Dose Of Dabigatran Research Articles

May 2022 Stroke Highlights

May 2022 <i>Stroke</i> Highlights

Rivaroxaban Reduces the Dabigatran Dose Required for Anticoagulation During Simulated Cardiopulmonary Bypass.

Heparin is the standard anticoagulant for cardiopulmonary bypass (CPB); however, there are problems with its use that make the development of suitable alternatives desirable. Currently, no ideal alternative exists. We have previously reported that the direct thrombin inhibitor dabigatran can prevent coagulation in simulated CPB at high concentrations. These high concentrations may cause difficulties in achieving the reversal of dabigatran with idarucizumab, given the markedly different pharmacokinetics of the 2 drugs. Herein, we test the hypothesis that the addition of the anti-Xa drug rivaroxaban would provide suitable anticoagulation at a lower concentration of dabigatran given likely synergy between the 2 classes of drugs. The primary goal of the study was to investigate whether the addition of rivaroxaban reduces the concentration of dabigatran necessary to allow 2 hours of simulated CPB. The study was performed in sequential steps. Blood collected from consenting healthy donors was used throughout. First, we added graded concentrations of dabigatran and rivaroxaban alone and in combination and assessed inhibition of anticoagulation using thromboelastometry. Using results from this step, combinations of dabigatran and rivaroxaban were tested in both Chandler loop and simulated CPB circuits. Dabigatran and rivaroxaban were added before recalcification, and the circuits were run for 120 minutes. In both models of CPB, 120 minutes of circulation without visible thrombus was considered successful. In the Chandler loop system, idarucizumab was added to reverse anticoagulant effects. In the CPB circuits, the arterial line filters were examined using scanning electron microscope (SEM) to qualitatively assess for fibrin deposition. In vitro analysis of blood samples treated with dabigatran and rivaroxaban showed that dabigatran and rivaroxaban individually prolonged clotting time (CT) in a dose-dependent manner. However, when combined, the drugs behaved synergistically. In the Chandler loop system, dabigatran 2400 and 4800 ng/mL plus rivaroxaban (150 ng/mL) effectively prevented clot formation and reduced the dynamics of clot propagation for 120 minutes. Idarucizumab (250-1000 µg/mL) effectively reversed anticoagulation. In the CPB circuits, dabigatran (2500 ng/mL) and rivaroxaban (200 ng/mL) were successful in allowing 120 minutes of simulated CPB and prevented fibrin deposition. Biomarkers of coagulation activation did not increase during simulated CPB. Heparin controls performed similarly to dabigatran and rivaroxaban. The dual administration of oral anticoagulant drugs (dabigatran and Rivaroxaban) with different pharmacologic mechanisms of action produced synergistic inhibition of coagulation in vitro and successfully prevented clotting during simulated CPB.

Left atrial appendage thrombus in patients referred for electrical cardioversion for atrial fibrillation: a prospective single‑center study.

Left atrial appendage thrombus (LAAT) is a risk factor for stroke; however, the actual health risk associated with LAAT in patients with atrial fibrillation (AF) on chronic anticoagulation is unknown. We aimed to assess the prevalence and predictors of LAAT, and its predictive role in relation to mortality, stroke, and systemic thromboembolic events among consecutive AF patients on oral anticoagulation (OAC) admitted for electrical cardioversion. This was a prospective, single‑ center cohort study. The participants underwent transesophageal echocardiography before electrical cardioversion. A total of 296 patients were enrolled. The primary outcome was the presence of LAAT. All participants were followed for 12 months to evaluate the incidence of systemic thromboembolic events, stroke, and death. Despite uninterrupted OAC in patients with AF of above 48-hour duration scheduled for cardio-version, we found a high prevalence of LAAT, reaching 14.5%. There was no difference in the prevalence of thrombi between different types of OAC (P = 0.26). The independent predictors of LAAT were chronic obstructive pulmonary disease, heart failure, prior myocardial infarction, greater left atrial diameter, lower left ventricular ejection fraction, higher CHA2DS2‑VASc score, and reduced dabigatran dose. The optimal cutoff values for the prediction of LAAT were the age of at least 74 years, left atrial diameter equal or greater than 52 mm, left ventricular ejection fraction equal or lower than 40%, and CHA2DS2‑VASc score equal or greater than 3. No strokes or systemic thromboembolic events occurred over the follow‑up period. The presence of LAAT had no practical value for predicting stroke, thromboembolic events, or death in patients with AF and on chronic anticoagulation.

Effects of direct oral anticoagulants dabigatran and rivaroxaban on the blood coagulation function in rabbits.

The aim of this study was to explore the effects of dabigatran and rivaroxaban on the activities of various coagulation factors. To achieve that, 60 rabbits were randomly divided into experimental groups that received different doses of dabigatran or rivaroxaban. The effects of dabigatran and rivaroxaban on the activities of FII, FV, FVIII, FX, and activated protein C (APC) were analyzed. In the dabigatran groups, activated partial thromboplastin time and thromboplastin time (TT) were prolonged after drug administration, and the activities of FII, FV, FVIII, and FX were inhibited as the drug concentration increased. Low doses of dabigatran inhibited APC activity. In the rivaroxaban groups, APTT and TT were not significantly prolonged after drug administration. In contrast, the high-dose rivaroxaban group exhibited prolonged PT, and the degree of inhibition of the activities of FII, FV, FVIII, and FX increased as the drug concentration increased. Rivaroxaban had no significant effect on APC activity regardless of dosage. As the drug concentration increased, both NOACs had more significant inhibitory effects on the activities of FII, FV, FVIII, and FX. Low concentrations of dabigatran generated an inhibitory effect on APC activity, while high concentrations of dabigatran had no significant effect. Rivaroxaban had no significant effect on APC activity.

Abstract 11742: Knowledge on Anticoagulation Use in Atrial Fibrillation With Left Atrial Appendage Thrombus Among Medicine Residents

Introduction: Left atrial appendage (LAA) thrombus increases thromboembolic risk in patients with atrial fibrillation (AF). Importantly, 40% of LAA thrombus patients will have an inadequate response to anticoagulation during follow-up. Of note, these patients are frequently followed by medicine residents in the clinic. Therefore, we aimed to explore residents' knowledge on anticoagulation use for the treatment of LAA thrombus. Hypothesis: Insufficient knowledge on anticoagulation for the treatment of LAA thrombus could contribute to inadequate treatment response during patients' follow-up. Methods: All medicine residents (n=96) at Rutgers University New Jersey Medical School were emailed a 26-question survey on the indication, dosing, pharmacokinetics and clinical experience using direct oral anticoagulants (DOACs) and vitamin-K-antagonists (VKA) in AF patients with LAA thrombus. Results: Of 62 responders, 42 (68%) have been prescribing DOACs in the clinic with apixaban being most commonly prescribed. Thirty-seven (61%) indicated DOACs as the first-line agents for LAA thrombus whereas 24 (39%) chose VKA. Nineteen (33%) responders indicated apixaban dosing correctly, and 51 (84%) indicated appropriately relation of apixaban with meals. If follow-up imaging reconfirmed LAA thrombus, 54 (89%) would switch to VKA whereas 7 (11%) would use other DOACs. Nineteen (32%) responders indicated rivaroxaban dosing correctly and only 10 (16%) indicated appropriately how to administer rivaroxaban with meals. If follow-up imaging reconfirmed LAA thrombus, 43 (71%) would switch to VKA whereas 18 (29%) would use other DOACs. Forty-one (72%) responders indicated dabigatran dosing correctly and 36 (58%) indicated no relation to food intake. If follow-up imaging reconfirmed LAA thrombus, 40 (65%) responders would switch to VKA whereas 22 (35%) would use other DOACs. For VKA, 51 (88%) indicated therapeutic INR range of 2-3 and 7 (12%) chose 2.5-3.5. If follow-up imaging reconfirmed LAA thrombus, 38 (61%) would increase INR goal whereas 24 (39%) would switch to DOACs. Conclusions: This survey identified knowledge gaps in dosing and pharmacokinetics of DOACs among medicine residents despite being more likely to prescribe DOACs over VKA to treat LAA thrombus.

Impact of Renal Function on Effectiveness and Safety Associated With Low Dose Dabigatran in Non-valve Atrial Fibrillation Patients After Catheter Ablation.

Aim: The purpose of this study is to compare the effectiveness and safety of 110 mg dabigatran in non-valve atrial fibrillation (NVAF) patients with different eGFRs.Methods: We conducted a single-center retrospective cohort study to investigate the effectiveness and safety of 110 mg dabigatran for NVAF patients between January 2017 and December 2018 based on the eGFR category.Results: A total of 560 NVAF patients who treated with 110 mg dabigatran were included for analysis. In 12 months, the Kaplan-Meier survival curves indicated that the lower eGFR subgroups were more likely to experience thrombosis, bleeding, and cumulative events earlier (P = 0.021 for thrombosis; P = 0.026 for bleeding; P = 0.001 for cumulative events). Gastrointestinal bleeding occurred more frequently in the moderate group than in other groups (6.94% in the moderate group vs. 1.54% in the mild group vs. 1.22% in the normal group, P = 0.028). By multivariate analysis, chronic kidney disease (P = 0.043; OR = 4.273, 95% CI 1.043–17.543) and diabetes mellitus (P = 0.023; OR = 2.194, 95% CI 1.114–4.323) were independent predictors of the composite endpoints. A positive linear relationship was observed between eGFR levels and occurrence rate of thrombosis and bleeding under anticoagulation patients with 110 mg dabigatran (R2 = 0.432 and R2 = 0.784, respectively).Conclusions: Impaired renal function was associated with decreased safety and increased thrombosis risks in NVAF patients taking low dose dabigatran.

Starting dose and dose adjustment of non-vitamin K antagonist oral anticoagulation agents in a nationwide cohort of patients with atrial fibrillation

This study aims to provide real-world data about starting-dose of NOACs and dose-adjustment in patients with atrial fibrillation (AF). In fact, even if new oral anticoagulation agents (NOACs) have a predictable effect without need for regular monitoring, dose-adjustments should be performed according to the summary of product information and international guidelines. We employed the Italian Medicines Agency monitoring registries comprising data on a nationwide cohort of patients with AF treated with NOACs from 2013 to 2018. Logistic regression analysis was used to evaluate the determinants of dosage choice. During the reference period, treatment was commenced for 866,539 patients. Forty-five percent of the first prescriptions were dispensed at a reduced dose (dabigatran 60.3%, edoxaban 45.2%, apixaban 40.9%, rivaroxaban 37.4%). The prescription of reduced dose was associated with older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, but not with CHA2DS2-VASc and HAS-BLED. A relative reduction of the proportion of patients treated with low dosages was evident overtime for dabigatran and rivaroxaban; whereas prescription of low dose apixaban and edoxaban increased progressively among elderly patients. Evidence based on real-world data shows a high frequency of low dose prescriptions of NOACs in AF patients. Except for older age, renal disease, bleeding risk and the concomitant use of drugs predisposing to bleeding, other factors that may determine the choice of reduced dose could not be ascertained. There may be potential under-treatment of AF patients, but further evaluation is warranted.

Measurement of Anticoagulation in Patients on Dabigatran, Rivaroxaban, and Apixaban Therapy by Novel Automated Thrombelastography.

Background Direct-acting oral anticoagulants (DOACs) do not require monitoring. Measurement of DOAC effect would be useful in the event of bleeding, trauma, and thromboembolism while on anticoagulation. We evaluated the effectiveness of the investigational DOAC assays on the TEG®6s Hemostasis Analyzer to assess the anticoagulant effect of DOACs in patients treated for atrial fibrillation or deep vein thrombosis (DVT). Methods Patients on treatment for a minimum of 7 days with standard doses of dabigatran, rivaroxaban, and apixaban were included. DOAC plasma concentrations and TEG®6s Reaction (R)-time were measured and correlated. The sensitivity, specificity, and negative predictive value (NPV) of R-time to detect DOAC concentrations of ≥30, ≥50, and ≥100 ng/mL were calculated. Results A total of 189 patients were included, ( n = 50) on apixaban, ( n = 62) on rivaroxaban, ( n = 53) on dabigatran, and ( n = 24) on no DOAC were studied. Using the direct thrombin inhibitor (DTI) channel, R-time demonstrated strong linear correlation with dabigatran levels (r = 0.93, p < 0.0001). Using the antifactor Xa (AFXa) channel, R-time demonstrated strong nonlinear correlation with rivaroxaban and apixaban levels ( r s = 0.92 and 0.84, respectively, p < 0.0001 for both). R-time revealed strong sensitivity and NPV in detecting low DOAC levels for the predefined concentrations. Conclusion R-time measured by TEG®6s DOAC-specific cartridge has a strong correlation with concentrations of the most commonly used DOACs with high sensitivity and NPV for detecting lower drug levels that are considered clinically relevant for patients in need of antidote, or prior to urgent surgery. Further studies to determine the relation of R-time to clinical outcomes are warranted.

A strategy of idarucizumab for pericardial tamponade during perioperative period of atrial fibrillation ablation.

To investigate theoptimal idarucizumab (dabigatran antagonist) usage strategy for patients with acute pericardial tamponade receiving uninterrupted dabigatran during catheter ablation for atrial fibrillation (AF). Ten patients presenting acute pericardial tamponade while receiving uninterrupted dabigatran during catheter ablation for AF in Beijing Anzhen Hospital from January 2019 to July 2020 were enrolled and retrospectively analyzed. A "wait and see" strategy of idarucizumab was carried out for all patients; in brief, idarucizumab was applied following pericardiocentesis, comprehensive evaluation of bleeding and hemostasis. There were five males, five paroxysmal AF, and the average age of the patients was 64.0 ± 9.8 years. Among the 10 patients, four were treated with dabigatran 110mg, six were treated with dabigatran 150mg, and one was simultaneously given clopidogrel. The average time from pericardial tamponade to the last dose of dabigatran was 8.2 ± 3.4 h. All patients underwent pericardiocentesis successfully, and the average drainage volume was 322.5ml (220.0 ± 935.0ml). For reversal anticoagulation, six patients received protamine, and five patients received idarucizumab. Of the five patients who were treated with idarucizumab, four presented exact hemostasis, except for one patient who underwent continuous drainage and finally received surgery repair. The average time to restart anticoagulation was 1.1 ± 0.3 days after the procedure, and no rebleeding, embolism or deaths were observed. The "wait and see" strategy of idarucizumab for acute pericardial tamponade during the perioperative period of catheter ablation for AF may be safe and feasible.

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

Addendum to British Society for Haematology guideline on the investigation, management and prevention of venous thrombosis in children (Br. J. Haematol. 2011; 154: 196-207).

Preferential Inhibition of Fibrin Mediated Thrombosis in Rodent Models By JNJ-9375, a Novel exosite1 Thrombin Inhibitor

We have previously reported an improved therapeutic index (TI) for JNJ-9375 vs apixaban in rat and cynomolgus monkey models of venous thrombosis and bleeding. We have also reported that JNJ-9375 preferentially inhibited the fibrin component of the thrombus without significant impact on the platelet component under low and high shear conditions in a human translational model of thrombosis (Badimon chamber model). We hypothesized that the novel mode of action of JNJ-9375 which by selectively inhibiting exosite 1 substrates from binding to thrombin (such as fibrinogen and PAR-1) may allow for other thrombin interactions at the active site and exosite 2 including platelet activation by PAR-4 and GP1b.In the present studies, we have compared the antithrombotic effects of JNJ-9375, the active site thrombin inhibitor dabigatran and the factor Xa inhibitor apixaban in well characterized and widely used rat AV-shunt and carotid ferric chloride models of venous and arterial thrombosis, respectively. JNJ-9375, dabigatran and apixaban all maximally inhibited thrombus formation in a dose dependent manner in the rat AV-shunt model of venous thrombosis. Significant inhibition of thrombus weights of 50%, 44% and 57% were observed at 0.3 mg/kg, i.v., 0.1 mg/kg, i.v. and 1 mg/kg, i.v. with JNJ-9375, dabigatran and apixaban respectively. Dose dependent prolongation in coagulation parameters were also observed ex-vivo with JNJ-9375 (TT, ECT, aPTT and PT), dabigatran (TT, ECT, aPTT) and apixaban (aPTT and PT). In addition, there were dose dependent increases in drug exposure.In the rat ferric chloride model of arterial thrombosis, JNJ-9375, dabigatran and apixaban administration also resulted in dose dependent inhibition of thrombus formation as assessed by the time to occlusion (TTO) of the carotid artery and area under the curve (AUC) for carotid blood flow. However, the dose required to inhibit arterial thrombosis Vs venous thrombosis varied substantially for the different agents. With JNJ-9375 we only observed a significant inhibition of arterial thrombosis (TTO and AUC) at a dose of 10 mg/kg, i.v. (Vs 0.3 mg/kg in the AV-shunt model) which represents a 33-fold shift in the dose required to inhibit arterial thrombosis (Vs venous thrombosis). In contrast, we observed a significant inhibition of arterial thrombosis with dabigatran (AUC) and apixaban (TTO and AUC) at doses of 0.3 mg/kg, i.v. and 3 mg/kg, i.v. (Vs 0.1 mg/kg and 1 mg/kg in the AV-shunt model) respectively. These doses of dabigatran and apixaban represent a 3-fold shift in the dose required to inhibit arterial thrombosis (Vs venous thrombosis). We have also documented dose dependent prolongations in coagulation parameters and drug exposure with all three agents in the these studies. In addition, we performed ex-vivo platelet aggregation in platelet rich plasma with various platelet agonists (ADP, collagen, AA, rat and human thrombin) in those animals dosed with JNJ-9375. As anticipated and consistent with its mechanism of action, JNJ-9375 only inhibited platelet aggregation to thrombin stimulation but not with other platelet agonists confirming the specificity of JNJ-9375. We observed about 50%, >95% and >95% inhibition of thrombin-induced platelet aggregation at 1, 3 and 10 mg/kg, i.v. with JNJ-9375 respectively. However, we only observed inhibition of arterial thrombosis at 10 mg/kg.In summary, we have demonstrated dose dependent inhibition of thrombosis with JNJ-9375, dabigatran and apixaban in venous and arterial model of thrombosis in rats. However, we have observed a larger difference in the dose required for inhibition of arterial Vs venous thrombosis with JNJ-9375 (33-fold) compared to a more modest 3-fold shift observed for dabigatran and apixaban. These findings with JNJ-9375 demonstrate an anticoagulant profile that preferentially inhibits fibrin mediated clot formation with a more modest impact on platelet driven thrombosis in the present models. This differential profile may account in part for the improved TI over apixaban we had reported earlier in animal models. This profile suggests JNJ-9375 which is currently in early clinical development may also be more amenable to dosing in combination with antiplatelet therapy for indications such as acute coronary syndromes and needs to be tested experimentally. DisclosuresChintala:Janssen Research & Development: Employment. Li:Janssen R&D: Employment. Huang Devine:Janssen Research & Development: Employment. Bunce:Janssen R&D: Employment.

Reclassification, Thromboembolic, and Major Bleeding Outcomes Using Different Estimates of Renal Function in Anticoagulated Patients With Atrial Fibrillation: Insights From the PREFER-in-AF and PREFER-in-AF Prolongation Registries.

The Cockcroft-Gault formula is recommended to determine a renal indication for dose reduction of dabigatran, edoxaban, and rivaroxaban. Nephrology guidelines now recommend the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulae as more accurate estimates of glomerular filtration rate. We analyzed anticoagulated patients with atrial fibrillation who were enrolled in the Prevention of Thromboembolic Events - European Registry in Atrial Fibrillation (PREFER in AF). The proportion of patients with dissimilar renal dosing indications was assessed when applying Cockcroft-Gault, MDRD, or CKD-EPI. Thromboembolic and major bleeding events at 1 year were compared in patients in whom Cockcroft-Gault and CKD-EPI provided concordant or discordant results around a threshold of 50 mL/minute. Out of 1288 patients with atrial fibrillation with chronic kidney disease in whom Cockcroft-Gault suggested a dose reduction of dabigatran, edoxaban, or rivaroxaban (creatinine clearance ≤50 mL/minutes), 19% and 16% were reclassified to the respective higher doses, and 24% and 23% to the respective lower doses by applying the MDRD and CKD-EPI formulae, respectively. In patients potentially receiving a different dose of dabigatran, edoxaban, or rivaroxaban when using CKD-EPI, we observed an excess of thromboembolic events (4.1% versus 0.8%; odds ratio, 5.5 [95% CI, 1.5-20.8]; P=0.01). Major bleeding rates were nonsignificantly different in the discordance versus concordance group (5.7% versus 2.7%; odds ratio, 2.2 [95% CI, 0.9-5.6]; P=0.09). The MDRD and CKD-EPI formulae suggest a different dosing in up to a quarter of anticoagulated patients with atrial fibrillation. This seems to impact hard outcomes.

Dose specific effectiveness and safety of DOACs in patients with non-valvular atrial fibrillation: A Canadian retrospective cohort study

BackgroundDirect oral anticoagulants (DOACs) have been proven to be effective and safe for prevention of ischemic stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). However, suboptimal adherence, variable dosing and use in patient populations that otherwise would have been excluded from clinical trials may impact the efficacy and safety profile of DOACs in a routine care setting. We compared stroke, bleeding, and mortality rates on and off therapy for standard and low-dose DOACs (apixaban, rivaroxaban, dabigatran) versus warfarin in a Canadian cohort. We also assessed persistence of DOACs compared to warfarin. MethodsWe conducted six 1-1 propensity-score matched retrospective cohort analyses using Quebec health administrative databases (2011–2017). NVAF patients (≥18 years) covered by the public medication insurance plan entered the cohort on the first OAC dispensation date. We excluded those with OAC use in the previous year or stroke or bleeding diagnoses in the previous two years. Follow-up ended at death, March 2017 or end of medication coverage by the public plan. Time-dependent Cox regression was applied. ResultsWe evaluated 10,893 patients initiated on apixaban (7206 standard, 3687 low-dose), 10,190 on rivaroxaban (7396 standard, 2794 low-dose), 5884 on dabigatran (2756 standard, 3128 low-dose), and propensity score-matched warfarin users. Across standard-dose DOACs, compared to warfarin, stroke risks were similar; bleeding risks were lower with apixaban (hazard ratio 0.63; 95% confidence interval 0.52–0.77) and dabigatran (0.47; 0.35–0.64) but not rivaroxaban (0.93; 0.79–1.10); death risks were lower with all DOACs. For low-dose DOACs, rivaroxaban demonstrated higher stroke (1.79; 1.21–2.64) and bleeding risks (1.37; 1.09–1.73); other agents had stroke risks similar to warfarin and bleeding risks lower than warfarin; only low-dose dabigatran had lower death risk (0.59; 0.52–0.68). Treatment discontinuation was lower with DOACs versus warfarin with the exception of low-dose rivaroxaban. The risks of stroke were 2–4 folds higher during time off any OAC versus time on warfarin. The risks of death were higher, while the risks of bleeding were generally lower during times off any OAC. ConclusionsStandard-dose DOACs had similar stroke, better persistence and mortality profiles than warfarin. Only standard dose apixaban and dabigatran had better bleeding profiles than warfarin. Low-dose rivaroxaban had worse persistence, stroke and bleeding profiles than warfarin, while low-dose apixaban and dabigatran had similar stroke and better bleeding profiles. Real-world use of DOACs may explain some of the differences observed in Canadian routine care versus the phase III clinical trials.

Improved efficacy/safety profile of factor XIa inhibitor BMS‐724296 versus factor Xa inhibitor apixaban and thrombin inhibitor dabigatran in cynomolgus monkeys

BackgroundInhibition of activated factor XI (FXIa) is a promising antithrombotic drug target. BMS‐724296 is a selective, reversible, small‐molecule inhibitor of human FXIa (Ki 0.3 nM). ObjectivesThis study assessed effects of BMS‐724296 versus standard‐of‐care oral anticoagulants apixaban (activated factor X inhibitor) and dabigatran (thrombin inhibitor) on arterial thrombosis, kidney bleeding time (KBT), and clotting time (CT) in nonhuman primate (NHP) cynomolgus monkey models. MethodsCarotid artery thrombosis was produced by electrical stimulation in anesthetized NHPs. Hemostasis was assessed with a provoked KBT model. Thrombosis, KBT, and CT were monitored. Vehicle and various doses of BMS‐724296, apixaban, and dabigatran were administered as bolus (intravenous [i.v.]) followed by infusion starting 30 minutes before initiation of thrombosis and continued until the experiment’s end (n = 3‐8/group). Primary end points included thrombus weight reduction (TWR), KBT, and CT (activated partial thromboplastin time [aPTT], prothrombin time [PT], and thrombin time [TT]). ResultsBMS‐724296 at 0.025 + 0.05, 0.05 + 0.1, 0.102 + 0.2, and 0.4 + 0.8 mg/kg+mg/kg/h i.v. (bolus + infusion) reduced thrombus weight by 0 ± 0, 35 ± 7*, 72 ± 4*, and 86 ± 4%*, respectively (*P< .05 vs vehicle; n = 5‐6/group). BMS‐724296 at the highest dose (0.4 + 0.8 mg/kg+mg/kg/h) did not increase KBT compared to vehicle (109 ± 6 vs 113 ± 20 seconds, respectively) and increased ex vivo aPTT by 2.9 ± 0.1‐fold without changing PT and TT. In companion NHP studies, high doses of apixaban and dabigatran produced similar TWR as BMS‐724296, but increased KBT 4.3 ± 0.5‐fold and 5.8 ± 0.5‐fold, respectively (n = 3‐4/group). ConclusionsBMS‐724296 produced similar antithrombotic efficacy as apixaban and dabigatran but with no increase in KBT in NHPs. These findings suggest that FXIa inhibitors may provide safe and effective antithrombotic therapy.

Dabigatran Etexilate for the Treatment of Acute Venous Thromboembolism in Children: Results of an Open-Label, Phase 2b/3, Randomised Clinical Trial

Background: Dabigatran etexilate, a direct oral anticoagulant, may be an effective and safe alternative for treating acute venous thromboembolism (VTE) in children. Methods: This open-label, randomised (2:1), phase 2b/3 trial evaluated the efficacy and safety of standard of care (SOC) versus dabigatran using a paediatric dabigatran dosing algorithm (age- and weight-adjusted nomogram) in children with acute VTE aged 12 to <18 years, 2 to <12 years, and birth to <2 years requiring anticoagulation therapy for ≥3 months. Primary composite efficacy endpoint: proportion of children with complete thrombus resolution, and freedom from recurrent VTE or VTE-related death. Secondary endpoints: safety (determined by major bleeding events), and pharmacokinetic/pharmacodynamic relationships. Findings: While target enrolment was 141 children, 90 randomised to SOC and 177 to dabigatran were analysed. Similar proportions of children treated with SOC and dabigatran met the composite efficacy endpoint (38/90 [42·2%] vs 81/177 [45·8%]; Mantel-Hanszel weighted difference, –0·04; 90% CI –0·14 to 0·07; p<0·0001 for non-inferiority), and major bleeding events were comparable (2/90 [2·2%] and 4/176 [2·3%]; HR 0·94; 95% CI 0·17 to 5·16; p=0·95). Incidence of adverse events was 66·7% and 76·7% for SOC and dabigatran, respectively, and 20·0% and 12·5% for serious adverse events. Dabigatran pharmacokinetic/pharmacodynamic relationships were similar to those for adults. Interpretation: This randomized trial confirmed that an age- and weight-adjusted dabigatran dosing algorithm was appropriate in children aged birth to <18 years. Dabigatran was non-inferior to SOC in terms of efficacy for acute VTE treatment, with similar pharmacokinetic/pharmacodynamic relationships to adults. Trial Registration: EudraCT No.: 2013-002114-12 Funding: Boehringer Ingelheim; DIVERSITY, NCT01895777. Conflict of Interest: JH is a member of a paediatric expert working group for Boehringer Ingelheim and has received honoraria from Boehringer Ingelheim for congress presentation.LRB is a member of a paediatric expert working group for Boehringer Ingelheim and has received advisory board fees from Boehringer Ingelheim.ML is a member of a paediatric expert working group for Boehringer Ingelheim.LB is a member of a paediatric expert working group for Boehringer Ingelheim and reports fees to her institution from Janssen Pharmaceuticals.EC is a member of a paediatric expert working group for Boehringer Ingelheim and reports personal fees from Roche, Sobi, Bristol-Myers Squibb, CSL Behring, and Shire/Takeda.LGM is a member of a paediatric expert working group for Boehringer Ingelheim and has received a research grant from Bristol-Myers Squibb.IN declares no competing interests.AS has received consulting fees from Takeda, CSL Behring, Bayer, and Kedrion.PS reports personal fees from Takeda and CSL Behring.KG declares no competing interests.IT, MS, FH, ZS, JK, SG, PR, and MB are all employees of Boehringer Ingelheim.DIVERSITY manuscript to submit_4June2020MA is a member of a paediatric expert working group for Boehringer Ingelheim and has received advisory board fees from Daiichi Sankyo. Ethical Approval: The design of this study (including the definition of endpoints and SOC comparators) is based upon the European Medicines Agency’s Paediatric Committee’s recommendations. This committee has previously reviewed and approved the principal design elements and endpoints of this trial.

Effectiveness and safety of idarucizumab in the management of perioperative complications of atrial fibrillation catheter ablation in atrial fibrillation patients under dabigatran therapy

Objective: To investigate the efficacy and safety of idarucizumab in the treatment of perioperative cardiac tamponade and thromboembolic events during catheter ablation in atrial fibrillation (AF) patients under dabigatran therapy. Methods: This study was a retrospective analysis enrolling patients under dabigatran therapy, who underwent catheter ablation for AF at Beijing Anzhen Hospital from January 2019 to December 2020 and developed perioperative cardiac tamponade or acute ischemic stroke (AIS) and received idarucizumab to reverse the anticoagulant effect of dabigatran. Patients' age, sex, renal function, coagulation test and safety events at 30 d after idarucizumab administration were collected and analyzed. The clinical presentation and prognosis were also analyzed. Results: A total of 7 patients were included, 2 (2/7) were male, mean age was (66.3±11.2) years, serum creatinine level was (66.3±13.6) μmol/L, estimated glomerular filtration rate was (89.4±11.2) ml·min-1·1.73 m-2, CHA2DS2-VASc and HAS-BLED scores were (3.2±1.9) and (1.3±1.3), respectively. Five patients (5/7) developed cardiac tamponade during the perioperative period and the time interval to the last dose of dabigatran was (6.3±2.6) h. Idarucizumab was given at (36.4±16.7) min after the definitive diagnosis of cardiac tamponade. A significant decrease of activated partial thromboplastin time was achieved after idarucizumab administration in all five cases. Pericardial puncture and drainage were applied to all patients (5/5) with cardiac tamponade, the drainage volume was (1 037.0±846.9) ml, the retention time of pericardial drainage catheter was (27.9±13.9) h, and the recovery time of anticoagulation was (28.4±13.2) h. One patient (1/5) underwent thoracotomy for hemostasis due to excessive blood loss with the aim of ensuring complete hemostasis. Bleeding occurred in 1 patient (1/5) after the first restart of anticoagulation. AIS occurred in 2 patients (2/7) after operation. One case (1/2) received intravenous thrombolysis after receiving 5.0 g idarucizumab, no hemorrhagic transformation was observed, and the recovery process was satisfactory. Another patient in this group experienced significantly prolonged onset time and 5.0 g idarucizumab was applied before intravascular thrombectomy, there was no bleeding complication in this patient after thrombectomy. At the time of discharge, the consciousness was not significantly improved, and the muscle strength of the right lower limb was recovered somehow compared with that before operation. No hypersensitivity reactions or thrombotic events occurred in these patients within 30 days of the administration of idarucizumab. Conclusion: In AF catheter ablation-associated cardiac tamponade and AIS, idarucizumab is safe and effective in rapidly reversing the anticoagulant effect of dabigatran, use of thrombectomy saves valuable time for timely hemostasis and improvement of cerebral blood circulation.

Risk of Stroke vs. Intracerebral Hemorrhage in Patients with Non-Valvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention: A Systematic Review and Meta-Analysis of Randomized Controlled Trials Comparing Dual vs. Triple Antithrombotic Therapy

BackgroundAbout 15% of patients with non-valvular atrial fibrillation might require percutaneous coronary interventions (PCIs) with stent placement to treat obstructive coronary artery disease. Dual antiplatelet therapy (DAPT) with acetylsalicylic acid (aspirin) and P2Y12 antagonist is recommended after PCI. Patients requiring DAPT also require treatment with oral anticoagulation for atrial fibrillation. We conducted a meta-analysis to identify the antithrombotic regimen associated with the lowest rate of bleeding and thromboembolic events in non-valvular atrial fibrillation after PCI. MethodsWe searched PubMed, Embase, Scopus and Cochrane databases to identify randomized trials that investigated the use of dual antiplatelet therapy and vitamin K antagonist and/or Non-vitamin K antagonist oral anticoagulants (NOAC) (triple antithrombotic therapy (TAT)) against single antiplatelet agent and NOAC (dual antithrombotic therapy (DAT)) in the setting of coronary artery disease (CAD) requiring PCI and non-valvular atrial fibrillation. Random-effect models were used to pool data. We used the I2 statistic to measure heterogeneity between trials. ResultsWe found 4 randomized clinical trials (ENTRUST, AUGUSTUS, PIONEER, REDUAL) using different NOACs. Overall, 9241 patients (median age 70 years, 41.4% female, mean CHADS2VASC Score 3.5) were included. We excluded patients in the very low dose rivaroxaban group from the PIONEER AF-PCI trial and low dose dabigatran group from the REDUAL PCI trial as these are not available in the United States. Our metanalysis showed that dual therapy was associated with less risk of intracranial hemorrhage (RR 0.55, 95% CI 0.31–0.99; p = 0.045; I2 = 42%) and major bleeding (RR 0.66; 95% CI 0.55–0.79; p < 0.0001; I2 = 27%) as compared to triple therapy. Further risk of ischemic stroke (RR 0.94, 95% CI 0.63–1.39; p = 0.75; I2=0%), myocardial infarction (RR 1.18, 95% CI 0.94-1.47; p = 0.16; I2 = 0), or stent thrombosis (RR 0.50, 95% CI 0.93–2.41; p = 0.10; I2 = 0%) were unchanged. Similar findings were also noted on analysis of NOAC specific DAT vs VKA based TAT. ConclusionsThe combination of an antiplatelet and NOACs (dual therapy) is associated with less risk of major bleeding and intracranial hemorrhage, with no significant difference in ischemic events (stroke myocardial infarction or stent thrombosis).

Quantitative Benefit-Risk Assessment of P-gp-Mediated Drug-Drug Interactions of Dabigatran Coadministered With Pharmacokinetic Enhancers in Patients With Renal Impairment.

Drug-drug interactions (DDIs) between dabigatran and ritonavir/cobicistat are of major concern in people living with HIV, particularly in those with impaired renal function, because they can result in increased dabigatran exposure and thus an increased risk of major bleeding events. However, the extent of this interaction and subsequent need for dose adjustment in subjects with varying degrees of renal function is currently not yet fully understood. To close this knowledge gap, we conducted an integrated population physiologically-based pharmacokinetic/pharmacodynamic analysis linking changes in dabigatran exposure due to DDIs and varying degrees of renal function to the probability of experiencing an ischemic stroke or major bleeding event within 1 year. The results of our analysis suggest that coadministration of dabigatran etexilate (dabigatran prodrug) and ritonavir/cobicistat should be avoided in subjects with severe renal impairment. A 2-hour dose separation or dabigatran etexilate dose reduction to 110mg b.i.d. (twice daily) should be considered in subjects with moderate renal impairment when coadministered with ritonavir, while the dabigatran etexilate dose should be further reduced to 75mg b.i.d. when coadministered with cobicistat. No dabigatran etexilate dose adjustment is needed in subjects with normal renal function receiving ritonavir, but dabigatran etexilate dose reduction to 110mg b.i.d. should be considered when coadministered with cobicistat.

Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial

Dabigatran etexilate is a direct oral anticoagulant with potential to overcome the limitations of standard of care in children with venous thromboembolism. The aims of this clinical trial were to study the appropriateness of a paediatric dabigatran dosing algorithm, and the efficacy and safety of dabigatran dosed according to that algorithm versus standard of care in treating children with venous thromboembolism. DIVERSITY is a randomised, controlled, open-label, parallel-group, phase 2b/3 non-inferiority trial done in 65 centres in 26 countries. Standard of care (low-molecular-weight heparins, unfractionated heparin, vitamin K antagonists or fondaparinux) was compared with a paediatric oral dabigatran dosing regimen (an age-adjusted and weight-adjusted nomogram) in children younger than 18 years with acute venous thromboembolism initially treated (5-21 days) with parenteral anticoagulation, requiring anticoagulation therapy for at least 3 months. Patients were randomised 1:2 (standard of care:dabigatran) and stratified by age (12 to <18 years, 2 to <12 years, and birth to <2 years) via interactive response technology. The primary composite efficacy endpoint (intention-to-treat analysis) was the proportion of children with complete thrombus resolution, and freedom from recurrent venous thromboembolism and venous thromboembolism-related death. A non-inferiority margin of absolute differences of 20% was used. Secondary endpoints included safety (determined by major bleeding events [time-to-event analysis on the treated set]), and pharmacokinetic-pharmacodynamic relationships (descriptive analyses). This trial is registered with ClinicalTrials.gov, NCT01895777 and is completed. 328 children were enrolled between Feb 18, 2014, and Nov 14, 2019. 267 were randomly assigned (90 [34%] to standard of care and 177 [66%] to dabigatran) and included in the analyses. Median exposure to standard of care was 85·0 days (IQR 80·0-90·0) and to dabigatran was 84·5 days (78·0-89·0). Similar proportions of children treated with standard of care and dabigatran met the composite efficacy endpoint (38 [42%] of 90 vs 81 [46%] of 177; Mantel-Haenszel weighted difference, -0·04; 90% CI -0·14 to 0·07; p<0·0001 for non-inferiority). On-treatment bleeding events were reported in 22 (24%) of 90 children receiving standard of care and 38 (22%) of 176 children receiving dabigatran (hazard ratio [HR] 1·15, 95% CI 0·68 to 1·94; p=0·61); major bleeding events were similar between the groups (two [2%] of 90 and four [2%] of 176; HR 0·94, 95% CI 0·17 to 5·16; p=0·95). Pharmacokinetic-pharmacodynamic curves showed a linear relationship between total dabigatran plasma concentration and diluted thrombin time and ecarin clotting time, and a non-linear relationship with activated partial thromboplastin time; curves were similar to those for adults. Serious adverse events were reported for 18 (20%) of 90 children receiving standard of care and 22 (13%) of 176 children receiving dabigatran. The most common severe adverse events were vascular disorders (standard of care three [3%] of 90, dabigatran two [1%] of 176), and gastrointestinal disorders (standard of care two [2%] of 90 and dabigatran five [3%] of 176). One on-treatment death occurred in the standard of care group (retroperitoneal bleeding, not considered treatment related by the study investigators). An age-adjusted and weight-adjusted dabigatran dosing algorithm was appropriate in children aged birth to less than 18 years with venous thromboembolism. Dabigatran was non-inferior to standard of care in terms of efficacy, with similar pharmacokinetic-pharmacodynamic relationships as those seen in adults, and might be a suitable alternative to standard of care. Boehringer Ingelheim.

Clinical performance of the atrial fibrillation in the Russian population depending on the antithrombotic therapy: findings from the GLORIA-AF registry phase 2

Aim. To analyze clinical characteristics of patients with nonvalvular atrial fibrillation (AF) in the Russian population, enrolled in the GLORIA-AF registry phase 2, depending on the antithrombotic therapy received, and to assess the potential for patient retention with dabigatran during a 2-year follow-up.Material and methods. In the Russian Federation, 408 patients were included in the second phase of GLORIA-AF which is a global prospective observational registry of newly diagnosed patients with AF. The patient characteristics are presented depending on received antithrombotic therapy (dabigatran, factor Xa inhibitors, vitamin K antagonist, antiplatelet agents, or no antithrombotic therapy), with a dabigatran dosing regimen of either 110 mg or 150 mg twice daily. Duration of patient retention on dabigatran therapy was also analyzed during a 2-year follow-up.Results. Of the 405 patients with recently diagnosed nonvalvular AF, 358 (88%) received oral anticoagulants (OAC), and 47 (12%) patients received antiplatelet drugs or received no antithrombotic therapy. Most patients were treated with dabigatran (n=275, 68%), and 75 (19%) patients received vitamin K antagonist. Clinical and demographic characteristics of patients receiving dabigatran were comparable with those in the general group of the Russian patients. The mean age was 63,5 years. The most common comorbidities in Russian patients receiving dabigatran were hypertension (93%), congestive heart failure (57%), coronary artery disease (35%). It is noteworthy that 12% and 10% of patients had a previous myocardial infarction and stroke, respectively. The mean CHA2DS2-VASc score for stroke risk for these patients was 3,2; 88% of patients had a high stroke risk (score of &gt;2). Of the 275 patients with AF who received dabigatran therapy, 164 (60%) patients received dabigatran at the dose of 150 mg twice daily, and 111 (40%) patients received 110 mg twice daily. Dabigatran doses of 110 mg twice daily were more frequently prescribed for female patients aged 65 years or older and patients with a previous coronary events and impaired renal function, who had a higher CHA2DS2-VASc score for stroke risk. There was a higher proportion of AF patients with marked symptoms in the dabigatran 150 mg twice daily group. A median duration of treatment with dabigatran with the initial dosing regimen was 24 months. The estimated dabigatran therapy retention rate was 0,87, 0,81 and 0,73 after 6, 12 and 24 months of follow-up, respectively.Conclusion. In the Russian Federation, patients with newly diagnosed AF who have an increased risk of stroke are more likely to receive OAC therapy, such as direct thrombin inhibitor (dabigatran), compared to the global cohort of the GLORIA AF Registry Program. Patients in the Russian cohort receiving dabigatran differ from the global cohort of patients by greater comorbidity. At the same time, patients receiving reduced doses of dabigatran, both in the Russian Federation and in the global Registry, are characterized by a greater proportion of patients aged &gt;75 years, a higher incidence of previous myocardial infarction, coronary artery disease, heart failure, impaired renal function, higher CHA2DS2-VASc score for stroke risk. The potential dabigatran therapy retention rate after 24 months in the Russian Federation and in the global cohort was high and amounted to about 70%.