Outcomes associated with non-recommended dosing of rivaroxaban: results from the XANTUS study

Amarenco, Pierre; Haas, Sylvia; Kirchhof, Paulus; Lambelet, Marc; Bach, Miriam; Turpie, Alexander G. G.; Camm, A. John

doi:10.1093/ehjcvp/pvy041

Cited by 33 publications

(32 citation statements)

References 14 publications

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“…Similar patterns have been observed in patients treated with other NOACs, with under-dosing observed to be associated with higher risk for adverse events. 20,21 Importantly, the current data set is not powered to assess small differences in stroke rates, but there was no signal for a higher stroke rate in patients receiving the non-recommended low dose of edoxaban. However, there are too few events in patients taking the non-recommended doses to determine a clinically relevant, substantial difference compared with those taking the recommended doses.…”

Section: Discussionmentioning

confidence: 97%

Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: 1-year follow-up of the prospective observational ETNA-AF-Europe study

Groot

Weiss

Kelly

et al. 2020

European Heart Journal - Cardiovascular Pharmacotherapy

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Aim Non-vitamin K oral anticoagulants (NOACs) are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of edoxaban in routine care are limited in Europe. We report one-year outcomes in patients with AF treated with edoxaban in routine care. Methods and results ETNA-AF-Europe is a prospective, multi-centre, post-authorisation, observational study enrolling patients treated with edoxaban in 10 European countries, the design of which was agreed with the European Medicines Agency as part of edoxaban’s post-approval safety plan. Altogether 13,092 patients in 852 sites completed the one-year follow-up (mean age: 73.6 ± 9.5 years; 57% male, mean follow-up: 352 ± 49 days [median: 366 days]). Most patients had associated comorbidities (mean CHA2DS2-VASc score: 3.1 ± 1.4). Stroke or systemic embolism was reported in 103 patients (annualised event rate: 0.82%/year), and major bleeding events was reported in 132 patients (1.05%/year). Rates of intracranial haemorrhage were low (30 patients [0.24%/year]). Death occurred in 442 patients (3.50%/year); cardiovascular death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and cardiovascular mortality were higher in patients receiving edoxaban 30 mg versus 60 mg, in line with the higher age and more frequent comorbidities of the 30 mg group. Major bleeding was also numerically more common in patients receiving edoxaban 30 mg versus 60 mg. Conclusion The rates of stroke, systemic embolism and major bleeding are low in this large unselected cohort of high-risk AF patients routinely treated with edoxaban.

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Section: Discussionmentioning

confidence: 97%

Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: 1-year follow-up of the prospective observational ETNA-AF-Europe study

Groot

Weiss

Kelly

et al. 2020

European Heart Journal - Cardiovascular Pharmacotherapy

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“…In the XANTUS study, of the 3,794 patients with a CrCl ≥ 50 mL/min, only 583 (15.4%) patients received under-dose rivaroxaban (15 mg od in a global population). Compared with patients who received the recommended dose (20 mg od), the patients who received under-dose rivaroxaban were higher-risk patients, more likely to be > 75 years old, less likely to have CrCl > 80 mL/min, and more likely to have comorbidities (hypertension, diabetes mellitus, prior stroke/SE/TIA, and congestive heart failure) and higher CHADS 2 , CHA 2 DS 2 -VASc, and HAS-BLED scores [19]. The trends in these studies are similar to the trends in our analysis.…”

Section: Discussionmentioning

confidence: 99%

“…In the XANTUS sub-analysis focused on outcomes associated with non-recommended dosing of rivaroxaban, the incidence rates in patients who received under-dosed rivaroxaban showed 3.9 events/100 patient-years for major bleeding and 2.7 events/100 patient-years for thromboembolic events (stroke, TIA, non-CNS SE, or MI) [19]. The rates in patients who received the recommended dose (20 mg od for patients with CrCl ≥ 50 mL/min and 15 mg od for patients with CrCl < 50 mL/min) were 2.6 events/100 patient-years and 1.9 events/100 patient-years, respectively.…”

Section: Discussionmentioning

confidence: 99%

Outcomes associated with under-dosing of rivaroxaban for management of non-valvular atrial fibrillation in real-world Japanese clinical settings

Ikeda

Ogawa

Kitazono

et al. 2019

J Thromb Thrombolysis

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The approved dose of oral anticoagulant rivaroxaban for patients with non-valvular atrial fibrillation (NVAF) in Japan is 15 mg once daily (od) in patients whose creatinine clearance is ≥ 50 mL/min, but recent real-world studies have demonstrated that these patients often received less than the recommended dose due to bleeding concerns. The effect of under-dosing on safety and effectiveness outcomes remains unclear. We used 1-year follow-up data from the XAPASS, a real-world Japanese prospective, single-arm, observational study. Of the 11,308 patients, 6521 patients who completed a 1-year follow-up and had a creatinine clearance ≥ 50 mL/min were included in this sub-analysis. Primary endpoints were any bleeding and a composite of stroke/non-central nervous system systemic embolism (non-CNS SE)/myocardial infarction (MI). Among the 6521 patients, 4185 (64.2%; mean CHADS2 score: 1.8) received the 15 mg od (recommended dose), whereas 2336 (35.8%; mean CHADS2 score: 2.3) received 10 mg od (under-dose). After adjusting for patient characteristics by propensity scoring and inverse probability of treatment weighting, incidence rates of major bleeding were comparable between under-dosed patients and patients who received the recommended dose (1.34 vs. 1.63 events/100 patient-years, p = 0.197), although the incidence rates of stroke/non-CNS SE/MI were higher in under-dosed patients than in those who received the recommended dose (2.15 vs. 1.48 events/100 patient-years, p = 0.009). In Japanese clinical practice, some NVAF patients receive rivaroxaban doses inconsistent with the recommendation. Considering the total clinical benefit, the recommended dose may be preferable in terms of balance of safety and effectiveness.Clinicaltrials.gov NCT01582737.Electronic supplementary materialThe online version of this article (10.1007/s11239-019-01934-6) contains supplementary material, which is available to authorized users.

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“…In a single-center experience, 23% of patients were either under- or overdosed with NOACs [ 18 ]. In larger populations, the rate of inappropriate dosing of apixaban ranged between 15 and 20% [ 19 – 21 ]. The reports about the consequences of inadequate underdosing are conflicting [ 19 – 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…In larger populations, the rate of inappropriate dosing of apixaban ranged between 15 and 20% [ 19 – 21 ]. The reports about the consequences of inadequate underdosing are conflicting [ 19 – 21 ]. It might very well be that the clinical judgement of the treating physician with respect to appropriate dose of the patient is as good as the recommendations given in the label.…”

Section: Discussionmentioning

confidence: 99%

Use, Persistence, Efficacy, and Safety of Apixaban in Patients with Non-Valvular Atrial Fibrillation in Unselected Patients in Germany. Results of the Prospective Apixaban in Atrial Fibrillation (APAF) Registry

et al. 2020

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Introduction Apixaban has been shown to be superior to warfarin in patients with non-valvular atrial fibrillation in the randomized ARISTOTLE trial and its use is recommended in current guidelines. There are only scarce data about its use, efficacy, and safety in unselected patients in Germany. Methods and Results The APAF registry is a prospective non-interventional study enrolling 5015 patients with non-valvular atrial fibrillation. Of these, 1349 (26.9%) patients were initially treated with apixaban and followed up at 3 and 12 months. The dose of apixaban used was 1 × 2.5 mg in 1.6%, 2 × 2.5 mg in 30.4%, and 2 × 5 mg daily in 68.0% of patients, respectively. Inappropriate underdosing of apixaban was observed in 22.3%, mostly in elderly patients with higher HAS-BLED Score and a history of bleeding. Persistence to apixaban after 1 year was 88.6%, while the dose was changed in 3.7% of patients. Switching to other NOACs or VKAs occurred in 5.1%. After 12 months, all-cause mortality was 5.0%, non-fatal stroke occurred in 0.4%, non-fatal myocardial infarction in 0.6%, ISTH major bleeding in 0.8%, moderate or minor bleeding in 4.3% of patients, respectively. Conclusions In this prospective experience in unselected patients with atrial fibrillation, persistence to apixaban was high, and efficacy and safety were comparable to the results in clinical trials, supporting its use in clinical practice. Electronic supplementary material The online version of this article (10.1007/s40119-020-00188-1) contains supplementary material, which is available to authorized users.

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Outcomes associated with non-recommended dosing of rivaroxaban: results from the XANTUS study

Abstract: No. of tables: 4 (plus 2 supplementary tables) No. of figures: 4 No. of references: 15

Cited by 33 publications

References 14 publications

Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: 1-year follow-up of the prospective observational ETNA-AF-Europe study

Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: 1-year follow-up of the prospective observational ETNA-AF-Europe study

Outcomes associated with under-dosing of rivaroxaban for management of non-valvular atrial fibrillation in real-world Japanese clinical settings

Use, Persistence, Efficacy, and Safety of Apixaban in Patients with Non-Valvular Atrial Fibrillation in Unselected Patients in Germany. Results of the Prospective Apixaban in Atrial Fibrillation (APAF) Registry

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