Venous Thromboembolism
Unapproved Dose of Direct Oral Anticoagulants for Venous Thromboembolism ― Right or Wrong? ―
2024 Volume 88 Issue 3 Pages 380-381
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2024 Volume 88 Issue 3 Pages 380-381
The efficacy and safety of direct oral anticoagulants (DOACs) for venous thromboembolism (VTE) have been demonstrated in multiple large-scale studies with stringent inclusion and exclusion criteria. However, the subject populations of these studies are very different from the patients encountered in everyday clinical practice. In the RIETE study, unapproved doses of DOACs were used for acute and chronic VTE treatment in proportions of 14–50%.1 Asian patients with VTE are more likely to have active cancer and to be older than non-Asian patients and are less likely to be obese,2 which may be one reason why DOACs are used at unapproved doses in Japan. Because the Japanese approved doses and dose-reduction criteria are different for nonvalvular atrial fibrillation (NVAF) and VTE, and the approved doses and dose-reduction criteria also differ between Japan and other countries, the dosages reported in several previous studies are different from those approved in Japan. These complexities may create confusion in clinical practice (Figure).
Differences between Japan and the USA and Europe in recommended doses of each direct oral anticoagulant for adult patients with venous thromboembolism (VTE). *Concomitant use of some certain P-glycoprotein inhibitors (P-gpi) such as ciclosporin, dronedarone, erythromycin corresponds to the dose-reducing criteria of edoxaban. **Rivaroxaban is indicated as a prophylactic dose for reducing the risk in adult patients at continued risk for recurrent VTE after completion of initial treatment lasting ≥6 months. BW, body weight; CLCr, creatinine clearance.
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There are several unsolved issues, starting with studies of the actual use of unapproved doses of DOACs in VTE treatment, but also including clarification of the status of use of DOACs in populations at high risk of thrombosis or hemorrhage, the efficacy and safety of unapproved doses, and the right timing for anticoagulant therapy. In Japan, dose-reduction criteria in VTE have only been specified for edoxaban; a postmarketing study of that drug in Japan showed that unapproved doses of 60 mg/day (overdose), 30 mg/day (reduced dose), and 15 mg/day (super-reduced dose) accounted for 11% of total usage.3 Although overdosing did not increase bleeding, recurrent VTE tended to increase at the super-reduced dose.
The efficacy and safety of reduced doses for treating VTE have been addressed by a number of studies. In the EINSTEIN CHOICE trial, with extended anticoagulation therapy after acute VTE, the rivaroxaban 20 mg and 10 mg groups had significantly reduced rates of recurrent VTE events compared with the aspirin group.4 However, that trial excluded patients who required continuous anticoagulation therapy, and the efficacy of low-dose rivaroxaban for patients who require long-term anticoagulant therapy is unclear. The AMPLIFY-EXT trial compared apixaban 5 mg or 2.5 mg twice daily with placebo as extended anticoagulation therapy after acute VTE, and showed that VTE events were suppressed by the 5 and 2.5 mg doses with no increase in significant bleeding events.5 The RENOVE trial,6 a Phase 3 trial including patients at high risk of recurrence who require long-term anticoagulant therapy, is currently underway. Although data for edoxaban are sparse, the ELDER-AF trial showed that an unapproved dose of 15 mg is effective for older patients with AF.7
With respect to VTE treatment in Japan, in this issue of the Journal Yamashita et al8 present their study of patients with VTE receiving edoxaban in the real world. They used a Japanese nationwide administrative database to investigate patient characteristics, recurrent VTE, and bleeding events at edoxaban doses of 15 mg, 30 mg, and 60 mg. As reported by them, not only do Japanese VTE patients include many who are older, low weight, and have chronic kidney disease and are thus at high inherent risk of bleeding, but the 15-mg group was at higher risk of both recurrent VTE and bleeding events, which sounds a warning bell for the use of edoxaban at a super-reduced dose.8 One study that compared blood concentrations in NVAF patients with impaired renal function (15≤CCr<30) treated with edoxaban 15 mg with those of patients with normal renal function treated at doses of 30 mg or 60 mg9 found that although there was no difference in the trough value for the 15-mg group compared with that of the 60-mg group, the peak value for 30 mg and 15 mg was significantly lower. From the viewpoint of blood concentration, the decision on a reduced dose must be made with caution. The interpretation of Yamashita et al’s study also requires caution on several points, as not only is it an analysis of a Japanese nationwide administrative database, which is subject to major bias, but it also excludes outpatients despite the fact that since 2015 VTE patients have increasingly been treated on an outpatient basis. It also does not include efficacy and safety evaluations of an overdose of 60 mg or use of an unapproved dose of 30 mg. The significance of this study thus lies in what must be studied next in light of its results, and it has stirred up the future of DOAC research.
Reviewing previous VTE studies raises a number of issues. The first is the designation of endpoints. When a recurrent event is understood as an episode of the same type (deep venous thrombosis [DVT] or pulmonary embolism [PE]) as the first episode, it may be necessary to stratify the endpoint as symptomatic central VTE or PE rather than as all recurrent VTE, as was done in the PADIS-PE trial.10 The second point is the differentiation between acute and chronic outcomes. Chronic outcomes were divided into initial PE and initial DVT for risk assessment, as described above, but for acute outcomes, in addition to assessments of VTE recurrence and cumulative death, investigations are also needed of the thrombus-eliminating effect, post-PE syndrome, and progression to chronic thromboembolic pulmonary disease with pulmonary hypertension (CTEPD with PH). The results of our own Nagoya PE study suggest that adequate anticoagulation therapy at the time of acute PE is necessary in order to avoid CTEPD.11 As a third point, the effect on subsequent prognosis of the timing of the switch to an unapproved dose may be an important topic for further study.
The number of VTE patients in Japan is increasing, and the aging of the population means that the number of older VTE patients can be expected to rise still further. At this point, there is little evidence to recommend an unapproved dose of edoxaban. Future VTE studies that specifically take Japanese demographics into account are awaited.
Nothing to declare.
