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Canadian Journal of Cardiology

Direct Factor Xa Inhibitors for Long-term Stroke Prevention in Atrial Fibrillation: Could the Lower Dose Fit All?

Published:February 07, 2018DOI:https://doi.org/10.1016/j.cjca.2018.02.003
      To the Editor:
      Anticoagulation is the mainstay of treatment for stroke prevention in nonvalvular atrial fibrillation (AF). Direct oral anticoagulants (DOACs) were developed to simplify management of patients with an indication to anticoagulation. Two dose levels exist: reduced dose to prevent venous thromboembolism (VTE) in patients who undergo hip/knee surgery, and full-dose to treat established VTE or AF (Table 1).
      Table 1Current dosing recommendations for direct factor Xa inhibitors in venous thromboembolic disease and nonvalvular atrial fibrillation
      AgentRivaroxabanApixabanEdoxaban
      VTE prophylaxis10 mg qd for 14-35 days2.5 mg bid for 12-35 days
      VTE treatment15 mg bid for 21 days →

      20 mg qd for 6-12 months →

      10 mg qd
      10 mg bid for 7 days →

      5 mg bid for 6 months →

      2.5 mg bid
      60 mg qd (30 mg qd if wt ≤ 60 kg or P-gp inhibitors or CrCl 15-50 mL/min)
      Nonvalvular atrial fibrillation20 mg qd (15 mg qd if CrCl 15-50 mL/min; consider 10 mg qd if HD)5 mg bid

      2.5 mg bid if 2 of 3 criteria: age ≥ 80 years, wt ≤ 60 kg, creatinine ≥ 132.6 μmol/L
      60 mg qd (30 mg qd if wt ≤ 60 kg or P-gp inhibitors or CrCl 15-50 mL/min)
      bid, twice daily; CrCl, creatinine clearance; HD, hemodialysis; P-gp, glycoprotein P; qd, once daily; VTE, venous thromboembolism; wt, body weight.
      Should full-dose be prescribed indefinitely? Or could dose reduction be considered after an initial treatment of 6 months with the full dose? Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment (AMPLIFY-EXT) and Reduced-dosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism (EINSTEIN CHOICE) trials studied this question for the extended treatment of VTE. Both studies showed that low-dose apixaban or rivaroxaban have a similar efficacy but better safety profile compared with the full dose. No similar data exist in AF.
      If reduced-dose DOACs are effective for the extended treatment of VTE, they might also be protective against stroke in AF. Notwithstanding, VTE and AF are pathophysiologically very different. If thromboembolism in primary VTE might be because of an unidentified prothrombotic tendency, blood stasis in the atria is the culprit in AF. However, both factors are part of the Virchow triad and might contribute to thrombus formation in a similar way.
      Reduced-dose anticoagulation in patients who do not meet the traditional criteria for dose reduction is not just a theoretical question. Recent data show that up to 16.5% of patients currently receiving rivaroxaban or apixaban are prescribed a reduced dose without an indication for dose reduction.
      • Steinberg B.A.
      • Shrader P.
      • Thomas L.
      • et al.
      Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry.
      • Yao X.
      • Shah N.D.
      • Sangaralingham L.R.
      • Gersh B.J.
      • Noseworthy P.A.
      Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction.
      A propensity-matched cohort study recently compared outcomes in patients with AF who received reduced-dose vs standard-dose apixaban or rivaroxaban.
      • Yao X.
      • Shah N.D.
      • Sangaralingham L.R.
      • Gersh B.J.
      • Noseworthy P.A.
      Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction.
      In this study, reduced-dose rivaroxaban was actually 15 mg daily and not the 10-mg daily dose used in VTE prophylaxis. Patients who received reduced-dose apixaban had more thromboembolic and similar major bleeding event rates compared with patients who received standard-dose apixaban. On the contrary, patients who received reduced-dose or standard-dose rivaroxaban had similar event rates.
      • Yao X.
      • Shah N.D.
      • Sangaralingham L.R.
      • Gersh B.J.
      • Noseworthy P.A.
      Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction.
      Because the rate of DOAC prescription is expected to increase, subtherapeutic anticoagulation might become an important issue causing more thrombotic events if reduced dose does not have efficacy similar to full dose for the extended treatment of patients with AF. However, if reduced-dose is appropriate after several months of full-dose, as is the current paradigm in VTE, DOACs might become a more attractive option in patients who do not currently receive any anticoagulation because of a perceived high bleeding risk. Randomized controlled trials are definitely necessary to address this question.

      Disclosures

      The authors have no conflicts of interest to disclose.

      References

        • Steinberg B.A.
        • Shrader P.
        • Thomas L.
        • et al.
        Off-label dosing of non-vitamin K antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II registry.
        J Am Coll Cardiol. 2016; 68: 2597-2604
        • Yao X.
        • Shah N.D.
        • Sangaralingham L.R.
        • Gersh B.J.
        • Noseworthy P.A.
        Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction.
        J Am Coll Cardiol. 2017; 69: 2779-2790