Safety Of Dabigatran Research Articles

Features of pharmacokinetics and safety of dabigatran, rivaroxaban and apixaban in elderly patients

Clinical practice guidelines suggest long-term use of oral anticoagulation in elderly patients. An increased risk of bleeding is associated with age, low body weight, limited renal function, and multiple comorbidities that may be exacerbated by anticoagulation therapy. There is currently very little relevant pharmacological and clinical data on direct oral anticoagulants (DOACs), especially in older geriatric patients. This is very relevant since pharmacokinetics and pharmacodynamics often differ significantly in this group of patients. Therefore, studying and understanding the pharmacokinetics and pharmacodynamics of DOACs in the elderly is necessary to achieve balance in anticoagulation strategies. We identified potentially relevant studies by searching the electronic databases PubMed, Web of Science, Cochrane Library, MEDLINE, and Google Scholar. Further, according to the inclusion and exclusion criteria, as well as independent selection, all the authors of this article selected sources that were suitable according to the criteria and compiled this review.

Study of Use of Dabigatran in Cerebral Venous Sinus Thrombosis.

Cerebral venous sinus thrombosis (CVST) is a challenging condition to diagnose and treat due to its diverse range of clinical presentations. The incidence of CVST is increasing, and although diagnostic techniques have improved, the mainstay of treatment is heparin followed by vitamin K antagonist (VKA), warfarinhas remained largely unchanged for the past three decades. However, new direct oral anticoagulants (NOACs) like dabigatran have been developed to address the limitations of VKA therapy. Magnetic resonance imaging (MRI) with magnetic resonance venography (MRV) is the current preferred diagnostic method for CVST due to its exceptional sensitivity and specificity. This prospective observational study was set out to investigate the efficacy and safety of dabigatran in treating cerebral venous sinus thrombosis. The study included 30 patients who reported regular intake of 150 mg dabigatran etexilate twice a day. Among the participants, headache was the most commonly reported symptom. The study found that patients treated with dabigatran experienced favorable outcomes, with all patients achieving re-canalization and reporting no major complications. These promising results suggest that dabigatran could be an effective treatment option for CVST cases. However, the study emphasizes the need for larger, multi-center studies to further validate these findings and improve the overall understanding of the condition and its treatment options.

Efficacy and safety of dabigatran and rivaroxaban in atrial fibrillation patients with impaired liver function: a multicenter retrospective cohort study.

The efficacy and safety of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) patients with impaired liver function (ILF) have not been sufficiently studied. The aim of this study was to evaluate the efficacy and safety of DOACs for stroke prevention in patients with AF and ILF. This study was based on data from 15 centers in China, including 4,982 AF patients. The patients were divided into 2 subgroups based on their liver function status: patients with normal liver function (NLF)(n = 4213) and patients with ILF (n = 769). Logistic regression analysis was used to investigate the risk of total bleeding, major bleeding, thromboembolism, and all-cause deaths in AF patients with NLF and ILF after taking dabigatran or rivaroxaban, respectively. Among AF patients treated with dabigatran or rivaroxaban, patients with ILF were associated with significantly higher major bleeding, compared with NLF patients (aOR: 4.797; 95% CI: 2.224-10.256; P < 0.001). In patients with NLF, dabigatran (n = 2011) had considerably lower risk of total bleeding than rivaroxaban (n = 2202) (aOR: 1.23; 95% CI: 1.002-1.513; P = 0.049). In patients with ILF, dabigatran (n = 321) significantly favored lower risks of major bleeding compared with rivaroxaban(n = 448) (aOR: 5.484; 95% CI: 1.508-35.269; P = 0.026). After using dabigatran or rivaroxaban, patients with ILF had remarkably increased risk of major bleeding compared with patients with NLF. In AF patients with NLF, dabigatran had the distinct strength of significantly reduced risk of total bleeding compared with rivaroxaban. In patients with AF and ILF, dabigatran use was associated with lower risk for major bleeding compared with rivaroxaban.

Dabigatran for Treatment and Secondary Prevention of Venous Thromboembolism in Pediatric Congenital Heart Disease.

Congenital heart disease (CHD) is common in children and associated with greater risk of thrombotic complications. Management of these complications with standard-of-care treatment is suboptimal for these children. The effectiveness and safety of dabigatran were demonstrated in pivotal pediatric studies for the treatment of acute venous thromboembolism (VTE; NCT01895777) and secondary VTE prevention (NCT02197416). We report safety and efficacy outcomes from subgroup analyses of these studies for children with CHD (diagnosed according to local practice) and those without. In NCT01895777, 17/21 (81.0%) and 16/27 (59.3%) patients with CHD (including cyanotic) treated with dabigatran and standard of care, respectively, met the primary end point (complete thrombus resolution, freedom from recurrent VTE, and freedom from VTE-related death; odds ratio [OR], 0.34 [95% CI, 0.08-1.23]). In patients without CHD, 41.0% (n=64) versus 34.9% (n=22) achieved this end point with the respective treatments (OR, 0.77 [95% CI, 0.42-1.41]). Although numerical differences were observed, no heterogeneity in treatment effect of dabigatran on the composite primary end point was detected in patients with and without CHD (interaction P =0.2674). In NCT02197416, recurrent VTE at 12 months occurred in 0/17 patients with CHD versus 3/194 (1.5%) without. No patient with CHD experienced major or clinically relevant nonmajor bleeding events. Data on favorable anticoagulant alternatives for the unmet needs of children with CHD are emerging, and our exploratory results suggest that dabigatran could be an appropriate treatment choice, although challenging sample size limitations in pediatric studies require cautious interpretation of findings. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01895777, NCT02197416.

Abstract TP240: Safety of Dabigatran in Patients With Acute Minor Non-Cardioembolic Ischemic Stroke or Transient Ischemic Attack and Cerebral Microbleeds: A Post Hoc Analysis of the DATAS-II Randomized Trial

Introduction: Cerebral microbleeds are reported to predict risk of hemorrhagic transformation (HT) in patients with acute ischemic stroke. We aimed to investigate whether the effect of dabigatran (vs. aspirin) in patients with acute minor non-cardioembolic ischemic stroke/TIA is modified by baseline microbleeds on MRI. Methods: This is a post hoc analysis of the DATAS-II trial that randomized 305 patients with acute minor non-cardioembolic ischemic stroke/TIA to dabigatran (150/110 mg twice daily) or aspirin (81 mg daily) for 30 days. MRIs of patients with T2*-weighted sequences on their baseline scans underwent blinded central adjudication for microbleeds. Results: A total of 251 participants (mean age=66±13 years, 36% women, median [IQR] time from symptom onset to randomization 40 [27-55] hours; mean NIHSS=1.5±1.9) were included in these analyses, of whom 82 (33%) had baseline microbleeds. On 30-day MRI, 6% (n=14) developed HT, and 80% (n=191) achieved mRS 0-1 at 90 days. In multivariable logistic regression analyses, we found no association between microbleeds and HT (adjusted odds ratio [aOR], 0.76; 95% CI, 0.18-3.23) on 30-day MRI or mRS 0-1 at 90 days (aOR, 1.54; 95% CI, 0.70-3.41). The rates of HT and mRS 0-1 in patients with microbleeds were 3% on dabigatran and 4% on aspirin (OR, 0.71; 95% CI, 0.06-8.17), and 74% on dabigatran and 84% on aspirin (OR, 0.54; 95% CI, 0.18-1.64), respectively. The presence, severity, or location of microbleeds did not modify the effect of dabigatran on these outcomes (p-interaction&gt;0.05). Conclusions: Early dabigatran treatment appears safe in patients with acute minor non-cardioembolic ischemic stroke/TIA and hemorrhage-prone cerebral small vessel disease marked by microbleeds on MRI.

The place of dabigatran in the treatment of patients with atrial fibrillation in the light of modern recommendations

This review is devoted to the aspects of anticoagulant therapy in patients with atrial fibrillation in the light of the modern understanding of this type of arrhythmia as a polymorbid continuously developing syndrome. According to experts, the management strategy of this category of patients is based on an integrated assessment, including the risk of stroke, the presence of symptoms, assessment of structural heart disease and mandatory accounting of concomitant pathology. In this approach, the appointment of anticoagulant therapy as a prevention of stroke in a patient with atrial fibrillation is put in the first place. At the same time, experts emphasize the need for a dynamic reassessment of risks, as well as the use of a multidisciplinary team of specialists to make a complex decision. The review summarizes the basic concepts of the integrated approach, describes various variants of clinical scenarios, including aspects of anticoagulant maintenance of cardioversion and catheter ablation, multicomponent therapy after percutaneous coronary intervention. A separate chapter is devoted to modern algorithms of perioperative management of a patient receiving oral anticoagulants, which is based on the stratification of interventions according to the risk of perioperative bleeding and the characteristics of the anticoagulant prescribed to the patient. The place of dabigatran in the primary and secondary prevention of stroke and systemic embolism in patients with atrial fibrillation is described, studies that served as the basis of the evidence base for the use of dabigatran in patients with atrial fibrillation are presented. The data of register observations, meta-analyses devoted to the evaluation of the efficacy and safety of dabigatran in certain categories of patients (elderly patients, patients with chronic heart failure, diabetes mellitus) are presented, which form the basis of decision-making in real clinical practice.

Long-term comparative effectiveness and safety of dabigatran, rivaroxaban, apixaban and edoxaban in patients with atrial fibrillation: A nationwide cohort study.

Background: Although non-vitamin K antagonist oral anticoagulants (NOACs) are recommended over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management, direct long-term head-to-head comparisons are lacking. Therefore, their risk-benefit profiles were investigated compared to VKAs and between NOACs. Methods: AF patients initiating anticoagulation between 2013-2019 were identified in Belgian nationwide data. Inverse probability of treatment weighted Cox regression was used to investigate effectiveness and safety outcomes and were additionally stratified by NOAC dose. Results: Among 254,478AF patients (328,796 person-years of follow-up), NOACs were associated with significantly lower risks of stroke or systemic embolism (stroke/SE) (hazard ratio (HR) 0.68, 95% confidence interval (CI) (0.64-0.72)), all-cause mortality (HR 0.76, 95%CI (0.74-0.79)), major or clinically relevant non-major bleeding (MB/CRNMB) (HR 0.94, 95%CI (0.91-0.98)) and intracranial hemorrhage (HR 0.73, 95%CI (0.66-0.79)), but non-significantly different risks of myocardial infarction, gastrointestinal and urogenital bleeding compared to VKAs. Despite similar stroke/SE risks, dabigatran and apixaban were associated with significantly lower MB/CRNMB risks compared to rivaroxaban (HR 0.86, 95%CI (0.83-0.90); HR 0.86, 95%CI (0.83-0.89), respectively) and edoxaban (HR 0.91, 95%CI (0.83-0.99); HR 0.86, 95%CI (0.81-0.91), respectively), and apixaban with significantly lower major bleeding risks compared to dabigatran (HR 0.86, 95%CI (0.80-0.92)) and edoxaban (HR 0.79, 95%CI (0.72-0.86)). However, higher mortality risks were observed in some risk groups including with apixaban in patients with diabetes or concomitantly using digoxin compared to dabigatran and edoxaban, respectively. Conclusion: NOACs had better long-term risk-benefit profiles than VKAs. While effectiveness was comparable, apixaban was overall associated with a more favorable safety profile followed by dabigatran.

The impact of ABCB1 and CES1 polymorphisms on the safety of dabigatran in patients with non-valvular atrial fibrillation

BackgroundThis study aimed to analyze associations between genetic variants and plasma concentrations along with clinical outcomes in dabigatran in patients with non-valvular atrial fibrillation (NVAF).MethodsWe conducted a prospective study and enrolled NVAF patients treated with dabigatran in the real world. A total of 86 patients treated with 110 mg DE twice daily were recruited for this study. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration. All bleeding and thromboembolic complications were recorded during the 1.5 years of follow-up.ResultsEighty-three patients provided samples at the trough plasma level of dabigatran, and 58 patients provided samples at the peak plasma level of dabigatran. There was a significant association between the CES1 SNP rs8192935 and trough plasma concentrations of dabigatran (P = 0.013). Our results showed that the CES1 SNP rs8192935 significantly influenced dabigatran trough concentrations in the Chinese population, and carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 SNP c.2482-2236G > A (rs4148738) was associated with major bleeding events in the addictive model (P = 0.046, OR = 3.29) and dominant model (P = 0.040, OR = 8.17). Additionally, the ABCB1 SNP c.3435 C > T (rs1045642) was associated with the incidence of major bleeding events in the addictive model (P = 0.043, OR = 3.34) and dominant model (P = 0.046, OR = 7.77). However, no significant associations were found between all the SNPs and the incidence of minor bleeding events.ConclusionOur results indicated that the CES1 polymorphism rs8192935 was associated with trough plasma concentrations of dabigatran. Carriers of the G allele had increased trough plasma concentrations of dabigatran compared to noncarriers. The ABCB1 polymorphisms rs4148738 and rs1045642 were associated with an increased risk for major bleeding events for the first time in a Chinese population.

Bleeding risk of oral anticoagulants in liver cirrhosis.

The safety of dabigatran is poorly studied in patients with liver cirrhosis and has rarely been compared to warfarin in terms of bleeding risks. We undertook a retrospective cohort study across three tertiary centres in Auckland, New Zealand, between 2008 to 2020. Adults 18 years and over and those with a clinically confirmed diagnosis of cirrhosis were included. Data collected included demographic data and clinical characteristics, baseline medication and comorbidities. The primary outcome measure was the incidence of any bleeding event that resulted in hospital admission. Overall, 100 patients were included in this study. A total of 52 patients took warfarin, and 48 took dabigatran. Baseline characteristics for both groups were generally similar. The incidence rate of bleeds for patients taking warfarin was 14.4 per 100 person-years (95% CI, 8.8-23.5) compared to 9.1 per 100 person-years (95% CI, 4.5-18.1) for patients taking dabigatran. The incidence rate ratio comparing dabigatran to warfarin was 0.63 (95% CI, 0.23-1.60), p=0.25. Our study found that patients on dabigatran may have a lower bleeding risk than patients taking warfarin, but this was not statistically significant.

Comparison of Dabigatran Versus Warfarin Treatment for Prevention of New Cerebral Lesions in Valvular Atrial Fibrillation

Warfarin is the standard anticoagulation therapy for valvular atrial fibrillation (AF); however, new oral anticoagulants have emerged as an alternative. We compared the efficacy and safety of dabigatran with conventional treatment in AF associated with left-sided valvular heart disease (VHD), including mitral stenosis (MS). Patients with AF and left-sided VHD were randomly assigned to receive dabigatran or conventional treatment. The primary end point was the occurrence of clinical stroke or a new brain lesion (silent brain infarct and microbleed) on 1-year follow-up brain magnetic resonance imaging. Patients in the dabigatran group were switched from warfarin (n=52), antiplatelets alone (n=5), or no therapy (n=2) to dabigatran. In the conventional group, 53 used warfarin (including 42 MS patients), and 7 used antiplatelets. No death or clinical stroke event occurred in either group during follow-up. Silent brain infarct and microbleed occurred in 20 and 2 patients in the dabigatran group and 20 and 4 patients in the conventional treatment group. The incidence rate of the primary end point did not significantly differ between groups (34% vs 40%, relative risk 0.87, 95% confidence interval 0.59 to 1.29, p=0.491). The primary end point rate was similar between groups in 82 patients (40 in the dabigatran group and 42 in the conventional group) with MS (32% vs 34%, relative risk 0.93, 95% confidence interval: 0.57 to 1.50, p=0.759). In conclusion, primary end point rates after treatment with dabigatran were similar to conventional treatment in patients with significant VHD and AF. New oral anticoagulants could be a reasonable alternative to warfarin in patients with AF and VHD, which should be confirmed in future large-scale studies.

Dabigatran versus aspirin for stroke prevention after cryptogenic stroke with patent foramen ovale: A prospective study

BackgroundMedical treatment for stroke prevention in cryptogenic stroke (CS) patients with patent foramen ovale (PFO) remains inconclusive. We compared the efficacy and safety of dabigatran with aspirin on stroke prevention for patients with recent CS and PFO. MethodsIn this prospective cohort study, we randomly assigned patients with PFO who had a cryptogenic stroke, in a 1:1 ratio, to dabigatran or aspirin group. Patients were followed for 2 years and the primary efficacy outcome was the recurrence of stroke or systemic embolism. The primary safety outcome was occurrence of bleeding complications. ResultsA total of 375 patients were enrolled in the study, 188 assigned to the dabigatran group and 187 to the aspirin group. During the 2-year follow-up, the primary efficacy outcomes occurred in 4 patients in the dabigatran group (annualized rate, 2.0%) and 11 patients in the aspirin group (annualized rate, 5.1%) (hazard ratio, 0.74; 95% confidence interval, 0.51–0.98; P = 0.049). TIA/acute ischemic stroke occurred in 3 patients in the dabigatran group and 8 patients in the aspirin group (hazard ratio, 0.72; 95% confidence interval, 0.52–0.95; P = 0.039). Bleeding complications occurred in 8 patients in the dabigatran group (annualized rate, 3.9%) and in 7 patients in the aspirin group (annualized rate, 3.5%) (hazard ratio, 1.24; 95% confidence interval, 1.01–1.52; P = 0.886). ConclusionFor cryptogenic stroke with PFO, dabigatran was superior to aspirin for stroke prevention. There is no increased risk of bleeding complication with dabigatran.

Abstract 9192: Efficacy and Safety of Dabigatran in the Treatment and Secondary Prophylaxis of Children With Congenital Heart Disease

Introduction: Congenital heart disease (CHD) is associated with an increased frequency of thrombotic events in children, particularly in cyanotic conditions (i.e., single ventricles). Phase IIb/III clinical trials in children with venous thromboembolism (VTE) reported the noninferiority of dabigatran etexilate (DE) versus standard of care in treating acute VTE (DIVERSITY, NCT01895777) and a favorable safety profile for VTE prevention (NCT02197416). Aim: To evaluate the efficacy and safety of DE in the treatment and secondary prophylaxis of VTE in children with CHD, including subsets with cyanotic CHD. Methods: The primary composite efficacy endpoint in DIVERSITY was complete thrombus resolution and freedom from VTE recurrence or VTE-related death; safety endpoints included bleeding events (BEs). Primary endpoints in the VTE prevention trial were VTE recurrence and BEs. CHD status was confirmed locally using standard diagnostic modalities. Results: In DIVERSITY, 48/267 (18.0%) children had CHD. DE was noninferior to standard of care in both the CHD and non-CHD groups for the composite primary endpoint ( Table ), irrespective of the presence of cyanotic or noncyanotic CHD ( Table ). BEs (mainly minor) appeared to be lower in the CHD (8.3%) than the non-CHD group (25.7%), regardless of treatment. In the secondary VTE prevention trial, 17/211 (8.1%) children had CHD. Recurrent VTE at 12 months occurred in 0 and 3 (1.5%) children in the CHD and non-CHD groups respectively ( Table ). Conclusions: In children with CHD, DE has an efficacy and safety profile consistent with the overall DIVERSITY trial. Furthermore, our results confirm the safety profile for secondary VTE prevention, suggesting that DE is a viable anticoagulant alternative for this population.

Dabigatran as first-line treatment for heparin-induced thrombocytopenia in the intensive cardiac care setting

Abstract Introduction Heparin-induced thrombocytopenia (HIT) is a rare immune-mediated disorder related to the use of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) which is associated with increased risk of vascular thrombosis. HIT constitute a relevant and not so uncommon clinical issue in the intensive cardiac care unit setting. Parenteral non-heparin anticoagulants are recommended for the treatment of HIT. The efficacy of dabigatran, direct oral anticoagulant, is poorly documented in this indication. In laboratory-confirmed HIT only few cases with short-term use and early conversion to and from another anticoagulant were reported. Purpose The purpose of our study was to evaluate the efficacy and safety of dabigatran as a first-line and the only one anticoagulant used in the treatment of HIT. Methods We prospectively enrolled 5 patients with the diagnosis of HIT who were hospitalized in our intensive cardiac care unit in 2017–2021. Heparin was stopped immediately on the suspicion of HIT and off-label dabigatran therapy was initiated the same day. There were no conversion to another non-heparin anticoagulant – dabigatran was used continuously from suspicion of HIT for at least 3 months. In all patients we used latex immunoassay to confirm the diagnosis of HIT. Lower-extremity compression ultrasonography was performed to exclude thrombosis. We distinguished HIT with thrombosis (HITT) and isolated HIT (HIT without thrombosis). The minimal follow-up period on dabigatran treatment was 3 months and the maximal 4 years. Results All the patients were male with the median age of 73 years (interquartile range, 52–78 years) and all were exposed to both, UFH and LMWH. The median platelet (PLT) count before exposition to heparin was 182000/μl (interquartile range, 171000/μl–321000/μl). Platelet count fall &amp;gt;50% was observed after a median time of 9 days (interquartile range, 7–11 days) after exposition to heparin and a median PLT count nadir was 87000 μl/l (interquartile range, 25000/μl–103000/μl). Two patients had intermediate and three high probability of HIT. HITT was diagnosed in one patient. The manifestation of HITT was upper-extremity arterial thrombosis and pulmonary embolism. Four patients were diagnosed with isolated HIT. PLT count recovery &amp;gt;15ehab724.2982/μl was observed after a median time of 3 days on dabigatran treatment (interquartile range, 2–7 days). In the patient with HITT, a complete resolution of upper-limb arterial thrombosis was observed. At the minimal observation period end point (3 months) all the patients survived without bleeding or new thrombotic event. Moreover, neither bleeding nor recurrence of HIT occurred during the total follow-up period. Conclusion Dabigatran is safe and efficient as first-line treatment for HIT and can be used as the only one anticoagulant in this challenging, clinical scenario. Funding Acknowledgement Type of funding sources: None.

Effectiveness and Safety of Dabigatran in Atrial Fibrillation Patients with Severe Obesity: a Real-World Retrospective Cohort Study.

Direct oral anticoagulants such as dabigatran are the preferred anticoagulant in treating atrial fibrillation (AF) patients due to their effectiveness and safety. Whether this applies to severely obese patients needs to be determined. To compare the effectiveness and safety of dabigatran with warfarin among AF patients with severe obesity. Retrospective cohort study. AF patients with a BMI >40kg/m2 or a weight >120kg receiving dabigatran or warfarin between 10/01/2010 and 12/31/2019 in a large integrated health system and followed through 08/01/2020. Not applicable. Primary effectiveness outcome was composite thromboembolism including transient ischemic attack, ischemic stroke, or systemic embolism. Primary safety outcome was composite bleeding including gastrointestinal bleeding, intracranial bleeding, or other bleeding. Secondary outcomes included the individual outcomes and all-cause mortality. Propensity score matching (PSM) was performed to create a 1:1 matched cohort and Cox proportional hazards model was used to estimate the hazard ratio (HR) of each outcome for dabigatran users compared to warfarin users. A total of 6848 patients receiving either dabigatran or warfarin were identified. In a 1:1 matched cohort, dabigatran users had a HR of 0.71 (95% confidence interval (CI): 0.56-0.91) for composite thromboembolism, a HR of 1.24 (95%CI: 1.07-1.42) for composite bleeding, and a HR of 0.57 (95% CI: 0.45-0.71) for all-cause mortality when compared to warfarin users. Among AF patients with a BMI >40kg/m2 or a weight >120kg in a real-world clinical setting, dabigatran was effective in reducing the risk of thromboembolism and mortality but was associated with an increased risk of bleeding when compared to warfarin. Dabigatran may be a reasonable option for AF patients with severe obesity.

Dabigatran, rivaroxaban, and apixaban are superior to warfarin in Asian patients with non-valvular atrial fibrillation: An updated meta-analysis.

BACKGROUNDMost of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with atrial fibrillation (AF) originated from western countries. AIMTo systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran, rivaroxaban, and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF.METHODSMedline, Cochrane, and ClinicalTrial.gov databases were reviewed. A random-effect model meta-analysis was used and I-square was utilized to assess the heterogeneity. The primary outcome was ischemic stroke. The secondary outcomes were all-cause mortality, major bleeding, intracranial hemorrhage, and gastrointestinal bleeding.RESULTSTwelve studies from East Asia or Southeast Asia and 441450 patients were included. Dabigatran, rivaroxaban, and apixaban were associated with a significant reduction in the incidence of ischemic stroke [hazard ratio (HR) = 0.78, 95% confidence interval (CI): 0.65-0.94; HR = 0.79, 95%CI: 0.74-0.85, HR = 0.70, 95%CI: 0.62-0.78; respectively], all-cause mortality (HR = 0.68, 95%CI: 0.56-0.83; HR = 0.66, 95%CI: 0.52-0.84; HR = 0.66, 95%CI: 0.49-0.90; respectively), and major bleeding (HR = 0.61, 95%CI: 0.54-0.69; HR = 0.70, 95%CI: 0.54-0.90; HR = 0.58, 95%CI: 0.43-0.78; respectively) compared to warfarin.CONCLUSIONDabigatran, rivaroxaban, and apixaban appear to be superior to warfarin in both efficacy and safety in Asians with non-valvular AF.

Safety of Dabigatran as an Anticoagulant: A Systematic Review and Meta-Analysis.

Background: Dabigatran is a univalent low-molecular-weight direct thrombin inhibitor which was developed as an alternative to vitamin K antagonists (VKAs). However, the safety of dabigatran remains controversial so far. In this study, we aimed to compare the risk of bleeding, fatal adverse events, and the all-cause mortality of dabigatran with those of the control group by a systematic review and meta-analysis of randomized controlled trials. Methods: We systematically searched PubMed, Web of Science, Cochrane Library, Medline, Embase, Wanfang database, Clinical trial, China National Knowledge Infrastructure Chinese Scientific Journal database (VIP), and Chinese Biological Medicine database (CBM), for clinical trials on conventional treatments compared with dabigatran, published between January 2014 and July 2020. The reported outcomes, including the endpoints of primary safety, were systematically investigated. Results: Seven RCTs (n = 10,743) were included in the present systematic review. Compared to the control groups, dabigatran was not associated with an increased risk of major bleeding (relative risk [RR] 0.86, 95% confidence interval [CI]: 0.61 to 1.21, p = 0.06), intracranial hemorrhage (RR 0.89, 95% CI: 0.58 to 1.36, p = 0.41), fatal adverse reactions (RR 0.87, 95% CI: 0.65 to 1.17, p = 0.66), all-cause mortality (RR 0.88, 95% CI: 0.70 to 1.11, p = 0.45, I2 = 0%), and significantly reduced risk of clinically relevant non-major bleeding (RR 0.96, 95% CI: 0.65 to 1.42, p = 0.0007). However, dabigatran is associated with an increased risk of gastrointestinal (GI) bleeding (RR 1.78, 95% CI: 1.02 to 3.13, p = 0.05). Conclusion: Dabigatran has a favorable safety profile in terms of major bleeding, intracranial hemorrhage, and life-threatening events, among other safety outcomes. The present study suggested that dabigatran may be a suitable alternative to VKAs as an oral anticoagulant. However, more data are necessary to clarify the incidence of other adverse events and serious adverse reactions.

Abstract 14825: Efficacy and Safety of Dabigatran, Rivaroxaban, and Apixaban Compared to Warfarin in Asian Patients With Non-valvular Atrial Fibrillation: A Systemic Review and Meta-analysis

Background: Most of the randomized clinical trials that led to the wide use of non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in patients with atrial fibrillation (AF) originated from western countries. We aimed to systematically review and quantitatively synthesize the real-world data regarding the efficacy and safety of dabigatran, rivaroxaban, and apixaban compared to warfarin for stroke prevention in Asian patients with non-valvular AF. Methods: Medline and Cochrane databases were reviewed. A random-effect model meta-analysis was used and I-square was utilized to assess the heterogeneity. The primary outcome was ischemic stroke. The secondary outcomes were all-cause mortality, major bleeding, intracranial hemorrhage, and gastrointestinal bleeding. Results: Twelve studies from East Asia or Southeast Asia and 429496 patients in total were included. Dabigatran, rivaroxaban, and apixaban were associated with a significant reduction in the incidence of ischemic stroke (HR=0.78, 95% CI, 0.65-0.94; HR=0.79, 95% CI, 0.74-0.85, HR=0.70, 95% CI, 0.62-0.78; respectively), all-cause mortality (HR=0.68, 95% CI, 0.56-0.83; HR=0.66, 95% CI, 0.52-0.84; HR=0.66, 95% CI, 0.49-0.90; respectively), and major bleeding (HR=0.61, 95%CI, 0.54-0.69; HR=0.70, 95% CI, 0.54-0.90; HR=0.58, 95% CI, 0.43-0.78; respectively) compared to warfarin. Conclusion: Dabigatran, rivaroxaban, and apixaban appear to be superior to warfarin in both efficacy and safety in Asian patients with non-valvular AF.

Efficacy and Safety of Dabigatran in the Treatment and Secondary Prophylaxis of Children with Venous Thromboembolism and Thrombophilia

Background: Thrombophilia in children is characterized by hypercoagulability and increased frequency of thrombotic events (Young G, et al. Circulation. 2008;118:1373-1378; Kenet G, et al. Circulation. 2010;121:1838-1847). Recently, phase IIb/III clinical trials in children with venous thromboembolism (VTE) have reported the non-inferiority of dabigatran etexilate (DE) versus standard of care (SOC) for the treatment of acute VTE (Albisetti M, et al. ISTH 2019, Abstract OC 57.3), and a favorable safety profile for DE in secondary VTE prevention in children with persistent VTE risk factor(s) (Brandão LR, et al. Blood. 2020;135:491-504). Aims: To perform a subgroup analysis evaluating the efficacy and safety of DE for the treatment and secondary prophylaxis of VTE in children with thrombophilia in the phase IIb/III DE clinical trials. Methods: In the open-label, phase IIb/III DIVERSITY trial (NCT01895777), children aged from birth to &amp;lt; 18 years (yrs) with an objectively confirmed VTE diagnosis (by imaging studies) initially treated with unfractionated heparin or low-molecular-weight heparin were randomized (2:1) to receive up to 3 months of DE or SOC. Primary composite efficacy endpoint: complete thrombus resolution and freedom from VTE recurrence, or VTE-related death. Safety endpoints included bleeding events (BEs). The open-label, phase III, secondary VTE prevention trial (NCT02197416) treated children aged from &amp;gt; 3 months to &amp;lt; 18 yrs with DE for up to 12 months or less, if the identified VTE clinical risk factor resolved. Eligible children had an objectively confirmed diagnosis of VTE treated with SOC for ≥ 3 months, or had completed DE or SOC treatment in DIVERSITY and had an unresolved clinical VTE risk factor requiring further anticoagulation. Primary endpoints included VTE recurrence and BEs. Thrombophilia status was confirmed according to the definitions used by the local experts. Results: In DIVERSITY, 23.2% of children had thrombophilia; demographics were comparable to the overall population, although they were slightly older (mean [standard deviation] age 13.2 [4.9] vs 11.1 [6.1] years in the overall population; p = 0.005). In children with thrombophilia, DE was found to be non-inferior to SOC for the primary endpoint (similar to the overall population), and more children treated with DE achieved the composite primary endpoint than with SOC (SOC 21.7% vs DE 35.9%; Mantel-Hänszel-weighted difference in rates for SOC minus DE [90% CI] −0.14 [−0.32 to 0.05]; p for non-inferiority = 0.0014), similar to the overall population (Table). Regardless of treatment, VTE recurrence appeared higher in children with thrombophilia than in the overall population, with numerically fewer VTE recurrences reported by children with thrombophilia treated with DE (7.7%) versus SOC (21.7%), although this was not significantly lower (p = 0.13). Numerical differences in residual thrombotic burden between SOC vs DE seen in the overall population appeared to be amplified in children with thrombophilia. Numerically fewer children with thrombophilia treated with DE reported thrombus progression (SOC 13.0% vs DE 5.1%) or stabilization (21.7% vs 10.3%), while more reported partial (34.8% vs 43.6%) or complete thrombus resolution (21.7% vs 35.9%). In the thrombophilia subgroup, BEs appeared to be lower in children treated with DE (SOC 26.1% vs DE 17.9%), while in the overall population BEs with SOC and DE were comparable. In the secondary VTE prevention trial, children with thrombophilia were also slightly older versus the overall population (mean [standard deviation] age 14.1 [3.6] vs 12.8 [4.6] yrs; p = 0.006). In this larger subgroup of children, rates of recurrent VTE at 12 months appeared to be higher in the thrombophilia group (2.8%) compared to the overall population (1.4%) (Table), with BEs largely comparable (27.4% and 22.5%, respectively). Conclusions: Unsurprisingly, numerically more children with thrombophilia appeared to report VTE recurrence, and in DIVERSITY thrombus progression/stabilization also seemed higher compared with the overall population. Compared with the overall populations, these subgroup analyses showed consistent results for DE in children with acute VTE and thrombophilia in the DIVERSITY trial, along with a favorable safety profile of DE for secondary VTE prevention. Disclosures Brandao: Boehringer Ingelheim: Other: Member of a paediatric expert working group. Tartakovsky:Boehringer Ingelheim: Current Employment. Albisetti:Boehringer Ingelheim: Other: Member of a paediatric expert working group; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Bomgaars:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Chalmers:CSL Behring: Honoraria; Shire/Takeda: Honoraria; Boehringer Ingelheim: Other: Member of a paediatric expert working group; Grifols: Honoraria; Roche: Honoraria; Sobi: Honoraria; Bristol-Myers Squibb: Honoraria. Mitchell:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Luciani:Boehringer Ingelheim: Other: Member of a paediatric expert working group. Lvova:Boehringer Ingelheim: Honoraria. Simetzberger:Boehringer Ingelheim: Current Employment. Sun:Boehringer Ingelheim: Current Employment. Gergei:Boehringer Ingelheim: Current Employment. Brueckmann:Boehringer Ingelheim: Current Employment. Halton:Boehringer Ingelheim: Other: Member of a paediatric expert working group. OffLabel Disclosure: dabigatran etexilate in paediatric VTE

Effectiveness and safety of dabigatran in Latin American patients with atrial fibrillation: Two years follow up results from GLORIA-AF registry.

BackgroundReal-world data from different regions are needed to support the external validity of controlled trials and assess the impact of new oral anticoagulants (NOAC) in clinical practice.Methods“GLORIA-AF” is a large, ongoing, multicenter, global, prospective registry program in patients with newly diagnosed non-valvular atrial fibrillation (NVAF) at risk of stroke. Newly diagnosed patients with NVAF (within 4.5 months) and a CHA2DS2-VASc score ≥ 1 were consecutively enrolled. The study objective was to estimate the incidence rate of stroke and major bleeding after a two year follow up of patients on dabigatran that participated in the “GLORIA-AF” study (Phase II) in Latin America.ResultsLatin America included 378 eligible patients that received dabigatran in eight countries (Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Perú, and Venezuela): 56.3% were male; mean age was 70.3 ± 10.8 years; 43.4% had paroxysmal AF; 36.0% persistent AF and 20.6% permanent AF. Mean CHA2DS2-VASc score was 3.2 ± 1.4; mean HAS-BLED score was 1.2 ± 0.8. Incidence rates for clinical events after 2-years of follow-up per 100 patient-years were as follows: stroke 0.33 (95% CI: 0.04–1.17), major bleeding 0.49 (95% CI: 0.10–1.42) and all-cause death 4.06 (95% CI: 2.63–6.00). Persistence with dabigatran at 6, 12 and 24 months was 91%, 86%, and 80%, respectively.ConclusionThese regional data shows the sustained safety and effectiveness of dabigatran over two years of follow-up, consistent with already available evidence. An increase in accessibility and incorporation of NOAC to anticoagulant treatment strategies could potentially have a positive impact on AF stroke prevention in Latin America.

Persistence, effectiveness and safety of dabigatran in "real-world" Chinese patients with nonvalvular atrial fibrillation.

The purpose of this study is to provide detailed data on treatment persistence and clinical outcomes in Chinese patients with nonvalvular atrial fibrillation (NVAF). A single-center retrospective observational study was conducted. A total of 26,663 NVAF patients were enrolled from January 1, 2014 to December 31, 2017, clinical information of whom were from inpatient and outpatients data system was collected. The 1-year treatment persistence rates of 11,350 dabigatran users were 24.5% in 2014, 36.6% in 2015, 37.7% in 2016 and 51.8% in 2017. The predominant reason of non-persistence patients was the cost of treatment. Incidence rates of all-cause death, ischemic stroke and embolism were 1.99/100 person-years, 2.56/100 person-years and 0.77/100 person-years, respectively. Incidence rates of minor bleeding events, intracranial hemorrhage and gastrointestinal hemorrhage were 10.05/100 person-years, 0.51/100 person-years and 0.85/100 person-years, respectively. In conclusion, it is of importance for Chinese clinicians to know about these information because dabigatran is a relatively new drug in China. Compared with other reported data, patients of this study have (1) lower dabigatran persistence and lower incident rates of all-cause death, systemic embolism, minor bleeding events and gastrointestinal hemorrhage and (2) higher incident rates of ischemic stroke and intracranial hemorrhage.