Doses Of Oral Anticoagulants Research Articles

Risk of major bleeding in elderly patients with atrial fibrillation on direct oral anticoagulants: real world experience.

Background The efficacy and safety of direct oral anticoagulants is well established in patients with atrial fibrillation. However, data on their use in the oldest old patients (≥ 85years), who have the highest risk of bleeding, is scarce. Objective The aim of this study was to evaluate the safety of direct oral anticoagulants in the oldest old patients with atrial fibrillation and assess the impact of age on major bleeding events. Setting Anticoagulation Clinic of the Department of Vascular Diseases, University Medical Centre Ljubljana, Slovenia. Methods From our single-centre prospective registry we enrolled 2260 consecutive atrial fibrillation patients aged ≥ 65years that were started on dabigatran, rivaroxaban or apixaban. The mean duration of treatment exposure was 735days. The primary outcome was the incidence of major bleeding. The incidence of thromboembolic events and death were also assessed. Potential risk factors for major bleeding were evaluated using Cox regression analysis. Main outcome measure Rate of major bleeding. Results During the follow-up 106 patients experienced major bleeding (2.3%/year). The oldest old patients (≥ 85years) had the highest risk of any major bleeding (HR 2.50, 95% CI 1.44-4.32, p = 0.001), intracranial bleeding (HR 4.74, 95% CI 1.48-15.14, p < 0.01) and major gastrointestinal bleeding (HR 2.32, 95% CI 1.10-4.89, p < 0.03) compared to the group of patients aged 65-74years, even though the majority of them were treated with reduced doses of direct oral anticoagulants. Significant predictors for major bleeding were age group ≥ 85years (HR 2.52, 95% CI 1.43-4.47, p = 0.001) and history of bleeding (HR 3.32, 95% CI 1.87-5.90, p < 0.001). The incidence of a composite of stroke, transient ischemic attack and systemic embolism was 1.3%/year. Conclusion In this prospective real-world clinical study we have shown that the oldest old patients have the highest risk of major bleeding, which is further increased with a patient's history of bleeding.

Rates of Potentially Inappropriate Dosing of Direct-Acting Oral Anticoagulants and Associations With Geriatric Conditions Among Older Patients With Atrial Fibrillation: The SAGE-AF Study.

BackgroundDirect‐acting oral anticoagulant (DOAC) dosing guidelines for atrial fibrillation recommend dose alteration based on age, renal function, body weight, and drug‐drug interactions. There is paucity of data describing the frequency and factors associated with prescription of potentially inappropriate doses.Methods and ResultsIn the ongoing SAGE‐AF (Systematic Assessment of Geriatric Elements in Atrial Fibrillation) study, we performed geriatric assessments (frailty, cognitive impairment, sensory impairments, social isolation, and depression) for participants with atrial fibrillation (age ≥65 years, CHA2DS2VASc ≥2, no anticoagulant contraindications). We developed an algorithm to analyze DOAC dose appropriateness accounting for drug‐drug interactions, age, renal function, and body weight. We also examined whether geriatric impairments were related to inappropriate dosing. Of 1064 patients prescribed anticoagulants, 460 received a DOAC. Participants were aged 74±7 years, 49% were women, and 82% were white. A quarter (23%; n=105) of participants received inappropriate DOAC dose, of whom 82 (78%) were underdosed and 23 (22%) were overdosed. Among participants receiving an inappropriate dose, 12 (11%) were identified using the drug‐drug interactions criteria and would have otherwise been misclassified. In multivariable regression analyses, older age, higher CHA2DS2VASc score, and history of renal failure were associated with inappropriate DOAC dosing (P<0.05). Geriatric conditions were not associated with inappropriate dosing.ConclusionsIn this cohort, over 20% of older patients with atrial fibrillation treated with DOACs were prescribed an inappropriate dose, with most being underdosed. Drug‐drug interactions were common. Factors that influence prescription of guideline‐nonadherent doses may be perception of higher bleeding risk or presence of renal failure in addition to lack of familiarity with dosing guidelines.

Effect of CES1 and ABCB1 genotypes on the pharmacokinetics and clinical outcomes of dabigatran etexilate in patients with atrial fibrillation and chronic kidney disease.

Background Despite the well-studied safety profile of dabigatran, its interactions with genetic polymorphism parameters are poorly understood, especially in patients with moderate chronic kidney disease (CKD). The study assessed whether genetic factors can contribute to CKD and alter dabigatran concentration. Methods Patients with atrial fibrillation (AF) and stage 3 CKD treated with dabigatran 110 or 150 mg have been included in the study. Real-time polymerase chain reaction was used to evaluate single-nucleotide polymorphisms of the ABCB1 gene (rs1045642 and rs4148738) and CES1 gene (rs2244613). A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Results A total of 96 patients aged 51-89 years (median age: 75 years) were evaluated. Patients on a reduced regimen of 110 mg twice a day were older (79.8 vs. 67.9, p < 0.0001) and had lower creatinine clearance (49.7 vs. 62.3 mL/min/1.73 m2, p = 0.015). Patients with the rs2244613 CC genotype had lower C/D values (70% reduction in the mean C/D vs. AA genotype, p = 0.001). Linear stepwise regression has shown the CKD epidemiology collaboration to be the only significant predictor of C/D among genetic factors and kidney function characteristics. During the median follow-up of 15 months, there were 15 bleedings in 13 patients. Conclusions Polymorphism of CES1 rs2244613 can contribute to the safety of dabigatran in patients with AF and CKD. There was no influence of the aforementioned polymorphisms of ABCB1 on dabigatran trough plasma concentrations and C/D. Kidney function is a mainstay of clinical decision-making on direct oral anticoagulant (DOAC) dose, and further knowledge should be accumulated on the role of genetic factors.

Acute Ischemic Stroke Outcome and Preceding Anticoagulation: Direct Oral Anticoagulants Versus Vitamin K Antagonists

Background and Purpose: Acute ischemic stroke (AIS) severity and clinical course are less known in direct oral anticoagulants (DOAC) users. We aimed to explore the outcome of AIS in patients pretreated with vitamin-K-antagonists (VKA) and DOAC. Methods: A retrospective study was performed. Patients pretreated with oral anticoagulants (OAC) for nonvalvular atrial fibrillation admitted for AIS in a stroke unit between 2016-01-01 and 2018-08-31 were included. The primary endpoint was mortality during the hospital stay, and secondary endpoints were neurologic improvement at stroke unit discharge and good functional outcome 90 days after AIS. Results: A total of 156 patients were included (83 on VKA and 73 on DOAC). Stroke severity (defined by NIHSS on admission) was comparable in both groups (AVK 13.0 [4.0-20.0] versus DOAC 11.0 [4.0-17.0], P = .435). Infratherapeutic levels and/or inappropriate low dose of OAC was also similar between groups (P = .152) and was not associated with stroke severity (P = .631) or mortality (P = .788). VKA (OR 12.616, P = .035, 95%CI 1.19-133.64) and PH2 hemorrhagic transformation (OR 7.516, P = .024, 95%CI 1.31-43.20) were associated with higher mortality in multivariate analysis. Higher stroke severity (OR .101, P < .001, 95%CI .037-.279) and VKA usage (OR .212, P = .003, 95%CI .08-.58) were associated with worse functional outcome at 3 months. Reperfusion therapy was significantly associated with neurologic improvement during stroke unit stay (OR 3.969, P = .009, 95%CI 1.42-11.11) but not with the functional outcome (P = .063). Conclusions: Nonvalvular atrial fibrillation patients pretreated with DOAC admitted for AIS had a better outcome when compared to VKA, although stroke severity was similar between groups.

Inappropriate direct oral anticoagulant dosing in atrial fibrillation patients is associated with prescriptions for outpatients rather than inpatients: a single-center retrospective cohort study

BackgroundInappropriate dosing of direct oral anticoagulants (DOACs) has been associated with clinical safety and efficacy; however, little is known about clinical data associated with an inappropriate DOAC dosing in Japan. In addition, there is no report in which the appropriateness of DOAC dosing between prescription for inpatients and for outpatients was examined. In this study, we aimed to investigate the prevalence and factors associated in the inappropriate dosing of DOACs in patients with atrial fibrillation (AF).MethodsThe retrospective cohort study was conducted at a single Japanese university hospital. Both inpatients and outpatients, who were diagnosed with AF and for whom treatment with either dabigatran, rivaroxaban, apixaban, or edoxaban was initiated between April 1, 2014 and March 31, 2018, were enrolled in the study. Appropriateness of DOAC dosing was assessed according to the manufacturer’s labeling recommendations (dose reduction criteria) of each DOAC. Inappropriate reduced dose, namely, underdosing, was defined as prescription of a reduced dose of DOAC despite the patient not meeting the dose reduction criteria. Inappropriate standard dose, namely, overdosing, was defined as prescription of a standard dose of DOAC despite the patient meeting the dose reduction criteria. Inappropriate DOAC dosing was defined as a deviation of the recommended dose (both underdosing and overdosing).ResultsA total of 316 patients (dabigatran, 28; rivaroxaban, 107; apixaban, 116; and edoxaban, 65) were included, with a median (interquartile range) age of 75 (66–81) years and 62.3% male. DOACs were prescribed at an appropriate standard dose in 39.2% of patients, an appropriate reduced dose in 36.7%, an inappropriate standard dose in 2.5%, and an inappropriate reduced dose in 19.3%. Multivariate analysis revealed that the inappropriate dosing of DOACs was significantly associated with prescriptions for outpatients (vs. inpatients; odds ratio [OR] 2.87, 95% confidence interval [CI] 1.53–5.62, p < 0.001) and those with higher HAS-BLED scores (OR 1.87, 95% CI 1.42–2.51, p < 0.001).ConclusionsOur results demonstrated that the inappropriate dosing of DOACs occurred in approximately 20% of AF patients, and was more frequent in outpatients (vs. inpatients) and in those with a higher risk of bleeding. It is recommended that pharmacists play a greater role in assisting in the prescription process to help physicians make better decisions.

Oral Anticoagulation in the Elderly and Frail.

The proportion of elderly patients will increase substantially over the next decades, and both atrial fibrillation (AF) and venous thromboembolism (VTE) are more common in the elderly. Age is a risk factor not only for stroke and thromboembolism but also for bleeding, particularly in frail patients, in whom numerous pathophysiological changes occur that alter drug kinetics and toxicity of standard doses of oral anticoagulants (OACs). AF trials showed that the relative benefits of direct OACs (DOACs) also applied to elderly patients, and due to their higher risk this translates into a higher absolute risk reduction compared with vitamin K antagonists, suggesting that DOACs are the better choice. All DOACs-at varying extent-are eliminated via the kidney and it is crucial to evaluate renal function at initiation and during follow-up, especially for dabigatran. The fear of falls is a common reason against OAC. However, there is still a benefit with OAC, particularly with DOACs given the lower risk of intracranial hemorrhage. Polypharmacy represents a common challenge, nevertheless DOACs and warfarin were classified as beneficial. Nonetheless, attempts should be undertaken to reduce comedication, and drug-drug interactions should be assessed. Coadministration of platelet inhibitors increases bleeding risk and should be avoided. In conclusion, elderly and frail patients requiring anticoagulation for AF or VTE are at higher risk of adverse outcomes, but also have a higher absolute benefit from OAC. Important practical aspects to improve efficacy and safety in this challenging population are summarized in this overview.

Rivaroxaban versus apixaban in non-valvular atrial fibrillation patients with end-stage renal disease or receiving dialysis.

We sought to evaluate the effectiveness and safety of rivaroxaban vs apixaban in non-valvular atrial fibrillation (NVAF) patients with end-stage renal disease (ESRD) and/or receiving dialysis in routine practice. Using US MarketScan claims data from January 1, 2014, to December 31, 2017, we identified new-users of rivaroxaban or apixaban during 2015 with at least 12months of insurance coverage prior to oral anticoagulant (OAC) initiation. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weighting based on propensity scores. Patients were followed for stroke or systemic embolism (SSE) or major bleeding hospitalizations. Cox proportion hazards regression was used to compare rivaroxaban and apixaban. Analyses stratified by age, sex, CHA2DS2-VASc score, prior stroke, prior bleed, diabetes, and reduced OAC dose were performed. We identified 787 rivaroxaban and 1836 apixaban users. Median (25, 75% range) age=70 (61, 79), CHA2DS2-VASc score=3 (2, 4), and follow-up=0.87 (0.38, 1.56) years. No differences in the risks of SSE (HR=1.18, 95% CI=0.53-2.63), ischemic stroke (HR=1.12, 95%CI=0.45-2.76), or major bleeding (HR=1.00, 95% CI=0.63-1.58) were observed. No significant interactions were observed upon subgroup analysis. In NVAF patients with ESRD and/or receiving dialysis, rivaroxaban and apixaban were associated with similar risks of SSE and major bleeding.

Potential Risk Factors Contributing to Development of Venous Thromboembolism for Total Knee Replacements Patients Prophylaxed With Rivaroxaban: A Retrospective Case-Control Study.

Rivaroxaban after total knee arthroplasty (TKA) is used to prevent postoperative venous thromboembolism (VTE); however, despite thromboprophylaxis, some patients still develop postoperative VTE. To determine whether tourniquet time, time to initiate rivaroxaban (TTIRIV), or Body Mass Index (BMI) was associated with postoperative VTE. A retrospective case-control study was conducted. Those patients that developed VTE despite prophylaxis (cases) were compared to controls (no VTE). A univariate analysis was conducted (p < 0.05 statistically significant). Seven VTE cases were identified from 234 TKA-patients. Patients with and without VTE had BMI of 40.1 ± 9.1 and 32.8 ± 7.5, respectively (p = 0.064). TTIRIV in VTE and control group was 28.2 ± 4.7 hours and 26.4 ± 4.2 hours, respectively (p = 0.39). Mean tourniquet time in VTE and control group was 65.0 ± 8.7 minutes and 49 ± 8.8 minutes, respectively (p = 0.0007). Statistically significant differences in tourniquet times were noted between VTE and non-VTE group but not for TTIRIV and BMI. Prolonged tourniquet use could pose a potential risk factor for postoperative VTE. Thromboprophylaxis management may need to be adjusted, based on patient-specific factors that could include increasing doses of oral anticoagulants and/or mechanical prophylaxis. However, further large-scale studies are required to establish pathophysiology.

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

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. The objective of this study was to compare the frequency and outcomes of labeled versus off-label DOAC dosing in patients with AF. 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. 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. 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.

Patients with higher body mass index treated with direct / novel oral anticoagulants (DOAC / NOAC) for atrial fibrillation experience worse clinical outcomes

IntroductionDue to fixed dosing of direct oral anticoagulants (DOACs), uncertainty exists about their efficacy in a population of obese/overweight patients. Patients and methodsWe retrospectively investigated a real-life cohort of 325 DOAC anticoagulated patients with atrial fibrillation [179 receiving dabigatran (55%), 74 apixaban (23%) and 72 rivaroxaban (22%)]. Patients were stratified according to the body mass index (BMI) into non-obese (233 with BMI <30 kg/m2), class I obesity (71 with BMI 30–34.9 kg/m2) and class II + obesity (21 with BMI ≥35 kg/m2). ResultsPatients with higher BMI receiving DOACs were more likely to experience stroke/systemic embolism sooner (P = 0.043), experience major bleeding sooner (P < 0.001) and have shorter time to composite event consisting of thrombosis, bleeding or death (P < 0.001) whereas there was no significant association with overall survival (P = 0.470). BMI was significantly associated with thrombosis but not bleeding among dabigatran treated patients, and significantly associated with bleeding but not thrombosis among patients treated with factor Xa inhibitors. Associations of higher thrombotic, bleeding and composite endpoint risks with higher BMI remained statistically significant in multivariate Cox regression models adjusted for age, gender, eGFR, CHA2DS2VASC and HAS-BLED. ConclusionOur findings indicate that obese patients receiving DOACs, especially ones with class II + obesity, might be under higher risks of stroke/bleeding depending on DOAC subtype. Loss of efficacy might be associated with dabigatran, whereas higher risk of major bleeding might be associated with factor Xa inhibitors.

P1255Comparative safety and effectiveness of standard doses of apixaban versus dabigatran, rivaroxaban, and VKAs in non-valvular atrial fibrillation patients in France: the NAXOS study

Abstract Background Real-world data comparing all available oral anticoagulants (OAC) on a nationwide scale (i.e. in France: apixaban, rivaroxaban, dabigatran and vitamin K antagonists – VKAs) are lacking. In everyday practice, oral anticoagulants are often underdosed, which may render comparisons between agents difficult. Purpose and methods NAXOS is a French real-world study comparing the safety (major bleeding), effectiveness (stroke, systemic thromboembolic events (STE)) and all-cause mortality for apixaban, dabigatran, rivaroxaban, and VKAs, in adult patients with non-valvular atrial fibrillation (NVAF) initiating a given OAC between 2014 and 2016. The French national health insurance data (SNIIRAM) were used. Analyses were performed with adjustment on propensity scores. To avoid bias potentially related to underdosing, the present analysis included only patients receiving standard doses of apixaban (5mg bid), rivaroxaban (20mg od), and dabigatran (150 mg bid), or VKAs. Only OAC naïve patients were included. Results In the OAC-naive cohorts treated with apixaban, rivaroxaban, and dabigatran, 54,575 (62.3%), 65,208 (65.2%), and 9,000 (42.4%), respectively, had the standard dose at the index dispensation, and 112,628 patients received VKAs. After adjustment on propensity scores, apixaban 5 mg was associated with a lower risk of major bleeding, compared to VKAs (Hazard Ratio: 0.47; 95% CI: 0.43–0.51) and rivaroxaban 20mg (HR: 0.64; 0.59–0.71), but not to dabigatran 150 mg (HR: 0.97; 0.79–1.18). Apixaban was associated with a lower risk of stroke and STE, compared to VKAs (HR: 0.62; 0.56–0.69) but not to rivaroxaban (HR: 1.03; 0.92–1.16), and dabigatran (HR: 0.96; 0.76–1.21). Apixaban showed a lower risk of all-cause mortality compared to VKAs (HR: 0.44; 0.41–0.47) and rivaroxaban (HR: 0.87; 0.81–0.94) but not to dabigatran (HR: 1.10; 0.92–1.32). Figure 1. Forest plot presenting the results of the standard dose analysis (PS adjusted). Conclusions The NAXOS population-based country-wide observational study shows that 42% to 65% of patients were treated with standard doses of OACs. Analyses of standard doses confirmed the superiority of apixaban compared with VKAs for the three studied outcomes and suggests better safety profile of apixaban compared to rivaroxaban but similar to dabigatran. Acknowledgement/Funding The Alliance Bristol-Myers Squibb/Pfizer

Thrombotic and hemorrhagic complications in atrial fibrillation patients, undergoing elective percutaneous coronary intervention

To evaluate efficacy and safety of reduced dose of direct oral anticoagulants (DOACs) as part of triple antithrombotic therapy in AF patients, undergoing elective percutaneous coronary intervention (PCI), and to identify factors, associated with this strategy. The study is a cohort analysis of AF patients with AF, who successfully underwent elective PCI and assigned DOACs as part of triple antithrombotic therapy (TAT).Influence of a reduced DOACs dose as a part of TAT on the frequency of thecomposite efficacy endpoint (acute coronary syndrome, ischemic stroke, venous thromboembolic events, cardiovascular death and angina pectoris aggravation/need for unplanned PCI) and safety endpoint (hemorrhagic complications BARC types 2-5) were assessed using the Log-Rank criterion. The study included 124 pts (69.4% women, mean aged 69±8.2 years). Themedian total score CHA2DS2-VASc was 5, the median of the Charlson index composed 7. Half (52%) of AF patients with high risk of thrombotic events after elective PCI received reduced-DOACs dose. Median follow up period was 11.0 month. 17 adverse thrombotic events were recorded during this period, BARC 2-5 bleedings occurred in 27 patients. Reduced DOACs doses in AF patients undergoing PCI were associated with significant increase of thrombotic events during follow up period compared to patients received full DOACs doses (0.79 vs 0.93, Log-Rank p=0.0292). Patients, who received full and reduced DOAC doses, were comparable in the frequency of BARC 2-5 bleedings (0.78 vs 0.75, Log-Rank p=0.06742). The administration of a reduced DOACs dose as a part of TAT in patients with AF, who underwent PCI, was associated with significant increase in the incidence of all thrombotic events, compared to patients, who received full dose of anticoagulants. The number of hemorrhagic complications was comparable.

Elderly Patients with Atrial Fibrillation: Focus on Comorbidity and Safety of Anticoagulant Therapy

The article discusses issues related to the prescription of anticoagulant therapy to elderly patients with atrial fibrillation (AF), especially those over 70 and 80 years of age. The relevance of the issue is primarily due to the prevalence of AF in this cohort of patients, and the second is due to the higher incidence of comorbidity. The presented material demonstrates the peculiarities of anticoagulant therapy application in groups of patients older than 75, based on the data of randomized clinical trials, and also presents extrapolation of the results of RCTs to the real clinical practice (data of registers and cohort trials). The use of unreasonably low doses of oral anticoagulants in elderly patients is debated. It often leads to a decrease in the efficacy of anticoagulant therapy without improving the drugs safety profile. A new validated scale (ABH) for evaluating of anticoagulant therapy safety is presented in the article. The ABH scale can be used before prescribing to patients exactly direct oral anticoagulants. This scale is simpler and more practical than the HAS-BLED scale. The data for the ABH scale are validated based on direct oral anticoagulants in 21,248 patients from the Norwegian register. The presented results demonstrate a favorable efficiency and safety profile of rivaroxaban in comparison with warfarin in patients 75 years and older. Thus, the overall benefit for the use of rivaroxaban against warfarin in patients &gt; 75 years of age in the subanalysis of the ROCKET-AF study was statistically significantly greater than in younger patients with AF. Data on 11121 patients with AF who were treated with rivaroxaban for the prevention of stroke and systemic embolism are included in the combined analysis of the XANTUS, XANAP and XANTUS-EL registers. 96% of patients in the study did not have serious thromboembolic events. The amount of major bleeding was 1.7 per 100 patient-years, and gastrointestinal bleeding was 0.7 per 100 patient-years. This turned out to be less than in some other registry studies. In addition, patients showed good adherence to rivaroxaban treatment: after a year, 77.4% of patients continued to take the drug.

Значение методов оценки функции почек у пациентов с фибрилляцией предсердий для принятии решения о коррекции дозы прямых оральных антикоагулянтов

Значение методов оценки функции почек у пациентов с фибрилляцией предсердий для принятии решения о коррекции дозы прямых оральных антикоагулянтов

Real-world assessment of off-label direct oral anticoagulant dosing for venous thromboembolism.

Preferred anticoagulation therapy for venous thromboembolism (VTE) has shifted from warfarin to direct oral anticoagulants (DOACs). Adherence to DOAC prescribing information is an important quality measure as off-label doses have been associated with increased risk of adverse events (AEs). To identify the prevalence, outcomes, and patient characteristics associated with off-label DOAC dosing during VTE treatment. Patients receiving DOAC for VTE treatment discharged from University of Utah Health (UUH) over a 90-day period were identified. Dosing was classified as "labeled" or "off-label" based on concordance with manufacturer prescribing information. AEs (thromboembolic events, bleeding, death) occurring within 90days after discharge were identified. Out of 195 patients, 154 (79.0%) received labeled dosing, 31 (15.9%) received off-label dosing, and 10 (5.1%) were indeterminate. Two-thirds of off-label doses were higher than recommended and three-fourths occurred during extended treatment (more than 90days post-VTE). Off-label dosing rates dropped to 5.6% when 6-month dose reductions were not required. Off-label dosing was associated with apixaban use and extended phase treatment (p < 0.001). No association was found between off-label dosing and age, renal function, prescriber rationale for dose selection, or Thrombosis Clinic referral. AEs were experienced by 18 (11.7%) and 3 (9.7%) patients in the labeled and off-label groups, respectively (p = 0.77). Bleeding events comprised 46.2% of AEs. The rate of off-label DOAC dosing for VTE at UUH was within rates reported in prior studies, occurred primarily with extended-duration apixaban, and did not result in a higher rate of AEs.

PF340 PATIENTS WITH HIGHER BODY MASS INDEX TREATED WITH DIRECT / NON VITAMIN K DEPENDENT ANTICOAGULANTS (DOAC / NOAC) EXPERIENCE WORSE CLINICAL OUTCOMES

Background:Advent of direct/non‐vitamin‐K‐dependent anticoagulants (DOAC/NOAC) has dramatically changed the practice of anticoagulation. Due to fixed dosing of direct oral anticoagulants (DOACs) and high lipophilicity, uncertainty exists about their efficacy/safety in a population of obese/overweight patients.Aims:We aimed to investigate in the real‐life setting whether DOAC anticoagulated patients with atrial fibrillation stratified according to the different BMI subgroups experience different risks of unwanted outcomes.Methods:We retrospectively investigated a real‐life cohort of 325 anticoagulated patients with atrial fibrillation who started anticoagulation in our institution in period 2011–2018. Patients received predominantly dabigatran [179/325 (55%)], followed by apixaban [74/325 (23%)] and rivaroxaban [72/325 (22%)]. Clinical data were obtained from the hospital information system. Patients were stratified according to the body mass index (BMI) subgroups: non‐obese with BMI &lt;30 kg/m2; class I obesity with BMI 30–34.9 kg/m2; class II+ obesity with BMI ≥35 kg/m2.Outcomes of interest were time to thrombosis (TTT; defined as time from inclusion to first occurrence of stroke or systemic embolism), time to bleeding [TTB; defined as time from inclusion to first occurrence of major bleeding event defined according to the International Society on Thrombosis and Haemostasis definition) and overall survival (OS; defined as time from inclusion to death of any cause). Time‐to‐event‐of‐interest curves were compared using the log‐rank test and log‐rank test for trend. Patients’ characteristics were compared using the Kruskal‐Wallis ANOVA and the χ2 test. P values &lt;0.05 were considered to be statistically significant. The study complies with the Declaration of Helsinki and it was approved by the Institutional Review Board.Results:Among 325 analyzed patients, there were 172/325 (53%) male patients. Median age was 70 years. Three investigated BMI subgroups did not significantly differ regarding sex (P = 0.778), age (P = 0.130), estimated glomerular filtration rate (P = 0.581), predetermined stroke risk [CHA2DS2‐VASC ≥2 (P = 0.729)] or predetermined major bleeding risk [HAS‐BLED ≥3 (P = 0.519)].Median follow‐up was 33 months. In the whole cohort of DOAC treated patients, those belonging to higher BMI subgroups were significantly more likely to experience shorter time to thrombosis (TTT, overall P = 0.083, P for trend = 0.043). This phenomenon was evident among dabigatran treated patients (TTT, overall P = 0.007, P for trend = 0.009), but not present in other DOAC subgroups. Similarly, considering whole cohort of patients, those belonging to higher BMI subgroups were significantly more likely to experience major bleeding sooner (TTB, overall P &lt; 0.001; P for trend &lt;0.001). Conversely, this phenomenon was most pronounced among patients treated with factor Xa inhibitors (TTB, overall P &lt; 0.001; P for trend &lt;0.001) but not evident in dabigatran treated patients. BMI subgroups did not differ regarding overall survival (OS, overall P = 0.470, P for trend = 0.279).Summary/Conclusion:Our findings indicate that obese patients receiving DOACs, especially ones with class II+ obesity, might be under higher risks of stroke/bleeding depending on DOAC subtype. Loss of efficacy might be associated with dabigatran, whereas higher risk of major bleeding might be associated with Xa inhibitors. Our results are limited by retrospective design, single center experience, limited number of patients and rareness of events, but deserve to be further evaluated in new and larger cohorts of patients.image

Apixaban Concentrations with Lower than Recommended Dosing in Older Adults with Atrial Fibrillation.

Lower than recommended doses of direct-acting oral anticoagulants are often prescribed to older adults with nonvalvular atrial fibrillation (NVAF). Our goal was to determine the consequences of lower than recommended dosing on plasma apixaban concentrations during the clinical care of older adults with NVAF. Convenience sample of patients receiving anticoagulation during 2017. Academic medical center. Stable adults older than 65 years with NVAF receiving apixaban on a chronic basis. Patient age, weight, creatinine, co-medications, and apixaban concentrations. A total of 110 older adults with NVAF (mean age = 80.4 y; range = 66-100 y with 45% women) were studied. Overall, 48 patients received recommended dosing of 5 mg twice/day, and 42 received lower than recommended dosing. One patient in each category had concentrations below the expected 5% to 95% range at time of peak concentrations. Differences in proportion of apixaban concentrations within or outside expected ranges were not significant between patients receiving lower than recommended doses and those dosed as recommended at 5 mg twice/day (P = .35). However, in patients dosed as recommended with 5 mg twice/day, four had concentrations above the 5% to 95% range for peak levels expected at 3 to 4 hours after dosing; in two, this occurred around the midpoint of the dosing interval. Twenty patients received 2.5 mg twice/day as recommended. One-third had apixaban concentrations higher than expected peak concentrations compared with the clinical trials, and more than two-thirds had levels above the reported median for peak concentrations. Apixaban concentrations in older adults with NVAF seen clinically were higher than expected based on clinical trial data. The findings raise questions about the optimal dosing of apixaban in older adults with NVAF encountered outside of clinical trials and suggest a role for the monitoring of apixaban concentrations during care of patients that differ from those in randomized trials or when considering dosing outside of published guidelines. J Am Geriatr Soc 67:1902-1906, 2019.

Evaluation of Direct Oral Anticoagulant Dosing and Monitoring in Two Geriatric Outpatient Clinics

OBJECTIVE: This study was conducted to evaluate direct oral anticoagulants (DOACs) prescribed to elderly patients in an outpatient setting, specifically evaluating if Food and Drug Administration (FDA) -approved dosing recommendations are followed.<br/> DESIGN: This study was a retrospective quality improvement project.<br/> SETTING: This study was conducted at geriatric hospital-based primary care clinics at the University of Pittsburgh Medical Center (UPMC), UPMC Senior Care Institute and UPMC Benedum Geriatric Center.<br/> PATIENTS: Subjects included were 65 years of age or older; had an office visit at UPMC Senior Care Institute or UPMC Benedum Geriatric Center from September 1, 2015, to August 31, 2017; and had a DOAC on their home medications.<br/> INTERVENTIONS: Data were obtained through retrospective chart review.<br/> MAIN OUTCOME MEASURE: The primary objective of the study was to evaluate the appropriateness of dosing of DOACs based on FDA-labeled recommendations.<br/> RESULTS: Of 232 patients included in analysis, 42.7% were found to have dosing inconsistent with FDAlabeled recommendations (47.3% apixaban, 35.8% rivaroxaban, and 31.6% dabigatran). No patients were prescribed edoxaban. The majority (72.7%) were dosed lower than FDA-recommended doses. Of all patients, the most frequent parameter (54.5%) for inappropriate dosing was patients meeting only 1 of 3 dose-reduction criteria when prescribed reduced-dose apixaban. Geriatrician and nongeriatrician prescribers had similar rates of prescribing DOACs with doses inconsistent with FDA-labeled recommendations (44.0% vs. 40.8%; P = 0.62).<br/> CONCLUSION: Results suggest that DOACs used in outpatient geriatric patients are frequently dosed inconsistent with FDA-approved dosing recommendations. Further research is needed regarding clinical outcomes in older patients receiving DOACs and in those with dose adjustments inconsistent with FDA-labeled recommendations.<br/>.

Appropriateness of Direct Oral Anticoagulant Dosing in Patients With Atrial Fibrillation: Insights From the Veterans Health Administration

Background: Direct oral anticoagulants (DOACs) have strict dosing guidelines, but recent studies indicate that inappropriate dosing is common, particularly in chronic kidney disease (CKD), for which it has been reported to be as high as 43%. Since 2011, the Veterans Health Administration (VA) has implemented anticoagulation management programs for DOACs, generally led by pharmacists, which has previously been shown to improve medication adherence. Objective: We investigated the prevalence of overdosing and underdosing of DOACs in the VA. Methods: Using data from the TREAT-AF cohort study (The Retrospective Evaluation and Assessment of Therapies in AF), we identified VA patients with newly diagnosed atrial fibrillation (AF) and receipt of a DOAC between 2003 and 2015. We classified dosing as correct, overdosed, or underdosed based on the Food and Drug Administration–approved dosing criteria. Results: Of 230 762 patients, 5060 received dabigatran (77.3%) or rivaroxaban (22.7%) within 90 days of AF diagnosis (age 69 [10[ years; CHA2DS2-VASc 1.6 [1.4]), of which 1312 (25.9%) had CKD based on estimated glomerular filtration rate <60. Overall, 93.6% of patients, 83.2% with CKD, received appropriate DOAC dosing. Incorrect dosing increased with worsening renal function. Conclusion: Compared to recent studies of commercial payers and health-care systems, incorrect dosing of DOACs is less common across the VA. Pharmacist-led DOAC management or similar anticoagulation management interventions may reduce the risk of incorrect dosing across health-care systems.

Clinical Outcomes of Off-Label Dosing of Direct Oral Anticoagulant Therapy Among Japanese Patients With Atrial Fibrillation Identified From the SAKURA AF Registry.

Off-label dosing of direct oral anticoagulants (DOACs) is encountered clinically among patients with atrial fibrillation (AF), although data on the clinical outcomes of over- and under-dosing are lacking in Japan. Methods and Results: We examined the clinical outcomes of off-label DOAC dosing using the SAKURA AF Registry, a prospective multicenter registry in Japan. Among 3,237 enrollees, 1,676 under any of the 4 DOAC regimens were followed up for a median of 39.3 months: 746 (45.0%), appropriate standard-dose; 477 (28.7%), appropriate low-dose; 66 (4.0%), over-dose; and 369 (22.2%) under-dose. Compared with the standard-dose group, patients in the under- and over-dose groups were significantly older and had a higher stroke risk. After multivariate adjustment, stroke/systemic embolism (SE) and death events were equivalent between the standard- and under-dose groups, but major bleeding events tended to be lower in the under-dose group (hazard ratio [HR] 0.474, P=0.0739). Composite events (stroke/SE, major bleeding, or death) were higher in the over-dose than in the standard-dose group (HR 2.714, P=0.0081). Clinical outcomes were not worse for under-dose than for standard-dose users among patients with different backgrounds. Over-dose users, however, were at higher risk for all clinical events and required careful follow-up. Further studies are needed to clarify the safety and effectiveness of off-label DOAC dosing in Japan.