Dabigatran Group Research Articles

Pharmacodynamics of Rivaroxaban and Dabigatran in Adults with Diffuse Large B-Cell Lymphoma Receiving R-CHOP Immunochemotherapy.

Background/Objectives: Rivaroxaban and dabigatran are commonly used for thromboembolic disease management in active cancer patients. However, limited research explores the impact of concurrent chemotherapy on the pharmacodynamics of direct oral anticoagulants (DOAC). The aim of our study was to evaluate the impact of combined chemotherapy with rivaroxaban and dabigatran on the pharmacodynamics in patients with diffuse large B-cell lymphoma (DLBCL).; Methods: This was a prospective, pharmacodynamic study. Eligible subjects were ≥18 years old, diagnosed with DLBCL and initiating R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immunochemotherapy. The enrolled adults received either rivaroxaban (10 mg once daily) or dabigatran etixalate (110 mg twice daily). Plasma anti-factor Xa (FXa) in participants on rivaroxaban and diluted thrombin time (dTT) in participants on dabigatran were assessed over the dosing interval before and after R-CHOP administration. Pharmacodynamic parameters of rivaroxaban and dabigatran were determined using a non-compartmental analysis.; Results: Twenty-six adults participated, with twelve in the rivaroxaban group and fourteen in the dabigatran group. The mean age was 59 ± 14.4 years. In the rivaroxaban group, the AUEC of FXa inhibition showed no significant change after R-CHOP (mean difference 3.8 ng·h/mL, 95% confidence interval (CI) -155.4 to 163.0, p = 0.96). Similarly, in the dabigatran group, the AUEC of dTT remained unchanged post R-CHOP (mean difference 54.41 ng·h/mL, 95% CI -99.09 to 207.9 ng/mL, p = 0.46). However, the median time-to-peak dTT was significantly faster with R-CHOP (3 h, [min-max, 1.5-8] compared to without it (4 h, [min-max, 3-8], p = 0.04); Conclusions: Concurrent R-CHOP chemotherapy did not significantly impact FXa inhibition by rivaroxaban or dTT by dabigatran. The time-to-peak dTT was faster when dabigatran was administered with R-CHOP.

A comparative study of the clinical benefits of rivaroxaban and dabigatran in patients with nonvalvular atrial fibrillation with high bleeding risk.

Rivaroxaban and dabigatran are approved to reduce the risk of stroke in patients with nonvalvular atrial fibrillation (NVAF). However, the clinical benefits of rivaroxaban and dabigatran in people with high bleeding risk are unclear. A retrospective study was conducted on NVAF patients admitted to the First Affiliated Hospital of Zhengzhou University from May 31, 2016 to May 31, 2019. These patients had a high risk of bleeding and were taking at least one study medication. The aim of the study was to evaluate clinical benefits by comparing the efficacy and safety risks of these two medications. A total of 1,301 patients with high bleeding risk were enrolled, including 787 patients in the rivaroxaban group and 514 patients in the dabigatran group. Results of the primary efficacy benefit endpoint were obtained from 104 patients (13.21%) in the rivaroxaban group and 81 (15.76%) patients in the dabigatran group [hazard ratio (HR): 0.860; 95% confidence interval (CI): 0.637-1.162; P = 0.327], this indicates that there was no significant difference between dabigatran and rivaroxaban in preventing stroke and systemic embolism in patients with high bleeding risk NVAF. The principal safety end points were observed in 49 (6.23%) patients in the rivaroxaban group and in 36 (7.00%) patients in the dabigatran group (HR: 0.801 in the rivaroxaban group; 95% CI: 0.512-1.255; P = 0.333), this indicates that there was no a significant difference in reducing fatal bleeding and critical organ bleeding. With respect to secondary efficacy and benefit endpoints, 28 (3.56%) patients in the rivaroxaban group and 26 (5.06%) patients in the dabigatran group died, with an HR of 0.725 (95% CI: 0.425-1.238; P = 0.239); 32 (4.07%) patients in the rivaroxaban group; and 31 (6.03%) patients in the dabigatran group had myocardial infarction (MI), with an HR of 0.668 (95% CI: 0.405-1.102, P = 0.114) in the rivaroxaban group, this indicates that there was no significant difference between dabigatran and rivaroxaban in preventing all-cause death and MI. In NVAF patients with high bleeding risk, there was no significant difference between dabigatran and rivaroxaban in preventing stroke and systemic embolism. There was also no significant difference between dabigatran and rivaroxaban in reducing fatal and critical organ bleeding. Chinese Clinical Trials Registry, identifier ChiCTR2100052454.

Application Value and Safety Analysis of Warfarin, Rivaroxaban, and Dabigatran Ester in Elderly Patients With Atrial Fibrillation.

This study aimed to evaluate the application value and safety of Warfarin, Rivaroxaban, and Dabigatran in elderly patients with atrial fibrillation. A total of 180 elderly patients with atrial fibrillation admitted to our hospital were retrospectively analyzed. According to their anticoagulant treatment regimen, patients were divided into three groups: Warfarin (57 cases), Rivaroxaban (61 cases), and Dabigatran (62 cases). General demographic information was collected, and coagulation function indicators-including fibrinogen (FIB), thrombin time (PT), activated partial thrombin time (APTT), and D-dimer (D-D)-as well as liver function indexes-including total bilirubin (TbiL), alkaline phosphatase (ALP), aspartate aminotransferase (AST), and alanine transferase (ALT)-were compared before and after 4 weeks of treatment. There were no significant differences in demographic characteristics such as gender, age, body mass index, or disease course among the three groups. The total effective rate in the Warfarin group (84.21%) was significantly lower than in the Rivaroxaban (98.36%) and Dabigatran (96.77%) groups (p < 0.05). However, there was no significant difference in the total effective rate between the Rivaroxaban and Dabigatran groups (p > 0.05). Additionally, no significant differences were found in the effects of the three drugs on coagulation function, liver function, or the incidence of bleeding (p = 0.052). Warfarin, Rivaroxaban, and Dabigatran can effectively prevent thrombosis in elderly patients with atrial fibrillation, with Rivaroxaban and Dabigatran showing superior effectiveness. All three drugs demonstrated similar low rates of bleeding events and had no significant impact on coagulation and liver function.

Anticoagulation and Antiplatelet Regimen in Cardiac Transplant. Clinical Characteristics, Outcomes, and Blood Product Transfusion.

We aimed to evaluate the characteristics, clinical outcomes, and blood product transfusion (BPT) rates of patients undergoing cardiac transplant (CT) while receiving uninterrupted anticoagulation and antiplatelet therapy. A retrospective, single-center, and observational study of adult patients who underwent CT was performed. Patients were classified into four groups: (1) patients without anticoagulation or antiplatelet therapy (control), (2) patients on antiplatelet therapy (AP), (3) patients on vitamin K antagonists (AVKs), and (4) patients on dabigatran (dabigatran). The primary endpoints were reoperation due to bleeding and perioperative BPT rates (packed red blood cells (PRBC), fresh frozen plasma, platelets). Secondary outcomes assessed included morbidity and mortality-related events. Of the 55 patients included, 6 (11%) received no therapy (control), 8 (15%) received antiplatelet therapy, 15 (27%) were on AVKs, and 26 (47%) were on dabigatran. There were no significant differences in the need for reoperation or other secondary morbidity-associated events. During surgery patients on dabigatran showed lower transfusion rates of PRBC (control 100%, AP 100%, AVKs 73%, dabigatran 50%, p=0.011) and platelets (control 100%, AP 100%, AVKs 100%, dabigatran 69%, p=0.019). The total intraoperative number of BPT was also the lowest in the dabigatran group (control 5.5 units, AP 5 units, AVKs 6 units, dabigatran 3 units; p=0.038); receiving significantly less PRBC (control 2.5 units, AP 3 units, AVKs 2 units, dabigatran 0.5 units; p=0.011). A Poisson multivariate analysis showed that only treatment on dabigatran reduces PRBC requirements during surgery, with an expected reduction of 64.5% (95% CI: 32.4%-81.4%). In patients listed for CT requiring anticoagulation due to nonvalvular atrial fibrillation, the use of dabigatran and its reversal with idarucizumab significantly reduces intraoperative BPT demand.

Direct factor Xa inhibitors and the risk of cancer and cancer mortality: A Danish population-based cohort study.

Preclinical animal studies have suggested that myeloid cell-synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran. This nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period. In this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort.

Association of Oral Anticoagulant Therapy with the Prevalence and Severity of Vascular Calcification among Patients with Atrial Fibrillation: A Cohort Study.

Many patients with atrial fibrillation (AF) requiring long-term use of oral anticoagulants (OACs) are at high risk for vascular calcification and anticoagulation therapy with warfarin exacerbate vascular calcification. However, the effect of nonvitamin K agonists on vascular calcification has not been clearly investigated. This study explored the effects of dabigatran etexilate, rivaroxaban, and warfarin on vascular calcification among 1527 patients with AF. Demographics, comorbidities, laboratory test data, medications, and the prevalence and severity of vascular calcification in different vascular beds were compared. After propensity score matching, the incidence of vascular calcification in the rivaroxaban and warfarin group was significantly higher than that in the nonanticoagulant group, while there was no difference between the dabigatran etexilate group and the nonanticoagulant group. Similarly, we found that the rivaroxaban group had more severe calcification in the overall vascular level (P < 0.001), thoracic aorta (P < 0.001), aortic arch (P = 0.001), and left common carotid artery (P = 0.005) than the nonanticoagulant group. In addition, in the left common carotid artery, there was more severe calcification in the rivaroxaban group than that in the dabigatran group (P = 0.005). Our results suggest that rivaroxaban can significantly increase both the incidence and severity of vascular calcification among patients with AF, while dabigatran etexilate has no such effect. Many patients with AF requiring long-term use of OACs are at high risk for vascular calcification. This is the first study to conduct a head-to-head comparison of the effects of dabigatran etexilate and rivaroxaban on vascular calcification. Rivaroxaban, rather than dabigatran etexilate, promotes vascular calcification in patients with AF, providing important implications to aid clinicians in their choice for OAC selection, especially those at high risk for vascular calcification.

Perioperative Treatment with Rivaroxaban and Dabigatran on Changes of Coagulation and Platelet Activation Biomarkers following Left Atrial Appendage Closure.

Insufficient data exist regarding the investigation of the impact of novel oral anticoagulants (NOACs) on coagulation activation biomarkers in the context of left atrial appendage closure (LAAC) and device-related thrombosis (DRT). The study was designed to investigate the changes and presence of coagulation activation biomarkers between different antithrombotic strategies following LAAC. A total of 120 nonvalvular atrial fibrillation patients intolerant of long-term anticoagulants, who underwent successful WATCHMAN closure implantation, were enrolled (rivaroxaban, n = 82; dabigatran, n = 38). Blood samples were obtained from left atrium (LA) and left atrial appendage (LAA) during the operation and fasting blood samples on the same day of LAAC and 45 days after discharge. The biochemical indicators, thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), von Willebrand factor (vWF), and CD40 ligand (CD40L), were measured by enzyme-linked immunosorbent assay. The primary endpoints of this study were the efficacy and safety characteristics of different antithrombotic strategies, including DRT incidence, stroke or transient ischemic attack, systemic embolism, and clinical major and nonmajor bleeding complications during the follow-up of 180 days. The results revealed that TAT, vWF, sP-selectin, and CD40L levels in vein were significantly reduced by 2.4% (p = 0.043), 5.0% (p < 0.001), 8.7% (p < 0.001), and 2.5% (p = 0.043) from their baseline levels after rivaroxaban treatment. Conversely, no significant changes were detected in the dabigatran group. Furthermore, the plasma levels of platelet activation biomarkers (CD40L and sP-selectin) in both LA and LAA groups were significantly lower after anticoagulation with rivaroxaban, as compared to dabigatran treatment (CD40L: 554.62 ± 155.54 vs. 445.02 ± 130.04 for LA p = 0.0013, 578.51 ± 156.28 vs. 480.13 ± 164.37 for LAA p = 0.0052; sP-selectin: 2849.07 ± 846.69 vs. 2225.54 ± 799.96 for LA p = 0.0105, 2915.52 ± 1402.40 vs. 2203.41 ± 1061.67 for LAA p = 0.0022). Notably, the present study suggests that rivaroxaban may be more effective in the prevention of DRT for patients undergoing LAAC.

Treatment of acute pulmonary embolism after catheter-directed thrombolysis with dabigatran vs warfarin: Results of a multicenter randomized RE-SPIRE trial

BackgroundThrombolytic therapy is effective method in the high-risk acute pulmonary embolism (PE) treatment. Reduced-dose thrombolysis (RDT) plus oral anticoagulation therapy is effective and safe method in the moderate and severe PE treatment. It is leading to good early and intermediate-term outcomes. In the RE-COVER and RE-COVER II studies, dabigatran showed similar effectiveness as warfarin in the treatment of acute PE. Dabigatran leads to fewer hemorrhagic complications and is not inferior in efficacy to warfarin in the prevention of PE after mechanical fragmentation and RDT (catheter-directed treatment [CDT]+RDT) in patients with high and intermediate to high PE risk. We sought to evaluate the efficacy and safety (incidence of clinically significant recurrence of venous thromboembolic complications and deaths) during a 6-month course of treatment with dabigatran or warfarin in patients with high and intermediate to high acute PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT). MethodsThe RE-SPIRE is a prospective, multicenter randomized double-arm study. Over a 5-year period, 66 consecutive patients with symptomatic high and intermediate to high PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT) were randomized into two groups within the next 48 hours. The first group continued treatment with dabigatran 150 mg twice a day for 6 months; the second group continued treatment with warfarin under the control of international normalized ratio (2.0-3.0) for 6 months. Both groups received low molecular weight heparins for 2 days after surgery. Then, group 1 continued to receive low molecular-weight-heparin for 5 to 7 days, followed by a switch to dabigatran at a dosage of 150 mg two times a day. Group 2 received both low-molecular-weight heparin and warfarin up to an international normalized ratio of >2.0, followed by heparin withdrawal. The follow-up period was 6 months. ResultsThere were 63 patients who completed the study (32 in the dabigatran group and 31 in the warfarin group). In both groups, there was a statistically significant decrease in the mean pulmonary artery pressure. The mean pulmonary artery pressure at the 6-month follow-up after surgery was 24 mm Hg (interquartile range, 20.3-29.25 mm Hg) in the dabigatran group and 23 mm Hg (interquartile range, 20.0-26.3 mm Hg) in the warfarin group. The groups did not differ statistically in the deep vein thrombosis dynamics. Partial recanalization occurred in 52.0% vs 73.1% in the dabigatran and warfarin groups, respectively (P = .15). Complete recanalization occurred in 28.0% vs 19.2% in the dabigatran and warfarin groups, respectively (P = .56). The groups did not differ in the frequency of major bleeding events according to the International Society for Thrombosis and Hemostasis (0% vs 3.2% in the dabigatran and warfarin groups, respectively; P = 1.00). However, there were more nonmajor bleeding events in the warfarin group than in the dabigatran group (16.1% vs 0%, respectively; P = .02). ConclusionsThe results of the study show that dabigatran is comparable in effectiveness to warfarin. Dabigatran has greater safety in comparison with warfarin in the occurrence of all cases of bleeding in the postoperative and long-term periods. Thus, dabigatran may be recommended for the treatment and prevention of PE after CDT with RDT in patients with high and intermediate to high PE risk.

Antithrombotic Usage, Including Three-Year Outcomes With Dabigatran and Vitamin K Antagonists for Atrial Fibrillation, in Eastern Europe: A Descriptive Analysis From Phase 3 of the GLORIA-AF Registry.

Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) is a prospective registry of outcomes from patients with newly diagnosed AF at risk of stroke. In the propensity score (PS)-matched global population of phase 3 GLORIA-AF, at 3 years, dabigatran-treated patients experienced reduced risk for major bleeding, and similar risk for stroke and myocardial infarction, compared with vitamin K antagonist (VKA)-treated patients. Do patients in Eastern Europe benefit from treatment with dabigatran versus VKA? Descriptive analysis, without PS matching. To contextualize the Eastern Europe results of GLORIA-AF phase 3, we also descriptively analyzed the global population without PS matching. Consecutive patients with newly diagnosed AF and CHA2DS2-VASc-score ≥1 were enrolled until December 2016 in 38 countries (9 in Eastern Europe). Three-year outcomes with dabigatran and VKA. In Eastern Europe, 1341 patients were eligible (6% of patients globally), and incidence rates (per 100 patient-years) for the following outcomes were numerically lower with dabigatran (N = 498) versus VKA (N = 466): major bleeding (0.26 vs. 0.90), all-cause death (2.04 vs. 3.50), and a composite of stroke, systemic embolism, myocardial infarction, life-threatening bleeding, and vascular death (1.37 vs. 1.92); stroke was comparable (0.51 vs. 0.50). All incidence rates were numerically lower in Eastern Europe versus the global population for both treatments. Chronic concomitant use of high bleeding risk medications (eg, nonsteroidal anti-inflammatories) was lower in Eastern Europe (dabigatran 3.8%, VKA 9.3%) than globally (dabigatran 14.8%, VKA 20.6%) and persistence with dabigatran was higher in Eastern Europe (76%) than globally (64%). Dabigatran was associated with numerically reduced major bleeding, all-cause death, and cardiovascular (CV) composite, with comparable risk of stroke versus VKA, in Eastern Europe. Limitations of this descriptive analysis include few CV events (n = 11 for stroke, in the dabigatran and VKA groups combined) and a lack of statistical analysis and PS matching, which precludes definitive conclusions; however, the CV outcomes in Eastern Europe were consistent with the beneficial impact of dabigatran versus VKA in the statistically analyzed global population with PS matching.

Comparison of Non-Vitamin K Antagonist Oral Anticoagulants on Ischemic Stroke and Bleeding

Objective: Non-vitamin K antagonist oral anticoagulants (NOACs) have become widely utilized for various clinical indications, including non-valvular atrial fibrillation (NVAF), deep vein thrombosis (DVT), and apical thrombus. Despite their increasing popularity, limited comparative data exist on the clinical outcomes associated with different NOACs. This study aims to address this gap by directly comparing NOACs in terms of ischemic stroke, hemorrhagic stroke, and gastrointestinal bleeding. Materials and Methods: A retrospective search of the electronic database was conducted to identify patients using NOACs for NVAF, DVT, and apical thrombus. Clinical outcomes, including ischemic stroke, hemorrhagic stroke, and gastrointestinal bleeding, were directly compared among different NOACs. The chi-square test and Fisher's exact test were employed to assess the relative incidence of stroke and extracranial complications across four patient groups. Results: Among the 4,112 retrospectively analyzed patients, 55 were included in the study. Demographic and clinical profiles showed no significant differences among patients in the four different drug groups (p &gt; 0.05). Ischemic stroke was observed in 90.9% of the patients, hemorrhagic stroke in 5.8%, and gastrointestinal bleeding in 3.3%. A statistically significant difference was identified between drug doses and the rate of ischemic stroke (p &lt; 0.001). Conclusion: The findings of this retrospective study carry significant implications, especially considering the widespread global use of NOACs. The study revealed no discernible difference in the risk of ischemic stroke among patients using different NOACs. Notably, the risk of hemorrhagic stroke was dose-dependent in the dabigatran group, while rivaroxaban was associated with the highest risk of gastrointestinal bleeding. Given the elevated rate of thromboembolism in patients and the relatively short half-life of NOACs, the study concludes that further optimization of NOAC use is imperative.

Comparison of the efficacy and safety between rivaroxaban and dabigatran in the treatment of acute portal vein thrombosis in cirrhosis

BackgroundNew oral anticoagulants (NOACs) have been becoming prevalent in recent years and are increasingly used in the treatment of port vein thrombosis. The difference of the efficacy and safety between rivaroxaban and dabigatran remains unclear in the treatment of cirrhotic patients with acute portal vein thrombosis (PVT).MethodsThis retrospective study included all consecutive cirrhotic patients with acute portal vein thrombosis in our institute from January 2020 to December 2021. The patients received oral anticoagulation with rivaroxaban or dabigatran. The demographic, clinical, and imaging data of patients were collected. The diagnosis of acute PVT was confirmed by imaging examinations. The severity of liver cirrhosis was assessed using Child–Pugh score and Model for End-Stage Liver Disease (MELD) score. Outcomes included recanalization (complete, partial, and persistent occlusion), liver function, bleedings, and survival. The log-rank test was used to compare Kaplan–Meier distributions of time-to-event outcomes. The Cox proportional hazards model was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs).ResultsA total of 94 patients were included, 52 patients (55%) received rivaroxaban and 42 (45%) with dabigatran. The complete and partial recanalization of PVT was observed in 41 patients. There was no significant difference in complete recanalization, partial recanalization, and persistent occlusion between the two groups. With multivariate analysis, D-dimer (HR 1.165, 95% CI 1.036–1.311, p = 0.011) was independent predictors of complete recanalization. The Child–Pugh score (p = 0.001) was significantly improved in both two groups after anticoagulation, respectively. However, there was no difference between the two groups. The probability of survival was 94%, 95% in the rivaroxaban and dabigatran groups (log-rank p = 0.830). Major bleedings were reported in 3 patients (6%) in rivaroxaban group and 1 patient (2%) in dabigatran group (p = 0.646). Six patients (12%) in rivaroxaban group experienced minor bleeding, and five (12%) from dabigatran group (p = 0.691).ConclusionsThe efficacy and safety were comparable between rivaroxaban and dabigatran in the treatment of cirrhotic patients with acute portal vein thrombosis. And D-dimer can contribute to the prediction of PVT recanalization in cirrhotic patients.

Outcome after intracranial hemorrhage under dabigatran and reversal with idarucizumab versus under vitamin-K-antagonists - the RIC-ICH study.

Intracranial hemorrhage (ICH) is a rare but serious side effect associated with the use of oral anticoagulants, such as dabigatran. The specific reversal agent for dabigatran, idarucizumab, is available for the management of individuals with ICH. The aim of this study was to provide real-world evidence on patients with ICH and effective treatment with dabigatran and reversal with idarucizumab in clinical routine compared to those under effective treatment with vitamin-K-antagonist (VKA). Registration of Idarucizumab for Patients with IntraCranial Hemorrhage (RIC-ICH) is a non-interventional study conducted in 22 German stroke units that prospectively enrolled dabigatran patients treated with idarucizumab. Retrospective data from VKA patients served as reference population. Main objective was in-hospital mortality. Further objectives included change in bleeding volume, stroke severity, and functional status. In-hospital mortality was 26.7% in 15 dabigatran and 27.3% in 88 VKA patients (hazard ratio 1.00, 95% CI 0.29-2.60). In patients with bleeding volume > 60 ml, mortality was lower in the dabigatran group (N = 6, 33%) compared to the VKA group (N = 15, 67%; HR 0.24, 95% CI 0.04-0.96). No differences were observed in secondary endpoints between dabigatran and VKA patients. These results, based on data from routine clinical practice, suggest that in-hospital mortality after idarucizumab treatment is comparable to that in patients pretreated with VKA. Due to the low precision of estimates, the results must be interpreted with caution.

Efficacy and Safety of Direct Oral Anticoagulants in Patients With Atrial Fibrillation Combined With Hypertension: A Multicenter, Retrospective Cohort Study.

Whether there are differences in direct oral anticoagulants efficacy and safety in patients with atrial fibrillation (AF) combined with hypertension is unclear. We therefore conducted a multicenter retrospective cohort study to assess the differences in the efficacy and safety of direct oral anticoagulants in patients with AF combined with hypertension. This multicenter retrospective cohort study was based on data from 15 centers in China and included 2086 patients with AF. We divided the patients into dabigatran and rivaroxaban groups according to their direct oral anticoagulants. Propensity score matching was used to balance the covariates between the groups. Due to our limited sample size, the number of cases of some clinical events with low incidence was small. During a mean follow-up period of 10 months, a total of 268 (12.9%) bleeding events occurred, including 27 (1.3%) major bleeding events and 241 (11.6%) minor bleeding events, and 45 (2.2%) thromboembolic events. In patients with AF combined with hypertension, rivaroxaban was associated with a higher major bleeding incidence than dabigatran (odds ratio [OR], 2.89 [95% confidence interval [CI, 1.22-6.87]; P = .012). In contrast, the risk of thromboembolism and minor bleeding was similar for rivaroxaban (OR, 0.55 [95%CI, 0.29-1.01]; P = .069) and dabigatran (OR, 0.82 [95%CI, 0.63-1.08]; P = .150). Based on the results of this study, in patients with AF and hypertension treated with direct oral anticoagulants, the incidence of thromboembolism and minor bleeding was not statistically different between dabigatran and rivaroxaban, but compared with rivaroxaban, dabigatran was associated with a lower risk of major bleeding.

Direct oral anticoagulants: patient reported adherence and minor bleedings

Data regarding adherence and minor bleeding on direct oral anticoagulants in everyday life are still sparse. Inclusion criteria: treatment initiated with dabigatran, rivaroxaban or apixaban in non-valvular atrial fibrillation patients from a center in northern Sweden between 2011 and 2019 (n = 668). Exclusion criteria: cognitive impairment, dose dispensing, need of interpreter or hospital admission (n = 67). By a telephone interview adherence was measured in 569 patients (response rate 94.8%) using the 8-item Morisky medication adherence scale and minor bleeding was asked for. CHA2DS2-VASc and HAS-BLED scores were collected from medical records. The number (n), mean age, mean treatment duration, mean (points) CHA2DS2-VASc and HAS-BLED scores was with dabigatran (n = 175, 73.3 years, 17.8 months, 3.6 p and 2.2 p), rivaroxaban (n = 198, 73.7 years, 21months, 3.8 p and 2.1 p) and apixaban (n = 196, 72.7 years, 15.2 months, 3.4 p and 2.1 p). Adherence was high for dabigatran, rivaroxaban and apixaban in 54%, 76% and 53%; intermediate in 37%, 20% and 37% or low in 9%, 4% and 10% respectively. High adherence (Morisky score 8) distinguished rivaroxaban (p < 0.0001) and in patients with CHA2DS2-VASc ≥ 4 p, (p < 0.0001). Patients on rivaroxaban/apixaban reported more minor bleedings (37% / 28%) compared to dabigatran (13%), (p < 0.001). Only 61% of the patients followed prescription. Adherence to rivaroxaban was significantly better, maybe due to the once daily dosing regimen, and furthermore among patients with higher risk for stroke. Minor bleedings were less common in the dabigatran group. The impact of minor bleedings on adherence and a possible relationship to clinical outcomes need to be further studied.

Intravenous Dabigatran Provides Adequate Anticoagulation for Cardiopulmonary Bypass Using a Rabbit Model.

Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 μg/ml at 5 min of CPB to 428 ± 150 μg/ml at 60 min, and 295 ± 35 μg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model.

Abstract TMP97: Comparison Of Severity And Mortality Among Patients With Atrial Fibrillation Who Developed Ischemic Stroke During Anticoagulation With Warfarin And Non-vitamin K Antagonist Oral Anticoagulants

Introduction: Non-vitamin K antagonist oral anticoagulant (NOAC) has been the drug of choice for preventing ischemic stroke in patients with atrial fibrillation since 2014. In previous studies, the stroke risk while taking warfarin was known to be 2 per 100 patient-years and 1.5% per year while taking NOACs. We hypothesized that even if ischemic stroke occurred during anticoagulation therapy with NOACs, the prognosis was likely to be better than that of warfarin. Methods: We obtained data from the nationwide claim database from 2009 to 2019. Patients with atrial fibrillation were identified using the International Classification of Disease Codes. After the diagnosis of atrial fibrillation, patients who developed ischemic stroke during anticoagulation were extracted. The severity of ischemic stroke in the patients was evaluated by the stroke severity index (SSI) calculated by the combination of claim codes. Patients who died within 3-months and within 1-year after ischemic stroke were identified. The patients were divided according to the drug of anticoagulation (warfarin, dabigatran, apixaban, rivaroxaban, edoxaban). Results: A total of 206,848 patients who were newly diagnosed with atrial fibrillation and started anticoagulation therapy were analyzed. Among them, 10,658 patients developed ischemic stroke during follow-up. The anticoagulants administered to these patients were warfarin in 4,423, dabigatran in 965, apixaban in 2,320, rivaroxaban in 1,702, and edoxaban in 1,248. The SSI was highest in the warfarin group (11.43±3.85), and lower in the edoxaban group (8.93±4.03). The order of mortality at 3-months after ischemic stroke was warfarin (17.88%), rivaroxaban (12.34%), dabigatran (9.53%), apixaban (8.28%), and edoxaban group (8.25%). The 1-year mortality rate also showed the same trend. Among NOACs, apixaban had the lowest hazard ratio (HR), HR for 3-months mortality was 0.431 (95% CI 0.367-0.505, p&lt;0.0001), and HR for 1-year mortality was 0.455 (95% CI 0.407-0.510, p&lt;0.0001). Conclusions: In our study, we confirmed that NOAC could lower the risk of death from ischemic stroke than warfarin in patients with atrial fibrillation. Except for rivaroxaban, there was no difference in mortality in the other three NOAC groups.

Peri-Interventional Triple Therapy with Dabigatran Modifies Vasomotion after Bare-Metal Stent Implantation in a Pig Coronary Artery Model

(1) Background: Coronary artery stenting leads to local inflammation, disturbs vasomotion, and slows endothelialization, increasing vascular thrombus risk. We used a pig stenting coronary artery model to assess how peri-interventional triple therapy with dabigatran ameliorates these effects. (2) Methods: In a total of 28 pigs bare-metal stents were implanted. Four days before the percutaneous coronary intervention (PCI), we started 16 of the animals on dabigatran, maintained through 4 days after the procedure. As controls, the remaining 12 pigs received no therapy. In both groups, dual antiplatelet therapy (DAPT) (clopidogrel, 75 mg plus aspirin, 100 mg) was administered until animals were euthanized. Just after the PCI and on day 3 after the procedure, we performed optical coherence tomography (OCT) in eight animals in the dabigatran group and four controls and euthanized them. We followed the eight remaining animals in each group with OCT and angiography for one month before euthanizing them and performed in vitro myometry and histology on harvested coronary arteries from all animals. (3) Results: The dabigatran group showed a significantly increased vasoconstriction at 3 days after PCI (10.97 ± 3.85 mN vs. 7.32 ± 5.41 mN, p = 0.03), but we found no differences between endothelium-dependent and -independent vasodilatation. We also found no group differences in OCT, quantitative angiography, or histomorphometry findings. (4) Conclusions: Starting a short course of dabigatran just before PCI and continuing for a 3-day window along with usual post-PCI DAPT is associated with enhanced vasoconstriction after bare-metal stent implantation without reducing neointimal formation at one month.

Dabigatran: Clinical correlation of drug and its dose with risk of stroke and bleeding.

Dabigatran is the first oral direct thrombin inhibitor which is endorsed by Food and Drug Administration in the prevention of embolic events in patients with nonvalvular atrial fibrillation. Suitable dose of the drug for the patient is selected based on CHA2DS2-VASc score and HAS-BLED score. To determine and compare the risk of occurrence of stroke and bleeding after the initiation of dabigatran therapy in patients prescribed with this drug. Patients with more than 18 years who were prescribed with dabigatran during 2017-2019 in a tertiary care hospital were selected for the study. Most of the patient's prescriptions contained an antiplatelet, so a comparison was made between the clinical outcomes of patients given with dabigatran alone and dabigatran with an antiplatelet because antiplatelet can have effects on the safety as well as efficacy profile of dabigatran. Out of 75 patients enrolled in the study, 42 patients were in the dabigatran with the antiplatelet group and 33 were in the dabigatran alone group. In both the groups, there was a significant reduction in CHA2DS2-VASc score, i.e., 2.58 ± 1.32-1.94 ± 1.21 in dabigatran-treated patients within 6 months, and the score was lowered from 3.76 ± 1.22 to 2.92 ± 1.22 in other groups. The mean value of the HAS-BLED score of dabigatran was reduced from 1.15 ± 0.83 to 0.84 ± 0.78 and that of dabigatran with antiplatelet group from 2.10 ± 0.94 to 1.74 ± 0.92. It was observed that within 6 months, both the treatment groups showed a reduction in the risk scores. The dabigatran group had lower background risks of stroke and bleeding in comparison to the dabigatran plus antiplatelet group.

A Comparison among Nonvitamin K Antagonist Oral Anticoagulants in Asian Patients with Venous Thromboembolism: A Multi-Institutional Study

The comparison of clinical effectiveness and safety across different nonvitamin K antagonist direct oral anticoagulants (DOACs) in Asian patients with venous thromboembolism (VTE) remains unclear. Therefore, we assessed the real-world benefits of different DOACs in these patients. A cohort of 1480 patients with VTE were identified from the Chang Gung Research Database between 1 January 2012, and 31 December 2019. The composite outcomes of recurrent VTE and major bleeding were evaluated for four DOACs. The composite outcomes of recurrent VTE and major bleeding occurred in 9.06%, 9.80%, 8.61%, and 10.86% of the apixaban, dabigatran, edoxaban, and rivaroxaban groups, respectively, within 12 months of treatment initiation. The risk of the composite outcomes was similar in the rivaroxaban group and the apixaban, dabigatran, and edoxaban groups, with a subdistribution hazard ratio (SHR) of 0.80 (95% CI, 0.49-1.29), 0.81 (95% CI, 0.34-1.95), and 0.76 (95% CI, 0.42-1.39), respectively. No significant differences in the rates of recurrent VTE or major bleeding were observed between the rivaroxaban and other DOAC groups at the 12-month follow-up. According to real-world practice in Asian patients with VTE, the DOAC type was not associated with the differences in the risk of recurrent VTE or major bleeding within 12 months of treatment initiation.

Differential effect of direct oral anticoagulants on thrombin generation and fibrinolysis in patients with atrial fibrillation and venous thromboembolism.

Recent reports suggest that direct oral anticoagulants (DOAC) may induce different anticoagulant and profibrinolytic responses. We performed a head-to-head comparison of the changes in thrombin generation (TG) parameters and tissue plasminogen activator (t-PA)-induced clot lysis produced by different DOAC. We tested 137 plasma samples from patients with non-valvular atrial fibrillation (n=72) and venous thromboembolism (n=65) under treatment with apixaban (n=38), edoxaban (n=29), rivaroxaban (n=39), or dabigatran (n=31). TG was evaluated by a fluorometric assay and fibrinolysis by measuring the lysis time of clots exposed to 40 ng/mL t-PA. Trough-to-peak changes of TG parameters, along with correlation analysis, showed that all DOAC prolonged the lag-time in a concentration-dependent fashion. As for the other parameters, anti-factor Xa drugs markedly reduced the thrombin peak and velocity index but had little (rivaroxaban) or no effect on endogenous thrombin potential (ETP); dabigatran, instead, reduced ETP, weakly decreased thrombin peak and did not influence the velocity index, as also inferred from the changes in TG values after neutralisation of dabigatran with idarucizumab. Concerning the profibrinolytic effect of DOAC, intergroup comparison showed that the clot lysis time of dabigatran samples was significantly shorter than that of the apixaban and rivaroxaban samples, at both C-Trough and C-Peak. Moreover, a significant correlation between trough-to-peak changes in drug level and clot lysis time was only observed in the dabigatran group (rho=0.53). Finally, after DOAC removal by DOAC-stop, only dabigatran samples showed a significant increase in lysis time. Our data show that dabigatran inhibits TG in a different way than anti-Xa DOAC; moreover, under our conditions, only dabigatran displayed profibrinolytic activity, most likely because of its distinctive effect on the TG curve.