Patients with mild impairment of liver function can receive novel OACs. Apixaban and rivaroxaban are contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk; for rivaroxaban this may include Child–Pugh B and C. Apixaban is not recommended in patients with severe hepatic impairment (Child–Pugh C). Dabigatran is contraindicated in circumstances in which hepatic impairment or liver disease is expected to have an impact on survival, and is not recommended in patients with elevated liver enzymes more than twice the upper limit of normal. Apixaban and dabigatran can be given with caution to patients with moderate hepatic impairment (Child–Pugh B). Hepatic function should be assessed in patients taking these drugs who have a history of or active liver disease.

Other cardiovascular conditions

Patients with AF who experience an acute coronary syndrome (ACS) event – myocardial infarction or unstable angina – need careful appraisal by their physicians to manage the risk of stroke from AF (OAC therapy), further cardiovascular events from ACS (dual antiplatelet therapy), and the heightened risk of bleeding associated with combined OAC and dual antiplatelet therapy. In the absence of prospective clinical trial data, guidelines such as those from the European Society of Cardiology (ESC) have made recommendations based on expert consensus. For patients with AF following an ACS event and/or percutaneous coronary intervention for ACS, the ESC recommends a staggered approach with a period of combined OAC and dual antiplatelet therapy, followed by an OAC plus a single antiplatelet drug, and after 1 year management with an OAC alone.

In general, the presence of heart failure in patients with AF should not affect the choice of anticoagulant. The ongoing phase III COMMANDER HF trial (NCT01877915) is the first large-scale, randomized prospective study to evaluate the potential of a novel OAC in patients with HF (but without AF). The study is assessing the efficacy and safety of rivaroxaban compared with placebo for reducing the risk of death, MI or stroke in patients with chronic HF and significant coronary artery disease following recent hospitalization for worsening of HF.

Patients with prosthetic heart valves or severe rheumatic or other mitral valvular disease should not receive novel OAC therapy. To date, only dabigatran has been evaluated in patients with AF and mechanical heart valves. In this phase II dose-validation study (RE-ALIGN), dabigatran was associated with increased rates of thromboembolic and bleeding events compared with warfarin, and the study was terminated early. The efficacy and safety of rivaroxaban compared with VKAs in patients with AF and bioprosthetic mitral valves is currently under investigation in RIVERA (NCT02303795), a phase II randomized, non-inferiority study.

Other co-medications*

Metabolism of novel OACs may be affected by drugs that inhibit or induce the P-glycoprotein (P-gp) or cytochrome P450 3A4 elimination pathways. Commonly, these are drugs used for the management of fungal infections, HIV and seizure disorders. Patients receiving azole antimycotics for fungal infections, e.g. ketoconazole, should not take rivaroxaban, apixaban or dabigatran because of shared common elimination pathways that significantly increase plasma anticoagulant levels and, therefore, bleeding risk. By way of an exception, fluconazole did not show a clinically relevant interaction with rivaroxaban. HIV protease inhibitors such as ritonavir also interfere with the elimination of rivaroxaban and apixaban to a clinically relevant degree, and co-administration is, therefore, contraindicated. In addition, phenytoin, carbamazepine, phenobarbital and St. John’s wort should be avoided when taking rivaroxaban, and used with caution with apixaban, because they reduce anticoagulant levels and leave patients at risk of thromboembolism. Caution should be exercised if co-administering dabigatran with mild-to-moderate inhibitors of P-gp, such as verapamil. Dabigatran should not be co-administered with tacrolimus, ketoconazole, cyclosporine or itraconazole, and neither rivaroxaban nor dabigatran should be given with dronedarone. On the basis of its US Prescribing Information, edoxaban should not be given to patients taking rifampicin (rifampin).

Care should also be taken if co-administering novel OACs with other drugs that increase bleeding risk, such as antiplatelet agents (including ASA, clopidogrel, ticlopidine, prasugrel and ticagrelor) and non-steroidal anti-inflammatory drugs. ASA is generally no longer recommended as an antithrombotic option for patients with AF who are at moderate or high risk of stroke (CHADS2/CHA2DS2-VASc >0), but may be prescribed to patients with vascular disease. Unless switching between anticoagulants, warfarin or other anticoagulants should not be given concurrently with a novel OAC.

Patients who require invasive procedures

Primary care providers may be confronted with queries from other healthcare professionals about minor invasive procedures, such as dental work or cataract removal, or may need to conduct a minor procedure in the office on a patient receiving a novel OAC. For minor interventions that carry little or no significant bleeding risk, the procedure may be performed at trough novel OAC concentration (i.e. 12 hours [apixaban, dabigatran] or 24 hours [rivaroxaban, edoxaban] after the last dose, and before the next dose) without interruption of therapy. Undertaking the procedure at peak drug concentration (in the first 6–12 hours after a dose) should be avoided. If it is felt necessary, one dose of a twice-daily drug could be missed and dosing restarted as normal when the next dose is due. For procedures associated with a higher bleeding risk, for which OAC therapy must be interrupted, periprocedural bridging with heparin is required for VKA but not for novel OAC therapy. The European Heart Rhythm Association (EHRA) and Thrombosis Canada provide helpful practical guidance on the use of novel OACs in these clinical situations.

Adequate haemostasis should be achieved before the patient leaves the clinic or office, and resumption of novel OAC therapy should be delayed until this point. It should be considered that peak anticoagulant effect with novel OACs is achieved 1–4 hours after administration, in contrast to the several days required with warfarin. The patient should be instructed to contact the responsible healthcare provider if bleeding occurs later. After dental procedures, the EHRA and Thrombosis Canada recommend that the patient could rinse their mouth with 5% tranexamic acid for a few days following the procedure.

Major surgery that is associated with significant bleeding risk, involves neuraxial anaesthesia or comprises procedures for which bleeding sites may not be easily accessible, including gastrointestinal polypectomy and percutaneous organ biopsy, often requires the novel OAC to be stopped several days prior to surgery. The timing of cessation depends on the drug, procedure and bleeding risk, and renal function of the patient. Although these interventions may be handled in hospital, it is important for the GP to communicate with the patient, hospital or surgical team prior to and following the procedure. Anticoagulant therapy should be restarted once adequate haemostasis has been attained.

Yours sincerely

Alan Bell,
Toronto, ON, Canada

*Recommendations based on the European Summary of Product Characteristics (apixaban, dabigatran, rivaroxaban) and US Prescribing Information (edoxaban); variations may exist elsewhere; †according to the Canadian Product Monograph, dabigatran is not recommended for patients with hepatic enzymes over three-times the upper limit of normal.

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