Off-label underdosed apixaban use in Asian patients with non-valvular atrial fibrillation

Abstract Funding Acknowledgements Type of funding sources: None. Background In Asian patients with atrial fibrillation (AF), off-label underdosed prescriptions of direct oral anticoagulants (DOACs) are common Purpose We aimed to compare the effectiveness and safety of off-label underdosed apixaban with on-label standard dose apixaban in Asian patients with AF. Methods Using the Korean nationwide claims database, we identified patients who prescribed apixaban and did not fulfill the dose reduction criteria of apixaban between January 2015 and December 2017. Multivariable Cox hazard regression model was performed and hazard ratios (HRs) for ischemic stroke, major bleeding (MB), all-cause death, and the composite clinical outcome were analyzed. Results Compared to patients prescribed on-label standard dose apixaban (n = 4,194), patients prescribed off-label underdosed apixaban (n = 2,890) were associated with higher risks of ischemic stroke (adjusted HR [aHR] 1.38, 95% confidence interval [CI] 1.06-1.81), all-cause death (aHR 1.19, 95% CI 1.01-1.39) and the composite clinical outcome (aHR 1.17, 95% CI 1.03-1.34), but with no significant differences in MB between the two groups (Figure). In patients without any dose reduction criteria, off-label underdosed apixaban use was associated with a significantly higher risk of ischemic stroke than on-label standard dose apixaban use (aHR 1.85, 95% 1.25-2.73); however, in patients who had single dose reduction criteria (age ≥80 years, serum creatinine ≥1.5mg/dL, or bodyweight ≤60 kg), off-label underdosed apixaban use did not show a significant overall benefit in the composite clinical outcome compared with on-label standard dose apixaban, but was associated with a higher risk of all-cause death (aHR 1.32, 95% CI 1.07-1.64). Conclusion Off-label underdosed apixaban use was associated with higher risks of ischemic stroke, all-cause death, and composite clinical outcome and comparable risk of MB compared with on-label standard dose apixaban use. Label-adherence of apixaban dosing should be emphasized to achieve the best clinical outcome for Asian patients with non-valvular AF, especially in those without any dose reduction criteria. Abstract Figure.

Download Full-text

P279 Standard dose of rivaroxaban in Asian patients with atrial fibrillation: 20ms vs.15mg? Off label dose reduction of rivaroxaban should be avoided

European Heart Journal ◽

10.1093/ehjci/ehz872.099 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

Author(s):

H K Jeong ◽

J M Won ◽

K H Lee ◽

N S Yoon ◽

H W Park ◽

...

Keyword(s):

Atrial Fibrillation ◽

Dose Reduction ◽

Major Bleeding ◽

Standard Dose ◽

Comparable Efficacy ◽

Systemic Embolism ◽

Off Label ◽

Safety Outcome ◽

Asian Patients ◽

Net Clinical Benefit

Abstract Background Rivaroxaban emerged as potential alternatives to warfarin for the prevention of thromboembolisim in patients with atrial fibrillation (AF). Because of the concern for the risk of major bleeding with rivaroxaban in Asian patients, off label rivaroxaban dose reduction to15mg is common in Asian real-world practice. We aimed to set standard rivaroxaban dose in Asian patients with AF by comparison between on-label rivaroxaban 20mg and off-label reduced rivaroxaban dose 15mg. Methods A total of 2,208 consecutive non-valvular AF patients were enrolled between 2011 and 2017. After propensity score matching, both warfarin (n = 804) and rivaroxaban group (n = 804) had comparable baseline characteristics. Rivaroxaban group was further divided into on-label rivaroxaban 20mg group (n = 390) and off-label reduced rivaroxaban 15mg group (n = 333). Efficacy outcome was stroke/systemic embolism. Safety outcome was major bleeding. Primary net clinical benefit (NCB) was defined as the composite of stroke, systemic embolism, major bleeding and all-cause mortality. Secondary NCB was defined as the composite of stroke, systemic embolism and major bleeding. Patients were followed upto one-year or until the first occurrence of any study outcomes. Results Both Rivaroxaban groups had comparable efficacy compared to warfarin. However, both on-label rivaroxaban 20mg (hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.18-0.90, p = 0.026) and off-label reduced rivaroxaban 15mg (HR 0.37, 95% CI 0.16-0.88, p = 0.025) significantly reduced major bleeding. There were no differences in efficacy and safety outcomes between on-label rivaroxaban 20mg and off-label reduced rivaroxaban 15mg group. On-label rivaroxaban 20mg significantly reduced primary (HR 0.44, 95% CI 0.25-0.79, p = 0.006) and secondary (HR 0.51, 95% CI 0.27-0.96, p = 0.038) NCBs compared to warfarin. However, off-label reduced rivaroxaban 15mg did not reduce both primary and secondary NCBs. Conclusion Off-label rivaroxaban dose reduction to 15mg had no benefit compared to on-label rivaroxaban 20mg. Compared to warfarin, on-label rivaroxaban 20mg significantly improved primary and secondary NCBs, whereas off-label reduced rivaroxaban 15mg did not. Therefore, rivaroxaban 20mg is favorable as standard dose in Asian patients.

Download Full-text

What is Standard Dose of Rivaroxaban in Elderly Asian Patients with Atrial Fibrillation: 20ms versus. 15mg?

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/10760296211061148 ◽

2021 ◽

Vol 27 ◽

pp. 107602962110611

Author(s):

Sung Soo Kim ◽

Ki Hong Lee ◽

Nam Sik Yoon ◽

Hyung Wook Park ◽

Jeong Gwan Cho

Keyword(s):

Atrial Fibrillation ◽

Elderly Patients ◽

Dose Reduction ◽

Major Bleeding ◽

Standard Dose ◽

Comparable Efficacy ◽

Systemic Embolism ◽

Off Label ◽

Korean Patients ◽

Asian Patients

Although there is no age criterion for rivaroxaban dose reduction, elderly patients with atrial fibrillation (AF) are often prescribed an off-label reduced dose. We aimed to evaluate whether age is a necessary criterion for rivaroxaban dose reduction in Korean patients with AF. Among 2208 patients who prescribed warfarin or rivaroxaban, 552 patients over 75 years without renal dysfunction (creatinine clearance >50 mL/min) were compared based on propensity score matching. The rivaroxaban group was further divided into a 20 mg (R20; on-label) and a 15 mg (R15; off-label). Primary net clinical benefit (NCB) was defined as the composite of stroke, systemic embolism, major bleeding, and all-cause mortality. Secondary NCB was defined as the composite of stroke, systemic embolism, and major bleeding. Patients were followed for 1 year, or until the first outcome occurrence. Both rivaroxaban groups had comparable efficacy compared with warfarin. However, both R20 (0.9% vs 7.4%, p = .014) and R15 (2.3% vs 7.4%, p = .018) had a significant reduction in major bleeding. There were no differences in efficacy or safety outcomes between R20 and R15. R20 had significantly reduced primary (hazard ratio [HR] 0.33, 95% confidence interval [CI]: 0.12–0.93) and secondary (HR 0.31, 95% CI: 0.10–0.93) NCBs compared with warfarin. However, primary and secondary NCBs were not reduced in R15. In real-world practice with elderly patients with AF, off-label rivaroxaban dose reduction to 15 mg conferred no benefits. Therefore, guideline-adherent rivaroxaban 20 mg is favorable in elderly Korean patients with AF.

Download Full-text

P4769Optimal rivaroxaban dose in Asian patients with atrial fibrillation and normal or mildly impaired renal function

European Heart Journal ◽

10.1093/eurheartj/ehz745.1145 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

E.-K Choi ◽

S R Lee ◽

K D Han ◽

J H Jung ◽

S Oh ◽

...

Keyword(s):

Atrial Fibrillation ◽

Renal Function ◽

Ischemic Stroke ◽

Clinical Outcome ◽

Major Bleeding ◽

Impaired Renal Function ◽

Gi Bleeding ◽

Nonsignificant Trend ◽

Off Label ◽

Asian Patients

Abstract Background Although rivaroxaban 15 mg was only given to patients with creatinine clearance (CrCl) <50mL/min in the pivotal clinical trial, this dose has been commonly prescribed in Asian patients with non-valvular atrial fibrillation (AF) regardless of renal function. There is a paucity of information regarding the clinical outcomes of rivaroxaban 15 mg compared to rivaroxaban 20 mg in patients with CrCl ≥50mL/min. This study aimed to examine the effectiveness and safety of two doses of rivaroxaban in Asian patients with AF and CrCl ≥50mL/min. Methods Using the Korean National Health Insurance Service database, patients with AF and normal or mildly impaired renal function (CrCl ≥50mL/min) and naïve to rivaroxaban or warfarin were included from January 2014 to December 2016. Three separate 1:1 propensity score-matched cohorts were conducted: rivaroxaban 20 mg (R20) vs. warfarin (n=15,584), rivaroxaban 15 mg (R15) vs. warfarin (n=11,554), and R20 vs. R15 (n=10,392). Hazard ratios (HRs) for ischemic stroke, intracranial hemorrhage (ICH), gastrointestinal (GI) bleeding, major bleeding, all-cause death, and composite clinical outcome were analyzed. Results Among the pooled total study population, mean age was 66.9±10.9 years, 62.2% were male, mean CHA2DS2-VASc score was 3.16±1.79, and mean CrCl was 83.6±42.0 mL/min (median 78.4 mL/min, IQR 67.7–91.0 mL/min). A substantial proportion (42.6%) of patients with CrCl ≥50 mL/min were prescribed off-label R15 for stroke prevention in the Korean AF population. Compared to warfarin, both R20 and R15 showed significantly lower risk for ischemic stroke, major bleeding (mainly through reduction of ICH), and all-cause death (Figure). Overall, both R20 and R15 had better results for the composite clinical outcome compared to warfarin (HR: 0.617, 95% CI: 0.550–0.691 for R20, and HR: 0.759, 95% CI: 0.675–0.853 for R15). Compared to off-label R15, on-label R20 showed a nonsignificant trend toward lower risks of ischemic stroke, hospitalization for GI bleeding, hospitalization for major bleeding, and all-cause death. Overall, on-label R20 had better results for the composite clinical outcome compared to off-label R15 in patients with CrCl ≥50 mL/min (HR: 0.852, 95% CI: 0.735–0.988). This benefit was consistently observed in patients aged ≥80 years and those <50 kg. In patients with CrCl 50–60 mL/min, R20 showed a nonsignificant trend toward a higher risk of hospitalization for major bleeding compared to R15 (HR: 1.828, 95% CI 0.994–3.452). Conclusions Among Asians with AF and CrCl ≥50mL/min, both R20 and R15 were associated with reduced risk of ischemic stroke, ICH, major bleeding, and all-cause death without significantly increased risk of GI bleeding compared with warfarin. In patients with CrCl ≥50mL/min, on-label R20 showed better results for the composite clinical outcome compared to off-label R15.

Download Full-text

Abstract WP236: Trends in Antithrombotic Therapy Use and Clinical Outcome in Acute Ischemic Stroke and Atrial Fibrillation in a Hispanic Population in the Era of Direct Oral Anticoagulants

Stroke ◽

10.1161/str.50.suppl_1.wp236 ◽

2019 ◽

Vol 50 (Suppl_1) ◽

Author(s):

Fernando Daniel Flores-Silva ◽

Erwin Chiquete ◽

Francisco Martinez-Carrillo ◽

Pedro Gomez-Brockmann ◽

Juan Esteban Montes-Ramirez ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Clinical Outcome ◽

Acute Ischemic Stroke ◽

Antithrombotic Therapy ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Hispanic Population

Download Full-text

Off-label underdosed apixaban use in Asian patients with non-valvular atrial fibrillation

European Heart Journal - Cardiovascular Pharmacotherapy ◽

10.1093/ehjcvp/pvab004 ◽

2021 ◽

Author(s):

So-Ryoung Lee ◽

Eue-Keun Choi ◽

Sang-Hyun Park ◽

Jin-Hyung Jung ◽

Kyung-Do Han ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Dose Reduction ◽

Clinical Outcomes ◽

Standard Dose ◽

Composite Outcome ◽

Claims Database ◽

Off Label ◽

Asian Patients ◽

Hazard Ratios

Abstract Aims To compare the effectiveness and safety of off-label underdosed apixaban with on-label standard dose apixaban in Asian patients with atrial fibrillation (AF). Methods and results Using the Korean nationwide claims database, we identified patients who were prescribed apixaban and did not fulfil the dose reduction criteria for apixaban between January 2015 and December 2017. A multivariable Cox hazard regression model was performed, and hazard ratios (HRs) for ischaemic stroke, major bleeding (MB), all-cause death, and composite outcome were analysed. Compared to patients prescribed on-label standard dose apixaban (n = 4194), patients prescribed off-label underdosed apixaban (n = 2890) showed a higher risk of ischaemic stroke [adjusted HR (aHR) 1.38, 95% confidence interval (CI) 1.06–1.81], all-cause death (aHR 1.19, 95% CI 1.01–1.39), and the composite outcome (aHR 1.17, 95% CI 1.03–1.34), but with no significant differences in MB between the two groups. Among the patients who did not meet any dose reduction criteria, off-label underdosed apixaban use was associated with a significantly higher risk of ischaemic stroke than on-label standard dose apixaban use (aHR 1.85, 95% CI 1.25–2.73). Among the patients who met a single dose reduction criterion, off-label underdosed apixaban use was associated with a higher risk of all-cause death than on-label standard dose apixaban (aHR 1.32, 95% CI 1.07–1.64). Conclusion The off-label underdosed apixaban group showed higher risks of ischaemic stroke, all-cause death, and composite clinical outcomes than the on-label standard dose apixaban group, but both showed comparable risks of MB. Label adherence to apixaban dosing should be emphasized to achieve the best clinical outcomes for Asian patients with AF.

Download Full-text

Direct oral anticoagulants vs warfarin in non-valvular atrial fibrillation. Meta-analysis, includes all published trials

European Heart Journal ◽

10.1093/eurheartj/ehab724.0343 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

C Arreaga-Perez ◽

D Evangelista-Barragan ◽

A Zarate-Zapata ◽

E Penaherrera ◽

J J Zuniga-Bohorquez ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Hemorrhagic Stroke ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Cardiovascular Death ◽

Phase Iii ◽

Funding Sources ◽

Selection Of

Abstract Introduction Warfarin, despite its limitations, is still used as standard treatment in patients with Atrial Fibrillation, but it has been demonstrated that Direct Oral Anticoagulants (DOAC) offer many advantages over warfarin in the prevention of strokes. Purpose The goal was to determinate the safety and effectiveness in reducing systemic thromboembolism, ischemic stroke, hemorrhagic stroke, cerebral hemorrhage and cardiovascular mortalityof the direct oral anticoagulants (DOACs) over warfarin in patients with non-valvular atrial fibrillation, conducting an analysis of the studies of DOACs, including the ENGAGE study on the use of edoxaban, affirming its safety including the pivotal essays available. Method A systematic search of PubMed's bibliographic database was made for the selection of the articles.Clinical essays from less than 10 years, in phase III and multicentric studies were selected. Results The main objective was the significant reduction in the incidence of stroke/systemic thromboembolism with the use of DOACs vs. Warfarin (2,73% vs. 3,24%), the reduction of hemorrhagic stroke was (0.41% vs. 0.94%), ischemic stroke (3.12% vs. 3.5%), cardiovascular death with DOACs was 6.02% vs. Warfarin 6.84%, (compared with previous studies that demonstrated effectiveness with max doses affirming safety and effectiveness). Conclusion Our meta-analysis is the first to date to evaluate all the pivotal trials published,we include the ENGAGE trial. In non-valvular atrial fibrillation, the use of DOACs, in comparison with Warfarin, significantly reduced the risk of stroke/systemic thromboembolism by 16.3%, ischemic stroke by 11.1%, hemorrhagic stroke by 54.6%, cardiovascular mortality by 12.9%. FUNDunding Acknowledgement Type of funding sources: None.

Download Full-text

Off-Label Under- and Overdosing of Direct Oral Anticoagulants in Patients With Atrial Fibrillation: A Meta-Analysis

Circulation Cardiovascular Quality and Outcomes ◽

10.1161/circoutcomes.121.007971 ◽

2021 ◽

Vol 14 (12) ◽

Cited By ~ 1

Author(s):

Xin-Lin Zhang ◽

Xiao-Wen Zhang ◽

Ting-Yu Wang ◽

Hong-Wei Wang ◽

Zheng Chen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Outcome ◽

Major Bleeding ◽

Controlled Trial ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Limited Data ◽

Off Label ◽

Safety Outcome

Background: Prescriptions of off-label under- and overdosing of direct oral anticoagulants (DOACs) are common for patients with atrial fibrillation, but their efficacy and safety remain unknown. Methods: Databases were searched for randomized controlled trial or adjusted observational study that compared an off-label versus on-label dosing of DOACs through June 15, 2021. The primary efficacy outcome was ischemic stroke/system embolism (IS/SE), and primary safety outcome was major bleeding. Net clinical outcome was generally defined as the composite of IS/SE, major bleeding, and all-cause death. Hazard ratios (HRs) with 95% CIs were pooled with random-effects models with Hartung-Knapp-Sidik-Jonkman method for adjustment. Results: Sixteen studies with 130 609 patients were included. Compared with on-labeling dosing, off-label underdosing of DOACs was associated with a higher risk of IS/SE (HR, 1.22 [95% CI, 1.05–1.42], P =0.01). The incidence of major bleeding was similar (HR, 0.95 [95% CI, 0.82–1.11], P =0.48). Off-label underdosing was associated with a higher risk of net clinical outcome (HR, 1.19 [95% CI, 1.04–1.40], P =0.04) and all-cause death (HR, 1.24 [95% CI, 1.04–1.48], P =0.02). Stratified analysis of off-label underdosing of DOACs for IS/SE showed subgroup differences among different DOAC types and study regions. Limited data showed that off-label overdosing was associated with a higher risk of IS/SE (HR, 1.26 [95% CI, 1.11–1.43], P =0.003) and major bleeding (HR, 1.30 [95% CI, 1.04–1.62], P =0.025). Conclusions: Compared with on-label dosing, off-label underdosing of DOACs increased the risk of thromboembolic events but did not decrease the risk of bleeding. Limited data for off-label overdosing showed higher risks of thromboembolic and bleeding. Further studies are warranted to confirm the results of off-label overdosing DOACs and subgroup results of underdosing DOACs.

Download Full-text

The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial Fibrillation

TH Open ◽

10.1055/s-0040-1721499 ◽

2020 ◽

Vol 04 (04) ◽

pp. e417-e426

Author(s):

Carline J. van den Dries ◽

Sander van Doorn ◽

Patrick Souverein ◽

Romin Pajouheshnia ◽

Karel G.M. Moons ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Routine Care ◽

P Value ◽

Risk Of Mortality ◽

Mortality Effect

Abstract Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0–5, 6–8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87–1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68–0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88–0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use (p-value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed (p-value for interaction <0.01). Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.

Download Full-text