Direct Oral Anticoagulants Dosing Research Articles

Outcomes of Patients with Extended Anticoagulation Using Low Dose Doacs Compared to Standard Therapeutic Anticoagulation

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 the therapeutic doses. The real-world effectiveness as well as utilization of this approach in clinical practice compared to continuing at therapeutic doses is unknown.Aims: Evaluate the efficacy of reduced-dose DOACs compared to standard therapeutic anticoagulation in patients with extended anticoagulation.Methods: Consecutive patients with VTE were identified using the Mayo Clinic VTE Registry from March 1st , 2013 to December 31st, 2020. 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. Type of anticoagulation and dose changes were recorded, and progressing to a low dose was treated as an endpoint. In the models relating it to the outcome, it was treated as a time-dependent covariate in the cox models. After completing standard anticoagulation treatment for 3 months with any anticoagulant, patients continuing anticoagulation were divided into two groups: standard therapeutic anticoagulation (any drug) vs those who transitioned to rivaroxaban 10 mg daily or apixaban 2.5mg twice daily any time after 3 months. Patients with recurrent VTE, major or CRNMB during the first 3 months were excluded from further analysis.Results: 219 patients (153 on Apixaban and 66 on Rivaroxaban) were identified in the low dose DOAC and 2521 in the standard anticoagulation group. The mean age was 60.7 years, mean weight was 93.2 Kg and 55.9% were males (Table 1). Patients on low dose DOACs were about the same age and weight compared to standard anticoagulation group. Among all diagnosis categories, patients with active cancer were less likely to be prescribed low dose DOACs (HR 0.56; 95%CI 0.42-0.73; P<0.001), while low dose DOACs prescription was more likely in patients with pulmonary embolism (HR 1.45; 95%CI 1.11-1.89; P=0.007). The median months to start a low dose DOAC after completing the 3 months was 3.1 months with standard deviation of 6.6 months and interquartile range 2.8 months. There was no statistically significant association in the likelihood of going to a low dose group in relation to VTE recurrence (HR 1.36; 95%CI 0.42-4.45; P=0.61) or major bleeding (HR 0.59; 95%CI 0.08-4.37; P=0.61). However, transitioning to low dose DOAC was associated with reduced mortality (HR 0.53; 95%CI 0.35-0.80; P=0.003). Also, patients on low dose DOACs were more likely to have a CRNMB (HR 2.76; 95%CI 1.15-6.62; P=0.02).Conclusion: In this study of patients continuing anticoagulation past 3 months for an initial acute venous thromboembolic event, transitioning to low dose DOACs was not associated with any statistically significant association with VTE recurrence or major bleeding. However, mortality was lower and CRNMB was higher in this unadjusted analysis. Our results show that physicians are not always waiting until 6 months to transition to low doses and low doses are being utilized in cancer patients. Further research is needed to better understand the higher risk for CRNMB identified in this group. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low Dose of Direct Oral Anticoagulants after Left Atrial Appendage Occlusion.

The optimal antithrombotic strategy following left atrial appendage occlusion (LAAO) is not yet clearly established. Low-dose non-vitamin K antagonist oral anticoagulants (NOAC) might represent a valid alternative, but data regarding their usage is scarce. The aim of this study was to examine the efficacy and safety of low-dose NOAC compared to single (SAPT) or dual antiplatelet therapies (DAPT) after LAAO. We included consecutive patients with non-valvular atrial fibrillation who underwent LAAO and received low-dose apixaban, SAPT, or DAPT at discharge. The primary objective of this study included an efficacy endpoint (thromboembolic events and device related thrombosis (DRT)) and a safety endpoint (incidence of major bleeding) within the first three months after LAAO. A total of 139 patients were included. This group involved SAPT in 26 (18%), DAPT in 73 (53%), and apixaban in 40 (29%) patients. Follow-up at three-months showed no significant differences in the primary efficacy endpoint (2 (8%) SAPT, 3 (4%) DAPT and 0 (0%) apixaban; p value = 0.25). In contrast, the primary safety endpoint occurred more frequently in DAPT patients (7 (10%) DAPT, 0 (0%), SAPT and 0 with apixaban; p value = 0.03). Combining both efficacy and safety outcomes, low dose apixaban had a lower rate of events (2 (8%) with SAPT, 9 (12%) with DAPT and 0 (0%) with apixaban; p = 0.046). Low-dose apixaban after LAAO may be a valid alternative to DAPT and SAPT as depicted by the reduction in the occurrence of major bleedings and combined DRT/major bleedings respectively. Randomized data will be necessary to validate this strategy.

Meta-analysis comparing inappropriately low dose versus standard dose of direct oral anticoagulants in patients with atrial fibrillation

BackgroundThe appropriateness of direct oral anticoagulant (DOAC) dosing has been the issue in the real-world setting, and inappropriately lower DOAC dose may not be as effective or safe as the standard dose in patients with atrial fibrillation (AF). Multiple real-world studies compared the inappropriately lower DOAC dose versus the standard dose, but their main findings were contradictory. MethodsA meta-analysis was performed to compare the efficacy and safety of the inappropriately lower DOAC dose with the standard DOAC dose in patients with AF. Database searches through May 30, 2021, were performed using Medline and Google Scholar. The primary efficacy outcome was stroke or systemic embolism, and the primary safety outcome was major bleeding. The secondary outcome was all-cause mortality. ResultsA total of 16 studies were included in this meta-analysis. It revealed that the inappropriately lower DOAC dose was significantly associated with a higher event rate of stroke or systemic embolism compared with the DOAC standard dose (odds ratio 1.21 [95% CI 1.02–1.43], P = 0.03, I2 = 66%). There was no significant difference in the major bleeding event rate between these groups (1.03, [0.92–1.15], P = 0.62; I2 = 27%). ConclusionThe inappropriately lower DOAC dose should be avoided to optimize DOAC effectiveness in patients with AF.

Outcomes of Direct Oral Anticoagulants Co-Prescribed with Common Interacting Medications

Direct oral anticoagulants (DOACs) can potentially interact with multiple prescription medications. We examined the prevalence of co-prescription of DOACs with interacting medications and its impact on outcomes in patients with atrial fibrillation (AF). Patients with AF treated with a DOAC from 2010 to 2017 at the Mayo Clinic and co-prescribed medications that are inhibitors or inducers of the P-glycoprotein and/or Cytochrome P450 3A4 pathways were identified. The outcomes of stroke, transient ischemic attack, or systemic embolism, major bleeding, and minor bleeds were compared between patients with and without an enzyme inducer. Cox proportional hazards model was used to assess the association between interacting medications and outcomes. Of 8,576 patients with AF (mean age 70 ± 12 years, 35% female) prescribed a DOAC (38.6% apixaban, 35.8% rivaroxaban, 25.6% dabigatran), 2,610 (30.4%) were on at least 1 interacting agent: the majority were on an enzyme inhibitor (n=2,592). Prescribed medications included non-dihydropyridine calcium channel blocker (n=1,412; 16.5%), antiarrhythmic medication (n=790; 9.2%), antidepressant (n=659; 7.7%), antibiotic/antifungal (n=77; 0.90%), antiepileptics (n=17; 0.2%) and immunosuppressant medications (n=19; 0.2%). Patients on an interacting medication were more likely to receive a lower dose of DOAC than indicated by the manufacturer's labeling (15.0% vs 11.4%, p <0.0001). In multivariable analysis, co-prescription of an enzyme inhibitor was not associated with risk of any bleeding (hazard ratio 0.87 [0.71 to 1.05], p=0.15) or stroke, transient ischemic attack, or systemic embolism (hazard ratio 0.82 [0.51 to 1.31], p=0.39). In conclusion, DOACs are co-prescribed with medications with potential interactions in 30.4% of patients with AF. Co-prescription of DOACs and these drugs are not associated with increased risk of adverse embolic or bleeding outcomes in our cohort.

Systematic errors in the choice of dose level of direct oral anticoagulants: urgency of an issue and approaches to its solution

The article presents updated information on the frequency of use of non-recommended low dosing of direct oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban). It gives substantiation of the urgency of the issue of providing the maximum efficiency of the use of anticoagulants in clinical practice, taking into account the high prevalence of atrial fibrillation and the pharmacological characteristics of the most commonly used drugs. The effects of such an unreasonable reduction in anticoagulant doses in elderly and senile patients are discussed. The results of recent observational studies that assessed the relationship between the use of direct oral anticoagulants and the risk of adverse clinical outcomes are presented. The data on the relationship between the use of unreasonably low dosing of anticoagulants in patients with atrial fibrillation, which were recently obtained during the implementation of the GARFIELD-AF registry, are discussed. The data on a rather high variability of concentrations of direct oral anticoagulants are presented. The frequency of using apixaban in an unreasonably reduced dose, as well as the effects of using non-recommended doses of apixaban hold a specific place in the article. The unreasonableness of attempts to further reduce the risk of bleeding due to unreasonable reduction of apixaban dosing is emphasized, taking into account the stable data on the high safety of recommended dosing of apixaban, as well as the possible decrease in the effect if the dose reduction is not recommended. The data on the criteria for dose reduction, which are adopted in different countries, are presented. The proposed terms to designate different doses of direct oral anticoagulants, depending on their study in the course of large, randomized trials are discussed.

Potential risks of substituting estimated glomerular filtration rate for estimated creatinine clearance for dosing of direct oral anticoagulants in atrial fibrillation and chronic kidney disease

Abstract Background In the clinical trials with direct oral anticoagulants (DOAC) estimates of creatinine clearance (CrCl) with Cockcroft-Gault equation were used to assess renal functions. Recently, most laboratories report renal function estimated with the Modification of Diet in Renal Disease (MDRD) or Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, which may lead to impaired dosing of DOACs by physicians. Purpose To compare estimated glomerular filtration rate and estimated creatinine clearance in a large group of patients with atrial fibrillation and chronic kidney disease. Methods Physicians from 423 institutions in the Czech Republic were asked to enroll 5 consecutive outpatients with atrial fibrillation (AF) treated by a DOAC with stage 3 chronic kidney disease and glomerular filtration rate (eGFR) 30–59 ml/min estimated by MDRD or CKD EPI equations into the registry. Besides eGFR, serum creatinine values were recorded and CrCl calculated by the Cockroft-Gault formula. Results of CrCl and eGFR obtained in individual patients were compared and statistically analyzed using two-sample t-test. Results A total of 2115 patients were enrolled. Mean CrCl was 47.43 ml/min, mean eGFR calculated by MDRD and CKD-EPI was lower 43.88 and 43.53 ml/min (P for difference &amp;lt;0.001 for both). Mean difference between CrCl and eGFR in individual patients calculated by MDRD and CKD-EPI was 8.8 and 9.41 ml/min. A difference beween CrCl and eGFR &amp;gt;10 ml/min was found in 31.5% and 34.8% patients when using MDRD and CKD-EPI formulas. The respective differences between CrCl and eGFR between 4.1 and 10 ml/min were found in 28.5% (MDRD) and 30.8% (CKD-EPI). At CrCl above or below 50 ml/min, 24.0% and 24.2% were misclassified when using eGFR calculated by MDRD and CKD-EPI. At CrCl above or below 30 ml/min, 9.8% (MDRD) and 10.0% (CKD-EPI) patients were misclassified (please see Figures). Conclusions When eGFR estimated by MDRD or CKD-EPI is used to assess renal function and guide DOAC dosing instead of CrCl calculated by the Cockroft-Gault formula in patients with AF and stage 3 CKD, more than a third of patients is misclassified and wrong DOAC dose can be recommended. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Boehringer-Ingelheim Differences between CrCl and CKD-EPIDifferences between CrCl and MDRD

Efficacy and safety of dual pathway inhibition in patients with cardiovascular disease

Abstract Background The use of low dose of direct oral anticoagulants (DOAC) in adjunct to antiplatelet therapy, known as dual pathway inhibition (DPI), has been tested as an antithrombotic treatment regimen for the prevention of ischemic events in patients with cardiovascular disease (CVD). Purpose The aim of this systematic review and meta-analysis is to determine the overall safety and efficacy of a DPI strategy in patients with CVD. Methods Randomized controlled trials (RCTs) comparing the use of a DOAC at a low dose (LD) regimen, defined as a dosage below that approved for stroke prevention, versus placebo among patients with CVD treated with single or dual antiplatelet therapy were included. Incidence Rate Ratios (IRRs) with 95% confidence Intervals (CIs) were used to overcome different follow-up durations among the included trials. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was major bleeding. A pre- specified subgroup analysis was performed according to the different low dose DOAC regimens used in the DPI arm [LD versus very low dose (VLD)]. Number needed to treat (NNT) and number needed to harm (NNH) were also calculated. Results A total of 55,782 patients from 7 RCTs were included. Compared with placebo, a DPI strategy was associated with a significant reduction in MACE (IRR 0.85, 95% CI 0.78–0.91; NNT 86) and a significant increase of major bleeding (IRR 2.05, 95% CI 1.50–2.80; NNH 89). Moreover, there was a significant reduction of myocardial infarction (IRR 0.86, 95% CI 0.78–0.97; NNT 355) and a significant increase of all bleeding (IRR 1.82, 95% CI 1.49–2.22; NNH 23) with DPI compared to placebo. There were no differences between groups for the outcomes of CV death (IRR 0.90, 95% CI 0.79–1.03; NNT 784), intracranial hemorrhage (IRR 1.18, 95% CI 0.71–1.96; NNH 1810) and fatal bleeding (IRR 1.13, 95% CI 0.76–1.69; NNH 3170). There was a borderline non-significant reduction of all-cause death (IRR 0.92, 95% CI 0.80- 1.01; NNT 821), and stroke (IRR 0.73, 95% CI 0.53–1.01; NNT 315) favouring DPI (Figures 1 and 2). At subgroup analyses a DPI strategy with the use of VLD dose of DOAC (i.e. rivaroxaban 2.5 mg twice daily) mitigated the risk of bleeding without any trade-off in efficacy compared to LD of DOAC regimens and a meta-regression analysis showed a significant interaction between dual antiplatelet therapy use and the risk of major bleeding, intracranial hemorrhage and stroke. Conclusions In patients with CVD, the use of a LD of a DOAC in combination with antiplatelet therapy as part of a DPI regimen is effective in reducing ischemic events, at the expense of increased major and all bleeding but no increase of intracranial hemorrhage and fatal bleeding. A DPI strategy can be particularly advantageous with the use of a VLD of DOAC (i.e. rivaroxaban 2.5 mg twice daily) combined with a single antiplatelet agent among patients at high ischemic and low bleeding risk. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): D.C. declares that he has received consulting and speaker fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, outside the present work. F.C declares that he has received consulting and speaker fees from Biotronic, Amgen, Astra Zeneca, Servier, Menarini, BMS, outside the present work. F.A. declares that she has received consulting and speaker fees from Amgen, Bayer, BMS-Pfizer and Daiichi Sankyo, outside the present work. D.J.A. declares that he has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PhaseBio, PLx Pharma, Pfizer, Sanofi, and The Medicines Company and has received payments for participation in review activities from CeloNova and St Jude Medical, outside the present work. D.J.A. also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, Renal Guard Solutions and Scott R. MacKenzie Foundation. The remaining authors report no disclosures. Figure 1Figure 2

Predictors of inappropriate dosing of direct oral anticoagulants in nonagenarian patients with atrial fibrillation

Abstract Background Direct oral anticoagulants (DOACs) are presented as a good option for older patients owing to their safety profile. However, the dosing can become challenging especially in this population. Objective Our aim is to evaluate the predictors of inappropriate dosing of DOACs. Methods The authors analyzed the use of DOACs in 726 patients aged ≥90 years with a diagnosis of atrial fibrillation (AF) from a retrospective multicenter registry from 3 health areas in Spain. We studied the dosing, differentiating between appropriate dose, underdosing or overdosing. To evaluate the best predictive model, the Akaike information criterion (AIC) was used. Results Follow-up was 27.7±18.3 months. Mean age was 93.0±5.2 years, and 60.1% of patients were female. 339 patients received rivaroxaban (47.3%), 237 apixaban (33.1%), 105 dabigatran (14.7%) and 35 edoxaban (4.9%). An important proportion of patients received a suboptimal dose (41.5%, n=297): 35.3% underdosed and 6.1% overdosed. The rate of suboptimal dosing was higher for apixaban and lower for dabigatran (Figure 1A). In our registry we found as a predictors of inappropriate dosing: kidney function (Chronic Kidney Disease Epidemiology Collaboration), odds Ratio (OR) 1.04; 95% CI: 1.03–1.05, P&amp;lt;0.001; weight measured in kilograms, OR 1.04; 95% CI: 1.01–1.07, P=0.012; and high blood pressure (HBP), OR 1.61; 95% CI: 1.02–2.53, P=0.041 (Figure 1B). Other variables such as HASBLED, CHADSVASc, anemia, prior bleeding, or concomitant use of antiplatelet therapy, were not significantly associated. Conclusions We want to highlight that the use of an inappropriate dose of DOAC in older patients is common, about 40% in our study. Apixaban was the most frequently underdosed DOAC. HBP, weight, and kidney function were associated with an inappropriate dosing prescription. Therefore, it is important to carefully evaluate the characteristics of the patient to prescribe the appropriate dose that guarantees a correct action. Funding Acknowledgement Type of funding sources: None. Dosing of DOACsPredictors of inappropriate dosing

535 Are Routine Post-Operative Blood Tests Necessary Following Hip or Knee Arthroplasty in Fit and Well Patients?

Abstract Introduction Enhanced recovery protocols in hip and knee arthroplasty have achieved same-day discharge in selected patients. However, abnormal serum sodium, haemoglobin and creatinine may affect postoperative management. In particular, Serum creatinine guides dosage of prophylactic direct oral anticoagulants (DOAC). In this study we aim to establish if post-operative blood tests following arthroplasty might affect management. Method Patients undergoing primary hip and knee arthroplasty surgery at our unit between April 2018 and March 2019 were included. National Joint Registry input forms were used to identify the patients and their American Society for Anaesthesiologists (ASA) grade. Patients with an ASA grade of 1 or 2 were included. The incidence of AKI, hyponatraemia, drop in haemoglobin below 80g/L (the threshold for consideration of transfusion) and altered DOAC dose were recorded. For statistical analysis, the z-test of single proportion was used to compare results to a hypothesised expected population proportion of 1% for group sizes greater than 10. The p-value was set to 0.05. Results Results leading to a change in management were seen in 19 of the 218 patients (8.7%) (p &amp;lt; 0.0001). Twelve patients (5.5%) developed stage 1 or 2 AKI (p &amp;lt; 0.0001). Three patients required a reduction in the DOAC dose in response to their post-operative creatinine result. Post-operative haemoglobin level was below 80 g/L in two patients. Hyponatraemia was observed in one fifth of the patients and required intervention in two patients. Conclusions Post-operative blood tests are essential prior to discharge for all patients following hip and knee arthroplasty, regardless of pre-operative status.

Effectiveness and safety of the direct oral anticoagulants in non-triple positive antiphospholipid syndrome without prior arterial thromboembolism.

Thrombotic antiphospholipid syndrome (TAPS) is an autoimmune disorder that manifests with venous thromboembolism (VTE) and/or arterial thromboembolism (ATE) in the presence of persistent antiphospholipid antibodies (aPLs). Recent trials have failed to demonstrate non-inferiority of the direct oral anticoagulants (DOACs) compared to vitamin K antagonists as anticoagulation in TAPS, but there is a subgroup of non-triple positive patients without prior ATE in who only limited data exists. The objective of this study was to assess the effectiveness and safety of DOACs in non-triple positive TAPS without prior ATE. We conducted a retrospective review of all non-triple positive TAPS patients without prior ATE who were anticoagulated with a DOAC at two tertiary care hospitals from January 2010 to July 2020. We assessed outcomes of VTE, ATE, major bleeding, and clinically relevant non-major bleeding (CRNMB). 50 patients were included in the analysis, encompassing 157.2 years of patient follow-up. There were no recurrent VTE, but one patient had a possible arterial thrombosis (0.64 events per 100 patient-years [95% confidence interval (CI 0.16-35.49)] as a transient ischemic attack (TIA) which occurred on reduced dose DOAC. There were no major bleeding events, but two patients had CRNMB (1.27 events per 100 patient-years [95% CI 1.5-46.0]), both as menorrhagia. DOACs were effective and safe as anticoagulation in non-triple positive TAPS patients without prior ATE with a low rate of recurrent thrombosis and bleeding. Larger, prospective controlled studies are required to confirm these findings prior to routine use of DOACs in this subgroup.

Uninterrupted Direct Oral Anticoagulants Without a Change in Regimen for Catheter Ablation for Atrial Fibrillation Is an Acceptable Protocol.

Background: In patients undergoing catheter ablation (CA) for atrial fibrillation (AF), the use of uninterrupted direct oral anticoagulants (DOACs) is the current protocol. This study evaluated bleeding complications following the uninterrupted use of 4 DOACs in patients undergoing CA for AF without any change in the dosing regimen. Moreover, we assessed differences between once- and twice-daily DOAC dosing in patients undergoing CA for AF who continued on DOACs without any change in the dosing regimen.Methods and Results: This study was a retrospective single-center cohort study of consecutive patients. All patients continued DOACs without interruption or changes to the dosing schedule, even in the case of morning procedures. The primary endpoint was the incidence of major bleeding events within the first 30 days after CA. In all, 710 consecutive patients were included in the study. Bleeding complications were less frequent in the uninterrupted twice- than once-daily DOACs group. However, the incidence of cardiac tamponade across all DOACs was low (0.98%; 7/710), suggesting that uninterrupted DOACs without changes to the dosing regimen may be an acceptable strategy. The rate of total bleeding events, including minor bleeding (12/710; 1.6%), was also satisfactory.Conclusions: Uninterrupted DOACs without any change in dosing regimen for patients undergoing CA for AF is acceptable. Bleeding complications may be less frequent in patients receiving DOACs twice rather than once daily.

Lower dose direct oral anticoagulants and improved survival: A combined analysis in patients with established atherosclerosis

Lower dose direct oral anticoagulants and improved survival: A combined analysis in patients with established atherosclerosis

Direct Oral Anticoagulants and Non-valvular Atrial Fibrillation: Compliance with Dose Level Guidelines in Patients Aged 80Years and Over.

Direct oral anticoagulants (DOACs) are currently recommended as first-line or (after vitamin K antagonists) second-line therapy for preventing stroke and systemic embolism in patients with non-valvular atrial fibrillation. In patients aged 80 years and over, however, the fear of DOAC-associated bleeding and the complexity of DOAC dosing regimes may prompt physicians to prescribe inappropriate dose levels. The objective of this study was to determine compliance with French and European guidelines of doses of three DOACs (apixaban, dabigatran and rivaroxaban) prescribed to patients aged over 80years in an indication of non-valvular atrial fibrillation, and to identify factors associated with poor compliance. We performed a retrospective single-centre study of patients aged over 80 years routinely treated with a DOAC (apixaban, dabigatran or rivaroxaban) for non-valvular atrial fibrillation at Valenciennes General Hospital (Valenciennes, France) between 1 January, 2016 and 31 December, 2017. We determined compliance with French and European guidelines of DOAC doses as a function of each patient's clinical and laboratory parameters, and thus classified the regime as being appropriately dosed, overdosed or underdosed. A total of 703 patients (371 taking apixaban, 92 taking dabigatran and 240 taking rivaroxaban) were included in the study. We found that 274 patients (39%) had been prescribed an inappropriate DOAC regime, with underdosing in 241 cases (34%) and overdosing in 33 cases (5%). Underdosing mainly concerned the two most widely prescribed DOACs, i.e. apixaban (39% of all apixaban prescriptions were underdosed) and rivaroxaban (40%). Concomitant treatment with an antidepressant was associated with underdosing of rivaroxaban or apixaban (p=0.0339). In contrast, initial management in a neurology department was associated with appropriate dosing (p=0.000146) for both these DOACs. Among patients with non-valvular atrial fibrillation aged 80 years and over, about 40% of DOAC prescriptions feature inappropriate dose levels. It might be possible to reduce inappropriate dosing by raising awareness among hospital-based and private-practice prescribers, providing prescription support tools for DOACs, and performing medication reconciliations and reviews at hospital and in private practice.

A retrospective study of indications and consequences of monitoring direct oral anticoagulant plasma concentrations on patient care in a university hospital: The Retro-AOD study

IntroductionThe use of direct oral anticoagulants (DOAC) is increasing. Specific concentrations are available and have been proven to be reliable and reproducible in optimising patient care. This retrospective, monocentric study aimed to describe the indications and consequences of monitoring DOAC plasma levels on patient care. Materials and methodsWe collected data of patients hospitalised at the Bordeaux University Hospital between January 2017 and December 2018. These included demographics, indications, type, dose of DOAC, standard coagulation tests, creatinine clearance and DOAC plasma concentration using specifically calibrated rivaroxaban and apixaban anti-Xa and dabigatran anti-IIa assays. The date of last DOAC intake, the time between intake and plasma level measurement were also collected and analysed. ResultsA total of 2197 DOAC assays in 1488 patients were obtained in various clinical situations: urgent or elective procedures, context of acute renal failure, suspicion or occurrence of ischemic strokes, intra-cranial and other bleeding sites. Interpretation of these assays led physicians to maintain, postpone or cancel invasive and high haemorrhagic risk procedures in 757, 261 and 56 cases respectively. The remaining 1123 assays were associated with no significant modification of patient care. DOAC plasma concentration was ≤30 ng ml-1 (sensitivity 85.4%, specificity 73.6%, positive predictive value 71.1%, negative predictive value 86.7%, AUC 0.81) after a last intake of at least 2 days. ConclusionsOur study is, to date, the largest report of real-life measurement of specific DOAC plasma level at a single institution. Patient care was not modified in more than half of the assays.

Outcome of transvenous lead extraction in patients on minimally interrupted periprocedural direct oral anticoagulation therapy.

Direct oral anticoagulants (DOACs) have increasingly been used for several indications for systemic anticoagulation in patients with cardiac implantable electronic devices (CIEDs). The optimal management of anticoagulation therapy in patients undergoing transvenous lead extraction (TLE) procedures remains uncertain. The aim of this study was to evaluate the feasibility and safety of TLE during minimally interrupted DOAC therapy. This is a single-center retrospective study of all patients who underwent TLE of a pacemaker or implantable cardioverter-defibrillator lead while on DOAC therapy. In patients deemed to be at high thromboembolic risk, the last DOAC dose was administered the morning of the day before the procedure (regardless of the type of DOAC) and was restarted as soon as possible after the procedure, without bridging with parenteral anticoagulation. During the study period, a total of 84 patients underwent TLE while on minimally interrupted DOAC therapy (54% female, mean age: 74 ± 12 years). TLE was attempted for 161 leads, with a median lead dwell time of 61 months (interquartile range, 38-101). Complete procedural success was achieved for 156 leads (96.9%) and partial success for additional two leads (1.2%). One patient developed RV perforation and required pericardiocentesis and blood transfusion, but no surgical repair. Two patients developed pocket hematomas requiring invasive evacuation. No systemic or venous thromboembolic events were observed. There was no in-hospital mortality. In selected CIED patients at high risk for thromboembolism, TLE during minimally interrupted DOAC therapy may be considered when performed at experienced centers.

A Survey of the Use of Direct Oral Anticoagulants in Patients' Possession at the Time of Hospitalization

The dose of direct oral anticoagulants (DOACs) must be determined based on package insert recommendations. There are reports on the rate of inappropriate DOAC dose usage defined as a dose deviating from the approved dose in the package insert but no reports on factors that led to such deviations. Thus, patients who were admitted to the Suzuka Kaisei Hospital between 1 April 2016 and 31 March 2017 were chosen as subjects. Moreover, the factors that during hospitalization led to dose deviation from the package-insert DOAC dose were retrospectively examined. The characteristics of patients administered doses deviating from the package insert were compared with those of patients in the appropriate-dose group. The finding was that the proportion concomitantly administered antiplatelet agents was higher in the underdose group. In contrast, deviations from the recommended dose did not occur when DOACs were combined with CYP3A4 inhibitors or P-glycoprotein (P-gp) inhibitors. It was suggested that increase in the risk of hemorrhage by antiplatelet agents in combination with oral anticoagulants could explain deviations from the stipulated DOAC dose. In addition, a higher proportion of patients in the overdose group showed depressed Ccr, and gastrointestinal bleeding. In future, it will be necessary to propose principle-based dose changes for patients administered doses deviating from the package insert. If an underdose is administered, it is important to make a dose change that takes the concomitant drugs into consideration.

B-AB02-04 FEASIBILITY AND SAFETY OF MINIMALLY INTERRUPTED PERIPROCEDURAL DIRECT ORAL ANTICOAGULATION THERAPY FOR TRANSVENOUS LEAD EXTRACTION

Up to one third of patients with pacemakers and ICDs require long-term anticoagulation therapy for various indications. Recently, direct oral anticoagulants (DOACs) have increasingly taken the place of warfarin for several indications for systemic anticoagulation. The optimal management of anticoagulation therapy in patients undergoing TLE procedures remains uncertain. The aim of this study was to evaluate the feasibility and safety of TLE during minimally interrupted DOAC therapy. This is a single-center retrospective study of all patients who underwent TLE of a pacemaker or ICD lead while on DOAC therapy. In patients deemed to be at high thromboembolic risk, the last DOAC dose was administered the morning of the day before the procedure (regardless of the type of DOAC), and was restarted as soon as possible after the procedure, without bridging using parenteral anticoagulation. Between January 2015 and June 2020, a total of 71 patient underwent TLE while on minimally interrupted DOAC therapy and were included in this analysis (53% female, mean age: 74.5 ± 13.1 years). TLE was attempted for 133 leads with complete success in 129 leads (97.0%), partial success in 2 leads (in the form of retained tips of right ventricular [RV] leads), and failure in 3 leads (in 1 patient). A laser sheath was required for extraction of 102 leads (in 52 patients), and a mechanical sheath was used for 3 leads (in 2 patients). The average length of time since lead implantation was 69 ± 54 months (median 64; range 12 to 194 months). One patient experienced a major complication, RV perforation and cardiac tamponade prompting requiring emergency pericardiocentesis but no surgical intervention. Six patients developed pocket hematoma (requiring intervention in 2 patients and managed conservatively in 4), and 1 patient required blood transfusion (n = 1). There was no in-hospital mortality. In selected patients at high risk for thromboembolism, TLE during minimally interrupted DOAC therapy may be considered when performed by experienced operators at high-volume centers.

Appropriateness of inpatient dosing of direct oral anticoagulants for atrial fibrillation.

Direct oral anticoagulant (DOAC) use for stroke prevention in atrial fibrillation (AF) has dose reduction criteria including age, weight, serum creatinine, and creatinine clearance. There is a paucity of data for rates of inappropriate inpatient DOAC dosing in Australia. The objective was to determine the rates of inappropriate inpatient DOAC dosing in AF and identifying its associated underlying factors. We conducted a retrospective cross-sectional study from December 2013 to November 2019 across six South Australian public hospitals utilising a centralised electronic health record. Multivariate analysis was used to identify factors associated with underdosing of patients prescribed apixaban. Of 1882 inpatients, 544 (28.9 %) were inappropriately dosed. Underdosing was the most common form of inappropriate dosing with rates of 22.9 % (n = 295), 7.1 % (n = 7), and 25.1 % (n = 124) for apixaban, dabigatran, and rivaroxaban, respectively. Independent factors predictive of apixaban underdosing included higher age (adjusted odds ratio (aOR) 1.63 [95 % Confidence Interval (CI): 1.47-1.81]), higher serum creatinine (aOR 1.13 [95 % CI: 1.08-1.19]), higher total number of drugs on discharge (aOR 1.08 [95 % CI: 1.04-1.11]), and being already prescribed a DOAC on admission (aOR 1.63 [95 % CI: 1.12-2.38]). Nearly one quarter of all apixaban prescribing was inappropriately underdosed. Older patients with multimorbidity, frailty and polypharmacy present a challenge for clinicians in balancing risks of thromboembolism and bleeding. It is likely prescribers are more conservative in their apixaban dosing in this population. Clinicians should consider alternative drug regimens to avoid DOAC use at inappropriate doses at unknown safety and efficacy.

A Novel Laboratory Assay for Monitoring Unfractionated Heparin in Patients Taking Direct Oral Anticoagulants Prior to Hospital Admission

Introduction: As conditions like atrial fibrillation and venous thromboembolism (VTE) become more prevalent in the United States, the use of direct oral anticoagulants (DOACs) is increasing. Patients presenting to the hospital with indications of thrombosis are often started on unfractionated heparin (UFH) infusion, which has traditionally been monitored using laboratory based PTT and anti-Xa assays. While monitoring UFH with anti-Xa assays have been shown to correlate with better outcomes than dose adjustments guided by PTT, anti-Xa assays are susceptible to interferences from DOACs taken prior to admission and can result in inappropriate dose adjustments that can negatively impact patient care.Methods: We derived a novel assay, termed corrected heparin (CH), using quantified values from a chromogenic anti-Xa assay with heparin calibrators prior to and following heparinase treatment to detect any residual DOAC still present within the patient sample. We retrospectively assessed 79 adult patients admitted to our institution who had their UFH infusion monitored using the CH assay due to known DOAC use. These patients were continually monitored by the CH assay and the PTT (unreported) if they had detectable DOAC levels (>0.1 IU/mL by anti-Xa). Of the patients included in the study, 92% were administered apixaban, while 8% were administered rivaroxaban prior to admission and all received UFH while admitted.Results: To assess linearity of anti-Xa assay for this purpose, patient samples with both UFH and apixaban present were diluted with drug-free plasma and displayed good correlation (R2=0.999) throughout the linear range of the assay. Of the 79 patients, 53 patients reached the therapeutic range by the PTT and CH assays, 17 reached the therapeutic range by the CH assay only, 2 reached the therapeutic range by PTT only, and 2 never reached the therapeutic range with either assay. The average time to therapeutic dosing level for the CH assay was 9 hours after initiation of UFH infusion. Using the CH assay, we were able to determine how long the DOAC persisted and was detected by the anti-Xa assay. At 12 hours after the last DOAC dose, more than 80% of patients still had detectable DOAC levels capable of interfering with the anti-Xa assays. The majority of patients (80%) still had measurable anti-Xa assay interference from the DOAC until 72 hours after the last dose. We evaluated the role of kidney function as a predictor for prolonged interference in the anti-Xa assay however, clearance rates of apixaban were difficult to predict based on kidney function status alone.Conclusions: Our CH assay has provided clinicians with an assay that accounts for the presence of residual DOAC and allows patients to reach therapeutic heparin levels faster. Our study also highlights the delayed clearance of commonly prescribed DOACs, which can be longer than expected and independent of kidney function status resulting in prolonged interference in anti-Xa assays that can lead to improper dose adjustments and potentially negative outcomes for patients on UFH infusion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Use of Direct Oral Anticoagulants in Inherited Thrombophilia

Introduction: Factor V Leiden mutation and prothrombin G20210A mutation are the most common causes of an inherited thrombophilia and together account for 50 to 60 percent of diagnoses. Traditionally, patients have been treated with oral warfarin therapy or injectable low molecular weight heparin (LMWH), which requires frequent laboratory monitoring or self-injections. The difficulty with administration and monitoring of traditional therapy has made direct oral anticoagulants (DOACs) increasingly favored for treatment of VTE. However, the efficacy and bleeding complication of DOAC use in inherited thrombophilia has not been well studied.Methods: We designed a retrospective analysis of patients with Factor V Leiden mutation and prothrombin G20210A mutation at the University of Virginia who were treated with a DOAC (rivaroxaban, apixaban, edoxaban, or dabigatran) for treatment of VTE or atrial fibrillation from January 28th, 2011 to May 30th, 2017. Adult patients with presence of either homozygous or heterozygous mutation for either Factor V Leiden mutation or prothrombin mutation were included. All patients were required to be treated for at least 48 hours with a documented follow-up of adverse events. Medical charts were reviewed for age, gender, weight, presence of Factor V Leiden mutation and/or prothrombin G20210A mutation, DOAC dose, and frequency, bleeding events, and recurrent thrombotic events. Our primary outcomes were efficacy defined as development of a recurrent VTE and safety defined as occurrence of any bleeding event. Efficacy was compared to the post-hoc sub-group analysis that was conducted on the data from the RE-MEDY trial, in which VTE/VTE-related deaths were observed to be 1.5% with patients taking dabigatran compared to 2.3% with patients taking warfarin (p=0.2277) (Skelley, et al. J Throm Thrombolysis, 2017). Major and minor events were defined per International Society of Thrombosis and Hemostasis (ISTH) anticoagulation committee guidelines.Results: Fifty eight patients were eligible for analysis. The median age was 52.7 ± 16.7 years with 39 (67.2%) females. Baseline patient characteristics, type of thrombophilia, and indication for DOAC therapy are represented in Table 1. Median length of time on a DOAC was 24 months.Four patients developed a recurrent VTE however on further analysis, 3 patients were found to be non-compliant with DOAC therapy. Excluding the noncompliant patients, the rate of a recurrent VTE was 1.7% (Table 2).Nine (15.5%) patients suffered a bleeding event, of which 4 were major and 5 were minor (Table 2). Of the 4 major bleeding events, 3 were gastrointestinal (GI). One patient bled due to arterio-venous malformations, the second patient developed a bleed at the esophagectomy site, and the third patient had biliary drainage from ischemic liver disease post liver transplant. One patient suffered an intracranial hemorrhage; this patient was concurrently taking aspirin and clopidogrel while on therapeutic apixaban. The minor bleeding events included epistaxis (n=1), hemoptysis (n=1) and GI (n=3). Hemoptysis was discovered simultaneously with the diagnosis of lung cancer. Three of the patients with minor bleeding events were taking ASA, including one who was also taking dual antiplatelet therapy with clopidogrel.Conclusion: DOACs have been shown to have similar efficacy and safety compared to warfarin in many patient populations. However, there are limited studies evaluating use of DOACs in patients with inherited thrombophilia. Substantial evidence supporting widespread DOAC use in these patients is lacking. Our study confirmed the efficacy of DOACs in this patient population with a thrombosis event of only 1.7% which is favorable compared to the warfarin historical control rate of 2.3% (Skelley, et al. J Throm Thrombolysis, 2017). There was a higher than expected rate of bleeding complications, however many patients were on dual antiplatelet therapy or had other risk factors for bleeding. It would be imprudent to attribute these bleeding events solely to DOAC use. Though this is the only study of its kind, it is limited by small numbers and retrospective design. Further studies are needed to evaluate the use of DOACs compared to warfarin and LMWH. We plan to conduct further analysis utilizing a control group of inherited thrombophilia patients on warfarin compared to those on DOACs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.