Dabigatran Administration Research Articles

Intra-cardiac thrombus resolution after anti-coagulation therapy with dabigatran in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy: a case report

IntroductionAlthough dabigatran, a novel oral anti-coagulant, has been approved for the prevention of thromboembolism in patients with non-valvular atrial fibrillation, the efficacy of dabigatran for the resolution of established intra-cardiac thrombi has not been validated. Herein is describe a case in which dabigatran was effective for thrombus resolution in a patient with a left ventricular aneurysm.Case presentationA 59-year-old Japanese man with a mid-ventricular obstructive hypertrophic cardiomyopathy-associated apical aneurysm presented with a left ventricular apical thrombus (15.0mm×17.0mm). Anti-coagulation therapy with dabigatran (150mg b.i.d. with meals) was initiated. Following dabigatran administration, weekly echocardiographic examinations demonstrated gradual decreases in thrombus size. After three weeks, no thrombus was detected and no systemic thromboembolic events had occurred.ConclusionsThe left ventricular apical thrombus resolved after dabigatran administration. Hence, dabigatran may represent an alternative to warfarin as a therapeutic option in patients with previously detected intra-cardiac thrombus.

Intravenous Lipid Emulsion Does Not Reverse Dabigatran‐induced Anticoagulation in a Rat Model

The anticoagulant dabigatran has no reversal agent and may cause life-threatening bleeding in patients with trauma or closed-space hemorrhage. Intravenous lipid emulsion (ILE) is thought to create a lipid compartment in serum that sequesters lipophilic drugs. Dabigatran is lipophilic, and its anticoagulant effects are concentration dependent. The study objective was to determine if ILE therapy reverses dabigatran's anticoagulant effects. Twenty rats were selected at random, 10 in the ILE group and 10 in a normal saline (NS) control group. Animals had a baseline tail bleeding time (T0), followed by oral dabigatran administration (15mg/kg). At 45minutes (T45), a second tail bleed time measurement was performed, followed by a 7-minute infusion of 15mL/kg ILE or NS. A final 60-minute (T60) bleed time measurement was obtained. An ILE-only group of five animals had bleeding times assessed prior to (T0) and 15minutes after (T15) ILE therapy. A mixed-effect repeated-measures analysis of variance modeling the effect of time, group, and the interaction of group and time on bleed times was conducted. There was a significant within-subject change in bleeding time across the assessment points (F(2,36)=33; p<0.001), but there were no effect of group (F(1,18)=1.42, p=0.25) or an interaction between group and assessment point on mean bleeding time (F(2,36)=0.59, p=56). Between T0 and T45, average bleeding times increased from 109.5seconds (95% confidence interval [CI]=94 to 125seconds) to 231.8seconds (95% CI=193 to 271seconds; p<0.0001) for both the ILE group and the NS control group. Between T45 and T60, bleeding times in the ILE group decreased by 31.5seconds (95% CI=-77 to 14seconds) and by 6seconds (95% CI=-67 to 55seconds) in the NS group (p=0.46). In the five ILE-only animals, the average bleeding time at T0 was 114seconds (95% CI=62 to 166seconds), which increased significantly at T15 to 237seconds (95% CI=161 to 313seconds; p=0.02). The anticoagulant effects of dabigatran are not reversed with ILE therapy. Although ILE itself significantly prolonged bleeding times, when administered to dabigatran-anticoagulated rats, bleeding times did not change significantly. There may be a complex interaction of ILE with dabigatran that this study was not able to elucidate.

Dabigatran for thromboprophylaxis after robotic assisted laparoscopic prostatectomy: Retrospective analysis of safety profile and effect on blood coagulation

Objective. The aims of this study were to analyse the efficacy and safety of orally administered dabigatran in prostate cancer patients who have undergone robotic assisted laparoscopic prostatectomy (RALP) and to analyse the effects of RALP on selected markers of coagulation activity. Material and methods. Data were collected prospectively on the first 400 patients who underwent RALP at Helsinki University Central Hospital between 2009 and 2011. As thromboprophylaxis, intermittent compression devices were used in association with anaesthesia. Dalteparin sodium at 2500 IU was administered on the preoperative evening and at 5000 IU daily until discharge. Then patients were prescribed 220 mg dabigatran etexilate once daily for the next 15 days. Bleeding and thromboembolic complications were recorded. A set of routine coagulation analyses was undertaken in 61 patients preoperatively, on the first, second and eight postoperative days. Results. One patient with obesity- and cancer-related risk factors developed venous thromboembolism 18 days after the operation. Nine patients (2.3%) had postoperative blood loss or bleeds, eight patients required blood transfusions and three underwent reoperation before dabigatran administration. Increased fibrinogen, factor VIII, d-dimer and thrombocytosis were observed postoperatively, reflecting coagulation activity. Conclusions. RALP activates coagulation, and thromboprophylaxis for high-risk patients even after minimally invasive surgery may be beneficial. Orally administered dabigatran after discharge from hospital appears safe for venous thromboembolism prophylaxis after RALP.

Dabigatran Compared with Warfarin for Stroke Prevention in Patients with Atrial Fibrillation: An Evidence Based Case Report

Background . Atrial fibrillation (AF) increases the risk of having stroke as high as five fold. Anticoagulant administration such as vitamin K antagonist has been used regularly to reduce the occurence of stroke. Despite the high efficacy, warfarin has several limitations, including a narrow therapeutic window, multiple food and drug interactions, and the need for frequent laboratory monitoring. Dabigatran, an oral thrombin inhibitor, displays some positive characteristics as the solution to warfarin’s limitations. Aim . To determine the efficacy of dabigatran compared to warfarin for stroke prevention in patients with atrial fibrillation. Methods . A search was conducted on PubMed and Google. The selection of title and abstract was done using inclusion and exclusion criteria. Five original articles were found, but only one study was used. The selected study was critically appraised for its validity, importance and applicability. Result . The administration of 150 mg of dabigatran was superior to warfarin with respect of stroke. The relative risk reduction was 36% in the 150 mg dabigatran group. The rate of stroke was 1.01% per year in the group that received 150 mg dabigatran, as compared with 1.57% per year in the warfarin group (relative risk 0.64; 95% confidence interval, 0.51 to 0.81, p<0.001). The administration of dabigatran increased the risk of gastrointestinal bleeding. Conclusion . In patients with atrial fibrillation, dabigatran given at a dose of 150 mg, as compared with warfarin, was associated with lower rate of stroke. Dabigatran administration requires closed gastrointestinal monitoring

Abstract 18552: The Thrombin Inhibitor Dabigatran Inhibits High Fat Diet-induced Obesity and Fatty Liver Disease in Mice

Inflammation associated with non-alcoholic fatty liver disease (NALFD) increases the risk of adverse cardiovascular events. NAFLD is the hepatic manifestation of obesity and the metabolic syndrome and significantly contributes to liver-related morbidity. We have shown previously that the thrombin receptor protease activated receptor-1 (PAR-1) is essential for hepatic inflammation and steatosis in mice fed a high fat diet (HFD), but PAR-1 deficiency does not affect weight gain in mice fed a HFD. To determine whether pharmacologic inhibitors of thrombin could reduce the progression of NAFLD in mice on a HFD, we utilized the direct thrombin inhibitor, dabigatran etexilate. Wild type C57Bl/6 mice were fed a HFD formulated to contain dabigatran (10 mg/g chow) or an identical HFD with starch substituted for drug for 3 months. Plasma thrombin time was significantly prolonged in mice fed HFD+dabigatran, but no adverse bleeding events were observed. Despite consuming a similar amount of chow, mice fed HFD+dabigatran gained significantly less body weight compared to mice fed HFD alone. Induction of inflammatory genes including TNFα, MCP-1, and the lipogenic genes SCD-1 and CD36, was significantly reduced in livers of mice fed HFD+dabigatran compared to mice fed HFD alone. In agreement, hepatic steatosis was dramatically reduced by dabigatran in mice fed a HFD. In summary, pharmacologic inhibition of thrombin with dabigatran reduced various features of NAFLD in mice fed a HFD. In contrast to PAR-1-deficient mice, dabigatran administration also dramatically reduced diet-induced obesity. Taken together, the results indicate that thrombin contributes to NAFLD in mice fed a HFD, and that thrombin promotes diet-induced obesity in a PAR-1-independent manner. Clinical evaluation of the potential for thrombin inhibition to reduce systemic and hepatic inflammation in obese patients taking dabigatran for another indication, such as atrial fibrillation, could reveal novel beneficial effects of oral thrombin inhibitors in metabolic disease.

A Survey of a Single Centerʼs Experience with Dabigatran (Pradaxa®) and Physicianʼs Knowledge in Management of Related Gastrointestinal Bleeding

Purpose: In 2010, the United States Food and Drug Administration approved dabigatran (Pradaxa®), a new oral anticoagulation drug. In addition to gaining FDA approval for use in atrial fibriliation, the RELY trial also demonstrated that patients taking dabigatran were 1.5 times more likely to have a major gastrointestinal (GI) bleeding event. To date, although there are proposed recommendations for withholding dabigatran peri-operatevily, clear evidence based guidelines on the timing of dabigatran administration both prior to and after an endoscopic procedure are lacking. We aimed to review clinicians' clinical experiences with and management approach to dabigatran related gastrointestinal bleeding events. Methods: We created a 12 question anonymous survey to assess clinicians' clinical experiences, level of knowledge of proper dabigatran administration and preferred management approach to any related GI bleeding events (Table 1). Included in the study were all internal medicine house staff, medical attendings, gastroenterology fellows and attendings employed in 2011 at the Beth Israel Medical center, New York, NY.Table: Respondent level of training ( N =71)Results: During the study period, a total of 71 physicians responded to our survey. The majority (70%) of respondents had cared for at least 1 patient taking dabigatran during the past year. Notably, 22.4% of respondents have cared for patients with GI bleeding secondary to dabigatran. The location of bleeding was essentially equally divided between upper (53.8%) and lower (46.2%) GI anatomy. Only half of the respondents (56.3%) believe that no serum marker is currently available to monitor dabigatran levels. Surprisingly, only 42% of respondents take into account renal function when making recommendations regarding holding dabigatran peri-endoscopy. While the majority (73.2%) of respondents would attempt optimal supportive care as a primary treatment for bleeding complication, approximately 40% of respondents would choose fresh frozen plasma as treatment for life threatening gastrointestinal hemorrhage. Finally, the majority (34%) of respondents would hold dabigatran 1-2 days prior to elective endoscopy, while the most common answer given for timing to withholding dabigatran post-endoscopy was “I don't know.” Conclusion: Despite our centers' growing experience with dabigatran use, we observed a wide range in knowledge and perception of peri-endoscopic dabigatran administration and any related GI bleeding complications. As the utilization and popularity of dabigatran continues to expand, there is an increasing need for more objective algorithms outlining the proper periendoscopic administration of dabigatran and management of any related GI bleeding complications.Table: [1429] Survey responses

Safe Use of Hemodialysis for Dabigatran Removal before Cardiac Surgery

To describe a case in which hemodialysis was performed before cardiac transplantation in an attempt to reverse the effects of dabigatran and reduce the risk of bleeding associated with surgery. A 59-year-old female with heart failure and atrial fibrillation was admitted for orthotropic heart transplant. She had been stable at home with continuous milrinone therapy 0.25 μg/kg/min, amiodarone 200 mg twice daily, and dabigatran 150 mg twice daily for stroke prevention secondary to atrial fibrillation. Upon notification of organ availability, the patient was admitted to the hospital for transplant surgery, with her last dose of dabigatran taken approximately 36 hours before admission. Coagulation studies indicated normal activated partial thromboplastin time, slightly elevated international normalized ratio of 1.2, and elevated thrombin time (TT) of 90.6 seconds (upper limit of normal 19.9 seconds). A hemodialysis catheter was emergently placed and dialysis was initiated. One hour after initiation, TT decreased to 65.5 seconds. After 2.5 hours of dialysis, TT further decreased to 60.2 seconds; at that time, the patient underwent transplantation with no abnormal bleeding during or following surgery. Minimal data exist on techniques to reverse the effects of dabigatran in cases of bleeding or emergent surgery. This case examines the efficacy of hemodialysis to decrease dabigatran's effect on clotting assays prior to surgery to reduce the risk of bleeding. In this case, a TT of 60.2 seconds with recent dabigatran administration did not result in abnormal bleeding associated with cardiac surgery. To our knowledge, this case report represents the first published data on the effects of hemodialysis on dabigatran removal and reversal of anticoagulation associated with dabigatran before surgery. The routine use of preoperative hemodialysis in patients on dabigatran is not recommended; however, the potential efficacy in such circumstances is supported by the successful results in this case.