Dosing Schemas of the NOACs for VTE Treatment

Patients who develop a venous thromboembolism (VTE; deep vein thrombosis [DVT] or pulmonary embolism [PE]) require fast, effective anticoagulation therapy to treat the acute event and prevent VTE recurrence.1 The non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) apixaban, dabigatran, edoxaban and rivaroxaban have proven efficacy and safety for the treatment and long-term secondary prevention of VTE through their respective phase III trials (AMPLIFY for apixaban, RE-COVER and RE-COVER II for dabigatran, Hokusai-VTE for edoxaban, and EINSTEIN DVT and EINSTEIN PE for rivaroxaban).2-7 European and American guidelines now recommend NOACs over, or as an alternative to, VKA therapy for the majority of patients with VTE.8,9 NOACs are also approved for the extended treatment of VTE (>6 months) based on studies versus placebo (AMPLIFY-EXT for apixaban, RE-SONATE for dabigatran and EINSTEIN EXT for rivaroxaban) or an active comparator (RE-MEDY for dabigatran versus warfarin and EINSTEIN CHOICE for rivaroxaban versus aspirin).6,10-12 For extended use of edoxaban, a post hoc analysis of Hokusai-VTE was completed.13 In selecting the best anticoagulant for VTE treatment and ensuring responsible use, it is important to note the differences in the dosing schemas between the available agents (Figure).

VKAs, dabigatran and edoxaban all require a period of parenteral anticoagulation therapy before use.14-16 VKAs require a bridging period during which they overlap with a parenteral agent until the desired anticoagulant effect is obtained (usually an international normalized ratio of 2.0–3.0, which takes at least 24 hours to achieve).14 Dabigatran and edoxaban should be given after at least 5 days of initial parenteral therapy.15,16 However, apixaban and rivaroxaban can be used immediately for acute-phase treatment as single-drug regimens (an intensified dosing regimen applies for acute-phase treatment) or they can be used following initial parenteral therapy.17,18 This single-drug approach follows dose-finding studies for rivaroxaban19,20 and the rationale that this approach might be effective with the NOACs apixaban, dabigatran, edoxaban and rivaroxaban having similar rapid onsets of action to low molecular weight heparin therapy.15-18,21 In switching from another anticoagulant to any NOAC, the appropriate dose for the treatment phase (whether acute, long-term or extended) should be considered.

The NOACs also differ in use of once-daily (od; edoxaban and rivaroxaban) or twice-daily (bid; apixaban and dabigatran) dosing for long-term and extended therapy.15-18 The rationale for a bid dosing regimen is to avoid extremes of peak and trough levels associated with od dosing in agents with a short half-life (as is the case for the NOACs). However, phase I/II testing for edoxaban and rivaroxaban showed consistent, dose-dependent plasma levels across a range of patient populations regardless of od or bid dosing.22,23

All NOACs have some degree of renal excretion as active metabolites (27% for apixaban, 85% for dabigatran and approximately one-third for edoxaban and rivaroxaban). A creatinine clearance of <30 ml/min is a contraindication for dabigatran use and <15 ml/min a contraindication for the remaining NOACs. Specified clinical circumstances associated with an increased risk of bleeding or prolonged drug exposure (e.g. age, impaired renal function, low body weight or concomitant use of drugs that affect NOAC metabolism) form part of criteria for dose reduction in some cases; these criteria are quite different for each NOAC and are detailed in the Figure.15-18

Decisions regarding the duration of therapy should be made after careful assessment of the risks of recurrent VTE and bleeding.8 For dabigatran and edoxaban, the same dosing schedules and criteria for dose reductions apply for long-term and extended use;15,16 however, the apixaban dosing regimen is usually de-intensified at 6 months, and for rivaroxaban, the dose can be maintained or reduced after careful assessment of an individual patient’s risk factors.17,18 For apixaban, 2.5 mg bid was selected based on this being effective for thromboprophylaxis after major orthopaedic surgery.10 For rivaroxaban, this is a relatively new update based on the results from EINSTEIN CHOICE, which compared two doses of rivaroxaban (10 mg od and 20 mg od) with aspirin as a commonly used antithrombotic for extended secondary prevention. Patients enrolled in this study were at clinical equipoise regarding the need for extended therapy.12 Based on these results, the lower 10 mg od dose is indicated for extended prevention of DVT and PE unless the risk of recurrent DVT or PE is high (e.g. in patients with complicated co-morbidities or who develop recurrent DVT or PE on extended prevention with rivaroxaban 10 mg od), in which case the 20 mg dose should be considered.18

Figure. Dosing schemas of oral anticoagulants approved for the treatment and/or secondary prevention of VTE.14-18

*When extended prevention of recurrent DVT and PE is indicated, the recommended dose is 10 mg od. In patients in whom the risk of recurrent DVT or PE is considered high, such as those with complicated co-morbidities, or who have developed recurrent DVT or PE on extended prevention with rivaroxaban 10 mg od, a dose of rivaroxaban 20 mg od should be considered. bid, twice daily; CrCl, creatinine clearance; DVT, deep vein thrombosis; INR, international normalized ratio; N/A, not applicable; od, once daily; PE, pulmonary embolism; VKA, vitamin K antagonist; VTE, venous thromboembolism.