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

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.

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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.

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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.

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

EP Europace ◽

10.1093/europace/euab116.281 ◽

2021 ◽

Vol 23 (Supplement_3) ◽

Author(s):

SR Lee ◽

EK Choi ◽

SH Park ◽

JH Jung ◽

KD Han ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Clinical Outcome ◽

Dose Reduction ◽

Standard Dose ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Off Label ◽

Funding Sources ◽

Asian Patients

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.

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Off-label dosing of non–vitamin K antagonist oral anticoagulants and clinical outcomes in Asian patients with atrial fibrillation

Heart Rhythm ◽

10.1016/j.hrthm.2020.07.022 ◽

2020 ◽

Vol 17 (12) ◽

pp. 2102-2110

Author(s):

Yi-Hsin Chan ◽

Tze-Fan Chao ◽

Shao-Wei Chen ◽

Hsin-Fu Lee ◽

Yung-Hsin Yeh ◽

...

Keyword(s):

Atrial Fibrillation ◽

Clinical Outcomes ◽

Vitamin K ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Off Label ◽

Asian Patients

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Impacts of off-label dosing noacs on clinical outcomes in very elderly patients with atrial fibrillation

European Heart Journal ◽

10.1093/eurheartj/ehab724.0565 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

T Chao ◽

Y.H Chan ◽

G.Y.H Lip ◽

S.A Chen

Keyword(s):

Atrial Fibrillation ◽

Clinical Outcomes ◽

Major Bleeding ◽

Lower Risk ◽

Oral Anticoagulants ◽

Systemic Embolism ◽

Very Elderly ◽

Off Label ◽

Funding Sources ◽

Clinical Events

Abstract Background Studies about the comparisons of on-label and off-label dosing non-vitamin K antagonist oral anticoagulants (NOACs) regarding the risks of clinical outcomes among atrial fibrillation (AF) patients have been published. However, data among the very elderly AF patients were limited. In the present study, we aimed to investigate the impacts of inappropriate dosing of NOACs on clinical outcomes in AF patients aged ≥85 years of age. Methods We used medical data from a multi-center healthcare system in Taiwan enrolling 1,836 and 268 AF patients aged ≥85 years treated with NOACs and warfarin, respectively. Among 1,836 patients receiving NOACs, underdosing, overdosing and on-label dosing NOACs were prescribed in 248, 149 and 1439 patients, respectively. The risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding were compared between warfarin and NOACs in different dosing groups. Also, the risks of clinical events of underdosing and overdosing NOACs were comapred to on-labeling dosing. Results Compared to warfarin, underdosing NOACs were associated with a higher risk of IS/SE (aHR 2.39; p=0.048) without a lower risk of major bleeding; while overdosing NOACs were not associated with a lower risk of IS/SE (aHR 0.74, p=0.604) (Figure 1). Compared to on-label dosing NOACs, underdosing NOACs were associated with a higher risk of IS/SE, while the risk was not lower for overdoing NOACs (Figure 2). Conclusions Even for very elderly AF patients aged ≥85 years, NOACs should still be prescribed at the dosing following the criteria defined in clinical trials and guideline recommendations. FUNDunding Acknowledgement Type of funding sources: None. Figure 1 Figure 2

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Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis

BioMed Research International ◽

10.1155/2020/3520764 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Ningning Zhang ◽

Yushu Ouyang ◽

Jianlan Chang ◽

Ping Liu ◽

Xiangyang Tian ◽

...

Keyword(s):

Clinical Outcomes ◽

Gene Dosage ◽

Meta Analysis ◽

Objective Response ◽

Progression Free Survival ◽

Gene Dosage Effect ◽

Asian Patients ◽

Hazard Ratios ◽

Platinum Based Chemotherapy ◽

Study Heterogeneity

Background. Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis. Methods. Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models. Results. Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln ( OR = 1.71 , 95% CI: 1.16-2.52, p = .007 , I 2 = 56.8 % ) and GlnArg ( OR = 1.23 , 95% CI: 1.07-1.40, p = .003 , I 2 = 29.0 % ) were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS ( HR = 0.60 , 95% CI: 0.40-0.88) and PFS ( HR = 0.64 , 95% CI: 0.46-0.90). We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles (TrpTrp vs. ArgArg: OR = 1.73 , 95% CI:1.31-2.27; TrpArg vs. ArgArg: OR = 1.28 , 95% CI: 1.06-1.55), suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS. Conclusion. Our results showed that rs25487 and rs1799782 of XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC.

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Long-term clinical outcomes after major bleeding in patients with atrial fibrillation: the Fushimi AF registry

European Heart Journal - Quality of Care and Clinical Outcomes ◽

10.1093/ehjqcco/qcaa082 ◽

2020 ◽

Author(s):

Hisashi Ogawa ◽

Yoshimori An ◽

Kenjiro Ishigami ◽

Syuhei Ikeda ◽

Kosuke Doi ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Clinical Outcomes ◽

Major Bleeding ◽

Bleeding Event ◽

Community Based ◽

Increased Risk ◽

All Cause Mortality

Abstract Aims Oral anticoagulants reduce the risk of ischaemic stroke but may increase the risk of major bleeding in atrial fibrillation (AF) patients. Little is known about the clinical outcomes of patients after a major bleeding event. This study assessed the outcomes of AF patients after major bleeding. Methods and results The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. Analyses were performed on 4304 AF patients registered by 81 institutions participating in the Fushimi AF Registry. We investigated the demographics and outcomes of AF patients who experienced major bleeding during follow-up period. During the median follow-up of 1307 days, major bleeding occurred in 297 patients (6.9%). Patients with major bleeding were older than those without (75.6 vs. 73.4 years; P < 0.01). They were more likely to have pre-existing heart failure (33.7% vs. 26.7%; P < 0.01), history of major bleeding (7.7% vs. 4.0%; P < 0.01), and higher mean HAS-BLED score (2.05 vs.1.73; P < 0.01). On landmark analysis, ischaemic stroke or systemic embolism occurred in 17 patients (3.6/100 person-years) after major bleeding and 227 patients (1.7/100 person-years) without major bleeding, with an adjusted hazard ratio (HR) of 1.93 [95% confidence interval (CI), 1.06–3.23; P = 0.03]. All-cause mortality occurred in 97 patients with major bleeding (20.0/100 person-years) and 709 (5.1/100 person-years) patients without major bleeding [HR 2.73 (95% CI, 2.16–3.41; P < 0.01)]. Conclusion In this community-based cohort, major bleeding is associated with increased risk of subsequent all-cause mortality and thromboembolism in the long-term amongst AF patients. Trial registration https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000005834. (last accessed 22 October 2020)

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The optimal drug adherence to maximize the efficacy and safety of non-vitamin K antagonist oral anticoagulant in real-world atrial fibrillation patients

EP Europace ◽

10.1093/europace/euz273 ◽

2019 ◽

Vol 22 (4) ◽

pp. 547-557 ◽

Cited By ~ 9

Author(s):

Daehoon Kim ◽

Pil-Sung Yang ◽

Eunsun Jang ◽

Hee Tae Yu ◽

Tae-Hoon Kim ◽

...

Keyword(s):

Myocardial Infarction ◽

Atrial Fibrillation ◽

Ischaemic Stroke ◽

Clinical Outcomes ◽

Vitamin K ◽

Major Bleeding ◽

Oral Anticoagulant ◽

Vitamin K Antagonist ◽

Increased Risk ◽

Optimal Drug

Abstract Aims To investigate the association between adherence to non-vitamin K antagonist oral anticoagulant (NOAC) and clinical outcomes and to determine the optimal cut-off level of NOAC adherence among patients with atrial fibrillation (AF). Methods and results Using the Korean National Health Insurance Service database, we identified 96 197 patients with non-valvular AF who initiated NOAC or warfarin in 2013–16. We compared clinical outcomes between adherent [proportion of days covered (PDC) ≥80%] vs. non-adherent (PDC <80%) NOAC users, and further with warfarin users. We assessed the outcomes according to different levels of adherence. The proportion of adherent NOAC users was 64.0%. Compared with non-adherent NOAC users, adherent NOAC users were at lower risks of ischaemic stroke/systemic embolism (SE) [adjusted hazard ratio (aHR) 0.73, 95% confidence interval (CI) 0.69–0.79], and myocardial infarction (aHR 0.82, 95% CI 0.72–0.93), whereas there was no significant risk alteration for major bleeding (aHR 1.01, 95% CI 0.91–1.11). Compared with warfarin, non-adherent NOAC use failed to have better efficacy against ischaemic stroke/SE (aHR 0.99, 95% CI 0.93–1.05) and rather had increased risk of myocardial infarction (aHR 1.13, 95% CI 1.03–1.25). In NOAC users, the risks of adverse outcomes decreased according to gradual increase of adherence rates with the lowest risks in ≥90%, except for major bleeding in which there were no significant associations. Conclusions In an adherence level-dependent fashion, adherent use of NOAC showed better clinical outcomes without increasing bleeding risk. Maintaining ≥90% of adherence optimizes effectiveness of NOAC therapy without compromising its safety.

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Improved Population-Based Clinical Outcomes of Patients with Atrial Fibrillation by Compliance with the Simple ABC (Atrial Fibrillation Better Care) Pathway for Integrated Care Management: A Nationwide Cohort Study

Thrombosis and Haemostasis ◽

10.1055/s-0039-1693516 ◽

2019 ◽

Vol 119 (10) ◽

pp. 1695-1703 ◽

Cited By ~ 28

Author(s):

Minjae Yoon ◽

Pil-Sung Yang ◽

Eunsun Jang ◽

Hee Tae Yu ◽

Tae-Hoon Kim ◽

...

Keyword(s):

Atrial Fibrillation ◽

Integrated Care ◽

Clinical Outcomes ◽

Care Management ◽

Care Pathway ◽

Holistic Approach ◽

Population Based ◽

Composite Outcome ◽

Care Approach ◽

Multivariable Regression

Background An integrated care approach might be of benefit for clinical outcomes of patients with atrial fibrillation (AF). This study evaluated whether compliance with the Atrial fibrillation Better Care (ABC) pathway for integrated care management (“A” Avoid stroke; “B” Better symptom management; “C” Cardiovascular risk and Comorbidity optimization) would improve population-based clinical outcomes in a nationwide AF cohort. Methods and Results From the Korea National Health Insurance Service database, a total of 204,842 nonvalvular AF patients were enrolled between January 1, 2005 and December 31, 2015. Patients that fulfilled all criteria of the ABC pathway were defined as the “ABC” group, and those who did not were the “Non-ABC” group.Over a mean follow-up of 6.2 ± 3.5 years, the ABC pathway compliant group had lower rates of all-cause death (0.80 vs. 2.72 per 100 person-years, p < 0.001) and the composite outcome of “death, ischemic stroke, major bleeding, and myocardial infarction” (2.34 vs. 5.92 per 100 person-years, p < 0.001) compared with the Non-ABC compliant group. Adjusted Cox multivariable regression showed that the ABC group had a significantly lower risk of all-cause death (adjusted hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.78–0.86) and the composite outcome (adjusted HR 0.86; 95% CI, 0.83–0.89). With the increasing numbers of ABC pathway criteria fulfilled, the risk of all-cause death and composite outcome were progressively lowered. Conclusion In the first study of a nationwide population cohort, we show that compliance with the simple ABC pathway is associated with improved clinically relevant outcomes of patients with AF. Given the high health care burden associated with AF, such a streamlined holistic approach to AF management should be implemented, to improve the care of such patients.

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Effectiveness and Safety of Non–Vitamin K Oral Anticoagulants in Comparison to Phenprocoumon: Data from 61,000 Patients with Atrial Fibrillation

Thrombosis and Haemostasis ◽

10.1160/th17-10-0733 ◽

2018 ◽

Vol 118 (03) ◽

pp. 526-538 ◽

Cited By ~ 30

Author(s):

Stefan Hohnloser ◽

Edin Basic ◽

Christopher Hohmann ◽

Michael Nabauer

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Standard Dose ◽

Oral Anticoagulants ◽

Proportional Hazard ◽

Systemic Embolism ◽

Cox Proportional Hazard ◽

Hazard Ratios ◽

Cox Proportional Hazard Models ◽

Baseline Characteristics

AbstractAll pivotal trials have evaluated non–vitamin K oral antagonists (NOACs) against warfarin. However, in some regions of the world, phenprocoumon is the most widely used vitamin K antagonist (VKA). There is little evidence documenting effectiveness and safety of NOACs compared with phenprocoumon in atrial fibrillation (AF). A retrospective cohort study using a German claims database was conducted to assess effectiveness (stroke, systemic embolism [SE]) and safety (bleeding leading to hospitalization) during therapy with NOACs and phenprocoumon in 61,205 AF patients. Hazard ratios (HRs) for effectiveness and safety outcomes were derived from Cox proportional hazard models, adjusting for baseline characteristics. Propensity score matching was performed as a sensitivity analysis. As a prespecified subgroup analysis, the effects of reduced NOAC dosing were compared with phenprocoumon. A total of 61,205 patients were identified in whom phenprocoumon (n = 23,823, 38.9%), apixaban (n = 10,117, 16.5%), dabigatran (n = 5,122, 8.4%), or rivaroxaban (n = 22,143, 36.2%) was initiated. After adjusting for baseline confounders, all three NOACs tested had significantly lower risks of stroke/SE compared with phenprocoumon (apixaban—HR: 0.77, 95% CI: 0.66–0.90; dabigatran—HR: 0.74, 95% CI: 0.60–0.91; rivaroxaban—HR: 0.86, 95% CI: 0.76–0.97). Apixaban (HR: 0.58, 95% CI: 0.49–0.69) and dabigatran (HR: 0.64, 95% CI: 0.50–0.80) were associated with lower bleeding risks than phenprocoumon, whereas the risk was similar for rivaroxaban and phenprocoumon. All three NOACs showed reduced risk of intracranial bleeding compared with phenprocoumon. Reduced doses of NOACs were predominantly used in patients with advanced age and comorbidities with generally similar effectiveness and safety benefits compared with phenprocumon as standard-dose NOACs.

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