Dose Of Dabigatran Research Articles

Dabigatran Dual Therapy Versus Warfarin Triple Therapy Post–PCI in Patients With Atrial Fibrillation and Diabetes

ObjectivesThe aim of this study was to evaluate dabigatran dual therapy versus warfarin triple therapy in patients with or without diabetes mellitus in the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial. BackgroundIt is unclear whether dual therapy is as safe and efficacious as triple therapy in patients with atrial fibrillation with diabetes following percutaneous coronary intervention. MethodsIn RE-DUAL PCI, 2,725 patients with atrial fibrillation (993 with diabetes) who had undergone PCI were assigned to warfarin triple therapy (warfarin, clopidogrel or ticagrelor, and aspirin) or dabigatran dual therapy (dabigatran 110 mg or 150 mg twice daily and clopidogrel or ticagrelor). Median follow-up was 13 months. The primary outcome was the composite of major bleeding or clinically relevant nonmajor bleeding, and the main efficacy outcome was the composite of death, thromboembolic events, or unplanned revascularization. ResultsAmong patients with diabetes, the incidence of major bleeding or clinically relevant nonmajor bleeding was 15.2% in the dabigatran 110 mg dual therapy group versus 27.5% in the warfarin triple therapy group (hazard ratio [HR]: 0.48; 95% confidence interval [CI] 0.35 to 0.67) and 23.8% in the dabigatran 150 mg dual therapy group versus 25.1% in the warfarin triple therapy group (HR: 0.87; 95% CI: 0.62 to 1.22). Risk for major bleeding or clinically relevant nonmajor bleeding was also reduced with both dabigatran doses among patients without diabetes (dabigatran 110 mg dual therapy: HR: 0.54; 95% CI: 0.42 to 0.70; dabigatran 150 mg dual therapy: HR: 0.63; 95% CI: 0.48 to 0.83). Risk for the efficacy endpoint was comparable between treatment groups for both patients with and those without diabetes. No interaction between treatment and diabetes subgroup could be observed, either for bleeding or for composite efficacy endpoints. ConclusionsIn this subgroup analysis, dabigatran dual therapy had a lower risk for bleeding and a comparable rate of the efficacy endpoint compared with warfarin triple therapy in patients with atrial fibrillation with or without diabetes following percutaneous coronary intervention.

Switching from vitamin K antagonist to dabigatran in atrial fibrillation: differences according to dose

In atrial fibrillation (AF) patients 150 mg b.i.d. dabigatran is the standard dose, yet guidelines recommend 110 mg b.i.d. when bleeding risk is high. It is unknown to which extend these recommendations are followed in patients switching from vitamin K antagonist (VKA) to dabigatran. The aim of this study was to investigate if AF patients are switched from VKA to the appropriate dose of dabigatran. Using nationwide registries (22 August 2011 to 31 December 2012), we identified VKA-experienced AF patients with available creatinine values who switched to dabigatran. European guidelines criteria 2012 on dabigatran dosing were examined: age ≥80 years, HAS-BLED ≥3, estimated glomerular filtration rate (eGFR)<50 mL/min/1.73 m2, or use of interacting drugs. We identified 1626 VKA-experienced AF patients who switched to dabigatran 110 mg (820 patients) or 150 mg (806 patients). Patients who switched to 110 mg compared with 150 mg were older [median age 82 years (Q1-Q3: 77-86) vs. 68 years (Q1-Q3: 64-74)], more often females (54% vs. 35%), had a higher comorbidity burden, higher proportion with CHA2DS2-VASc score ≥2 (98% vs. 80%), and more with a HAS-BLED score ≥3 (46% vs. 28%). Patients switched to 110 mg had a higher absolute risk of mortality compared with patients switched to 150 mg. Overall, 26% were inappropriately dosed and 14% were switched to 110 mg although the higher dose was indicated. Furthermore, 39% of patients switched to 150 mg fulfilled one or more criteria for 110 mg, this mostly driven by high HAS-BLED scores (28.2% of patients on 150 mg). Female sex, age ≥80 years, eGFR < 50 mL/min/1.73 m2, drugs interacting with dabigatran, and prior bleeding were associated with switch to 110 mg. Patients inappropriately dosed had similar risk of mortality as patients appropriately dosed. Among VKA-experienced AF patients one in four were switched to a dabigatran dose contrary to guideline recommendations.

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.

Reduced dose of rivaroxaban and dabigatran vs. vitamin K antagonists in very elderly patients with atrial fibrillation in a nationwide cohort study.

The real-life benefits and risks of the non-vitamin K antagonist oral anticoagulants for stroke prevention in very elderly patients with atrial fibrillation (AF) are still debated. Cohorts of new users of rivaroxaban 15 mg, dabigatran 110 mg, or vitamin K antagonists (VKA) for AF ≥85 years old in 2013 or 2014 were identified in the nationwide French claims database and followed-up for 1 year. Cohorts were compared after 1:1 matching using high-dimensional propensity score. Compared to VKA use and considering 1-year cumulative incidences, risk of stroke, and systemic embolism was not different with rivaroxaban use [hazard ratio 1.14, 95% confidence interval (CI): 0.93-1.40] and lower with dabigatran use (0.77, 95% CI: 0.60-0.99), risk of major bleeding was not different with rivaroxaban use (0.91, 95% CI: 0.74-1.11) and with dabigatran use (0.81, 95% CI: 0.64-1.03), risk of all-cause death was borderline to significance lower with rivaroxaban use (0.91, 95% CI: 0.83-1.00), and lower with dabigatran use (0.87, 95% CI: 0.78-0.97). The risk for a composite of all events above was not different with rivaroxaban use (0.96, 95% CI: 0.88-1.04) and lower with dabigatran use (0.87, 95% CI: 0.79-0.96) as compared with VKA use. The risk for the composite of all events was not different with rivaroxaban use as compared with dabigatran use (1.09, 95% CI: 0.97-1.23). This study shows for the first time in more than 25000 new real-life anticoagulant users for AF aged ≥85 years a neutral overall benefit-risk of rivaroxaban 15 mg vs. VKA and a favourable overall benefit-risk of dabigatran 110 mg vs. VKA on relevant clinical events. European Medicines Agency EUPAS14567 (www.encepp.eu) and Clinicaltrials.gov id NCT02864758.

P4767VTE-BLEED score predicts major bleeding in patients with atrial fibrillation

Abstract Background Bleeding risk scores in atrial fibrillation (AF) are used to identify risk factors for bleeding but not to determine anticoagulant therapy since high bleeding risk strongly correlates to high risk of stroke. VTE-BLEED is a simple bleeding risk score (Klok FA Eur Respir J 2016) that predicts major bleeding (MB) in patients with venous thromboembolism, but has never been evaluated in AF. Aims To evaluate VTE-BLEED in AF and whether dabigatran dose reduction in VTE-BLEED high-risk patients would result in a lower incidence of MB and the composite endpoint of MB plus stroke/systemic embolism. Methods Assessment of VTE-BLEED in 18040 patients of the RE-LY trial (Connolly SJ NEJM 2009) that compared dabigatran (both 150mg BID and 110mg BID) to warfarin. The score was calibrated to fit the AF population. Hazard ratios (HR) were obtained for the VTE-BLEED high-risk patients randomized to dabigatran. The risk ratios for MB and the composite outcome of MB plus stroke/systemic embolism between dabigatran 150mg and 110mg were calculated for the VTE-BLEED high-risk group. Results The adapted VTE-BLEED score classified 4060 patients (22.5%) as high-risk. A high score indeed predicted MB in patients treated with dabigatran 150mg BID or 110mg BID, for HRs of 2.48 (95% CI 1.96–3.13) and 2.61 (95% CI 2.04–3.33), respectively. In VTE-BLEED high-risk patients, the risk ratio between the two dabigatran doses was 0.53 (95% CI 0.35–0.78) for MB and 0.55 (95% CI 0.38–0.79) for the composite outcome, both in favor of dabigatran 110mg BID (Figure 1). Compared to the current European label of dabigatran, application of VTE-BLEED to determine dabigatran dosing would result in a different dose for 21% of patients. Figure 1 Conclusions VTE-BLEED was validated for AF. Our data suggest that dabigatran dose reduction in VTE-BLEED bleed high-risk patients -in addition to targeting individual modifiable risk factors for bleeding- may lower the risk of MB and improve patient outcome. This finding could have important clinical implications but should be confirmed in future studies.

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

P4750Uninterrupted and minimally-interrupted direct oral anticoagulant therapy in patients undergoing catheter ablation for atrial fibrillation. An updated meta-analysis

Abstract Background Adequate anticoagulation in catheter ablation of atrial fibrillation (AF) is crucial in preventing both thromboembolic events and life-threatening bleeding. As clinicians gain more experience and reassurance with data from clinical trials, the usage of Direct Oral Anticoagulants (DOAC) in patients undergoing catheter ablation of AF has rapidly increased over the last years. The purpose of this updated meta-analysis was to assess the latest evidence and compare the safety and efficacy of uninterrupted and minimally interrupted periprocedural DOAC anticoagulation protocols with uninterrupted Vitamin K Antagonists (VKA) in this setting. Methods Randomized or prospective controlled observational studies comparing DOACs to VKAs were identified with multiple databases (Embase, PubMed, Cochrane, and Scopus). Uninterrupted and minimally interrupted DOAC (single dose of dabigatran or apixaban withheld) were distinguished, VKA therapy was always uninterrupted. The primary outcomes were stroke or transient ischemic attack (TIA), major bleeding, and net clinical benefit. Results 32 studies were included in the final analysis, encompassing a total of 19.437 patients. The incidence of thromboembolic events was rare (less than 0.2%), with no significant difference between groups. Occurrence of major bleeding and net clinical benefit were significantly improved in patients assigned to uninterrupted DOAC treatment compared to VKAs (1.5% vs 2.2%, POR: 0.74, CI: 0.56–0.98, I2=0,0% and 1.7% vs 2.4%, POR: 0.76; CI: 0.59–0.99, I2=0,0%, respectively). Net clinical benefit Conclusion This updated meta-analysis, based on a large database, showed that DOAC therapy is equally effective as VKA in preventing stroke and TIA. Minimally-interrupted DOAC therapy is a non-inferior peri-procedural anticoagulation strategy, however, uninterrupted DOAC therapy showed superiority when compared to VKA regarding major, life-threatening bleeding. Our findings showed that uninterrupted periprocedural DOAC therapy is a safe and preferable alternative to VKAs in patients undergoing catheter ablation for atrial fibrillation. Acknowledgement/Funding This study was supported by an Economic Development and Innovation Operative Programme Grant (GINOP 2.3.2-15-2016-00048).

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.

Retrospective cohort study of the efficacy and safety of dabigatran: real-life dabigatran use including very low-dose 75\u2009mg twice daily administration

BackgroundDabigatran is a direct thrombin inhibitor and an anticoagulant that is prescribed to prevent ischemic stroke and systemic embolism in non-valvular atrial fibrillation. Dabigatran (150 mg twice daily) is non-inferior to warfarin for the prevention of stroke and systemic embolism. A dose reduction to 110 mg twice daily should be considered for patients with decreased renal function, elderly patients, and those with a history of gastrointestinal bleeding. A small number of patients are prescribed 75 mg twice daily; however, excessive dose reduction below that indicated on the package insert may decrease the effectiveness of dabigatran. In this study, we investigated the incidence of thromboembolic events and hemorrhagic complications in patients receiving different doses of dabigatran, including patients receiving the very low-dose of 75 mg twice daily.MethodsFive hospitals in Meguro and Setagaya areas of Tokyo were included in this study. The subjects were patients receiving dabigatran in the hospitals from March 2011 to February 2014. Thromboembolic events (stroke, systemic embolism, and transient cerebral ischemic attack) and hemorrhagic complications occurring before December 2014 were retrospectively evaluated.ResultsA total of 701 subjects received dabigatran during the study period: 187 patients (26.7%) received 150 mg twice daily (normal dose), 488 patients (69.6%) received 110 mg twice daily (low-dose), and 26 patients (3.7%) received 75 mg twice daily (very low-dose). Thromboembolism occurred in 4 (2.1%), 11 (2.3%), and 3 patients (11.5%), in the normal dose, low-dose, and very low-dose groups, respectively. The odds ratio of the 75 mg dose to the 150 and 110 mg doses was 5.73 (95% CI, 1.55–21.2; p = 0.009), and the incidence with the 75 mg dose was higher than that with the other doses. Although the number of events was limited, it should be noted that 3 patients in the very low-dose group had thromboembolic events.ConclusionsThe results suggest that sufficient anticoagulation efficacy may not be maintained when the dabigatran dose is excessively reduced to 75 mg twice daily.

SAT-154 Anticoagulants and the kidney: 10 years of clinical and experimental experience

Ten years ago we reported a case of acute kidney injury (AKI) with occlusive red blood cell (RBC) tubular casts in a patient on warfarin therapy, who had high international normalized ratio (INR). We termed this condition warfarin related nephropathy (WRN). Later, we and others demonstrated that WRN is a part of the broader syndrome, when patients on other anticoagulants may develop AKI. This new syndrome is referred nowadays as anticoagulant related nephropathy (ARN). We developed an animal model that reproduces the main histologic findings of ARN in humans. Renal pathology database was searched for kidney biopsies from patients on anticoagulant therapy. Cases with acute kidney injury were analyzed. Rtas were used to create 5/6 n4phrectomy model. Based on our renal pathology database, among 8636 native kidney biopsies reviewed at our institution, there were 47 (0.54 %) patients in whom deterioration in the kidney function could not be explained by kidney biopsy findings alone if anticoagulation was not taken into the equation. Thirty five of those patients (74%) were on warfarin therapy, five (11%) were on anti-platelet medications (including two on heparin, two on enoxaparin and one on Plavix/aspirin) and one (2%) on Factor Xa inhibitor (apixaban). Six (13%) did not have records of anticoagulation therapy, but they had acute coagulopathy (such as disseminated intravascular coagulation syndrome) at the time of deterioration of kidney function and their biopsy findings suggested of ARN. In addition to acute tubular necrosis (ATN) and numerous RBC casts, these patients had underlying glomerular changes, but the severity of that glomerular disease was out of proportion to the number of RBC casts and/or hematuria in these patients. Among these glomerular changes, the most common was mild glomerular immune complex deposits without significant proliferative lesions (23 cases, 49%), followed by mild focal pauci-immune crescentic glomerulonephritis (7 cases, 15%), diabetic glomerulosclerosis (5 cases, 11%) and focal segmental glomerular sclerosis (FSGS, 5 cases, 11%). We demonstrated that 5/6 nephrectomy in rats is a suitable models to study ARN. Thus, 5/6 nephrectomy rats had increase in serum creatinine and RBC tubular casts in the kidney when treated with high dose of warfarin or dabigatran (direct thrombin inhibitor). We demonstrated that the mechanisms of ARN include oxidative stress that plays a significant role in the acute tubular injury, but not in the glomerular filtration barrier injury. Anticoagulant-treated animals developed hypertension with more pronounced increase in the systolic blood pressure than in diastolic blood pressure. ARN is an uncommon diagnosis in renal pathology practice, but it should be considered when there is a disproportion between the severity of glomerular changes and the number of RBC casts and/or hematuria in a kidney biopsy in patients on anticoagulant therapy or who presented with acute coagulopathy. The glomerular changes in patients with suspected ARN are insufficient to explain the occurrence of substantial blood in tubules. Animal model of 5/6 nephrectomy in rats reproduces the main clinical and pathologic features of ARN.

Fully automated thromboelastograph TEG 6s to measure anticoagulant effects of direct oral anticoagulants in healthy male volunteers

BackgroundThe ability to assess the hemostatic effect of the direct oral anticoagulant (DOACs) may be valuable in clinical situations such as bleeding or thrombosis, before urgent surgery, or reversal of anticoagulation. We sought to assess the anticoagulant effect of DOACs with the new‐generation fully automated thrombelastograph TEG 6s using resonance‐frequency viscoelasticity measurements and disposable multichannel microfluidic cartridges. MethodsA single dose of oral dabigatran 150 mg, rivaroxaban 20 mg, or apixaban 5 mg was given to 9 healthy males. Phlebotomy was performed at 0, 1, and 3 hours after administration of DOAC. TEG parameters were measured using TEG_6s. Concentrations of DOACs were measured using chromogenic assays. The TEG parameters were correlated to the DOAC concentrations. ResultsThe reaction time (R) demonstrated the strongest response to DOAC intake. There were no correlations between other TEG parameters and DOAC concentrations. Using the direct thrombin inhibitor (DTI) channel, R was significantly correlated with dabigatran levels (r=0.94, P<0.0001). Using the anti–factor Xa (AFXa) channel, R was significantly correlated with rivaroxaban and apixaban levels (r=0.93 and r=0.83, respectively; P<0.0001 for both). R >2.5 minutes for dabigatran (DTI channel), >2.5 minutes for apixaban, and >1.8 minutes for rivaroxaban (AFXa channel) were associated with 100% sensitivity and ≥ 90% specificity to detect DOAC levels of ≥ 50 ng/mL. ConclusionWe have demonstrated that TEG_6s R has significant correlation with DOAC blood concentrations and has potential for monitoring the DOAC's effect on hemostasis with reasonable sensitivity in the small sample analyzed. This novel technology is easy to use on a small volume of whole blood without requiring a specialized laboratory. Further study is warranted to correlate R with clinical outcomes.

Appropriateness of dabigatran dosing in patients with nonvalvular atrial fibrillation (NVAF): A retrospective study conducted in a tertiary care university hospital in the eastern province of Saudi Arabia

BackgroundEstablishment of thromboembolism prevention remains a challenge despite the widespread consensus that thromboprophylaxis safely reduces patient morbidity and mortality. Dabigatran is a nonvitamin K antagonist oral anticoagulant (NOAC) which reduces the risk of thromboembolism. Proper dosing is important to achieve the maximum prophylactic benefit with a maintained safety profile. ObjectiveTo evaluate the appropriateness of dabigatran dosing for stroke and systemic embolism prevention in patients with nonvalvular atrial fibrillation (NVAF). MethodsThis is a retrospective cohort study of adults with NVAF. The data were collected from the electronic filing system of the hospital. Patients receiving dabigatran therapy were divided into two treatment groups according to the dose of dabigatran received. The indications for dabigatran as an oral direct anticoagulant, including age, risk of bleeding, creatinine clearance (CrCl), were collected. Appropriateness of dose reduction included any of the following factors: HAS-BLED score >2 points, age ≥75 years, or CrCl of 30–50 mL/min. The two groups were evaluated according to dose appropriateness. ResultsDabigatran dose of 110 mg was found to be inappropriately low in a large number of patients (31.3%). Multivariate regression analysis showed significant association of age and dose appropriateness (p < 0.001). ConclusionThis study revealed inappropriate prescription of reduced doses of dabigatran in a large number of patients. Age was identified as the main driving factor for underdosing. Physicians’ and pharmacists’ awareness regarding this type of high-risk medication should be improved to ensure appropriate and safe use of this commonly used drug.

Heparin dosing in uninterrupted anticoagulation with dabigatran vs. warfarin in atrial fibrillation ablation: RE-CIRCUIT study.

AimsTo describe heparin dosing requirements in patients who underwent catheter ablation of atrial fibrillation with uninterrupted anticoagulation using dabigatran etexilate (dabigatran) or warfarin to attain therapeutic activated clotting time (ACT) in the RE-CIRCUIT® study. The RE-CIRCUIT study showed significantly fewer major bleeding events in the dabigatran vs. warfarin treatment group. Unfractionated heparin was administered during the procedure to maintain ACT >300 s.Methods and resultsPatients were randomly assigned to dabigatran 150 mg bid or international normalized ratio-adjusted warfarin. Ablation was performed with uninterrupted anticoagulation and continued for 8 weeks after the procedure. Heparin was administered after placement of femoral sheaths before or immediately after transseptal puncture. Ablation was performed in 635 patients (dabigatran, 317; warfarin, 318); data were available from 396 patients administered heparin (dabigatran, 191; warfarin, 205). Most frequent time window from last dose of study drug to septal puncture was 0 to <4 h in the dabigatran (41.3%) and 16 to <24 h in the warfarin arms (44.7%). Overall mean (standard deviation) heparin dose was similar between the dabigatran and warfarin groups [12 402 (10 721) vs. 11 910 (8359) IU, respectively]. Heparin dosing requirement to reach therapeutic ACT was lowest when time from last dose of dabigatran to septal puncture was 0 to <4 h.ConclusionPatients treated with dabigatran required a similar amount of unfractionated heparin as those treated with warfarin to achieve an ACT of >300 s during ablation. More heparin units were required when the time from the last dose of dabigatran to septal puncture increased.

Effectiveness and safety of long-term dabigatran among patients with non-valvular atrial fibrillation in clinical practice: J-dabigatran surveillance

BackgroundThe effectiveness and safety of dabigatran etexilate (DE) have not been elucidated thoroughly in clinical practice for Japanese patients with non-valvular atrial fibrillation (NVAF). In particular, those of DE at a reduced dose due to dose reduction recommendations (DRR) remain unknown. MethodsNVAF patients who had newly initiated DE treatment for prevention of thromboembolic events between December 2011 and November 2013 were enrolled. They were followed until August 2016. Outcome events included thromboembolism, major bleeding, and all-cause death. ResultsThe study group consisted of 6443 patients (mean age, 70.9 years; male, 66.9%; and mean CHADS2 score, 1.8). During a follow-up period of 610 days (median), stroke, transient ischemic attack (TIA), and systemic embolism (SE) occurred at 1.4%/year for DE 110mg twice daily (BID) (DE220, n=4759) and 0.8% for dabigatran 150mg BID (DE300, n=1571, unadjusted p=0.0317). Major bleeding occurred at 1.3 and 0.6%/year for DE220 and DE300, respectively (unadjusted p=0.0097). All-cause death occurred at 1.5 and 0.5%/year for DE220 and DE300, respectively (unadjusted p=0.0005). When patients were divided into four groups based on DRR and DE doses (DE300 groups meeting and not meeting DRR, and DE220 groups meeting and not meeting DRR), incidence rates of stroke/TIA/SE and major bleeding differed among the four groups (unadjusted p=0.0026 and 0.0194 for trend, respectively); DE220 group meeting DRR had the highest rates (1.7% and 1.4%/year, respectively). However, in multivariate analysis, no differences between doses were observed regarding any outcomes. ConclusionsThe present results are indicative of the favorable benefit-risk profile of dabigatran in Japanese clinical practice. Dabigatran dose was not independently associated with thromboembolic and bleeding events in Japanese NVAF patients.

Abstract TP517: Characteristics and Outcomes in Patients With Atrial Fibrillation (af) Receiving Direct Oral Anticoagulants (doacs) in off-Label Dose

Objective: We evaluated adherence to FDA-approved dosing criteria for patients with AF who initiated dabigatran and rivaroxaban, and the impact of off-label dosing on ischemic stroke and bleeding events. Methods: We identified 17,622 and 37,452 Humana Medicare beneficiaries age &gt;=65 years with AF who initiated dabigatran or rivaroxaban, respectively, during 2010-2016. Patients were excluded if they had pulmonary embolism, deep vein thrombosis, or underwent hip surgery within the previous 6 weeks, or were not enrolled in Humana Medicare for at least 1 year prior to initiating the index drug. Stroke, major bleeding, and medication termination in patients who were either ‘potentially over-dosed’ (i.e., receive the standard dose but were eligible for low dose), or ‘potentially under-dosed’ (i.e., received the low dose but were not eligible for low dose) were identified. Multivariable methods controlled for differences in characteristics of patients prescribed low and standard dose within eligibility category. Results: Overall, 1734 (9%) and 10,045 (27%) of patients who received dabigatran and rivaroxaban met criteria for low dose, respectively. Of those, 1,161 (67%) and 4,868 (48%) received the standard dose (“potentially over-dosed”). In contrast, 2154 (13%) and 6,480 (23%) of patients eligible for standard dose dabigatran and rivaroxaban received a lower dose, respectively (“potentially under-dosed”). Increased age, female sex, black race, low weight, bleeding history, and heart failure were associated with receipt of lower than recommended dose for patients receiving dabigatran or rivaroxaban. There was modest evidence of increased risk of intracranial hemorrhage in patients overdosed with dabigatran (p=0.07). Among rivaroxaban users, medication termination was significantly higher for rivaroxaban users who were potentially overdosed (Hazard Ratio [HR] = 1.05; p=0.04); and significantly lower among rivaroxaban users who were potentially underdosed (HR = 0.96; p=0.03). No other significant outcomes differences were noted. Conclusions: Significant proportions of patients receive off-label dosing of dabigatran and rivaroxaban. Nevertheless, we found little evidence of significant impact on clinical outcomes.

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.

Advances in Antiplatelet and Anticoagulant Therapies for NSTE-ACS.

The treatment of patients requiring anticoagulation who develop acute coronary syndrome (ACS) and/or require percutaneous coronary intervention (PCI) must balance the reduction in major adverse cardiovascular events, stroke, and major bleeding. The development of direct oral anticoagulants (DOACs) for the treatment of atrial fibrillation has ushered in an era of potential treatment options for these complex patients. PURPOSE OF REVIEW: To review the clinical evidence underlying the use of DOACs for the treatment of patients with atrial fibrillation and ACS or PCI. RECENT FINDINGS: Three trials studied this particular patient population; WOEST showed that dual therapy with warfarin and clopidogrel decreased hemorrhage at 1year compared with standard triple therapy (19.4 vs. 44.4% HR 0.36; 95% CI 0.26-0.50; P< 0.0001), without increasing thromboembolic events (11.1 vs. 17.6% HR 0.60; 95% CI 0.38-0.94; P= 0.025). PIONEER AF-PCI showed that 10-15mg rivaroxaban plus P2Y12 inhibitor for 12months significantly lowered bleeding rates than standard triple therapy (16.8 vs. 26.7% HR 0.59; 95% CI 0.47-0.76; P< 0.001) and had equivalent rates of MACE. Finally, REDUAL-PCI compared two different doses of dabigatran (110mg twice daily and 150mg twice daily) plus P2Y12 inhibitor with standard triple therapy and reported reduced ISTH bleeding with both doses; HR 0.52 with 110mg dabigatran (95% CI 0.42-0.63, P< 0.001) and HR 0.72 with 150mg dabigatran (95% CI 0.58-0.88; P= 0.002). The rate of the composite of thromboembolic events, death, or unplanned revascularizations was similar between pooled dabigatran dual therapy and triple therapy groups (13.7 vs 13.4% HR 1.04; 95% CI 0.84-1.29; P= 0.005). Recent evidence shows that DOACs plus one antiplatelet agent can decrease bleeding in patients with atrial fibrillation undergoing PCI for ACS. Although not powered to detect non-inferiority or superiority, large studies suggest rivaroxaban 10-15mg plus P2Y12 inhibitor for 12months or dabigatran 150mg twice daily plus P2y12 inhibitor for 12months will have similar rates of MACE and stent thrombosis as triple therapy. In patients who have contraindications to DOACs, the strategy of INR-adjusted warfarin plus clopidogrel appears to be safer than warfarin plus dual antiplatelet therapy.

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.

Reduced Doses of Direct Oral Anticoagulants in Ischemic Stroke Patients with Nonvalvular Atrial Fibrillation

Background: The choice of standard or reduced doses of direct oral anticoagulants (DOACs) depends on patients’ age, body weight, and renal function based on package instructions. Our aim was to conduct a simulation of DOAC dose using patients’ data obtained on admission. Methods: This retrospective study included 314 ischemic stroke patients with nonvalvular atrial fibrillation admitted to our hospital between September 2014 and February 2018. Data on age, body weight, creatinine, and creatinine clearance were collected for each subject, and simulation was conducted for the dose of each DOAC. Results: The mean age of 314 subjects was 77.2 years; those aged 75 years or older accounted for 61.5% (193 patients). It was suggested that a standard dose of rivaroxaban could be used in 67.5% of patients and that of apixaban in 65.9%. By contrast, a standard dose of dabigatran could be used in only 16.9% of patients and that of edoxaban in only 32.5%. The simulation analysis for patients aged 75 years or older showed that a standard dose of rivaroxaban could be used in 54.9% of patients and that of apixaban in 44.6%, while that of edoxaban could be used in only 19.7% of patients. Conclusions: When DOACs are prescribed for secondary prevention of cerebral infarction in patients with nonvalvular atrial fibrillation, the rate of standard or reduced dose varies depending on the kind of DOAC. Further analysis is required to clarify whether a standard dose of one DOAC or reduced dose of another DOAC yields the best result for each patient.

PRM261 - INCORPORATION OF OBSERVATIONAL DATA INTO NETWORK META-ANALYSIS: A CASE STUDY

The RCT represents the ‘gold standard’ for generating estimates of relative treatment effect. However observational data are considered more direct, relevant and generalisable to the wider population. Meta-analyses are usually conducted based on RCT evidence but interest in the inclusion of observational data in the decision-making process is growing. A case study that incorporates observational data in a network meta-analysis (NMA) is presented. A previously conducted systematic review and NMA based on RCT data of treatments for stroke prevention in atrial fibrillation was updated. A single comparative observational study (comparing 110/150 mg dabigatran versus vitamin K antagonist [VKA]) was identified and incorporated into the NMA analysis for the outcome of mortality by i) using this study to inform prior distributions and ii) using a design-adjusted analysis; adjusting the estimates from the observational data for potential bias. The inclusion of the observational data in the NMA at face value resulted in lower odds of mortality of 150 mg/110 mg dabigatran versus VKA. In comparison, the associated 95% CrIs of the same treatment comparison estimates did not include the null value when the NMA was restricted to RCT evidence only. When 30% overestimation of observational evidence is assumed in the analysis, the observational evidence requires further discounting (adjustment for overprecision) before it could be concluded that the 110 mg or 150 mg dose of dabigatran does not decrease the odds of mortality compared with adjusted dose VKA. In the exploratory analyses the conclusions around the relative efficacy of the NOACs are robust to the beliefs around the bias in terms of overprecision and overestimation within the observational data. Observational data can provide additional information on relative treatment effects and it may be relevant to include such data in meta-analyses to allow a decision-making process which includes all available data.