Effectiveness and Safety of Off-Label Dose-Reduced Direct Oral Anticoagulants in Atrial Fibrillation

Arbel, Ronen; Sergienko, Ruslan; Hammerman, Ariel; Greenberg-Dotan, Sari; Batat, Erez; Avnery, Orly; Ellis, Martin

doi:10.1016/j.amjmed.2019.01.025

Cited by 78 publications

(90 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, approved prescribing information indicates that DOAC doses should be individualized based on weight, renal function, age, and concomitant medications 1,5-7. Previous studies have examined prescribing patterns and off-label DOAC dosing in various settings 1,8-12. Off-label dosing is defined as any dose that is inconsistent with approved prescribing information.…”

Section: Introductionmentioning

confidence: 99%

Real-world study of direct oral anticoagulant dosing patterns in patients with atrial fibrillation

Gustafson¹,

Saunders²,

Vazquez³

et al. 2019

Pharm Pract (Granada)

View full text Add to dashboard Cite

Background:Direct oral anticoagulants (DOACs) are preferred for stroke prevention in atrial fibrillation (AF). However, off-label doses have been associated with increased risk of adverse events.Objective:The objective of this study was to compare the frequency and outcomes of labeled versus off-label DOAC dosing in patients with AF.Methods:This retrospective cohort study included adults diagnosed with nonvalvular AF (NVAF), discharged from University of Utah Health on DOAC therapy between 7/1/2017 and 9/30/2017. The primary outcome was off-label DOAC dosing frequency, defined as dosing inconsistent with manufacturer labeling. Secondary outcomes included variables associated with off-label dosing and a composite of adverse events (major bleeding, thromboembolism, and all-cause mortality) in the 90 days following the index hospital discharge.Results:Of 249 included patients, 16.1% were discharged with off-label dosing. Factors associated with off-label dosing included advanced age, lower body mass index, decreased renal function, use of rivaroxaban, and hepatic impairment. The majority of off-label patients (70%) received lower-than-recommended DOAC dosing. Prescriber rationale for off-label prescribing was documented in 25% of patients and included anti-Xa guided dosing, high risk for bleeding or thromboembolism, and prior history of on-therapy adverse events. The rate of adverse events between labeled and off-label DOAC doses was not statistically different (10.0% vs. 6.7%, p=0.299), although this is likely due to small sample size.Conclusions:Off-label DOAC prescribing for stroke prevention in NVAF at University of Utah Health was consistent or lower than previously published studies. Off-label dosing most often involved under-dosing of rivaroxaban. Future research should investigate the role of provider rationale and insight in optimizing DOAC therapy outcomes.

show abstract

Section: Introductionmentioning

confidence: 99%

Real-world study of direct oral anticoagulant dosing patterns in patients with atrial fibrillation

Gustafson¹,

Saunders²,

Vazquez³

et al. 2019

Pharm Pract (Granada)

View full text Add to dashboard Cite

show abstract

“…This, despite numerous studies that have shown no benefit and possible harm in lacking treatment or unwarranted reduced-dose DOAC. 19,27,28 In our study, there was a 29.3% increase in adequate treatment between admission to discharge from hospitalization (from 34.4% to 44.5%), demonstrating that hospitalization due to any cause may serve as an effective intervention point for correction of errors in AC treatment, and plausibly other medication types as well. Disappointingly, our data also show that there is a substantial number of patients that are either admitted and discharged with an error in AC treatment (46.9% of patients) or are discharged with a de novo error in AC F I G U R E Study cohort derivation process.…”

Section: Discussionmentioning

confidence: 50%

Hospitalization as an opportunity to correct errors in anticoagulant treatment in patients with atrial fibrillation

Angel

Zeltser

Berliner

et al. 2019

Brit J Clinical Pharma

View full text Add to dashboard Cite

lant therapy among patients with atrial fibrillation (AF). Methods: Our cohort included patients admitted to our institution with a history of AF between 2016 and 2018. We categorized patient's treatment upon admission and discharge as lacking (no treatment despite indication), inadequate (according to individual characteristics) or adequate. We assessed adequacy of treatment upon discharge and determined factors associated with correcting admission errors. Results: Of 4427 patients admitted with a history of AF, the categorization to lacking, inadequate and adequate treatment was 1746 (39.4%), 1237 (27.9%) and 1444 (32.6%) patients, respectively. Of those with inadequate treatment, the most common types of errors were direct oral anticoagulant (DOAC) underdosing (n = 578; 46.7%), vitamin-K antagonists when DOAC was indicated (n = 258; 20.9%), DOAC despite contraindication to DOAC (n = 166; 13.4%) and DOAC overdosing (n = 124; 10%). Upon discharge 688 (18.6%, out of n = 3694) corrections but also 316 (8.6%) new mistakes were found. On multivariate logistic regression, the factors associated with correction of an error on admission were hospitalization due to AF (odds ratio [OR] 2.94 [2.39-3.61]), hospitalization in the neurologic or geriatric wards (OR 2.79 [2.04-3.80]), female sex (OR 1.34 [1.10-1.63]) and a history of stroke (OR 1.47 [1.17-1.86]), while the presence of a contraindication to DOAC decreased the chance of correction (OR 0.10 [0.06-0.18]). Conclusion: Hospitalization for any reason may contribute to correction of errors in AC treatment in patients with AF. Unfortunately, a significant portion of patients remains inadequately treated by both outpatient and inpatient providers.

show abstract

“…[23][24][25][26][27][28][29][30][31] In addition, our results indicate that in both observational and randomized studies, patients treated with the lower dose of apixaban demonstrate a consistent pattern of higher rates of both bleeding and mortality in addition to a higher rate of thromboembolic events. Several authors and guidance documents have advocated against the off-label use of the 2.5-mg dose, 23,29,[32][33][34][35][36] on the grounds that it is an important cause of the excess of S/SEE reported in observational studies and daily clinical practice. 23,29,[32][33][34] However, our findings provide an additional explanation and suggest that enrolment of patients with worse risk profiles in observational studies (vs. RCTs) is an important contributor to the high rates of thromboembolic events in those receiving the 2.5-mg dose of apixaban.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, several observational studies have reported that the 2.5-mg dose of apixaban is used much more frequently in clinical practice than in RCTs, 1,2,7,9,10,12,13,15,16,19,20 that approximately 50% of patients who receive this dose do not meet two or more of the ABC criteria (i.e., off-label use), [23][24][25][26][27][28][29][30][31] and that such use is associated with an increased risk of thromboembolic events. 23,29,[32][33][34] On these grounds, several authors and guidance documents advocate against the off-label use of the 2.5-mg dose in all patients. 23,29,[32][33][34][35][36] Based on the above considerations, we sought to determine the factors contributing to the higher thromboembolic event rates.…”

Section: Introductionmentioning

confidence: 99%

“…23,29,[32][33][34] On these grounds, several authors and guidance documents advocate against the off-label use of the 2.5-mg dose in all patients. 23,29,[32][33][34][35][36] Based on the above considerations, we sought to determine the factors contributing to the higher thromboembolic event rates. To achieve this aim, we estimated the prevalence of off-label use in contemporary practice, and compared baseline characteristics and rates of thromboembolic events, bleeding, and death in patients with AF by dose of apixaban (2.5 vs. 5 mg twice daily) and by study design (observational studies vs. RCTs).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?—A Systematic Review

Vries

Hirsh

et al. 2020

Thromb Haemost

View full text Add to dashboard Cite

Background Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients. Objectives To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis. Results and Discussion We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs. Conclusion The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

show abstract

Effectiveness and Safety of Off-Label Dose-Reduced Direct Oral Anticoagulants in Atrial Fibrillation

Cited by 78 publications

References 17 publications

Real-world study of direct oral anticoagulant dosing patterns in patients with atrial fibrillation

Real-world study of direct oral anticoagulant dosing patterns in patients with atrial fibrillation

Hospitalization as an opportunity to correct errors in anticoagulant treatment in patients with atrial fibrillation

Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?—A Systematic Review

Contact Info

Product

Resources

About