Original Article: Deep Venous Thrombosis and Pulmonary Embolism: Current Therapy

Issue Date: March 1, 2017

See additional reader comments at:https://www.aafp.org/afp/2017/0301/p295.html

To the Editor: We thank the authors for a very well-written and thorough review of the current treatment landscape for deep venous thrombosis and pulmonary embolism. Table 1 reviews direct oral anticoagulant dosing, including renal dose adjustments. Apixaban (Eliquis) renal dosing was included as 2.5 mg orally twice daily if at least one criterion is met: serum creatinine 1.5 mg per dL (133 μmol per L) or more, age 80 years or older, or weight 60 kg (132 lb, 4 oz) or less. The AMPLIFY trial looked at apixaban for treatment of deep venous thrombosis/pulmonary embolism and excluded patients with a serum creatinine level of 2.5 mg per dL (221 μmol per L) or greater, or a creatinine clearance less than 25 mL per minute per 1.73 m² (0.42 mL per second per m²).¹ On the other hand, per the manufacturer, no dosage adjustment is required for renal function, although it is noted that patients with a creatinine clearance less than 15 mL per minute per 1.73 m² (0.25 mL per second per m²) and patients on dialysis were not included in clinical trials; all the conclusions we drew from the literature regarding these patients were based on pharmacokinetic and pharmacodynamic (anti–factor Xa activity) data.^2,3 The dosing the authors list in Table 1 is most similar to dosing guidelines for reduction of the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, t hat recommendation requires an adjustment to the 2.5-mg dose when two of the three criteria are met based on the ARISTOTLE and AVERROES trials.^4,5 Given this contradictory information, we would appreciate some clarification on the need to adjust apixaban dosing in patients with impaired renal function.

In Reply: Thank you for your inquiry regarding our article. In Table 1, we recommended modified dosing of apixaban (2.5 mg twice daily) if at least one of the following criteria is met: serum creatinine 1.5 mg per dL (133 μmol per L) or greater, age 80 years or older, weight 60 kg (132 lb, 4 oz) or less. However, as Drs. Naik and Ragheb correctly state, the manufacturer does not recommend any adjustment for renal insufficiency, age, or weight when treating venous thromboembolism.¹ According to the U.S. Food and Drug Administration, no renal adjustment is necessary for apixaban when used to treat venous thromboembolism, even in patients with end-stage renal disease and/or patients on hemodialysis.²

To our knowledge, the only clinical trial that addresses the question of apixaban use for venous thromboembolism in patients with impaired renal function is the AMPLIFY study.³ Patients were excluded from the study if the serum creatinine level was greater than 2.5 mg per dL (221 μmol per L) or the calculated creatinine clearance was less than 25 mL per minute per 1.73 m² (0.42 mL per second per m²). However, no dosage adjustments were made for patients in the study with mild renal dysfunction.

Upon further consideration and to provide a recommendation that is most consistent with current knowledge, we would like to remove our recommendation for dose adjustment of apixaban. However, we recommend careful monitoring for any patient prescribed apixaban for venous thromboembolism whose renal function falls outside of the population that was studied in clinical trials.