Dose Of Apixaban Research Articles

Direct comparisons of effectiveness and safety of treatment with Apixaban, Dabigatran and Rivaroxaban in atrial fibrillation

IntroductionDirect oral anticoagulants (DOACs) have been proven non-inferior or superior to warfarin in preventing stroke and systemic embolism, with a lower risk of major hemorrhage, in patients with non-valvular atrial fibrillation (NVAF). We sought to investigate whether effectiveness and safety differs among apixaban, rivaroxaban and dabigatran. Materials and methodsPatients with newly initiated DOAC treatment were identified from the Swedish anticoagulation quality registry, ranging from January 1, 2013 to December 31, 2015. Patients were assigned to apixaban, dabigatran or rivaroxaban cohorts based on initiated DOAC and dose (standard or reduced). Baseline characteristics and endpoints were retrieved from validated Swedish quality registers and the National Patient Registry. Cohorts were matched using full optimal matching and directly compared. ResultsA total of 25,843 NVAF patients were included. Patients treated with standard dose apixaban or dabigatran had lower risk of major bleeding than patients treated with rivaroxaban, HR 0.69 (95% CI 0.54–0.88) and HR 0.64 (95% CI 0.48–0.87). Regarding reduced dose, patients treated with apixaban had lower risk of major bleeding than those treated with dabigatran or rivaroxaban, HR 0.62 (95% CI 0.44–0.88) and HR 0.45 (95% CI 0.33–0.61). In reduced dose, patients treated with dabigatran had the lowest all-cause mortality. No differences in effectiveness were found. ConclusionsIn this large real-world NVAF cohort, direct comparisons show a favorable bleeding risk profile for dabigatran and apixaban in standard dose, and for apixaban in reduced dose. No differences in effectiveness were found. This study confirms previous indirect DOAC comparisons. Further studies are needed.

P4752Apixaban 2.5 mg twice daily is effective and safe for patients with atrial fibrillation and combinations of advanced age, low body weight, and elevated creatinine: insights from ARISTOTLE

Abstract Background In ARISTOTLE, patients with atrial fibrillation and ≥2 dose-reduction criteria [age ≥80 years, weight ≤60 kg, and creatinine ≥1.5 mg/dL (133 μmol/L)] were randomized to apixaban 2.5 mg twice daily (b.i.d) or warfarin. Purpose To determine whether the apixaban dose adjustment in ARISTOTLE resulted in similar efficacy and safety compared to warfarin. Methods The effects of apixaban 2.5 mg b.i.d versus warfarin on stroke or systemic embolism, major bleeding and death in ARISTOTLE patients with ≥2 dose-reduction criteria were compared with the effects of apixaban 5 mg b.i.d in patients with 0 or 1 dose-reduction criterion. Results Of 751 (4.1%) patients with ≥2 dose-reduction criteria, 386 were assigned to apixaban 2.5 mg b.i.d and 365 to warfarin. Compared to patients with 0 or 1 dose reduction criteria (n=17,322), these patients had a higher risks of stroke/systemic embolism (HR =1.78; 95% CI [1.24–2.57]), major bleeding (HR =1.73; 95% CI [1.28–2.32]) and death (HR=3.21; 95% CI [2.69–3.83]), irrespective of whether they were assigned to apixaban or warfarin. The benefits of apixaban 2.5 mg b.i.d compared with warfarin on stroke or systemic embolism, major bleeding, and death in patients with ≥2 dose-reduction criteria were consistent with that of apixaban 5 mg b.i.d in patients with either 0 or 1 dose-reduction criteria (Figure). Conclusions While they are at higher overall risk, patients with appropriate dose reduction criteria have consistent benefits with apixaban 2.5 mg b.i.d. over warfarin. Additional analyses investigating the relationship between apixaban dose and both apixaban plasma concentrations and levels of thrombosis biomarkers are underway. Acknowledgement/Funding Bristol-Myers Squibb and Pfizer, Inc.

P4743Inappropriate dosing of non-vitamin K oral anticoagulants (NOACs) in atrial fibrillation patients in Europe

Abstract Background Prescription of Non-vitamin K oral anticoagulants (NOACs) has increased since the first therapies were launched in Europe in 2011, and they are becoming the standard of care in prevention of stroke in patients with non-valvular atrial fibrillation (NVAF). There are concerns about inappropriate NOAC dosing in clinical practice. Purpose This paper examines the extent of inappropriate dose prescription among NOAC patients in Germany, Italy, Spain and United Kingdom. Inappropriate dosing refers to patients who do not meet the criteria for dose reduction (under-dose) or patients who should be on the reduced dose as they meet the criteria for dose reduction (overdose). Methods Ipsos' Stroke Prevention in Atrial Fibrillation Therapy Monitor was fielded for 6 weeks between January 2017 to February 2017 and 6 weeks between January 2018 to March 2018, with 450 treating doctors in 2017 and 509 in 2018 providing data from 5,692 (2017: n=2,497, 2018: n=3,195) patients with non-valvular atrial fibrillation in Europe. We analysed the results for the 3,477 patients with a NOAC prescription that had sufficient data to decide on the appropriate dose. Results Overall, 23.4% of patients (n=813) were receiving an inappropriate dose of dabigatran, rivaroxaban, apixaban or edoxaban. Receiving an under-dose was more common than an overdose (19.2% vs 4.2%). Ipsos data indicate 32.8% of NOAC patients in EU4 (n=1,139) were prescribed a reduced dose, and Italy had a higher proportion of patients who received a reduced dosed; Italy: 41.0% (n=345), Germany: 30.2% (n=402), Spain: 30.6% (n=216) and UK: 29.4% (n=176). Among these patients, a considerable proportion did not meet the criteria for dose reduction in EU4 (58.6%). This suggests that reduced dose is frequently prescribed to patients when not indicated. Conclusion Overall, the majority of patients were prescribed a correct dose according to the product label. However, we see evidence that nearly half of patients receiving a reduced dose were not indicated for a dose reduction. Further research is needed to identify reasons prompting the over-use of reduced dose.

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

Evaluating Prescribing Practices of Apixaban in the Elderly

OBJECTIVE: The aim of this study was to evaluate prescribing practices for elderly patients started on apixaban in multiple practice settings.<br/> DESIGN: Retrospective, chart review.<br/> SETTING: One outpatient and three inpatient settings in Arizona and Massachusetts.<br/> PATIENT, PARTICIPANTS: Patients who received a new order for apixaban between July 1, 2015, and December 31, 2016. Inclusion criteria included adults 65 years of age and older who were receiving apixaban for atrial fibrillation or venous thromboembolism (VTE) at a current treatment dose.<br/> There were 1,045 patients included, the average age was 78 years, 52% were male, and 90% had atrial fibrillation.<br/> MAIN OUTCOME MEASURE: Appropriate prescribing of apixaban based on Food and Drug Administration (FDA)-labeling (age, weight, serum creatinine).<br/> RESULTS: Six patients who were on hemodialysis were excluded from the analysis, leaving 1,039 patients to be analyzed. 16.2% (168/1,039) of patients had an incorrect dose of apixaban prescribed based on their indication. Of those, 75% (126/168) were taking the medication for atrial fibrillation and 25% (42/168) for VTE. For those with atrial fibrillation (n = 126), the majority of inappropriate orders resulted from doses that were lower than indicated (113/126).<br/> CONCLUSION: This research suggests that elderly patients may receive inappropriately lower doses of apixaban than indicated, which may decrease the effectiveness of the medication. This research supports the fact that pharmacists can play a vital role in anticoagulation stewardship by verifying apixaban doses for accuracy.

Unexpected excessive apixaban exposure: case report of a patient with polymorphisms of multiple apixaban elimination pathways

BackgroundApixaban effectively lowers the risk of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation. Systemic exposure to a given apixaban dose depends on multiple clearance pathways. Though routine quantification of direct oral anticoagulants (DOACs) in neurological emergency situations has not been widely established, suspected associations of DOAC peak concentrations with bleeding events and DOAC trough concentrations with efficacy and safety suggest that such information might support clinical decision making.Case presentationWe describe the case of a 75 year-old woman with atrial fibrillation maintained on apixaban who was admitted due to suspected acute stroke. Clinical work-up did not confirm ischemic or hemorrhagic stroke but routine quantification of apixaban revealed an excessively high apixaban plasma concentration (~ 3 h after the last drug intake: 1100 ng/ml (expected range: 91–321 ng/ml); ~ 12 h after drug intake: 900 ng/ml (expected range: 41–230 ng/ml)) and a substantially prolonged elimination half-life (~ 31 h). The corresponding apixaban concentration-to-dose ratio was 9900 (ng/ml)/(mg/kg/d) and 8100 (ng/ml)/(mg/kg/d), respectively (expected range: 249–463 (ng/ml)/(mg/kg/d)). Renal function was only moderately impaired (creatinine 1.36 mg/dl (0.5–1.1 mg/dl), creatinine clearance 40 ml/min). Genotype analyses revealed that the patient was a CYP3A5*3/*3 non-expressor, a heterozygous carrier of the ABCG2 c.421C/A alleles, and a homozygous carrier of ABCB1 c.2677 T/T and ABCB1 c.3435 T/T. In the absence of known drug interactions explaining apixaban clearance impairment, excessive apixaban concentrations were most probably caused by moderate renal impairment combined with multiple functional polymorphisms of apixaban clearance pathways.ConclusionsThis case suggests that concurrent genetic polymorphisms can impair multiple apixaban elimination pathways and thus substantially increase its exposure.

Safety and effectiveness of reduced-dose apixaban in Japanese patients with nonvalvular atrial fibrillation in clinical practice: A sub-analysis of the STANDARD study

BackgroundThe safety and effectiveness of reduced-dose apixaban 2.5mg twice daily (BID) have not been elucidated thoroughly in Japanese patients with nonvalvular atrial fibrillation (NVAF). MethodsA post-marketing survey study included NVAF patients who newly initiated apixaban for prevention of thromboembolism, and followed them for 104 weeks. Apixaban doses were selected at the discretion of treating physicians. Hemorrhagic and thromboembolic (ischemic stroke, systemic embolism, and transient ischemic attack) events were examined. The relationship between dose reduction criteria (DRC), selected doses, and outcome events was also examined. ResultsOf 6306 patients, 3600 (57.1%) received the standard dose (5mg BID) and 2694 (42.7%) received the reduced dose. Compared with the standard-dose group, the reduced-dose group had more female patients; the patients were older, of lower body weight, with reduced creatinine clearance, higher thromboembolic and hemorrhagic risk scores, and more frequent antiplatelet use. Incidence rates of major hemorrhage and thromboembolism were higher in the reduced-dose group compared with the standard-dose group (3.00%/year vs 1.93%/year, p=0.001 and 1.40%/year vs 0.72%/year, p=0.001, respectively). In the standard-dose group, 90.0% of patients did not meet the DRC (recommended standard-dose group). In the reduced-dose group, 62.4% of patients met the DRC (recommended reduced-dose group) and 34.9% did not (non-recommended reduced-dose group). Incidence rates of major hemorrhage and thromboembolism were numerically highest in the recommended reduced-dose group (3.30%/year, p=0.007 and 1.69%/year, p<0.001, respectively), followed by the non-recommended reduced-dose group. In multivariate analysis, apixaban dose was not associated with these outcome events. ConclusionThe reduced-dose group showed higher incidence rates of thromboembolic and major hemorrhagic events than the standard-dose group due to baseline clinical characteristics. The safety and effectiveness of reduced-dose apixaban need to be carefully monitored in clinical practice.

PF795 EXPLORING THE REAL‐LIFE CLINICAL VALUE OF LOW DOSE DIRECT ANTICOAGULANTS FOR SECONDARY PREVENTION OF THROMBOEMBOLISM

Background:Anticoagulation is the mainstay of acute venous thromboembolism (VTE) therapy. Until recently Vitamin‐K antagonists (VKAs) were the standard of care for extended treatment of VTE. In the last decade, direct oral anticoagulants (DOACs) have been studied and approved for use in treatment and secondary prevention of VTE. The apixaban AMPLIFY‐EXTEND clinical trial and the rivaroxaban EINSTEIN CHOICE study, have offered evidence that low dose anticoagulation up to 12 months following completion of standard VTE treatment, can be equally effective to standard dose apixaban/rivaroxaban for secondary prevention of thromboembolism. To date there is no real‐life study recording the outcomes of patients on low dose DOACs in this setting.Aims:In this audit, we sought to identify patients on long term low dose apixaban/rivaroxaban for secondary prevention of VTE and record their outcomes.Methods:Between January 2015 and September 2018, 4,625 patients were initiated to DOACs in our clinics. Amongst them 394 patients were put on either apixaban 2.5 mg bd (N = 352) or rivaroxaban 10 mg od (N = 42). Their median age was 65(16–98) years. The index event to offer long term anticoagulation was unprovoked VTE in 271 patients while 123 had suffered a provoked VTE with permanent risk factors. Cancer‐associated thrombosis was recorded in 42 patients, 69 individuals had documented thrombophilia and/or family history of thrombosis. Recurrent VTE was recorded in 41 patients. The median time from thrombosis to low‐dose anticoagulation switch was 7.26(3–280) months. The median follow‐up time on low dose anticoagulation was 15(3–45) months.Results:Major bleeding occurred in 3/394 patients (0.76%), all 3 patients were on low dose apixaban. Major plus clinically relevant non‐major bleeding was recorded in 30 patients (7.6%). Recurrent VTE occurred in 13/352 patients (3.69%) in the apixaban group and 1/42 patients (2.3%) in the rivaroxaban group (p = NS). No statistical differences in bleeding rate and VTE recurrence were identified between the total patient population, the cancer related thrombosis and the thrombophilia/family history of VTE subgroup respectively (table).Summary/Conclusion:Our study although small, is the first to record the clinical experience of using long term low dose DOACs to prevent VTE recurrence in real life. Our results confirm that low dose DOACs are very safe with major bleeding rate oof &lt;1% in 15 months. We did however find a higher incidence of recurrent VTE (3.55%) compared to the AMPLIFY‐EXTEND (1.7%) and the EINSTEIN CHOICE (1.2%) trials.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.

Update in thrombosis and hemostasis: ASH meeting 2018

In the field of thrombosis and hemostasis the focus was laid on the prophylaxis and treatment of venous thromboembolism in patients with active cancer during this years’ meeting of the American Society of Hematology (ASH) in San Diego. The Adam-VTE trial completed the series of studies using Xa-antagonists for the treatment of cancer-associated thromboembolism. Apixaban reduced the number of recurrent thromboembolic events compared to treatment with dalteparin without increasing the bleeding risk. Furthermore, the use of a prophylactic dose of rivaroxaban or apixaban showed positive results in the primary prevention of venous thromboembolism in ambulatory cancer patients being at high risk for thromboembolic events. A safe standardized perioperative management for direct oral anticoagulants was also presented during the meeting in noncancer patients with atrial fibrillation. This short review will summarize the most clinically relevant highlights in the field of thrombosis and hemostasis of the ASH meeting 2018.

Safety and effectiveness of apixaban in Japanese patients with nonvalvular atrial fibrillation in clinical practice: A regulatory postmarketing surveillance, the STANDARD study.

BackgroundApixaban, a non‐vitamin K oral anticoagulant (NOAC), was approved in Japan in 2012 for the prevention of thromboembolic events in patients with nonvalvular atrial fibrillation (NVAF). However, the safety and effectiveness of apixaban in clinical practice have not yet been elucidated thoroughly among Japanese NVAF patients.MethodsA postmarketing surveillance study was conducted to determine the safety and effectiveness of apixaban. Patients were followed‐up for 104 weeks. Outcome events included adverse drug reactions (ADRs), hemorrhages, and thromboembolic events (ischemic stroke, systemic embolism [SE], and transient ischemic attack [TIA]).ResultsAmong 6306 NVAF patients in the safety analysis set (age, 74.5 ± 10.1 years; women, 41.1%; and CHADS 2 score, 2.0 ± 1.4), 3600 patients (57.1%) received the standard dose (5 mg twice daily) and 2694 (42.7%) received a reduced dose (2.5 mg twice daily) of apixaban. ADRs occurred in 604 patients (9.58%), with the most common being epistaxis (0.86%), subcutaneous hemorrhage (0.67%), and hematuria (0.57%). Incidence rate of any hemorrhages and major hemorrhage was 5.52% per year and 2.36% per year, respectively. Incidence rate of ischemic stroke/SE/TIA was 1.00% per year among 6286 patients in the effectiveness analysis set. Among three subgroups (3106 apixaban initiators, 2038 patients switched from warfarin, and 1118 patients switched from other NOACs), incidence rates of major hemorrhage (P = 0.221 for trend) and ischemic stroke/SE/TIA (P = 0.686 for trend) were comparable.ConclusionsNo new safety signals of apixaban were identified in Japanese NVAF patients. Safety and effectiveness of apixaban were consistent with those in the ARISTOTLE study.

Safety assessment of new oral anticoagulants

ObjectiveTo compare the occurrence of haemorrhages among the different oral anticoagulants (OAC) and to analyse factors that influence it. Material and methodsSingle-centre, observational, retrospective study. After studying the total population treated with OAC, patients who were treated with an OAC from July 2015 to December 2015 in the II Sector of the Zaragoza Hospital, who consulted the Emergency Department of the Miguel Servet University Hospital and presented a haemorrhagic event, were analysed. Patients’ demographic data, clinical variables and data on the haemorrhagic event characteristics were gathered. ResultsThere were 9452 patients treated with an OAC, 371 (3.9%) of which presented a haemorrhagic event. The frequency per OAC was; 4.1% (311) in patients treated with vitamin K antagonists, 3.8% (33) with rivaroxaban, 3.3% (19) with dabigatran and 2.1% (8) with apixaban. In the multivariate analysis, only the choice of anticoagulant and sex had a statistically significant influence of a lower risk of haemorrhage, in particular the dose of apixaban at 2.5mg and being female (OR=0.1, CI=0.014–0.71 and OR=0.688, CI=0.55–0.85, respectively). ConclusionAccording to the results obtained, females and patients undergoing treatment with apixaban presented lower haemorrhagic risk, although there are doubts about whether this better safety profile is related to underdosing, which could influence its effectiveness. Therefore, these results should be analysed with caution and further studies are needed to confirm this data.

Apixaban for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in France: The PAROS cross-sectional study of routine clinical practice

Non-vitamin K antagonist oral anticoagulants (NOACs), including apixaban, are recommended for prevention of stroke and systemic embolism in non-valvular atrial fibrillation (NVAF). To describe the characteristics of patients starting anticoagulant treatment, identify the characteristics associated with apixaban prescription, and describe apixaban use in France. This was a non-interventional multicentre French study. Patients with NVAF (aged≥18 years) with anticoagulant treatment started in the preceding 3 months were evaluated in four groups (NOAC [apixaban, dabigatran or rivaroxaban] or vitamin K antagonist [VKA]). Data from 2027 patients were eligible for analysis. Mean age was 73.0±11.2 years, 56.6% were men and 80.2% were anticoagulant naïve. Stage≥4 chronic kidney disease was present in 2.2% of patients prescribed apixaban, none of those prescribed dabigatran or rivaroxaban, and 16.8% of those prescribed VKAs. The median CHA2DS2-VASc score was 3 for all three NOACs and 4 for VKAs; the median HAS-BLED score was≥3 for 2.5-5.9% of patients prescribed NOACs and 12.0% of those prescribed VKAs. Apixaban was more likely to be prescribed than other NOACs in older patients with higher bleeding risk and decreased renal function, and VKAs in patients with lower bleeding risk and better renal function. Patients received a reduced dose (5mg/day; 30.4% patients) or a full dose (10mg/day; 69.6% patients) of apixaban. Only 79.3% of patients prescribed apixaban had doses consistent with the summary of product characteristics; underdosing was more frequent than overdosing. Off-label use of apixaban was observed, mainly in elderly patients, despite normal renal function and weight. Initiation of apixaban versus NOACs was more common among patients with increased age, higher bleeding risk and decreased renal function, whereas initiation of apixaban versus VKAs was more common among patients with lower bleeding risk and better renal function.

Use of specific anti-Xa levels in acute kidney injury to transition patients from oral factor Xa inhibitors to i.v. heparin infusion.

This case series presents 3 patients with acute kidney injury taking apixaban or rivaroxaban and transitioning to a heparin infusion. Case 1 was a 78-year-old man admitted with respiratory failure, acute decompensated heart failure, and acute kidney injury. He was taking apixaban for atrial flutter. He was transitioned to an i.v. heparin infusion and had 2 consecutive heparin antifactor-Xa levels greater than 2 units/mL. Heparin was held and resumed about 36 hours later when the apixaban anti-Xa level was less than 50 ng/mL. Case 2 was a 55-year-old man admitted with acute kidney injury, taking apixaban for a recent deep vein thrombosis. Apixaban anti-Xa levels were monitored and i.v. heparin was initiated when the level was less than 100 ng/mL, about 56 hours after the last apixaban dose. Case 3 was a 64-year-old woman admitted with sepsis and acute kidney injury taking rivaroxaban for pulmonary embolism, which occurred 2 weeks prior to admission. Rivaroxaban anti-Xa levels were monitored and i.v. heparin was initiated about 36 hours after the last dose when the level was less than 100 ng/mL. The management strategy did not lead to any thrombotic outcomes; however, 1 patient experienced bleeding. Specific anti-Xa levels for rivaroxaban and apixaban appeared to be helpful in the transition of 3 patients to unfractionated heparin infusions in the setting of acute kidney injury. These levels provided enhanced, individualized care and likely helped avoid over and under anticoagulation.

Abstract 242: Comparison of Pharmacist-Managed Initial Dosing of Direct Oral Anticoagulants with Non-Pharmacist Practitioner Prescribing Patterns

Background: There is currently a lack of data regarding pharmacist-managed DOAC (direct oral anticoagulant) therapy. The objective of this study was to assess the impact of pharmacist-managed initial dosing of apixaban and rivaroxaban utilizing a Pharmacy and Therapeutics Committee approved guideline when compared with general practitioner/cardiologist practitioner prescribing practices for patients with Non-Valvular Atrial Fibrillation (NVAF). Methods: A retrospective, chart review was performed during the period of January 2015 to January 2018 and included adults 18-95 years old, who were prescribed apixaban or rivaroxaban for documented NVAF. Patients eligible for this study were split up into two cohorts: a pharmacist-managed cohort and a non-pharmacist-managed cohort. The primary endpoint of the study was the percentage of patients who received appropriate initial apixaban or rivaroxaban dosing. Any incorrect initial doses of apixaban or rivaroxaban were then analyzed to determine the reason for error. The secondary endpoints included thromboembolic and hemorrhagic adverse events. Exploratory analyses included: provider follow up-time, inappropriate DOAC use in valvular atrial fibrillation (VAF), and correct transition from warfarin to DOAC. Results: For the primary endpoint, the pharmacist practitioner was significantly more accurate when initially dosing apixaban and rivaroxaban compared to non-pharmacist practitioners (97% [63 out of 65] vs. 74% [48 out of 65] correct prescriptions, p=0.001). When evaluating the reason for error in prescribing, non-pharmacist providers were significantly less likely to dose the patient appropriately based on renal function or drug interactions (p=0.003). For the secondary endpoint of hemorrhagic or thromboembolic events, there were no statistically significant differences among the two provider types. The exploratory analyses revealed that 3% (2 out of 65) of the patients in the non-pharmacist managed cohort had VAF and received a DOAC for antithrombotic therapy. The patients in the pharmacist managed cohort had zero patients receive a DOAC for VAF. The pharmacist was also significantly better at transitioning patients from warfarin to DOACs correctly compared to non-pharmacist practitioner (100% [12 out of 12] vs. 50% [3 out of 6], p=0.025) and following up with patients within a four-month time frame compared to non-pharmacist practitioners (100% [65 out of 65] vs. 82% [53 out of 65], p=0.001). Conclusion: Additional research is required to evaluate the benefits of pharmacist-managed anticoagulation; however, based on the results of this study, pharmacists are significantly better equipped to initiate DOAC therapy for patients with NVAF. Based on the findings of the study results, pharmacist-managed DOAC services may be transferrable to a variety of different disease states requiring anticoagulation therapy.

A Prospective Study to Examine the Need to Adjust the Dose of Apixaban When Used in Atrial Fibrillation and Obesity

A Prospective Study to Examine the Need to Adjust the Dose of Apixaban When Used in Atrial Fibrillation and Obesity

Evaluation of the Effect of Apixaban on INR in the Inpatient Population.

Direct oral anticoagulants (DOACs), particularly direct factor Xa inhibitors, have been associated with prolongation of the prothrombin time and the international normalized ratio (INR). Although DOACs do not require monitoring, elevations in the INR have been reported in in vitro and observational studies. The literature surrounding the extent of elevation and the clinical significance is limited. The objective of this study was to quantify the degree of INR elevation in hospitalized patients receiving apixaban. This was a single-center, retrospective, observational analysis of adult patients who received at least 1 dose of apixaban during their hospital admission and had at least 1 INR sample collected prior to and following administration. The major end point of this study was to characterize the effect of apixaban on the INR by determining the percentage of patients with an INR higher than our laboratory defined normal (defined as INR > 1.1). Minor end point outcomes included the incidence of an INR increase >0.3 from baseline INR and additional patient-specific factors that may influence INR elevation. Seventy-nine patients were included in the analysis. On day 1 of therapy, the median (interquartile range, IQR) INR was 1.4 (1.3:1.6) with 84.5% of patients having an elevated INR. The median (IQR) INR increased to 1.5 (1.4:1.6) and 1.7 (1.5:1.9) on day 4 and day 7, respectively. Of patients whose INR increased by more than 0.3, the median (IQR) change in INR from baseline was 0.5 (0.4:0.6). Apixaban is associated with a notable increase in INR in hospitalized patients, although it is not clear the clinical impact of the increase. Although literature does not support monitoring INR as a marker of apixaban activity, it is important for clinicians to understand the association apixaban has on the INR to avoid inappropriate interpretation of routine coagulation assays.

Comparative Stroke, Bleeding, and Mortality Risks in Older Medicare Patients Treated with Oral Anticoagulants for Nonvalvular Atrial Fibrillation

BackgroundNonvitamin K antagonist oral anticoagulants (NOACs) are alternatives to warfarin in patients with nonvalvular atrial fibrillation. Randomized trials compared NOACs with warfarin, but none have compared individual NOACs against each other for safety and effectiveness. MethodsWe performed a retrospective new-user cohort study of patients with nonvalvular atrial fibrillation enrolled in US Medicare who initiated warfarin (n = 183,318), or a standard dose of dabigatran (150 mg twice daily; n = 86,198), rivaroxaban (20 mg once daily; n = 106,389), or apixaban (5 mg twice daily; n = 73,039) between October 2010 and September 2015. Propensity score-adjusted Cox proportional hazards regression was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the outcomes of thromboembolic stroke, intracranial hemorrhage, major extracranial bleeding, and all-cause mortality, comparing each NOAC with warfarin, and with each other NOAC. ResultsCompared with warfarin, each NOAC was associated with reduced risks of thromboembolic stroke (20%-29% reduction; P = .002 [dabigatran], P < 0.001 [rivaroxaban, apixaban]), intracranial hemorrhage (35%-62% reduction; P < 0.001 [each NOAC]), and mortality (19%-34% reduction; P < .001 [each NOAC]). The NOACs were similar for thromboembolic stroke but rivaroxaban was associated with increased risks of intracranial hemorrhage (vs dabigatran: HR = 1.71; 95% CI, 1.35-2.17), major extracranial bleeding (vs dabigatran: HR = 1.32; 95% CI, 1.21-1.45; vs apixaban: HR = 2.70; 95% CI, 2.38-3.05), and death (vs dabigatran: HR = 1.12; 95% CI, 1.01-1.24; vs apixaban: HR = 1.23; 95% CI, 1.09-1.38). Dabigatran was associated with reduced risk of intracranial hemorrhage (HR = 0.70; 95% CI ,0.53-0.94) and increased risk of major extracranial bleeding (HR = 2.04; 95% CI, 1.78-2.32) compared with apixaban. ConclusionsAmong patients treated with standard-dose NOAC for nonvalvular atrial fibrillation and warfarin users with similar baseline characteristics, dabigatran, rivaroxaban, and apixaban were associated with a more favorable benefit–harm profile than warfarin. Among NOAC users, dabigatran and apixaban were associated with a more favorable benefit–harm profile than rivaroxaban.

Les traitements anticoagulants oraux chez les personnes âgées : faut-il encore prescrire des antivitamines K ?

Vitamin-K antagonists (VKA) have been the standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two classes of direct oral anticoagulants (DOA) are currently available in France: (a) direct thrombin inhibitors: dabigatran; and (b) direct factor Xa inhibitors: rivaroxaban, apixaban and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring. Several randomized trials have shown that DOA are non-inferior to VKA for treating venous thromboembolic disease (prophylactic or curative treatment) and atrial fibrillation (prevention of associated embolisms). DOA might be also effective for long-term treatment of coronary disease, in some cases. No trial has specifically studied older patients. In the context of atrial fibrillation, subgroup analysis show similar results between patients above and below 75-years-old. Lower doses of dabigatran and apixaban should be used in many older people. All DOA are eliminated at least partly by kidneys. Their dose must be reduced in moderate renal failure (filtration glomerular rate (FGR) 30 to 50mL/min) and they are contraindicated in older patients with severe renal failure (FGR<30mL/min). DOA also have other problems: (a) important drug interactions are still possible, (b) the clinical application of specific coagulation tests need to be defined, (c) their safety in some subgroups of elderly patients, very different from patients included in clinical trials, is not known.

Pharmacokinetics and Pharmacodynamics of an Oral Formulation of Apixaban in Horses After Oral and Intravenous Administration.

Horses with inflammatory and infectious disorders are often treated with injectable heparin anticoagulants to prevent thrombotic complications. In humans, a new class of direct oral acting anticoagulants (DOAC) appear as effective as heparin, while eliminating the need for daily injections. Our study in horses evaluated apixaban, a newly approved DOAC for human thromboprophylaxis targeting activated factor X (Xa). Our goals were to: (1) Determine pharmacokinetics and pharmacodynamics of apixaban after oral (PO) and intravenous (IV) administration in horses; (2) Detect any inhibitory effects of apixaban on ex vivo Equid herpesvirus type 1 (EHV-1)-induced platelet activation, and (3) Compare an anti-Xa bioactivity assay with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) for measuring apixaban concentrations. In a blinded placebo-controlled cross-over study, five horses received a single dose (0.2 mg/kg) of apixaban or placebo PO or IV. Blood was collected before and at 3 (IV) or 15 (PO) min, 30 and 45 min, and 1, 2, 3, 4, 6, 8, and 24 h after dosing for measuring apixaban UPLC-MS concentrations and anti-Xa activity. Pharmacodynamic response was measured in a dilute prothrombin time (dPT) assay. Flow cytometric EHV-1-induced platelet P-selectin expression and clinical pathologic safety testing were performed at baseline, 2 and 24 h and baseline and 24 h, respectively. We found no detectable apixaban in plasma PO administration. After IV administration, plasma apixaban levels followed a two-compartment model, with concentrations peaking at 3 min and decreasing to undetectable levels by 8 h. The elimination half-life was 1.3 ± 0.2 h, with high protein binding (92–99%). The dPT showed no relationship to apixaban UPLC-MS concentration and apixaban did not inhibit EHV-1-induced platelet activation after IV dosing. Apixaban anti-Xa activity showed excellent correlation to UPLC-MS (r2 = 0.9997). Our results demonstrate that apixaban has no apparent clinical utility as an anticoagulant for horses due to poor oral availability.