Dabigatran Etexilate Therapy Research Articles

Dabigatran etexilate versus warfarin in cerebral venous thrombosis in Chinese patients (CHOICE-CVT): An open-label, randomized controlled trial.

The efficacy and safety of dabigatran etexilate for Chinese patients with cerebral venous thrombosis (CVT) has not been well established. CHOICE-CVT was an exploratory, single-center, randomized, open-label study in the National Center for Neurological Disorders involving Chinese patients with CVT aged 18 to 80 years who were randomly assigned (1:1) to either dabigatran etexilate or warfarin. Oral anticoagulants were initiated after 10-15 days of LMWH. The primary efficacy and safety endpoints included the number of patients with recurrent CVT and/or deep venous thrombosis (DVT) and major clinical bleeding within 180 days. Secondary efficacy endpoints included venous recanalization and change in papilledema at day 180. Secondary safety outcomes comprised death, clinical nonmajor bleeding, and any bleeding. The study was registered with ClinicalTrials.gov under NCT03930940. Between October 2017 and February 2023, a total of 89 patients were enrolled and randomly assigned to receive either dabigatran etexilate (n = 44) or warfarin (n = 45). At day 180, the dabigatran etexilate group showed a statistically nonsignificant but likely clinically significant number of patients with recurrent CVT and/or DVT (8 (18.2%; 95% CI, 6.3-30.0) vs 3 (6.7%; 95% CI, 0.0-14.2), p = 0.099, with a power (1-β) of 38.401%) compared with the warfarin group. The dabigatran etexilate group showed a comparable number of patients with clinical major bleeding (0 (0) vs 0 (0) p = 1.000), and clinical nonmajor bleeding (1 (2.3%; 95% CI, 0.0-6.9) vs 1 (2.2%; 95% CI, 0.0-6.7)) but demonstrated a lower risk of any bleeding (1 (2.3%; 95% CI, 0.0-6.9) vs 9 (20.0%; 95% CI, 7.8-32.2)) compared with the warfarin group. Most patients in both groups achieved venous recanalization according to the Modified Qureshi scale (27 (75%; 95% CI, 60.1-89.9) in the dabigatran etexilate group vs 34 (82.9%; 95% CI, 70.9-95.0) in the warfarin group) and exhibited improvement in papilledema as per the Frisén classification (35 (97.2%; 95% CI, 91.6-100.0) in the dabigatran etexilate group vs 37 (88.1%, 95% CI, 77.9-98.3) in the warfarin group). These findings regarding efficacy and safety support the consideration of dabigatran etexilate therapy as a viable treatment option for Chinese patients with CVT.

Dabigatran for stroke prevention in real life in a sample of population from Turkey: D-SPIRIT registry.

The D-SPIRIT registry is designed to investigate the safety and effectiveness of dabigatran etexilate in patients with atrial fibrillation in routine clinical practice. D-SPIRIT is the first national, multicenter, prospective, observational, postmarketing registry that investigates the usage of dabigatran in real life. A total of 326 noveloral anticoagulant-eligible patients with atrial fibrillation who have been taking dabigatran etexilate therapy for stroke prevention at least 6 months from 9 different centers were enrolled into the registry. Patients were followed up for 2 years to evaluate the effectiveness and safety of the treatment. All adverse clinical events including bleeding, thromboembolic events, stroke, systemic embolism, transient ischemic attack, myocardial infarction, and all-cause death were recorded. The mean age was 71.1±9.6 years, and 57.4% of the study participants were female. The mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischemic attack [TIA], vascular disease, age 65-74 years, sex category) score was 3.4±1.6. The cumulative adverse clinical events rate was 6.30% per year. The rate for embolic events including TIA, ischemic stroke, and peripheral embolism was 1.26% per year. The rate for major bleeding was 2.20% per year, and the mortality rate was 0.94% per year. This registry obtained an important overview of the current safety and effectiveness of the dabigatran etexilate in Turkey. Our results indicate similar rates of thromboembolic and bleeding events with pivotal phase 3 trial and other real-life registries. However, rate of undertreatment usage of dabigatran etexilate in real life was found to be considerable.

Cholestatic liver injury as a side-effect of dabigatran and the use of coagulation tests in dabigatran intoxication and after reversal by idarucizumab in bleeding and sepsis

Idarucizumab, an antidote specific for dabigatran, became available recently. Dabigatran is not associated with increased risk of hepatotoxicity in comparison with warfarin, but it is seen as a rare side-effect. Cases of cholestatic liver injury due to dabigatran have not been reported previously. We present a case of severe gastro-intestinal bleeding with underlying dabigatran intoxication in a patient with renal failure and the effect of reversal of dabigatran using idaruzicumab on coagulation assays. International normalized ratio (INR) and activated partial thromboplastin time (APTT) results were elevated in a setting of sepsis, possibly due to liver failure. INR and APTT can be elevated if sepsis is complicated by disseminated intravascular coagulation (DIC) or liver failure, making it challenging to determine dabigatrans contribution to their prolongation. A rebound effect after administration of idarucizumab and slow elimination of dabigatran due to reduced kidney function could be detected using the Hemoclot® diluted thrombin time (dTT) in this situation, in contrast to with non-dilutional assays. Before admission, cholestatic liver injury started shortly after initiation of dabigatran etexilate therapy. As no other cause was found, this liver injury was likely to be drug-induced. Bleeding cessated promptly after administration of idarucizumab in dabigatran intoxication. In conclusion, the anticoagulant effect of dabigatran can be measured by Hemoclot® dTT in sepsis and cholestatic liver injury was seen as a possible rare side-effect of dabigatran treatment.

Results of prophylaxis of venous thromboembolism after orthopedic operations

OBJECTIVE. The research compared efficacy and safety of application of dabigatran and rivaroxaban in prevention of venous thromboembolism after orthopedic operations. MATERIAL AND METHODS. An analysis of prophylaxis and treatment results of venous thromboembolism was made in 208 patients who underwent knee and hip arthroplasty. The patients were divided into two statistically homogeneous groups. The first group consisted of 102 patients where dabigatran etexilate therapy was used in fixed dose 220 mg/day. The second group included 106 patients who had prophylaxis by rivaroxaban in dose 10 mg/day. RESULTS. Venous thromboembolic complications were noted in 36 (17,3) patients equally in both groups. Internal bleedings of different nature were found in 18 (8,65 %) patients with deep venous thrombosis. It occurred more often against a background of therapeutic dose of anticoagulants in the second group (on 2,29 %). CONCLUSIONS. There wasn’t noted any statistically significant difference in efficacy and safety between dabigatran etexilate and rivaroxaban.

Design and rationale of dabigatran's stroke prevention in real life in Turkey (D-SPIRIT).

The D-SPIRIT registry is designed to investigate the safety and efficacy of dabigatran etexilate in patients with nonvalvular atrial fibrillation (NVAF) and to collect data on outcomes in clinical practice. The D-SPIRIT is a national, prospective, observational, post-marketing registry involving patients with NVAF who have been taking dabigatran etexilate therapy for stroke prevention for a minimum of 6 months prior to enrollment. The registry will collect and analyze data from routine care, enrolling up to 600 patients in 9 centers. Patients will be followed up for 2 years to evaluate effectiveness and safety. A sample size of 600 subjects is proposed based on the following assumptions; Two-sided significance level of 0.05 (1-sided significance level of 0.025), ischemic stroke incidence rate of 0.768%-1.111%, hemorrhagic stroke incidence rate of 0.109%-0.130%, transient ischemic attack incidence rate of 0.722%-0.623%, therapy discontinuation incidence rate of 40% at day 730, and duration of enrollment period of 12 months with non-uniformed enrollment rate. Ethics approval was given by Dokuz Eylül University Ethics Committee of Clinical Research (2014/54) and approved by the Turkish Ministry of Health. Potential results of D-SPIRIT registry will add data from clinical practice to those from the RE-LY trial to expand knowledge of dabigatran etexilate treatment in patients with NVAF.

Massive Life-Threatening Hemorrhages Due to Toxic Oral Intake of 3750 Mg Dabigatran Etexilate As a Suicide Attempt and the Clinical Management

The direct thrombin inhibitor dabigatran etexilate is a novel oral anticoagulant agent. The drug is used for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. There is no specific antidote for the reversal of the anticoagulant effects of dabigatran etexilate. Therefore, the management of the clinical bleeding due to dabigatran etexilate represents a great challenge for the clinician. We would like to share our experience regarding the massive life-threatening hemorrhages due to toxic oral intake of 3750 mg dabigatran etexilate as a suicide attemp and the clinical management.A 83-year-old man with a medical history of atrial fibrillation, coronary artery disease, hypertension and myelodisplastic syndrome presented to the emergency room with massive hematuria. Because of atrial fibrilation, he was using dabigatran etexilate as a prophylaxis of stroke or systemic embolism. He had received about 50 capsules of dabigatran etexilate (3750 mg) with the purpose of suicide, 30 hours before transfer to hospital. On the admission, physical assessment showed hypotension, massive hematuria and spontaneous pethechial areas and purpuras on the skin. The thrombin clotting time (TT) was 130 s (normal range 20- 30 s), activated partial thromboplastine time (aPTT) was 59 s (normal 22-35 s), prothrombin time - international normalized ratio (INR) was 1,4. Complete blood count showed that hemoglobin was 7,4 g/dL and platelets were 30000 /µL. The patient received 1000 U prothrombin complex concentrates (PCC), for two days. And 2 units of erytrocyte suspensions were administered. The bleeding ceased within the first day and the thrombin time normalized 3 days later.Dabigatran etexilate is a safer drug than the other anticoagulants. When compared to the warfarin and enoxaparin, dabigatran etexilate has been shown to reduce the rates of bleeding. However, the patients receving dabigatran etexilate have still a risk of bleeding. Because of the predictable pharmacokinetic and pharmacodynamic profile of dabigatran etexilate, there is no need for routine therapeutic coagulation monitoring while using the drug. In case of active bleeding, a possible overdose, or the need for an invasive procedure, the monitoring gains importance. TT and aPTT are the most sensitive laboratory assays to determine the dabigatran etexilate levels. Since the prothrombin time is not affected by dabigatran etexilate, it is not sensitive. There is a strong correlation between the TT measurements and dabigatran etexilate plasma levels. So in monitoring effectivity of therapy or determining the dabigatran etexilate levels in plasma, thrombin clotting time is very useful. However, at dabigatran etexilate concentrations above 600 ng/mL, the maximum measurement of the test is exceeded, correlating to a TT of greater than 120 seconds. Our patient on admission had an elevated TT of >120 seconds indicating accumulation of dabigatran etexilate with levels >600 ng/mL and massive hematuria. There were a bleeding associated dabigatran etexilate and overdose of drug. In order to stop bleeding we need to reverse anticoagulant effects of dabigatran etexilate. There is no specific antidote for dabigatran etexilate and there is limited guidance for treatment in these situations. Fortunately, dabigatran etexilate has short half-life which provides a relatively quick decline in plasma concentrations after discontinuance of the drug in a patient with normal renal function In case of overdose, it is suggested that discontinuing dabigatran etexilate therapy, initiating supportive care, the potential use of hemodialysis, and investigating the source of the bleed. In patients who require more urgent reversal of their anticoagulation, the use of prothrombin complex concentrates (PCCs) may be helpful. PCCs contain vitamin K–dependent coagulation factors II, VII, IX, and X. We started the patient PCCs at the dose of 1000 IU/d and supportive care. The bleeding was ceased in the first day and there was no need to hemodialysis.Thus, the advantages of using dabigatran etexilate instead of warfarin will lead to widespread use. But it must be kept in mind that dabigatran etexilate is not completely innocent drug and the patients using dabigatran etexilate still have the significant risk of bleeding. And acute reversal of the effects of dabigatran etexilate in the actively bleeding patient is a significant challenge. DisclosuresNo relevant conflicts of interest to declare.

Adverse events in patients initiated on dabigatran etexilate therapy in a pharmacist-managed anticoagulation clinic

Vitamin K antagonists have been the treatment of choice in preventing thromboembolic events, but problems such as frequent dose adjustment and monitoring of coagulation status, including multiple drug and food interactions, make their use difficult. Dabigatran etexilate is a new oral direct thrombin inhibitor not requiring routine monitoring and since its approval in the United States, many clinicians have been interested in utilizing this new therapy. This study documented adverse drug events (ADEs) recorded in patients started on dabigatran therapy, including those who were previously controlled on warfarin and those who were anticoagulant naïve. In an outpatient pharmacist-managed anticoagulation clinic, a total of 221 patients were initiated on dabigatran therapy over an 18-month period. 43.0% of these patients were previously controlled on warfarin. 54 of the 221 patients (24.4%) developed an ADE while on dabigatran. The average time to event was 48.4 days. Nine of the fifty-four patients experienced a major bleeding ADE; six patients developed a serious non-bleeding ADE. Five of these fifteen patients died; one death was directly related to dabigatran therapy. The remaining thirty-nine of the fifty-four patients experienced a clinically relevant non-major ADE. Of the fifty-four patients who experienced an ADE, thirty were male. The average age was 73.8 years and the average weight was 92.8kg. Fifty-four percent of those who experienced an ADE were previously anticoagulant naïve. While many clinicians have been interested in utilizing the new direct thrombin inhibitor dabigatran etexilate, this new therapy is not without risks. This study documented adverse drug events in 24.4% of patients who were initiated on dabigatran etexilate therapy over an eighteen month period. ADEs were more common in patients who were anticoagulant naïve prior to dabigatran etexilate therapy and not those who were previously controlled on warfarin therapy.

Usefulness of Dabigatran Etexilate as Periprocedural Anticoagulation Therapy for Atrial Fibrillation Ablation

The usefulness of dabigatran etexilate for the prevention of stroke in patients with atrial fibrillation (AF) has been reported. In this study the efficacy and safety of dabigatran etexilate for anticoagulation for AF ablation were examined. Patients were divided into three groups: Group 1, interrupted warfarin bridged by heparin between pre- and post-ablation; Group 2, continuous warfarin therapy; and Group 3, dabigatran etexilate therapy. Anticoagulation therapy with warfarin or dabigatran etexilate was performed from 30 days before to at least 90 days after AF ablation. Dabigatran etexilate was administered at 110 or 150 mg twice daily, depending on renal function and age. Patients' clinical characteristics, associated disorders, echocardiographic parameters and arrhythmia status were not different among the three groups. Procedural parameters such as procedural time and radiofrequency energy supply were also not different among the three groups. The dabigatran etexilate group and the warfarin groups had no embolic complications (stroke, cerebral transient ischaemic attack, deep venous thrombosis or pulmonary embolism). No pericardial tamponade was observed in the dabigatran etexilate group, while two patients in each of Group 1 (2/194, 1.0 %) and Group 2 (2/203, 0.98 %) developed cardiac tamponade, though the differences were not significant. Pericardial effusion and groin haematoma were observed in one patient each (1/105, 0.9 %) in the dabigatran etexilate group, and the incidences were not different from the warfarin group (Group 1: 4/194, 2.1 % and 2/194, 1.0 %; Group 2: 3/203, 1.5 % and 2/203, 1.0 %, respectively). As a whole, the safety outcomes did not differ among the three groups. Dabigatran etexilate is an effective and safe anticoagulation therapy for AF ablation. Thus, dabigatran etexilate appears to be useful as an alternative anticoagulant therapy to warfarin for AF ablation.

Rash Associated with Dabigatran Etexilate

Patients experiencing atrial fibrillation are at an increased risk for thromboembolic events. Therefore, anticoagulation therapy is imperative to prevent thrombus formation and stroke. Dabigatran etexilate was approved by the Food and Drug Administration in 2010 as anticoagulant prophylaxis for patients with nonvalvular atrial fibrillation. The frequency of dermatologic reactions to dabigatran etexilate is estimated in the product labeling to be less than0.1%. To date, five cases of dabigatran etexilate-associated rash have reported, including three published cases. We describe the sixth reported case of dabigatran etexilate-associated rash, in a 59-year-old man with a history of atrial fibrillation who received dabigatran etexilate 150mg twice/day for atrial flutter before cardioversion. The patient had taken dabigatran etexilate for 5days before the rash was noted on hospital admission. He had no known previous drug allergies, and his platelet count, serum creatinine concentration, and hepatic function were normal. The rash resolved 7days after the discontinuation of dabigatran etexilate, and the patient was stabilized on warfarin therapy. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 5) between the patient's development of the rash and dabigatran etexilate therapy. Clinicians should be aware of this adverse effect of dabigatran etexilate and monitor for dermatologic reactions during follow-up visits.

Rectal Bleeding and Hemostatic Disorders Induced by Dabigatran Etexilate in 2 Elderly Patients

To report rectal bleeding associated with hemostatic disorders in 2 elderly patients treated with dabigatran etexilate. A 79-year-old woman (weight, 69 kg) was hospitalized in a gastroenterology unit for severe rectal bleeding. She had been treated for 2 months with dabigatran etexilate 110 mg twice daily for chronic atrial fibrillation. On admission, her creatinine clearance (CrCl) was 20.7 mL/min/1.73 m(2), prothrombin time (PT) less than 10% (reference range 70-130%), and international normalized ratio (INR) 14.5 (venous blood). Eleven days after admission, hematologic and renal function were normalized and rectal bleeding stopped. An 84-year-old man (weight, 71 kg) was admitted for rectal bleeding with acute renal failure and dehydration that began while he was treated with dabigatran etexilate 110 mg twice daily for atrial fibrillation. On admission, CrCl was 33.5 mL/min/1.73 m(2), PT 13%, and INR 7.53 (venous blood). Dabigatran etexilate was stopped on admission. At the end of the hospitalization, CrCl was 66.5 mL/min/1.73 m(2), PT 54%, and INR 1.53. In both cases, an objective causality assessment revealed that those adverse reactions were probably related to dabigatran etexilate. In these 2 cases of rectal bleeding during dabigatran etexilate therapy, coagulation monitoring showed elevated PT and INR; neither patient had been exposed to vitamin K antagonists. These cases indicate the importance of PT and INR monitoring when using dabigatran etexilate, mainly in patients with a high risk of overdose, such as elderly patients or those with renal function impairment. It is critical to identify and subsequently manage dabigatran etexilate toxicity because there is no specific antidote to reverse the drug's anticoagulant effects.

Hemopericardium in a Patient Treated with Dabigatran Etexilate

Dabigatran etexilate is a new oral anticoagulant used for the prevention of systemic thromboembolism in patients with atrial fibrillation. Acute bleeding episodes are known to occur with dabigatran etexilate therapy; however, only a few case reports in the literature describe such events. We describe a 70-year-old man treated with dabigatran etexilate for newly diagnosed, nonvalvular atrial fibrillation who developed a large hemopericardium that appeared to be temporally related to dabigatran etexilate administration. One month after starting the drug, an incidental finding of a small pericardial effusion was found on echocardiography. One month later, the patient came to his pulmonologist's office complaining of shortness of breath; a large pericardial effusion was found on a noncontrast computed tomographic scan, and the patient was admitted to the hospital. Laboratory monitoring of his coagulation status was limited due to the lack of assays available to directly monitor the therapeutic effects of dabigatran. The internal laboratory was able to perform a dilute thrombin time (DTT) test as part of a quality improvement project aiming to validate an assay for monitoring patients receiving dabigatran therapy. A DTT was therefore performed in conjunction with routine coagulation assays to evaluate the patient's coagulation status. After pericardiocentesis, the patient recovered without incident and was discharged without anticoagulant therapy. Although the Naranjo adverse reaction probability scale only indicated a possible relationship (score of 1) between the patient's development of hemopericardium and dabigatran etexilate therapy, investigation into the patient's clinical course, comorbidities, and laboratory results led us to conclude that dabigatran etexilate was responsible for the hemopericardium. To our knowledge, this report is the first to describe a case of potentially life-threatening pericardial bleeding that was temporally related to starting dabigatran etexilate therapy. Although we found that the DTT was a viable method of monitoring coagulation status in a patient receiving dabigatran etexilate therapy, the assay lacks approval by the United States Food and Drug Administration, which limits its clinical utility and widespread use at this time. Clinicians should be aware of the potential for life-threatening bleeding with use of this agent and the difficulty associated with monitoring and reversing this therapy in the setting of acute bleeding.

Plasma-Diluted Thrombin Time to Measure Dabigatran Concentrations During Dabigatran Etexilate Therapy

New anticoagulants, like the orally available direct thrombin inhibitor (DTI) dabigatran etexilate, have recently been introduced into the market for venous thromboembolic prophylaxis and for stroke prevention in atrial fibrillation. While dabigatran has been approved for use without the need for routine therapeutic monitoring, there are clinical scenarios in which monitoring can help guide clinical management. We report herein the application of a recently described plasma-diluted thrombin time (DTI assay) used to monitor intravenous DTI as a useful and easily implemented method to monitor oral DTIs.

Dabigatran Etexilate: A Possible Replacement for Heparinoids and Vitamin K Antagonists?

Dabigatran etexilate is the first oral anticoagulant to be approved in the United States in decades. It works directly by inhibiting clot-bound and free factor IIa (ie, thrombin) and indirectly by inhibiting platelet aggregation induced by thrombin. It is approved in the United States for stroke prophylaxis in nonvalvular atrial fibrillation. There is evidence to suggest that it is also effective for the treatment of acute venous thromboembolism and venous thromboembolism prophylaxis after knee and hip replacement surgery. Dabigatran etexilate therapy does not require laboratory monitoring, an advantage over warfarin. Unlike the earlier direct thrombin inhibitor, ximelagatran, it has demonstrated no potential for serious hepatotoxicity. It is also subject to a much lower degree of interpatient variability in dose response, has no diet–drug interactions, and has fewer clinically significant drug–drug interactions compared with warfarin. Dabigatran etexilate appears to be a valuable addition to our anticoagulant armamentarium.