Characteristics of patients with non-valvular atrial fibrillation using dabigatran or warfarin in the US.

OBJECTIVE: In order to understand characteristics of atrial fibrillation patients in the era of new oral anticoagulants (NOACs), this study explores differences in characteristics between patients treated with dabigatran etexilate (DE) and warfarin (W) that may be due to patient channeling in 'real-world' clinical practice. RESEARCH DESIGN AND METHODS: Medco claims data were used to characterize 41,805 non-valvular atrial fibrillation (NVAF) patients from the US with a DE (N = 7055) or W (N = 34,750) prescription between February 2011 and April 2012. The first prescription for each treatment in this period defined the index date. The treatment groups were stratified by newly diagnosed or warfarin-experienced patients. Characteristics, comedications, and comorbidities in the 12 month period prior to index date were assessed. RESULTS: Newly diagnosed patients initiating DE had overall lower use of comedications compared to W patients. In contrast, warfarin-experienced patients switching from W to DE showed higher use of antibiotics, beta blockers, gastrointestinal drugs and NSAIDs compared to patients remaining on W. Newly diagnosed NVAF patients initiating DE showed lower proportions for comorbidities such as myocardial infarction, congestive heart failure, and renal disease. This was also reflected in the Charlson comorbidity index (CCI) (mean DE 2.1 vs. W 3.0) and the CHA2DS2-VASc score (mean DE 3.4 vs. W 4.0). For warfarin-experienced NVAF patients, these differences were not seen. Interpretation of results is limited by the fact that administrative claims data are not gathered for scientific research. Underreporting of non-serious conditions might occur and life-style variables, laboratory values and over-the-counter medication were not available. CONCLUSIONS: As also seen for other newly marketed drugs, differences in baseline characteristics, comedication, and comorbidities were detected between DE and W in newly diagnosed patients, as well as in warfarin-experienced patients. This channeling may have significant impact on comparative outcome studies if not properly addressed in study design and analysis.

Thromboembolism in a patient with a mechanical mitral valve during anticoagulation with dabigatran etexilate.

Recently, several new anticoagulants have been used instead of warfarin for preventing thromboembolism. In the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial, the direct thrombin inhibitor dabigatran etexilate was as an effective and safe as dose-adjusted warfarin for prevention of stroke in high-risk patients with atrial fibrillation. However, the safety and efficacy of thromboprophylaxis after mechanical valve replacement is uncertain. We report a 57-year-old man with a mechanical heart valve who experienced acute upper limb thromboembolism during dabigatran intake. Dabigatran might be inadequate for thromboprophylaxis after mechanical valve replacement.

Genetic determinants of dabigatran plasma levels and their relation to bleeding.

BACKGROUND: Fixed-dose unmonitored treatment with dabigatran etexilate is effective and has a favorable safety profile in the prevention of stroke in atrial fibrillation patients compared with warfarin. We hypothesized that genetic variants could contribute to interindividual variability in blood concentrations of the active metabolite of dabigatran etexilate and influence the safety and efficacy of dabigatran. METHODS AND RESULTS: We successfully conducted a genome-wide association study in 2944 Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) participants. The CES1 single-nucleotide polymorphism rs2244613 was associated with trough concentrations, and the ABCB1 single-nucleotide polymorphism rs4148738 and the CES1 single-nucleotide polymorphism rs8192935 were associated with peak concentrations at genome-wide significance (P<9×10(-8)) with a gene-dose effect. Each minor allele of the CES1 single-nucleotide polymorphism rs2244613 was associated with lower trough concentrations (15% decrease per allele; 95% confidence interval, 10-19; P=1.2×10(-8)) and a lower risk of any bleeding (odds ratio, 0.67; 95% confidence interval, 0.55-0.82; P=7×10(-5)) in dabigatran-treated participants, with a consistent but nonsignificant lower risk of major bleeding (odds ratio, 0.66; 95% confidence interval, 0.43-1.01). The interaction between treatment (warfarin versus all dabigatran) and carrier status was statistically significant (P=0.002), with carriers having less bleeding with dabigatran than warfarin (hazard ratio, 0.59; 95% confidence interval, 0.46-0.76; P=5.2×10(-)5) in contrast to no difference in noncarriers (hazard ratio, 0.96; 95% confidence interval, 0.81-1.14; P=0.65). There was no association with ischemic events, and neither rs4148738 nor rs8192935 was associated with bleeding or ischemic events. CONCLUSIONS: Genome-wide association analysis identified that carriage of the CES1 rs2244613 minor allele occurred in 32.8% of patients in RE-LY and was associated with lower exposure to active dabigatran metabolite. The presence of the polymorphism was associated with a lower risk of bleeding. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Prothrombin complex concentrates reduce blood loss in murine coagulopathy induced by warfarin, but not in that induced by dabigatran etexilate.

BACKGROUND: Both established oral anticoagulants such as warfarin and newer agents such as dabigatran etexilate (DE) effectively prevent thromboembolic disease, but may provoke bleeding. Limited clinical data exist linking oral anticoagulant reversal and bleeding tendency, as opposed to surrogate laboratory markers. OBJECTIVE: To quantify bleeding in warfarin-anticoagulated and DE-anticoagulated mice by tail transection with or without pretreatment with potential reversal agents: prothrombin complex concentrate (PCC); activated PCC (APCC); recombinant factor VIIa (rFVIIa); or murine fresh-frozen plasma (FFP). METHODS: CD1 mice were given warfarin or DE by gavage, and the effects on in vitro coagulation assays, volume of blood loss and the bleeding time following tail transection injury were evaluated with different reversal agents. RESULTS: PCC (14.3 IU kg(-1) ), but not rFVIIa (3 mg kg(-1) ) or FFP (12 mL kg(-1) ), normalized blood loss and bleeding time in mice with warfarin-induced elevations of mean prothrombin time at two intensities (prothrombin time ratios of either 4.3 or 24). Neither separate nor combined PCC and/or rFVIIa treatment nor APCC (100 U kg(-1) ) treatment significantly reduced blood loss in mice anticoagulated with 60 mg kg(-1) DE 75 min prior to tail transection. Both combined PCC plus rFVIIa treatment and APCC treatment significantly reduced bleeding time in the DE-treated mice. CONCLUSIONS: Our data suggest that PCC treatment prevents excess bleeding much more effectively in warfarin-induced coagulopathy than in DE-induced coagulopathy.

Dabigatran etexilate: a novel oral thrombin inhibitor for thromboembolic disease.

OBJECTIVE: To evaluate the efficacy and safety of dabigatran etexilate, approved by the Food and Drug Administration (FDA) in October 2010 for the prevention of cardioembolic stroke in patients with atrial fibrillation; potential off-label use is treatment and prevention of venous thromboembolic disorders. DATA SOURCES: Literature was accessed through MEDLINE (1977-April 2011) and International Pharmaceutical Abstracts (1977-April 2011) using the terms dabigatran, dabigatran etexilate, BIBR 1048, direct thrombin inhibitor, anticoagulant, and thromboembolism. In addition, US government Web sites, including clinicaltrials.gov and fda.gov, were reviewed for pertinent information. Lastly, reference citations from publications identified in the initial search were reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. For the evaluation of clinical efficacy and safety, only Phase 2 and 3 studies are included in this review. DATA SYNTHESIS: In 6 published Phase 3 trials to date, dabigatran has exhibited a similar efficacy and safety profile to that of comparator drugs, including dose-adjusted warfarin and enoxaparin, at various dosages. In the largest of these trials, RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy), dabigatran was at least as effective as dose-adjusted warfarin in reducing stroke or systemic embolism. Overall bleeding risks were similar; however, dabigatran may be associated with a lower incidence of intracranial bleeding and hemorrhagic stroke but a higher incidence of gastrointestinal bleeding. Although dabigatran is not approved for venous thromboembolism (VTE) prevention or treatment, results of the RE-MODEL and RE-NOVATE trials suggest similar efficacy to once-daily dosing of enoxaparin 40 mg but inferior efficacy to the FDA-approved twice-daily dosing of enoxaparin 30 mg in the RE-MOBILIZE trial. CONCLUSIONS: Dabigatran is an effective and safe alternative to oral vitamin K antagonists for stroke prevention in patients with nonvalvular atrial fibrillation, with fewer drug interactions and monitoring requirements. Additionally, dabigatran may be a viable alternative to enoxaparin in VTE prevention and warfarin in VTE treatment, although current trial data are limited.

Dabigatran etexilate (Pradaxa)--a new oral anticoagulant.

The FDA has approved the oral direct thrombin inhibitor dabigatran (da big' a tran) etexilate (Pradaxa--Boehringer Ingelheim) for prevention of thromboembolic stroke in patients with non-valvular atrial fibrillation.It has been available in Canada (Pradax) since 2008 for prevention of thromboembolism in patients undergoing knee or hip replacement surgery and was recently approved there for use in atrial fibrillation.

[New oral anticoagulants: better than vitamin K antagonists?]. / Neue orale Antikoagulanzien: Werden sie die Vitamin-K-Antagonisten verdrängen?

Many years of practical use and intensive scientific research have allowed vitamin K antagonists to become a cornerstone of treatment of internal diseases. Nevertheless, limitations in pharmacokinetics and -dynamics of vitamin K antagonists and the availability of new drugs in regard to a targeted anticoagulation therapy ask for a new review of the situation. Proof of effectiveness for the perioperative prophylaxis of venous thrombosis after hip and knee replacement has already been achieved for the direct thrombin inhibitor dabigatran etexilate as well as for the factor Xa inhibitors rivaroxaban und apixaban compared to low molecular weight heparins. These new drugs are now also investigated in patients with internal diseases. For the long-term application (6 or 12 months) concerning the treatment of venous thrombosis and/or stroke prophylaxis in patients with atrial fibrillation data is already available for the direct thrombin inhibitor dabigatran etexilate. Depending on its dosage its effectiveness in comparison with vitamin K antagonists is equal or even better without disadvantages in safety. However, vitamin K antagonists will remain the standard oral anticoagulation until open questions regarding e.g. insufficient therapy adherence (with termination rates up to 20%) or problems with drug interactions of the new competitive products have been completely answered.

Antithrombin-α for the prophylaxis of venous thrombosis in congenital antithrombin deficiency.

ATryn(®) is a transgenically produced recombinant antithrombin (AT) concentrate licensed in Europe and the USA for the thromboprophylaxis of hereditary AT-deficient patients undergoing surgical procedures who are at a high risk of venous thromboembolism. It is also licensed, in the USA only, for prevention the of venous thromboembolism in association with delivery and the immediate post-partum period. ATryn is administered as a continuous intravenous infusion, with weight-adjusted loading and maintenance dosing regimens. Recombinant AT has an identical amino acid structure with minor glycosylation differences to endogenous AT. ATryn has a shorter half-life but an equivalent efficacy to that of plasma-derived AT concentrates in the prevention of venous thromboembolism in this rare distinct group with a high thrombotic risk. In addition, this recombinant product should be free from the risk of human viral or prion transmission.