Table 5.

Warfarin compared with the new oral anticoagulants in AF

CONSIDERATIONS	WARFARIN	NEW ORAL ANTICOAGULANTS
Experience	Approximately 60 y	Lack long-term safety and efficacy data Landmark AF trials were approximately 1.5–2 y
Efficacy	Reduces the risk of stroke by 64% Depends on time spent in therapeutic range	Apixaban and 150 mg of dabigatran twice daily had less stroke and systemic embolism versus warfarin. NNT ranged from 88–167 over approximately 2 y. Lower mortality rates with apixaban; NNT was 132 over approximately 2 y Rivaroxaban and 110 mg of dabigatran twice daily were as effective as warfarin for the same end point
Safety	Risk of nonhemorrhagic stroke when INR < 2 Risk of bleed when INR > 3, particularly with an INR > 4.5	Less intracranial bleed compared with warfarin NNT ranged from 96–250 over approximately 2 y Apixaban had least amount of bleeding Increased risk of GI bleed with dabigatran and rivaroxaban (NNH = 100/y for both drugs) Dabigatran also had more dyspepsia and an increasing trend toward MI
Antidote	Vitamin K 1–10 mg If no significant bleeding and INR >10: - hold warfarin and give vitamin K 2.5–5 mg orally, then - reduce weekly dose by 20% and resume once INR in therapeutic range	No established antidote or procedure for reversal Potential options with apixaban and rivaroxaban: prothrombin complex concentrate, recombinant factor VIIa, activated charcoal if < 2–3 h of administration Potential options with dabigatran: dialysis, activated charcoal if ≤ 2 h of administration
Monitoring	Routine and frequent INR tests Frequency can be extended to every 1–3 mo once dose stabilized Can provide reassurance of drug efficacy and safety (ie, within target range)22	SCr and calculated CrCl—at least annually
Pharmacokinetics	Longer half-life (2.5 d) - Benefit: therapeutic levels despite a few missed doses	Shorter half-life (8–17 h) - Benefit: shorter half-life allows drug to be cleared more quickly, but half-life extended with renal impairment Concern in noncompliant patients
Drug interactions	Numerous well-documented drug interactions INR monitoring and dosage adjustments often required with concomitant acute and chronic therapy	Fewer drug interactions but lacking experience to determine clinical significance of these Strong inhibitors of both CYP 3A4 and P-glycoprotein are contraindicated with all 3 new agents (eg, azoles, ritonavir) Caution with CYP 3A4 and P-glycoprotein inducers (eg, rifampin, phenytoin carbamazepine, St John’s wort) and inhibitors (eg, verapamil, amiodarone, dronedarone, quinidine)
Dosage	Once daily Target INR 2–3 Might require more than 1 pill per d or alternating dosing schedule	Dose and frequency depends on the indication Stroke-prevention regimens are as follows: - apixaban 5 mg twice daily - apixaban 2.5 mg twice daily in patients with ≥ 2 of the following criteria: age ≥ 80 y, body weight ≤ 60 kg, and SCr ≥ 133 μmol/L - dabigatran 150 mg twice daily - dabigatran 110 mg twice daily in patients who are ≥ 80 y or who are 75–79 y with ≥ 1 bleeding risk factor - rivaroxaban 20 mg once daily with food
Renal impairment (CrCl < 30 mL/min)	No dose adjustment required	Reduce dose Patients with renal impairment were excluded from trials Apixaban: excluded patients with CrCl < 25 mL/min. Reduce dose to 2.5 mg twice daily in patients with 2 of the following: age ≥ 80 y, body weight ≤ 60 kg, and SCr ≥ 133 μmol/L (CrCl < 25 mL/min) Dabigatran: excluded patients with CrCl < 30 mL/min. This degree of renal impairment is considered a contraindication in Canada. Consider 110 mg twice daily in patients with CrCl 30–50 mL/min Rivaroxaban: excluded patients with CrCl <30 mL/min. Reduce dose to 15 mg/d if CrCl 30–49 mL/min
Cost/mo	Approximately $40 (includes INR monitoring cost) Warfarin remains more cost effective than the new oral anticoagulant even after considering the cost of INR monitoring19	Apixaban $150–$290 Dabigatran $110 Rivaroxaban $100 Might not be covered by provincial or hospital formularies
Other	Anticoagulant-management clinics might be available and increase monitoring efficiency and time in therapeutic range	Apixaban: not approved by Health Canada for stroke prevention Dabigatran: capsules; packaged in blister packs or bottles; must be stored in original container (ie, cannot be pill or compliance packaged); capsules from bottles must be used within 4 mo of opening

AF—atrial fibrillation, CrCl—creatinine clearance, CYP—Cytochrome P450, GI—gastrointestinal, INR—international normalized ratio, MI—myocardial infarction, NNH—number needed to harm, NNT—number needed to treat, SCr—serum creatinine.

Data from Granger et al,¹⁰ Connolly et al,¹¹ Patel et al,¹² Canadian Agency for Drugs and Technologies in Health,¹⁹ Jin et al,²¹ Holbrook et al,²² Jensen et al.²³