Direct Oral Anticoagulants Dosing Research Articles

Long-Term Efficacy and Safety of Direct Oral Anticoagulants at Reduced Doses in the Secondary Prevention of Venous Thromboembolism and Post-Thrombotic Syndrome.

Background: Anticoagulation for venous thromboembolism (VTE) is required for at least three to six months; however, it is advisable to extend the duration in certain cases, in which case a reduced dose of Direct Oral Anticoagulants (DOACs) may be an option. Our objective was to investigate the efficacy and safety of reduced-dose DOACs in extended anticoagulation treatment compared to full doses. Methods and Results: This retrospective single-centre study included 185 patients treated with DOACs for at least 6 months who were divided into two groups: (1) the Full Dose (FD) group (n = 113) and (2) the Reduced Dose (RD) group (n = 72), which included patients treated with Apixaban at 2.5 mg bis in die (BID) and Rivaroxaban at 10 mg once daily (OD). Post-thrombotic syndrome (PTS) and its progression were evaluated. During an overall follow-up of 48.32 ± 29.49 months, no VTE occurred, and no patients experienced major bleeding; clinically relevant non-major bleeding occurred in three patients in each group (2.7% vs. 4.2% in FD vs. RD, respectively, p = 0.57). From baseline to follow-up, the prevalence of PTS was not significantly decreased in either group (FD: 54.9% vs. 51.3%, p = 0.29; RD 51.4% vs. 44.4%, p = 0.12); conversely, the Villalta score values were significantly decreased at the last follow-up (FD: 5.51 ± 4.18 vs. 5.51 ± 4.18, p < 0.001; RD 5.49 ± 4.06 vs. 5.11 ± 3.73, p = 0.006). Conclusion: In this real-world retrospective registry, very long-term extended anticoagulant therapy with DOACs at full or reduced doses showed comparable efficacy, safety, and impact on PTS progression. Larger studies are needed.

Appropriateness of antithrombotics in geriatric inpatients with atrial fibrillation: a retrospective, cross-sectional study

BackgroundAtrial fibrillation occurs in nearly half of geriatric inpatients and is a major cause of morbidity and mortality. Suboptimal anticoagulation use is an important concern in this population. This study...

Inappropriate Underdosing of Direct Oral Anticoagulants in Atrial Fibrillation Patients: Results from the START2-AF Registry.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients' demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2-2.0), major bleedings (RR 1.8; 95% CI 1.3-1.7), and mortality (RR 2.8; 95% CI 1.9-4.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight <60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events.

Use of Direct Oral Anticoagulants Among Patients With Hip Fracture Is Not an Indication to Delay Surgical Intervention.

To compare outcomes in patients on direct oral anticoagulants (DOACs) treated within 48 hours of last preoperative dose with those with surgical delays >48 hours. Retrospective cohort study. Three academic Level 1 trauma centers. Patients 65 years of age or older on DOACs before hip fracture treated between 2010 and 2018. Patients were excluded if last DOAC dose was >24 hours before admission, patient suffered from polytrauma, and/or delay to surgery was not attributed to DOAC. Primary outcome measures were the postoperative complication rate as determined by diagnosis of deep venous thrombosis or pulmonary embolus, wound breakdown, drainage, or infection. Secondary outcomes included transfusion requirement, perioperative bleeding, length of stay, reoperation rates, readmission rates, and mortality. Two hundred five patients were included in this study, with a mean cohort age of 81.9 years (65-100 years), 64% were (132/205) female, and a mean Charlson Comorbidity Index of 6.4 (2-20). No significant difference was observed among age, sex, Charlson Comorbidity Index, or fracture pattern between cohorts (P > 0.05 for all comparisons). Seventy-one patients had surgery <48 hours after final preoperative DOAC dose; 134 patients had surgery >48 hours after. No significant difference in complication rate between the 2 cohorts was observed (P = 0.30). Patients with delayed surgical management were more likely to require transfusion (OR 2.39, 95% CI, 1.05-5.44; P = 0.04). Patients with early surgical management had significantly shorter lengths of stay (5.9 vs. 7.6 days, P < 0.005). There was no difference in estimated blood loss, anemia, reoperations, readmissions, 90-day mortality, or 1-year mortality (P > 0.05 for all comparisons). Geriatric patients with hip fracture who underwent surgical management within 48 hours of their last preoperative DOAC dose required less transfusions and had decreased length of stay, with comparable mortality and complication rates with patients with surgery delayed beyond 48 hours. Providers should consider early intervention in this population rather than adherence to elective procedure guidelines. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Minimally invasive left atrial appendage occlusion plus reduced dose direct oral anticoagulant to prevent stroke in patients with atrial fibrillation-the LAAO-PlusRE.

The onset of atrial fibrillation (AF) has a direct association with left atrial appendage (LAA) function, as demonstrated by recent studies demonstrating the link between left atrial (LA) wall fibrosis, impaired contractility, and the development of AF. Non-valvular AF (NVAF) affects almost 30 million people worldwide, with this number expected to increase in the next 20 years. It is the main cause of ischemic stroke, with significant subsequent economic and social impact. Currently, the mainstay of stroke prevention in patients with NVAF is oral anticoagulation (OAC), which reduces the incidence of ischemic events at the stake of increased hemorrhagic events. Despite the introduction and widespread use of direct oral anticoagulants (DOACs), which almost completely replaced vitamin K antagonists (VKAs), the adherence to OAC is still low, hindering the efficacy of stroke prevention. Percutaneous LAA occlusion (LAAO) is now indicated (class IIB) in patients with NVAF at increased ischemic risk who cannot undergo OAC. Recently published data demonstrated that a reduced dose of DOAC after percutaneous LAAO is superior to long-term dual antiplatelet therapy (DAPT) for stroke prevention in the mid-term. One of the possible pitfalls of percutaneous LAAO is postprocedural peri-device leaks (PDLs) that have been associated with increased thromboembolic events. According to LAAOS III results, surgical LAAO during cardiac surgery brings a 33% reduction in risk of stroke at five years, independently from the OAC regimen with a high rate of complete appendage occlusion. The combination of surgical LAAO and reduced dose DOAC might ensure adequate embolic prevention, lowering the hemorrhagic risk. The present manuscript aims to describe the rationale and design of the Minimally Invasive Left Atrial Appendage Occlusion Plus REduced Dose DOAC To Prevent Stroke In Patients With Atrial Fibrillation Randomized Clinical Trial (LAAO-PlusRE).

Unapproved Dose of Direct Oral Anticoagulants for Venous Thromboembolism　- Right or Wrong?

Unapproved Dose of Direct Oral Anticoagulants for Venous Thromboembolism　- Right or Wrong?

Assessment and predictors of inappropriate dose of direct oral anticoagulants

Direct-Acting Oral Anticoagulants (DOACs) have revolutionized the management of Atrial Fibrillation (AF) and Venous Thromboembolism (VTE). However, recent audits reveal a significant burden of inappropriate dosages in the prescribing of direct-acting oral anticoagulants. Our aim is to identify the prevalence and predictors of such inappropriate dosing in our patients. This retrospective study was conducted from June 2016 to January 2018. Patients who received dabigatran, rivaroxaban, or apixaban for treatment of venous thromboembolism or atrial fibrillation were included. Appropriateness of direct-acting oral anticoagulants dosing was assessed using US Food and Drug Administration guidelines. Data was analyzed using IBM® SPSS Version 26. 337 patients were included, with a mean age of 62.9±18.7 years. The majority were female (196, 58.3%). Of the patients, 194 (57.6%) received apixaban, 99 (29.4%) received rivaroxaban, and 44 (13.1%) received dabigatran. A total of 242 (71.8%) patients were prescribed direct-acting oral anticoagulants appropriately. Under-dosing and over-dosing were identified in 74 (22%) and 21 (6.2%) patients, respectively. Predictors of inappropriate dosing were age greater than 75 years (OR: 2.76, 95% CI: 1.67-4.56, p&lt;0.001) and creatinine clearance less than 50 ml/minute (OR: 0.38, 95% CI: 0.19-0.74, p: 0.005). Inappropriate dosing was significantly associated with mortality (p=0.010).One-third of our patients received an inappropriate dose of direct-acting oral anticoagulants, mostly from underdosing. Elderly age and low creatinine clearance are significant predictors of inappropriate dose administration.

Comparison of different direct oral anticoagulant regimens in atrial fibrillation patients with high bleeding risk

BackgroundThe optimal dose of direct oral anticoagulants (DOACs) to prevent ischemic stroke (IS) and systemic thromboembolism (STE) in atrial fibrillation (AF) patients with a predisposing bleeding risk remains unclear. ObjectiveThe purpose of this study was to compare the effectiveness and safety of different DOAC dosage regimens in AF patients with high bleeding risk but low thrombosis risk. MethodsThis retrospective observational study was conducted with the National Health Insurance claims database in Taiwan to include AF patients aged 20 up to 75 years, under DOAC therapy, with CHA2DS2-VASc score of 1 for males and 2 for females and HAS-BLED score ≥3. Standard-dose regimen was defined as dabigatran 300 mg, rivaroxaban 20 mg, apixaban 10 mg, or edoxaban 60 mg per day. Any other lower-dose regimen were defined as the low-dose regimen. The primary outcomes were IS and major bleeding (MB). The secondary outcomes were STE, gastrointestinal bleeding, intracranial hemorrhage, and cardiovascular death. ResultsA total of 964 patients were included (52.1% standard-dose regimen). Median HAS-BLED score was 3 [interquartile range 3–3]. Compared with standard-dose group, patients in the low-dose group had a significantly increased risk of IS (adjusted hazard ratio [aHR] 5.13; 95% confidence interval 1.37–19.22) and STE (aHR 3.14 [1.05–9.37]) but similar risk of MB (aHR 0.45 [0.12–1.67]). The risks of other hemorrhage and cardiovascular death were similar between the 2 dose groups. ConclusionAmong patients with a predominant bleeding risk but relatively low thrombosis risk, the low-dose DOAC regimen is not a more appropriate selection than standard-dose regimen.

Challenges to Laboratory Monitoring of Direct Oral Anticoagulants.

Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels-in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups.

Anticoagulation management in elderly patients with proximal femur fractures- overview of current concepts.

Proximal femur fractures (PFF) are common injuries in elderly patients and can have considerable effects on their quality of life, morbidity, and mortality. Due to pre-existing comorbidities, the prevalence of anticoagulated patients is increasing. The right timing for surgery and perioperative anticoagulation treatment remains controversial. This overview aims to summarize current practices in the pre- and postoperative anticoagulation management and the recommended time to surgery in elderly patients with PFF. Time to surgery for anticoagulated patients is often prolonged due to worries about serious perioperative bleeding and higher transfusion demands. But the delay of surgical PFF treatment increases the risk for perioperative complications like pulmonary embolism, pneumonia, deep vein thrombosis and urinary tract infections. Early surgery can be achieved with a consistent and interdisciplinary perioperative anticoagulation management. Antiplatelets do not have to be discontinued and surgery should be performed early without delay. For patients taking vitamin K antagonists (VKA) an INR less than 1.5 is recommended prior to surgery, which can be achieved by pausing VKA intake or by administering vitamin K, prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP). For the treatment with direct oral anticoagulants (DOAC) a plasma drug level of under 50 pg/mL is considered safe for surgery. If the plasma level can not be determined, a gap of 24 h between the last DOAC dose and surgery is recommended. The systemic administration of tranexamic acid can reduce overall blood loss and transfusion rates in anticoagulated patients with PFF. Surgical treatment of PFF should be performed within 24 h, as delayed surgery increases the risk for perioperative complications. This also applies to anticoagulated patients, when clinically appropriate. International and interdisciplinary guidelines are necessary to ensure early and appropriate treatment of anticoagulated elderly patients with PFF.

Effectiveness of Early Direct Oral Anticoagulant Monotherapy within One Year of Coronary Stent Implantation in Patients with Atrial Fibrillation: A Nationwide Population-Based Study

We evaluated the effectiveness of early direct oral anticoagulant (DOAC) monotherapy within one year after percutaneous coronary intervention (PCI) in patients with atrial fibrillation (AF) using Korean National Health Insurance Service data. AF patients who underwent PCI were included and divided into the DOAC monotherapy group and the combination therapy group (DOAC with an antiplatelet agent) based on the medications used at 6 months after PCI. A major adverse cardiovascular event (MACE) was defined as a composite of cardiovascular death, acute myocardial infarction (AMI), stroke, or systemic thromboembolic event between 6 and 12 months after PCI. In the overall study population, the DOAC dose reduction rate was high in both the monotherapy group (70.8%) and the combination therapy group (79.1%). After propensity score matching, the MACE incidence was not significantly different between the two groups (hazard ratio [HR] 1.42 [0.90–2.24]). The numerical trend for higher MACE in the monotherapy group was mainly driven by the difference in stroke incidence (HR 1.84 [0.97–3.46]). All-cause death (HR 1.29 [0.61–2.74] or the incidence of major bleeding (HR 1.07 [0.49–2.35]) results were similar in the two groups. In conclusion, early DOAC monotherapy was not significantly associated with MACE risk between 6 and 12 months after PCI.

Surveillance reports to identify duplicate anticoagulant prescribing

Abstract Introduction A number of patients admitted to hospital on direct oral anticoagulants (DOACs) are often switched to low molecular weight heparin (LMWH) for a limited period of time as part of their clinical management. Electronic prescribing systems (EPMA) allow DOACs to be suspended temporarily and then re-started when clinically indicated. However the system does not generate an alert when DOACs are re-started, leading to unintentional co-prescribing of LMWH which could lead to severe patient harm.1,2 Aim To determine whether anticoagulation surveillance reports reduce the number of inappropriate duplicate anticoagulation prescriptions. Methods A retrospective review of duplicate anticoagulation errors was carried out between September 2017 and March 2022 across the 3 main Royal Cornwall hospital sites. Data on all anticoagulant administrations and the administration time was collected from EPMA via Crystal Reporting pre and post intervention with each period covering 831 days. Data was analysed using Excel. As part of the intervention, surveillance reports were set up in December 2019 to identify patients who were prescribed both LMWHs and DOACs. Reports were generated twice a day, 7 days a week and reviewed for patients who were prescribed both LMWHs and DOACs. The ward pharmacists were then alerted of co-prescribing to complete the necessary interventions. As this project falls under the definition of a service evaluation, according to UK NHS Research Ethics Committees, formal ethical approval was not required. This project was registered on the hospital’s clinical audit database. Results 948,036 doses of LMWH and DOACs were administered (September 2017 to March 2022) with 817 duplicate prescribing identified, a 0.09% error rate. The longest time on duplicate therapy was dramatically reduced pre and post intervention from 322 hrs to 36 hrs with mean number of hours reduced from 14.03 to 8.07. The number of patients receiving more than two doses of co-prescribed LMWH and DOAC before the error was rectified, also reduced from 56 (pre-intervention) to 30 (post-intervention). Likewise, the average duration of more than 2 doses of co-prescription reduced from 48.3 to 18.7 hours before the error was corrected. Discussion/Conclusion Some limitations of the study are that staffing is more limited on weekends which may have prevented pharmacists actioning these alerts over weekends. Data will only include anticoagulants prescribed on EPMA so excludes some infusions such as unfractionated heparin. Timestamps associated with administrations on EPMA are user-entered so may not be exact to the time given. Although EPMA generates an alert when patients on DOACs are prescribed LMWHs, it does not provide a similar alert when suspended DOACs are re-started. EPMA providers are planning to develop alerts to correct this. In the interim we have shown that surveillance reports capture co-prescribing of DOACs and LMWH at an earlier stage preventing potential serious patient harm. It also allows for pharmacists to educate prescribers on risks of anticoagulation co-prescribing. This report is now routine practice, including additional monitoring - patients on warfarin, fondaparinux, LMWH prescribed twice daily and INR levels. We will re-evaluate to include new parameters.

Extended Full Dose Versus Low Dose Direct Oral Anticoagulants in Cancer and Overweight Patients

Background: Reduced or low-dose direct oral anticoagulants (DOACs) have been studied in randomized control trials for the extended prevention of venous thromboembolism (VTE) after 6 months of treatment at full, therapeutic doses. The real-world effectiveness as well as utilization of this approach in clinical practice compared to continuing at therapeutic doses is unclear. Aims: Examine the effectiveness, safety and utilization of reduced-dose DOACs in cancer patients and overweight patients. Methods: Consecutive patients with VTE were identified using the Mayo Clinic VTE Registry from March 1st, 2013 to December 31st, 2021. Patients were followed prospectively for outcomes of VTE recurrence, death, major bleeding and clinically relevant non major bleeding (CRNMB) either in person or by survey. Patients with recurrent VTE or bleeding during the first 3 months were excluded from further analysis. After completion of anticoagulation treatment for 3 months with either rivaroxaban or apixaban, patients continuing anticoagulation were evaluated in a nested case-control study. Results: A total of 404 patients (283 (70%) on apixaban and 121 (30%) on rivaroxaban) were identified in the low dose DOAC and 3060 in the full dose anticoagulation group. Overall, the mean age was 60.7 years (SD 14.4), mean weight was 89.9 kg (SD 23.8) and 55.1% were males. Within the full cohort, patients with active cancer were less likely to be prescribed low dose DOACs (HR 0.56; 95%CI 0.42-0.73; p&amp;lt;0.001). However, low dose DOAC prescription was more likely in patients with pulmonary embolism alone (HR 1.48; 95%CI 1.21-1.80; p&amp;lt;0.001) or in combination with DVT (HR 1.54; 95%CI 1.25,1.90; p&amp;lt;0.001). Patients transitioned to low dose DOACs had similar age, sex and weight compared to the full dose anticoagulation group, however, fewer patients with weight ≥120 kg had reduced dosing (HR 0.68; 95%CI 0.46,0.99; p=0.046). The mean time to start of a low dose DOAC was 5.1 months overall, 5.4 months in cancer patients, and 3.6-4.9 months in non-cancer patients (Table 1). Non-cancer patients had significantly lower transition numbers in those ≥120kg (HR 0.62; 95%CI 0.40,0.97; p=0.038). In non-cancer patients In comparing weight, ≥120kg to &amp;lt;120kg, in the low dose group, only death was statistically different with higher risk in those ≥120kg (HR 6.44; 95%CI1.27,32.81; p=0.025). Cancer patients transitioned to low dose DOACs around 5 months on average with a median of 3.3 months. Apixaban continued to be the dominant DOAC used (78%) in the low dose group. The cancers with the most patients on low dose DOACs include lymphoma, prostate, melanoma, ovarian, and breast. There was no significant difference in VTE recurrence or death in the cancer group on different DOAC doses. Conclusion: Our results show that anticoagulant prescribers are not always waiting until 6 months to transition to low doses and low doses are being utilized in cancer patients despite lack of cancer-specific studies during the analyzed time period. Although the sample size limits the precision of this analysis, we did not find statistically significant increases in VTE recurrence with low dose DOACs in either cancer patients or with elevated body weight. We did find CRNMB but not MB was observed more frequently in weights above 120kg, possibly from unadjusted confounding in this unadjusted analysis.

Time-in-therapeutic-range defined warfarin and standard dose direct oral anticoagulants in atrial fibrillation: Ischemic stroke, intracranial hemorrhage and death in a nationwide registry study

Abstract Background and aims Direct oral anticoagulants (DOACs) have almost replaced warfarin in stroke prevention of patients with atrial fibrillation (AF). However, little is known whether DOACs are more efficacious or safer than warfarin having information on time-in-therapeutic-range (TTR) in the warfarin-treated patients. Methods The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide study of AF patients combining data from several Finnish health care registers. We analyzed all new-onset AF patients from 2011 to 2018 with available laboratory data. The rates of ischemic stroke (IS), intracranial hemorrhage (ICH) and mortality during oral anticoagulation (OAC) use were analyzed until maximum follow-up of 730 days. Confounding factors by baseline characteristics as well as medications were taken into account by an inverse probability of treatment weighted analysis. For warfarin users, TTR was calculated and patient quartiles by TTR were assigned. The rates of IS, ICH and mortality in TTR quartiles for warfarin users were compared to standard dose dabigatran (150 mg bd.), apixaban (5mg bd.) and rivaroxaban (20mg od.). Results Altogether, 73 469 new-onset AF patients with OAC therapy (50.4 % male, mean age 73.0 years, 43 548 on warfarin, with mean TTR 66% and median TTR 72%) were followed for 76 546 patient years (py). The rate of IS among patients with standard dose DOACs was 0.73/100 py for dabigatran (n=4 545)[HJK1] , 1.05/100 py for apixaban (n=12 426) and 0.83/100 py for rivaroxaban (n=12 950). In the TTR quartiles of patients on warfarin, rates of IS were 3.5, 1.8, 1.2 and 0.74/100 py from the lowest (mean TTR 32%) to the highest quartile (mean TTR 90%), respectively. The weighted rates of IS were 1.3, 1.1 and 0.87/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.2, 1.7, 1.2 and 0.7/100 py. The respective rates of ICH were 0.47, 0.62 and 0.67/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.6, 0.99, 0.51 and 0.32/100 py. The weighted rates of ICH were 0.70, 0.65 and 0.73/100 py for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 3.4, 0.96, 0.51 and 0.30/100 py. For mortality, the raw incidence rates were 1.2, 2.8 and 2.1/100 py for for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 16.5, 5.3, 2.3, and 1.5/100 py. The weighted rates were 1.6, 2.9, and 2.6, for dabigatran, apixaban and rivaroxaban, and for warfarin from the lowest to the highest quartile: 14.6, 4.8, 2.0, and 1.3/100 py. The Figures provide cumulative incidence of IS and total mortality (crude rates) of the analyzed OAC groups. Conclusions The rates of IS, ICH and mortality were highest among patients on warfarin in the two lowest TTR quartiles, whereas the differences between high TTR groups and standard dose DOACs were only modest.Cumulative incidence of ischemic strokeCumulative mortality rate

Abstract 13741: Off-Label Dosing of Direct Oral Anticoagulants Among Inpatients With Atrial Fibrillation

Introduction: Among patients hospitalized for atrial fibrillation (AF), the frequency of off-label direct oral anticoagulant (DOAC) dosing, associated factors, hospital-level variation, and temporal trends in contemporary practice are unknown. Methods: Using the Get With The Guidelines® Atrial Fibrillation (GWTG-AF) registry, patients admitted from January 1 st , 2014 to March 31 st , 2020, and discharged on DOAC were stratified according to receipt of under, over, or recommended dose. Factors associated with off-label dosing were identified using logistic regression. Hospital-level variation and temporal trends were assessed. Results: Of 22,470 patients prescribed a DOAC at discharge from hospitalization (66% apixaban, 29% rivaroxaban, 5% dabigatran), underdosing occurred among 2006 (8.9%), overdosing among 511 (2.3%), and recommended dosing among 19953 (88.8%). Patient factors associated with off-label use included age (underdosing: OR 1.06 per 1-year increase [95% CI 1.06-1.07] and overdosing: OR 1.07 per 1-year increase [1.06-1.09]), dialysis dependence (underdosing: OR 5.50 [3.76-8.05] and overdosing: OR 5.47 [2.74-10.88]), female sex (overdosing: OR 0.79 [0.63-0.99]) and weight (overdosing: OR 0.96 per 1-Kg increase [0.95-1.00]). Across hospitals, the adjusted median odds ratio for off-label DOAC use was 1.45 [95% CI 1.34-1.65] (underdosing: 1.52 [1.39-1.76] and overdosing: 1.32 [1.20-1.84]), indicating significant hospital-level variation. Hospital characteristics associated with underdosing included West vs. Northeast location (OR: 1.55 [1.04-2.31]), rural vs. urban setting (OR: 0.48 [0.28-0.83]), and number of beds (&lt;200 vs. 500+, OR: 1.95 [1.29-2.95]). Recommended dosing significantly increased over time (81.9% in 2014 to 90.9% in 2020, p&lt;0.0001 for trend) with a corresponding decline in under (14.4% in 2014 to 6.6% in 2020, p&lt;0.0001 for trend) and overdosing (3.8% in 2014 to 2.5% in 2020, p=0.001 for trend). Conclusion: One of 10 patients hospitalized for atrial fibrillation is discharged on off-label dosing of DOAC with significant variation across hospitals. While the proportion of patients receiving recommended dosing has significantly improved over time, opportunities to improve DOAC dosing persist.

Off-Label Dosing of Direct Oral Anticoagulants Among Inpatients With Atrial Fibrillation in the United States.

Among patients hospitalized for atrial fibrillation, the frequency of off-label direct oral anticoagulant (DOAC) dosing, associated factors, hospital-level variation, and temporal trends in contemporary practice are unknown. Using the Get With The Guidelines-Atrial Fibrillation registry, patients admitted from January 1, 2014, to March 31, 2020, and discharged on DOACs were stratified according to receipt of underdosing, overdosing, or recommended dosing. Factors associated with off-label dosing (defined as underdosing or overdosing) were identified using logistic regression. Median odds ratio (OR) and time-series analyses were used to assess hospital-level variation and temporal trends, respectively. Of 22 470 patients (70.1±12.1 years, 48.1% female, 82.5% White) prescribed a DOAC at discharge from hospitalization for atrial fibrillation (66% apixaban, 29% rivaroxaban, and 5% dabigatran), underdosing occurred among 2006 (8.9%), overdosing among 511 (2.3%), and recommended dosing among 19 953 (88.8%). The overall rate of off-label dosing was 11.2%. Patient-related factors associated with off-label dose included age (underdosing: OR, 1.06 per 1-year increase [95% CI, 1.06-1.07]; overdosing: OR, 1.07 per 1-year increase [95% CI, 1.06-1.09]), dialysis dependence (underdosing: OR, 5.50 [95% CI, 3.76-8.05]; overdosing: OR, 5.47 [95% CI, 2.74-10.88]), female sex (overdosing: OR, 0.79 [95% CI, 0.63-0.99]), and weight (overdosing: OR, 0.96 per 1-kg increase [95% CI, 0.95-1.00]). Across hospitals, the adjusted median OR for off-label DOAC dose was 1.45 (95% CI, 1.34-1.65; underdosing: OR, 1.52 [95% CI, 1.39-1.76]; overdosing: OR, 1.32 [95% CI, 1.20-1.84]), indicating significant hospital-level variation. Over the study period, recommended dosing significantly increased over time (81.9%-90.9%; P<0.0001 for trend) with a corresponding decline in underdosing (14.4%-6.6%; P<0.0001 for trend) and overdosing (3.8%-2.5%; P=0.001 for trend). Over 1 in 10 patients hospitalized for atrial fibrillation are discharged on an off-label DOAC dose with significant variation across hospitals. While the proportion of patients receiving recommended dosing has significantly improved over time, opportunities to improve DOAC dosing persist.

Benefits and Harms of Standard Versus Reduced-Dose Direct Oral Anticoagulant Therapy for Older Adults With Multiple Morbidities and Atrial Fibrillation.

Background Dose reduction of direct oral anticoagulant (DOAC) medications is inconsistently applied to older adults with multiple morbidities, potentially due to perceived harms and unknown benefits of standard dosing. Methods and Results Using 2013 to 2017 US Medicare claims linked to Minimum Data Set records, we conducted a retrospective cohort study. We identified DOAC initiators (apixaban, dabigatran, rivaroxaban) aged ≥65 years with nonvalvular atrial fibrillation residing in a nursing home. We estimated inverse-probability of treatment weights for DOAC dose using propensity scores. We examined safety (hospitalization for major bleeding) and effectiveness outcomes (all-cause mortality, thrombosis [myocardial infarction, stroke, systemic embolism, venous thromboembolism]). We estimated hazard ratios (HRs) and 95% CIs using cause-specific hazard-regression models. Of 21 878 DOAC initiators, 48% received reduced dosing. The mean age of residents was 82.0 years, 66% were female, and 31% had moderate/severe cognitive impairment. After estimating inverse-probability of treatment weights, standard dosing was associated with a higher rate of bleeding (HR, 1.18 [95% CI, 1.03-1.37]; 9.4 versus 8.0 events per 100 person-years). Standard-dose therapy was associated with the highest rates of bleeding among those aged >80 years (9.1 versus 6.7 events per 100 person-years) and with a body mass index <30 kg/m2 (9.4 versus 7.4 events per 100 person-years). There was no association of dosing with mortality (HR, 0.99 [95% CI, 0.96-1.06]) or thrombotic events (HR, 1.16 [95% CI, 0.96-1.41]). Conclusions In this nationwide study of nursing home residents with nonvalvular atrial fibrillation, we found a higher rate of bleeding and little difference in effectiveness of standard versus reduced-dose DOAC treatment. Our results support the use of reduced-dose DOACs for many older adults with multiple morbidities.

Safety of Direct Oral Anticoagulants for Gastrointestinal Hemorrhage in Patients With Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-analysis of Real-world Studies.

Since the introduction of Direct Oral Anticoagulants (DOACs), "real-world" studies have investigated their safety profile on gastrointestinal hemorrhage (GIH) when used by patients with Non-Valvular Atrial Fibrillation. We performed a systematic review and meta-analysis to compile and summarize this data after Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Medline and Embase were systematically searched until April 2021. Observational studies that met predefined inclusion criteria were included and hazard ratios (HRs) with 95% CI were extracted. Subgroup analyses based on DOAC doses, history of chronic kidney disease, stroke, prior exposure to VKA (vitamin K antagonist), age, gender, geographic location of population samples, as well as Leave-One-Out and Low/Moderate Risk of Bias sensitivity analyses were performed. A random effects model was used. A total of 46 studies were included. Apixaban was associated with a reduced risk of GIH compared with Dabigatran (HR: 0.67, 95% CI, 0.56 to 0.81, I2 : 53.28%), Rivaroxaban (HR: 0.56, 95% CI, 0.44 to 0.70, I2 : 79.17%), and VKA (HR: 0.68, 95% CI, 0.60 to 0.78, I2 : 71.93%). Rivaroxaban was associated with increased GIH risk compared with Dabigatran (HR: 1.19, 95% CI, 1.02 to 1.40, I2 : 72.96%) and VKA (HR: 1.16, 95% CI, 1.05 to 1.27, I2 : 81.95%). Dabigatran was associated with similar GIH risk compared with VKA (HR: 1.11, 95% CI, 0.98 to 1.26, I2 : 87.28%). Our study shows that Apixaban was associated with a reduction in GIH risk compared with Dabigatran, Rivaroxaban and VKA, whereas Rivaroxaban was associated with an increase in GIH risk compared with both Dabigatran and VKA.

Inappropriate dosing of direct oral anticoagulants: findings from a clinical vignette study and physician survey

ABSTRACT Objective Direct oral anticoagulants (DOACs) are first-line therapy for stroke prevention for 1.4 million atrial fibrillation (AF) patients in the UK. However, the rates of DOAC dosing below evidence-based recommendations are estimated between 9% and 22%. This study explores specific patient and physician factors associated with prescribing inappropriate DOAC underdoses. Methods DOAC-prescribing physicians within the UK completed both a clinical vignette survey, which contained 12 hypothetical patient profiles designed to replicate DOAC prescribing scenarios, and a physician survey to capture sociodemographic, clinical experience, and prescriber-related beliefs and motivations related to DOAC prescribing. Eight patient factors based on a literature search and an expert consultation process were varied within the vignettes. Associations between the prescribers’ dosing choices and patient factors were explored via multilevel logistic regression. The analysis is focused on the most frequently selected DOACs, apixaban and rivaroxaban, both of which have different dosing guidelines. Results In all, 336 prescribers (69% male; 233/336) completed the survey, mostly general physicians (GPs) (45%) or cardiology specialists (36%) with a mean of 17.9 years’ experience. Most prescribers (73%; 244/336) inappropriately underdosed at least once; rates between GPs and specialists were nearly identical. Patient factors most strongly associated with apixaban inappropriate underdosing included a history of major bleeding and falls. For rivaroxaban, these were major bleeding and severe frailty. Only 32% (106/335) of prescribers reported DOAC dosing guidelines as the sole influence on their prescribing behaviour. Among prescribers who did not inappropriately underdose, greater prescribing confidence was aligned to increased perception of inappropriate underdose risk. Conclusions Overall, patient factors such as major bleeding and severe frailty were found to be associated with inappropriate underdosing of apixaban and rivaroxaban. Furthermore, prescribers who were more confident in DOAC prescribing, and were more worried about the risk of stroke, were significantly less likely to inappropriately underdose. These findings suggest that all prescribers, regardless of speciality, may benefit from education and training to raise awareness of the risks associated with inappropriate DOAC underdosing.

Characteristics of patients with atrial fibrillation treated with direct oral anticoagulants and new insights into inappropriate dosing: results from the French National Prospective Registry: PAFF.

Since the introduction of direct oral anticoagulant (DOAC) for atrial fibrillation (AF) therapy, inappropriate and/or underdosing of these drugs has been a major clinical challenge. We evaluated the characteristics of patients with AF treated with inappropriate and low-dose DOACs. Patients with AF treated with inappropriate and low-dose DOACs from October 2021 to December 2021 were evaluated from the French National Prospective Registry (PAFF). We evaluated 1890 patients with AF receiving DOACs (apixaban 55%, dabigatran 7%, and rivaroxaban 38%). Inappropriate dosing was noted in 18% of the population. Patients with appropriate dosing had less comorbidities: younger age (75 ± 10 vs. 82 ± 8 years old, P < 0.0001), reduced chronic renal failure (26 vs. 61%, P < 0.0001), and lower CHA2DS2VASc and HASBLED scores (3 ± 2 vs. 4 ± 3, P < 0.0001; 2 ±1 vs. 2 ± 2, P < 0.0001), respectively. In multivariate analysis, older age (P < 0.0001) and a higher CHA2DS2VASc score (P = 0.0056) were independently associated with inappropriate DOAC dosing. Among 472 patients (27%) treated with low-dose rivaroxaban or apixaban, 46% were inappropriately underdosed. Patients inappropriately underdosed were younger (82.3 ± 8.4 vs. 85.9 ± 5.9 years, P < 0.0001) with less chronic renal disease (47 vs. 98%, P < 0.0001). However, these patients had higher rates of prior haemorrhagic events (18 vs. 10%, P = 0.01), clopidogrel use (11 vs. 3%, P = 0.0002), and apixaban prescription (74 vs. 50%, P < 0.0001). Within this large registry, DOACs were associated with inappropriate dosing in 18% of cases. Independent predictors of inappropriate dosing were high CHA2DS2VASc scores and older age. Moreover, 46% of patients treated with low-dose DOACs were inappropriately underdosed and more frequently in patients treated with apixaban.