Under-Dose Prescription of Direct Oral Anticoagulants in Japanese Elderly Patients ― Are One Fifth of the Prescriptions All “Inappropriate”? ―
論文ID: CJ-23-0531
この記事には本公開記事があります。
詳細
論文ID: CJ-23-0531
More than 10 years have passed since the introduction of direct oral anticoagulants (DOACs). Anticoagulation therapy was under-used in patients with atrial fibrillation (AF) during the warfarin era because of the inconvenience of PT-INR monitoring, drug and food interactions, and potential bleeding risks,1 so DOAC use has spread worldwide because of the safer profile vs. warfarin and guideline changes to recommend use in patients with lower CHADS2 or CHA2DS2-VASc score. The safety and effectiveness of DOACs over the past decade were recently reported, and the contributions to clinical outcomes and national public health have been considered as significant.2 However, a possible overestimation of bleeding risk for octogenarians is still present, reflected in the significant number of under-dose prescriptions worldwide. Although DOACs do not require measurement of drug concentration and PT-INR, which clearly improves their utility, it may also be one of the reasons for under- or over-dosing prescriptions, and even for off-label use. In this issue of the Journal, Akao et al give us new insights into real-world dose-setting by focusing on under-dose prescription of DOAC in elderly Japanese patients (>75 years) as a subanalysis of the ANAFIE registry.3
Article p ????
In this registry, a significant number of patients (~20%) took under-doses of DOAC. As is well known, the body weight of Japanese patients (mean 62 kg in men, 51 kg in women >70 years in 2019) is much lower than that of Western patients. In this regard, it is notable that only rivaroxaban is adjusted for Japanese patients, in whom 15 mg is recommended, different from the dose setting of 20 mg outside Japan, as the standard dose (Table). Although the DOAC dosage is adjusted according to body weight for edoxaban and apixaban, the cutoff value is just one. We not infrequently encounter female octogenarians weighing <40 kg with frailty and mild renal failure in Japanese clinical practice, and it is not incomprehensible to me that general physicians would hesitate to prescribe the standard dose simply according to the guideline. In real-world clinical practice, there are innumerable factors and situations favoring under-dose prescription, and it may be difficult to include them all in the analyses of registries. The efforts and hopes of physicians dealing directly with patients to reduce bleeding risk should be respected against the complex backgrounds and profiles of these patients. In my own experience, I recently saw a male patient aged 74 years old suffering from unstable angina requiring percutaneous coronary intervention of the left main trunk. He had a history of permanent AF and stroke. He took aspirin 100 mg and clopidogrel 75 mg (dual antiplatelet therapy), and also a reduced dose of rivaroxaban 10 mg because of mild renal failure (estimated glomerular filtration rate [eGFR] 45 mL/min/1.73 m2). During follow-up, his eGFR improved to 55 mL/min/1.73 m2 and thus could not meet the reduction criteria. However, I continued to prescribe 10 mg of rivaroxaban for 1 year after stenting (i.e., an “under-dose”), and thereafter increased the dose to 15 mg with single antiplatelet therapy of clopidogrel 75 mg after discontinuing the aspirin.
| Apixaban 10 or 5 mg/day |
Dabigatran 300 or 220 mg/day (suggestion for reduced dose) |
Edoxaban 60 or 30 mg/day |
Rivaroxaban 15 or 10 mg/day |
|
|---|---|---|---|---|
| Reduced-dose criteria (*if patients meet 2 of the criteria for apixaban) | ||||
| Age (years) | *80 | (70) | NA | NA |
| CrCL (mL/min)/Cre (mg/dL) | NA/*1.5 | (30–50/NA) | 15–50/NA | 15–50/NA |
| Weight (kg) | *60 | NA | 60 | NA |
| Other factors | • (Major bleeding history) • (Taking verapamil or other P-glycoprotein inhibitors) |
Taking P-glycoprotein inhibitors |
||
| Additional reduced-dose criteria |
Approval of 15 mg for patients aged >80 years with high bleeding risk (only in Japan) |
|||
| Outside Japan | Reduced dose can be taken by patients with end-stage renal disease on dialysis |
• No approval of 15 mg • No approval of 60 mg once daily in patients with CrCL >95 mL/min in North America |
20 mg once daily of standard dose |
|
| Concomitant stable coronary artery disease (>1 year after stenting) |
DOAC alone without antiplatelet therapy can be taken (Class I) | |||
CrCL, creatinine clearance; DOAC, direct oral anticoagulant; NA, not applicable.
Although over-dosing may not be common in clinical practice, I recently permitted myself to prescribe edoxaban at 60 mg for a patient weighing 58 kg with diabetes and hypertension (i.e., an “over-dose”), who was schelduled to undergo catheter ablation soon. As an electrophysiologist, I believe that DOACs must not be under-dosed before planned electrical cardioversion and during the periprocedural period of catheter ablation to prevent procedure-related stroke. In my opinion, although no clear evidence is present, over-dosing within a limited period (e.g., 1–2 months) can be allowed without disturbing the risk–benefit balance. Just these 2 cases alone reveal the uncertainty of dose setting under various patient backgrounds and in the fluctuating situations of the true, real world.
After the period of the ANAFIE registry, at least 2 important studies were published from Japan, which may affect our decisions on dose setting. One was the ELDERCARE-AF trial, which revealed that a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism without a significantly higher incidence of major bleeding than placebo in very elderly Japanese patients with AF and high bleeding risk.4 During the study period of this subanalysis of the ANAFIE registry, just 243 patients were receiving off-label use of edoxaban, including 15 mg once daily. We should be aware that a significant number of bleeding events could occur even when a very low-dose prescription of edoxaban is used (major bleeding: 3.3% per patient-year). I believe, however, that more choices allowing “on-label” use are better under the actual presence of many factors and situations affecting dose setting.
The other study was the AFIRE trial, which revealed that rivaroxaban monotherapy is non-inferior to combination therapy with rivaroxaban plus a single antiplatelet agent for efficacy and superior for safety in patients with AF and stable coronary arterial disease.5 Although detailed information regarding the prevalence of stable coronary artery disease was unclear in this subanalysis of the ANAFIE registry, a significant number of patients (~15%) were receiving antiplatelet therapy, and the use of an antiplatelet agent was also one of the significant factors associated with DOAC under-dosing. Although the patients in the AFIRE trial were younger than those in the ANAFIE registry, and there may be a difference in the perception of this result between electrophysiologists and coronary interventionists, this evidence could contribute to reducing the choice of under-dosed DOAC. In the ongoing aging society, a guide for the dose-setting of DOACs in elderly patients with AF and multiple comorbidities may be further updated by future studies from Japan such as ELDERCARE, AFIRE, and the ANAFIE registry, and I wonder if some of the currently “inappropriate” under- or over-dosed prescriptions will come to be considered “reasonable”.
None.
