Dabigatran Treatment Research Articles

Comparison of Dabigatran vs. Warfarin in Acute Vnous Thromboemboly: Systematic Review.

Acute Venous Thromboembolism (VTE) is a common disease associated with the significant morbidity and mortality. We reviewed clinical outcomes systematically with Dabigatran as a direct oral anticoagulants (DOAC) for treatment of acute VTE. We used Ovide, PubMed, Cochrane (CENTRAL), EMBASE, Scopus, Science Direct, LILAC(for article written not English) and also Iranian database; Magiran, Isc, Iran Medex, Iran DOC, Doaj up to May 2014 to identify randomized clinical trials of Dabigatran compared with conventional treatment for VTE. Two investigators extracted data independently. Number of 5107 patients including two trails were selected. The risk of recurrent VTE was similar with the Dabigatran and standard treatment (Hazard Ratio, 95% confidence interval 1.09 (0.76-1.57). Dabigatran reduced the risk of minor bleeding in comparison with standard treatment; Warfarin (0.62) (0.50-0.76). Finally-in minor bleeding-the Dabigatran seemed as effective as, and probably safer than standard treatment of acute VTE. But in some aspects such as adherence to treatment, pregnant patient, impact on quality of life, new researches are needed to be clarified.

Prediction of rates of thromboembolic and major bleeding outcomes with dabigatran or warfarin among patients with atrial fibrillation: new initiator cohort study

Objectives To compare stratified event rates from randomized controlled trials with predicted event rates from models developed in observational data, and assess their ability to accurately capture observed rates of...

Should We Use Bridging Therapy during Switching Patients from Warfarin to Novel Oral Anticoagulants?

Rivaroxaban is a new anticoagulant that was approved by the Food and Drug Administration in 2011 for stroke and systemic embolism prophylaxis in patients with nonvalvular atrial fibrillation. Several characteristics have made rivaroxaban an attractive alternative to warfarin: once-daily dosing, obviating the need for monitoring the international normalized ratio (INR), noninferiority to warfarin for preventing stroke in patients with atrial fibrillation, and comparatively lower risk of intracranial hemorrhage. Both The European Summary of Product Characteristics and the US Prescribing Information recommend to discontinue warfarin and to start rivaroxaban on the following day if the initial INR level is below 3.0, yet many clinics convert patient from warfarin to rivaroxaban when INR level is <2.0 due to increased risk of hemorrhage. Since there are no conventional coagulation measures to reliably demonstrate the level of anticoagulation in patients on rivaroxaban, there is an increased risk of adverse events, especially for patients with high ischemic burden. We report a case of acute ischemic stroke in a patient who switched from warfarin to rivaroxaban (20 mg once daily). A 68-year-old female patient with multiple co-morbidities was admitted to our clinic with ischemic stroke. After 1 week follow-up with parenteral anticoagulation in the neurology clinic, she was discharged with mild deficits and with dabigatran treatment (150 mg twice daily). Novel oral anticoagulants are attractive options for anticoagulation particularly in patients who are incompatible with warfarin therapy. On the other hand, physicians should be alert during switching patients from warfarin to novel oral anticoagulants.

Long-term evaluation of dabigatran 150 vs. 110 mg twice a day in patients with non-valvular atrial fibrillation

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively. The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54). Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant.

Bleeding events with dabigatran or warfarin in patients with venous thromboembolism

Dabigatran was as effective as warfarin for the acute treatment of venous thromboembolism in the RE-COVER and RE-COVER II trials. We compared the incidence of bleeding with dabigatran versus warfarin in pooled data from these studies. The localisation, bleeding severity, and the impact of key factors on the incidence of bleeding, were compared between the dabigatran and warfarin treatment group. Altogether, 2553 patients received dabigatran and 2554 warfarin, each for a mean of 164 days. The incidence of any bleeding event was significantly lower with dabigatran (hazard ratio [HR] 0.70; 95% confidence interval [CI], 0.61-0.79), as was the incidence of the composite of MBEs and clinically relevant non-major bleeding events (HR 0.62; 95% CI, 0.50-0.76). The incidence of major bleeding events (MBEs) was also significantly lower with dabigatran in the double-dummy phase (HR, 0.60; 95%CI, 0.36-0.99) but not statistically different between the two treatment arms when the entire treatment period is considered (HR 0.73 95% CI, 0.48-1.11). Increasing age, reduced renal function, Asian ethnicity, and concomitant antiplatelet therapy were associated with higher bleeding rates in both treatment groups. The reduction in bleeding with dabigatran compared to warfarin was consistent among the subgroups and with a similar pattern for intracranial, and urogenital major bleeding. In conclusion, treatment of venous thromboembolism with dabigatran is associated with a lower risk of bleeding compared to warfarin. This reduction did not differ with respect to the location of bleeding or among predefined subgroups.

Effect of Adherence to Oral Anticoagulants on Risk of Stroke and Major Bleeding Among Patients With Atrial Fibrillation.

BackgroundIn comparison to warfarin, non–vitamin K antagonist oral anticoagulants (NOACs) have the advantages of ease of dosing, fewer drug interactions, and lack of need for ongoing monitoring. We sought to evaluate whether these advantages translate to improved adherence and whether adherence is associated with improved outcomes in patients with atrial fibrillation.Methods and ResultsWe performed a retrospective cohort analysis by using a large US commercial insurance database to identify 64 661 patients with atrial fibrillation who initiated warfarin, dabigatran, rivaroxaban, or apixaban treatment between November 1, 2010, and December 31, 2014. During a median of 1.1 y of follow‐up, 47.5% of NOAC patients had a proportion of days covered of ≥80%, compared with 40.2% in warfarin patients (P<0.001). Patients with CHA 2 DS 2‐VASc (risk based on the presence of congestive heart failure, hypertension age 65–74 y, age ≥75 y, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, sex category) score ≥4 were at increased risk of stroke when they were not taking anticoagulation ≥1 month versus <1 week (1–3 months: hazard ratio [HR] 1.96, 3–6 months: HR 2.64, ≥6 months: HR 3.66; all P<0.001). Patients with CHA 2 DS 2‐VASc score 2 or 3 were at increased risk of stroke when they were not taking anticoagulation ≥6 months (HR 2.73, P<0.001). In these patients with CHA 2 DS 2‐VASc score ≥2, nonadherence was not associated with intracranial hemorrhage. Among patients with CHA 2 DS 2‐VASc score 0 or 1, time not taking anticoagulation was not associated with stroke, but not taking anticoagulation ≥3 months was associated with a significant reduction of bleeding.ConclusionsAdherence to anticoagulation is poor in practice and may be modestly improved with NOACs. Adherence to therapy appears to be most important in patients with CHA 2 DS 2‐VASc score ≥2, whereas the benefits of anticoagulation may not outweigh the harms in patients with CHA 2 DS 2‐VASc score 0 or 1.

Dabigatran treatment simulation in patients undergoing maintenance haemodialysis.

Patients with atrial fibrillation requiring maintenance haemodialysis are at increased risk of ischaemic stroke and bleeds. Currently, vitamin K antagonists such as warfarin are predominantly used in these patients as limited data are available on the use of non-vitamin K oral anticoagulants, including dabigatran etexilate (dabigatran). Dabigatran is approximately 85 % renally eliminated, thus, its half-life is prolonged in renal impairment. This study simulated the doseexposure relationship of dabigatran in patients undergoing haemodialysis. Dabigatran exposure was modelled at once- and twice-daily doses of 75 mg, 110 mg and 150 mg and at variations in non-renal clearance and dialysis settings. Resultant dose exposure (area under the curve [AUC]) was compared with values simulated from typical patients in the RE-LY® trial (based on a previously characterised pharmacometric model). In this simulation, all twice-daily dosages resulted in exposures above those simulated from typical RE-LY patients (1.5- to 3.3-fold increase in AUC) and thus may not be optimal for use in haemodialysis patients. However, dabigatran doses of 75 mg or 110 mg once daily produced exposures comparable to those simulated in typical RE-LY patients (-13.3 and +4.4 %, respectively). Of patient and dialysis variables, non-renal clearance had the highest impact on exposure (≤ 30.8 % change). These data could potentially inform dose selection in patients undergoing maintenance haemodialysis and the findings warrant investigation in future clinical trials.

Dabigatran but not rivaroxaban or apixaban treatment decreases fibrinolytic resistance in patients with atrial fibrillation

IntroductionMost anticoagulants stimulate fibrinolysis in vitro through mechanisms dependent on and independent of thrombin activatable fibrinolysis inhibitor (TAFI). We evaluated the effect of dabigatran, rivaroxaban and apixaban treatment on plasma fibrinolysis in patients with non-valvular atrial fibrillation. Methods and resultsPatients treated with dabigatran etexilate (n=22), rivaroxaban (n=24) or apixaban (n=22) were studied. Plasma was obtained before (trough) and 2h after drug intake (peak). Fibrinolytic resistance of clots exposed to exogenous tissue plasminogen activator was significantly lower in peak than in trough samples and correlated with drug concentration only in dabigatran group. Moreover, fibrinolytic resistance at peak was lower in dabigatran than in rivaroxaban and apixaban groups. This difference disappeared if the TAFI pathway was inhibited. Thrombin generation and TAFI activation were markedly lower in peak than in trough samples in all three groups. However, TAFIa levels in trough and peak samples were significantly lower in dabigatran group than in rivaroxaban and apixaban groups. Circulating levels of prothrombin fragment F1+2 (reflecting in vivo thrombin generation) and plasmin-antiplasmin complex (reflecting plasmin generation) were not or barely influenced by drug levels in all groups. ConclusionsOur data suggest that dabigatran, contrary to rivaroxaban and apixaban, reduces fibrinolytic resistance by virtue of its greater impact on TAFI activation. The profibrinolytic effect of dabigatran may play a role locally, at sites of fibrin formation, by making the nascent thrombus more susceptible to plasminogen-dependent degradation.

Dabigatran Etexilate or Warfarin in the Treatment of Acute Venous Thromboembolism in Western European Patients: A Pooled Analysis of RE-COVER® and RE-COVER II™

Introduction: In the RE-COVER®/RE-COVER II™ global randomized trials investigating the treatment of acute venous thromboembolism (VTE), efficacy and safety outcomes of dabigatran etexilate (dabigatran) versus warfarin were compared. This sub-analysis of pooled RE-COVER®/RE-COVER II™ data compares the safety and efficacy of dabigatran versus warfarin in the Western European sub-population.Methods: In the RE-COVER®/RE-COVER II™ trials, patients with acute VTE, initially receiving parenteral anticoagulation, were randomized to warfarin (INR 2-3) or dabigatran (150 mg twice daily) for 6 months and followed up for 30 days. The primary efficacy outcome was recurrent, symptomatic VTE/VTE-related death. Safety outcomes were major bleeding events (MBEs), a composite of MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeding during the 6-month, oral-only treatment period. All outcomes were centrally adjudicated. Data from the Western European sub-population were analyzed using a Cox regression model with factor treatment stratified by study, assuming different baseline hazards per study.Results: This sub-analysis included 1239 patients for the efficacy analysis (dabigatran n = 613; warfarin n = 626) and 1192 patients for safety (dabigatran n = 588; warfarin n = 604) from all 13 Western European countries participating in the RE-COVER®/RE-COVER II™ trials. For the primary efficacy outcome, the rate of VTE/VTE-related death in patients receiving dabigatran was 2.1% (n = 13) compared with 2.9% (n = 18) in those receiving warfarin. However, this difference did not reach statistical significance (hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.36-1.5). Of the safety outcomes, rates of MBEs were similar between both treatment groups (1.4% for dabigatran [n = 8] and 1.3% for warfarin [n = 8]; HR 1.02; 95% CI, 0.38-2.71). Rates of MBEs/CRBEs were significantly lower in patients receiving dabigatran than in those receiving warfarin at 5.1% (n = 30) and 9.4% (n = 57), respectively (HR 0.52; 95% CI, 0.34-0.82). Any bleeding events were also statistically lower in the dabigatran group (17.5%; n = 103) compared with warfarin (23.8%; n = 144) (HR 0.7; 95% CI, 0.54-0.90).Conclusions: In this Western European sub-analysis of pooled data from the RE-COVER®/ RE-COVER II™ trials, dabigatran was as effective as warfarin in the treatment of acute VTE. There was a significant reduction in MBE/CRBE and in any bleeding events in the dabigatran treatment group. DisclosuresSchellong:Boehringer Ingelheim: Consultancy. Eriksson:Boehringer Ingelheim: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy, Research Funding. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Kreuzer:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Schulman:Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria; Baxter: Honoraria; Octapharma: Research Funding. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding.

Dabigatran-related axillary hematoma and coagulopathy in a patient with a pacemaker: The lesson we learned from a case report

A 70-year-old man, a retired worker, had a history of hypertension and gouty arthritis. He was found to have irregular bradycardia with complete atrioventricular block 4 years previously, and he subsequently received a pacemaker. He was stable under dabigatran treatment (110 mg twice daily) until atrial fibrillation was found under the pacing rhythm 2 years later. Bisoprolol (5 mg) 0.5 tab QD and digoxin (0.25 mg) 0.5 tab QD were also prescribed 2 years ago. Thirteen days before admission, he helped mow the lawn around his home and suffered mild dehydration, left axillary pain and bruising. He denied any trauma or contusion. He went to our emergency room 10 days before admission due to an enlarged left axillary hematoma and limited movement of his left arm, and leukocytosis (WBC: 11,700/uL), elevated aPTT (61.8 seconds) and creatinine level (1.48 mg/dL) were found. Fresh frozen plasma (FFP) 6U was transfused and the aPTT decreased (43.2 seconds) the following day, when he was discharged from the emergency room and dabigatran was discontinued. Heparinoid gel was prescribed for the bruising, however it progressed over his left chest, upper arm and wrist with a left axillary tender, hot and swollen mass. He was therefore brought to our emergency room again 1 day before admission. He denied fever, chills, hematuria, bloody stool or bleeding gums. Under the impression of dabigatran-related coagulopathy and the suspicion of an infected hematoma, he was admitted (Table 1). As the bruising left axillary fusiform hematoma (11.4 cm in size) were suspected to be an infection, we administered an

Safety and efficacy of switching from low molecular weight heparin to dabigatran in patients undergoing elective total hip or knee replacement surgery.

BackgroundThe aim of this study was to assess the safety and efficacy of switching therapy from low molecular weight heparin (LMWH; enoxaparin) to dabigatran for prevention of venous thromboembolic events (VTE) in patients undergoing elective total hip or knee replacement surgery (THR/TKR).MethodsThis was a prospective, multicenter, open-label, single-arm, observational, study in patients undergoing THR or TKR who were to receive enoxaparin 40 mg for thromboprophylaxis. Enoxaparin was initiated before or after surgery according to local practice, and was switched to dabigatran 220 mg once daily at a time point chosen by the investigator. The coprimary endpoints were major bleeding events, and the composite of symptomatic VTE and all-cause mortality, from last use of enoxaparin to 24 h after last intake of dabigatran.ResultsAltogether, 168 (81 THR, 87 TKR) patients were enrolled, of whom 161 received both enoxaparin and dabigatran, 2 received dabigatran only and 5 received enoxaparin only. The median time of the first dabigatran tablet was 24.0 h after the last LMWH dosage and the median number of days on dabigatran treatment was 36 days. No symptomatic VTE or death occurred during the study. One major bleeding event was seen at the surgical site and required treatment cessation. Three minor bleeding events were observed.ConclusionsIn the normal clinical setting, switching from LMWH to dabigatran in patients who had undergone THR and TKR was safe and effective in preventing VTE. The reported adverse events and serious adverse events were consistent with the known safety profile for dabigatran. Switching from a subcutaneous to an oral anticoagulant may offer greater convenience in the outpatient setting after discharge.Trial registrationClinicalTrials.gov identifier NCT01153698.

Abstract 17126: Efficacy and Safety of Dabigatran Compared With Warfarin in Patients With Atrial Fibrillation and Normal Renal Function Over Time: Insights From the RE-LY Trial

Background: In patients with atrial fibrillation (AF) and normal renal function it has been reported that one oral factor-Xa inhibitor is associated with decreased efficacy compared to warfarin. In the RE-LY trial of patients with AF dabigatran, with approximately 80% renal elimination, was superior to warfarin for prevention of stroke and systemic embolism (SEE) with the 150 mg dose and non-inferior with the 110 mg dose and associated with significantly less major bleeding with the 110 mg dose. This is a post hoc analysis of the efficacy and safety of dabigatran vs. warfarin treatment in patients with normal renal function during the study. Methods: In the RE-LY trial among patients who received at least one dose of study medication, 17882 had creatinine measurements available at baseline, out of which 91% also had measurements after randomization. There were a total of 382 stroke/SEE, 280 ischemic strokes, and 1018 major bleed events during median follow-up of 1.8 years. The relations between outcomes, treatment, and renal function (Cockcroft-Gault estimated glomerular filtration rate (eGFR)) during follow-up were evaluated using Cox regression including treatment, eGFR as a continuous time dependent covariate, fitted using restricted cubic splines, and interaction. Hazard ratios (95% CI) comparing treatment effects were analyzed according to eGFR level. Results: In patients with normal renal function the relative risk of stroke/SEE was consistently lower in those treated with dabigatran as compared with warfarin. The patterns were similar for major bleeding with a trend of greater relative risk reduction with dabigatran as compared to warfarin at normal renal function. Conclusions: In patients with AF and normal renal function during treatment the efficacy of dabigatran compared to warfarin was consistent with the overall result of the RELY study. Both dabigatran doses were associated with lower risk of major bleeding in patients with normal renal function.

Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry.

The effectiveness and safety of dabigatran for stroke prevention in atrial fibrillation (SPAF) demonstrated in RE-LY needs to be confirmed in daily care. To evaluate treatment persistence, effectiveness and safety of dabigatran therapy in SPAF patients in daily care, we used data from an ongoing, prospective, non-interventional registry of more than 2,500 patients on novel oral anticoagulants in daily care. Between October 1, 2011 and February 28, 2013, a total of 341 SPAF patients receiving dabigatran were enrolled. The combined endpoint of stroke/transient ischaemic attack/systemic embolism occurred at a rate of 2.93/100 patient-years in the intention-to-treat analysis (95%-CI 1.6-4.9) and at 1.9/100 patient-years in the on treatment analysis (events within three days after last intake). On-treatment rates were higher in patients selected for 110 mg dabigatran (n=183) BID compared to the 158 patients selected for 150 mg BID (2.88 [95% CI 1.16- 5.93] vs 0.86/100 patient-years [95% CI 0.10, 3.12]). On treatment, major bleeding occurred at a rate of 2.3/100 patient-years and numerically more often in patients receiving the 110 mg BID dose compared to the 150 mg BID dose (2.9 vs 1.7/100 patient-years). Dabigatran treatment discontinuation occurred in a total of 124 patients during follow-up (25.8 per 100 patient-years in Kaplan Meier analysis). Main reasons for treatment discontinuation were non-bleeding side effects. Our data contribute to the confirmation of effectiveness and relative safety of dabigatran in unselected patients in daily care. However, discontinuation rates are not lower than those reported for patients treated with vitamin K antagonists.

Healthcare utilization and costs associated with dabigatran compared to warfarin treatment in newly diagnosed patients with non-valvular atrial fibrillation

Purpose:Real-world healthcare resource utilization and costs were compared among patients with non-valvular atrial fibrillation (NVAF) receiving either dabigatran or warfarin.Methods:A retrospective cohort study was conducted using administrative claims data from the United States Department of Defense (DOD) Military Health System. Patients with newly diagnosed AF initiated on dabigatran or warfarin were identified using ICD-9 diagnosis, procedure and drug codes. Patients were observed for 3 months prior to treatment initiation to ascertain a diagnosis of valvular heart disease and 12 months for exclusion of those with a history of anticoagulation therapy. Propensity score matching was used to balance baseline characteristics between the two treatment cohorts. Medical and pharmacy utilization and costs were compared between the dabigatran and warfarin treatment groups for 3 and 12 months following treatment initiation.Results:A total of 1102 patients with newly diagnosed NVAF initiated on dabigatran were matched with corresponding warfarin-treated patients. In the 12 months following initiation of anticoagulation, the mean medical costs for patients initiated on dabigatran were significantly lower than for patients initiated on warfarin (−$6299, p < 0.001), largely due to fewer hospitalizations (−0.162, p = 0.009). While pharmacy costs were higher ($4369, p < 0.001) for dabigatran, overall healthcare costs were significantly lower compared with patients on warfarin (12 months: −$1940, p < 0.001). Mean hospital length of stay between these two groups were similar (6.033 days for dabigatran vs 6.318 days for warfarin, p = 0.139).Conclusion:Despite higher pharmacy costs for NVAF patients initiated on dabigatran vs warfarin, this was more than offset by lower utilization of medical care resources.

Dabigatran Effect on Left Ventricular Thrombus in a Patient with Acute Ischemic Stroke.

Dabigatran Effect on Left Ventricular Thrombus in a Patient with Acute Ischemic Stroke.

Effect of the oral thrombin inhibitor dabigatran on allergic lung inflammation induced by repeated house dust mite administration in mice.

Asthma is a chronic disease of the airways; asthma patients are hampered by recurrent symptoms of dyspnoea and wheezing caused by bronchial obstruction. Most asthma patients suffer from chronic allergic lung inflammation triggered by allergens such as house dust mite (HDM). Coagulation activation in the pulmonary compartment is currently recognized as a feature of allergic lung inflammation, and data suggest that coagulation proteases further drive inflammatory mechanisms. Here, we tested whether treatment with the oral thrombin inhibitor dabigatran attenuates allergic lung inflammation in a recently developed HDM-based murine asthma model. Mice were fed dabigatran (10 mg/g) or placebo chow during a 3-wk HDM airway exposure model. Dabigatran treatment caused systemic thrombin inhibitory activity corresponding with dabigatran levels reported in human trials. Surprisingly, dabigatran did not lead to inhibition of HDM-evoked coagulation activation in the lung as measured by levels of thrombin-antithrombin complexes and D-dimer. Repeated HDM administration caused an influx of eosinophils and neutrophils into the lungs, mucus production in the airways, and a T helper 2 response, as reflected by a rise in bronchoalveolar IL-4 and IL-5 levels and a systemic rise in IgE and HDM-IgG1. Dabigatran modestly improved HDM-induced lung pathology (P < 0.05) and decreased IL-4 levels (P < 0.01), without influencing other HDM-induced responses. Considering the limited effects of dabigatran in spite of adequate plasma levels, these results argue against clinical evaluation of dabigatran in patients with asthma.

Cost-Effectiveness of Dabigatran Compared to Vitamin-K Antagonists for the Treatment of Deep Venous Thrombosis in the Netherlands Using Real-World Data.

BackgroundVitamin-K antagonists (VKAs) present an effective anticoagulant treatment in deep venous thrombosis (DVT). However, the use of VKAs is limited because of the risk of bleeding and the necessity of frequent and long-term laboratory monitoring. Therefore, new oral anticoagulant drugs (NOACs) such as dabigatran, with lower rates of (major) intracranial bleeding compared to VKAs and not requiring monitoring, may be considered.ObjectivesTo estimate resource utilization and costs of patients treated with the VKAs acenocoumarol and phenprocoumon, for the indication DVT. Furthermore, a formal cost-effectiveness analysis of dabigatran compared to VKAs for DVT treatment was performed, using these estimates.MethodsA retrospective observational study design in the thrombotic service of a teaching hospital (Deventer, The Netherlands) was applied to estimate real-world resource utilization and costs of VKA monitoring. A pooled analysis of data from RE-COVER and RE-COVER II on DVT was used to reflect the probabilities for events in the cost-effectiveness model. Dutch costs, utilities and specific data on coagulation monitoring levels were incorporated in the model. Next to the base case analysis, univariate probabilistic sensitivity and scenario analyses were performed.ResultsReal-world resource utilization in the thrombotic service of patients treated with VKA for the indication of DVT consisted of 12.3 measurements of the international normalized ratio (INR), with corresponding INR monitoring costs of €138 for a standardized treatment period of 180 days. In the base case, dabigatran treatment compared to VKAs in a cohort of 1,000 DVT patients resulted in savings of €18,900 (95% uncertainty interval (UI) -95,832, 151,162) and 41 (95% UI -18, 97) quality-adjusted life-years (QALYs) gained calculated from societal perspective. The probability that dabigatran is cost-effective at a conservative willingness-to pay threshold of €20,000 per QALY was 99%. Sensitivity and scenario analyses also indicated cost savings or cost-effectiveness below this same threshold.ConclusionsTotal INR monitoring costs per patient were estimated at minimally €138. Inserting these real-world data into a cost-effectiveness analysis for patients diagnosed with DVT, dabigatran appeared to be a cost-saving alternative to VKAs in the Netherlands in the base case. Cost savings or favorable cost-effectiveness were robust in sensitivity and scenario analyses. Our results warrant confirmation in other settings and locations.

Dabigatran Therapy in Acute Ischemic Stroke Patients Without Atrial Fibrillation.

Acute ischemic stroke patients are at risk of early recurrence. We tested the feasibility and safety of initiating dabigatran in patients, within 24 hours of minor stroke in patients without atrial fibrillation. Minor stroke patients (National Institutes of Health Stroke Scale score ≤3) without atrial fibrillation and evidence of acute infarction on magnetic resonance imaging were treated with dabigatran. Treatment began within 24 hours of onset and was continued for 30 days. The primary end point was symptomatic hemorrhagic transformation. A total of 53 patients with median (interquartile range) age of 68 (57-77) years and National Institutes of Health Stroke Scale score of 1 (0-2) were enrolled. Baseline diffusion-weighted imaging volume was 0.8 (0.3-2.4) mL. No patients experienced symptomatic hemorrhagic transformation. Three patients had evidence of asymptomatic petechial hemorrhagic transformation on day 7, which remained stable at day 30, while continuing dabigatran. Dabigatran treatment within 24 hours of minor stroke is feasible. A larger randomized trial is required to confirm the safety and efficacy of this treatment approach. URL: http://www.clinicaltrials.gov. Unique identifier: NCT 01769703.

Impact of dabigatran on platelet function and fibrinolysis

BackgroundWe sought to evaluate the potential enhanced fibrinolytic and antiplatelet activity of dabigatran etexilate (DE) due to decreased thrombin levels in patients with stroke or transient ischemic attack and non-valvular atrial fibrillation (NVAF). MethodsConsecutive patients with cerebrovascular diseases and NVAF that were treated with DE in a tertiary university hospital. Fibrinolysis and platelet function were assessed by thromboelastometry (ROTEM) and platelet function analyzer (PFA)-100, respectively, before and after treatment with DE. Conventional coagulation tests, endogenous thrombin potential (ETP) and hemoclot thrombin inhibitors (HTI), were also performed in order to detect any possible correlation between dabigatran plasma levels, its anticoagulant activity and the intensity of platelet dysfunction or fibrinolysis. ResultsA total of nineteen patients fulfilled our inclusion criteria (mean age 62.3±7.2years; 47% males; median CHADS2-score: 3; interquartile range: 2–4). DE treatment was associated with a significant reduction of the lysis index (LI60) at 60min (p=0.036), and prolongation of the PFA-100 CEPI closure time (p=0.024). After dabigatran treatment, abnormal PFA-100 results were obtained in two patients (11%, 95% CI: 2%–33%). DE levels (determined by HTI) were strongly inversely correlated (rho=–0.85; p<0.001) with the area under the curve (AUC) values in ETP assay. Νo association was found between HTI and PFA-100 CEPI CT (p=0.64), or LI60 measurements (p=0.60). ConclusionsOur findings indicate that DE might affect platelet function and fibrinolysis and highlight the potential role of ETP as an alternative option in DE monitoring. The intensity and clinical relevance of DE antiplatelet and fibrinolytic effects require further investigation.

A sanguineous pleuro pericardial effusion in a patient recently treated with Dabigatran

Dabigatran, a direct thrombin inhibitor, is one of the new oral anticoagulants. As more patients receive treatment with Dabigatran, and as the clinical indications for Dabigatran use expand, reporting serious adverse effects is fundamental to future safety assessment. Although patients taking Dabigatran had fewer life-threatening bleeds when compared to Coumadin, those events continue to be reported. We describe, in the same patient, a sanguineous pleuro pericardial effusion that was diagnosed incidentally on a pre-ablation cardiac CT angiography. The diagnosis was made approximately two months after initiating Dabigatran treatment for non-valvular atrial fibrillation in a 63-year-old patient.