Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial

BACKGROUND: Oral anticoagulants, such as dabigatran etexilate, an oral, direct thrombin inhibitor, that do not require monitoring or dose adjustment offer potential for prophylaxis against venous thromboembolism (VTE) after total knee replacement surgery. METHODS: In this randomized, double-blind study, 2076 patients undergoing total knee replacement received dabigatran etexilate, 150 mg or 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery, for 6-10 days. Patients were followed-up for 3 months. The primary efficacy outcome was a composite of total VTE (venographic or symptomatic) and mortality during treatment, and the primary safety outcome was the incidence of bleeding events. RESULTS: The primary efficacy outcome occurred in 37.7% (193 of 512) of the enoxaparin group versus 36.4% (183 of 503) of the dabigatran etexilate 220 mg group (absolute difference, -1.3%; 95% CI, -7.3 to 4.6) and 40.5% (213 of 526) of the 150 mg group (2.8%; 95% CI, -3.1 to 8.7). Both doses were noninferior to enoxaparin based on the pre-specified noninferiority criterion. The incidence of major bleeding did not differ significantly between the three groups (1.3% versus 1.5% and 1.3% respectively). No significant differences in the incidences of liver enzyme elevation and acute coronary events were observed during treatment or follow-up. CONCLUSIONS: Dabigatran etexilate (220 mg or 150 mg) was at least as effective and with a similar safety profile as enoxaparin for prevention of VTE after total knee-replacement surgery.     

Comparison of the efficacy of rivaroxaban and dabigatran etexilate in preventing venous thrombosis after arthroplasty: A protocol of randomized controlled trial

Background:New oral anticoagulants (NOAC) are gradually accepted by clinical practice for its convenient route of administration and stable effect. Both rivaroxaban and dabigatran etexilate have been used in the prevention and treatment of venous embolism after arthroplasty, but there is a lack of direct comparison between the 2 effects. Therefore, the purpose of this randomized controlled trial was to evaluate the efficacy and safety of 2 new oral anticoagulants, rivaroxaban, and dabigatran etexilate, in the prevention of venous thromboembolism after joint replacement.Methods:This is a prospective randomized controlled trial to study the efficacy and safety of rivaroxaban and dabigatran etexilate in the prevention of venous thromboembolism after joint replacement, and is approved by the clinical research ethics of our hospital. Patients were randomly divided into 1 of 2 treatment regimens:

• (A)rivaroxaban oral group and
• (B)dabigatran etexilate oral group.

Patients, doctors, nurses, and data collection assistants were blinded to group allocation. The indicators of observation include:

• (1)validity indicators: asymptomatic deep venous thrombosis (DVT), symptomatic DVT, symptomatic pulmonary embolism (PE) incidence, all-cause mortality;
• (2)safety indicators: incidence of major bleeding and clinically related non-major bleeding events and other adverse events.

Data were analyzed using the statistical software package SPSS version 25.0 (Chicago, IL).Discussion:This study will evaluate the efficacy and safety of rivaroxaban and dabigatran etexilate in preventing venous thrombosis after joint replacement. The results of this experiment will provide clinical basis for the use of rivaroxaban or dabigatran etexilate to prevent venous thrombosis after joint replacement.Ethics and dissemination:Private information from individuals will not be published. This systematic review also does not involve endangering participant rights. Ethical approval was not required. The results may be published in a peer-reviewed journal or disseminated at relevant conferences.OSF Registration number:DOI 10.17605/OSF.IO/QVDCW.     

Warfarin versus dabigatran etexilate: an assessment of efficacy and safety in patients with atrial fibrillation

Introduction: Oral anticoagulation is the mainstay for stroke and thromboembolic event prevention in patients with atrial fibrillation (AF). Given limitations of warfarin therapy, non-vitamin K oral anticoagulants have been developed including direct thrombin inhibitors (i.e., dabigatran etexilate). Dabigatran etexilate has been tested thoroughly in terms of efficacy and safety in clinical trials and studies, involving ‘real-world’ cohorts. In this review, currently available evidence in patients with non-valvular AF is discussed.

Areas covered: The pharmacology, efficacy and safety, and current aspects of use of dabigatran etexilate in patients with non-valvular AF are reviewed in a comparative manner to warfarin both for chronic anticoagulation and in different clinical settings.

Expert opinion: Dabigatran etexilate appeared to have several pharmacokinetic and pharmacodynamic advantages over warfarin, as well as a favorable efficacy and safety profile being at least noninferior and often superior to warfarin in patients with non-valvular AF. The latter was shown in the clinical trials, meta-analyses and studies with ‘real-world’ data. Currently ongoing trials will expand the body of evidence on warfarin and will aid decision making in currently controversial areas. Important limitations of dabigatran etexilate include contraindications for its use in patients with prosthetic heart valves and end-stage chronic kidney disease.     

Safety and efficacy of non-vitamin K oral anticoagulants in non-valvular atrial fibrillation: a Bayesian meta-analysis approach

Introduction: Choosing between different non-vitamin K antagonist oral anticoagulants (NOACs) in non-valvular atrial fibrillation (NVAF) is difficult due to the absence of head to head comparative studies. We performed a Bayesian meta-analysis to explore similarities and differences between different NOACs and to rank treatments overall for safety and efficacy outcomes.

Areas covered: Through a systematic literature search we identified randomized controlled Phase III trials of dabigatran, rivaroxaban, apixaban, and edoxaban versus adjusted-dose warfarin in patients with NVAF.

Expert opinion: Warfarin ranked worst for all-cause mortality and intracranial bleedings and had a nil probability of ranking first for any outcome. The risk of major bleeding versus warfarin was lower with apixaban, dabigatran 110 mg, and both doses of edoxaban. All agents reduced the risk of intracranial bleeding versus warfarin. Edoxaban 30 mg was the best among the treatments being compared for major and gastrointestinal bleeding. Dabigatran 150 mg was the best for stroke and systemic embolism. This study suggests that NOACs are generally preferable to warfarin in patients with NVAF. However, safety and efficacy differences do exist among NOACs, which might drive their use in specific subsets of AF patients, allowing prescribers to tailor treatment to distinct patient profiles.     

Dose tailoring of dabigatran etexilate: obvious or excessive?

Introduction: Dabigatran etexilate is used for preventing blood clots and tends to replace older anticoagulants in many of their indications. However, the ‘one dose fits all’ policy is subject to criticism. Recent findings assert the anxiety of the scientific community concerning the pharmacokinetic properties of dabigatran etexilate, that is, an important interindividual variability including an important genetic variant with a significant dependence of the renal function as route of elimination.

Areas covered: This meta-opinion provides an overview of the current knowledge and evidence on the dose tailoring of dabigatran etexilate. It also discusses the remaining challenges to benefit from this perspective strategy to enhance the benefit–risk balance of dabigatran etexilate. Data were searched in the published literature and on regulatory agencies’ websites. Additionally, unpublished data were searched and discussed.

Expert opinion: Causality between dabigatran exposure and bleeding risk is now established and recommendations on how to best estimate the drug exposure are published. Additionally, simulating studies revealed that a dose adaptation based on dabigatran plasma concentration estimations could improve the benefit–risk profile of the drug. This accumulating evidence suggests that some patients under dabigatran etexilate may benefit from a tailoring of the dose beyond the ones already proposed by the manufacturer.     

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.     

Less abnormal uterine bleeding with dabigatran than warfarin in women treated for acute venous thromboembolism

Essentials

• Factor Xa inhibitors cause more abnormal menstrual bleeding (AUB) than vitamin‐K antagonists (VKA).
• We analyzed data of AUB in women, evaluating dabigatran versus VKA.
• We observed a 41% lower risk of AUB in women on dabigatran compared to those on VKA.
• Our findings of lower AUB risk on dabigatran should be corroborated in future studies.

Summary

Introduction

Although direct oral anticoagulants (DOACs) are associated with a better safety profile than warfarin in patients with acute venous thromboembolism (VTE), direct factor Xa inhibitors involve a higher risk of abnormal uterine bleeding (AUB). We aimed to determine the risk of AUB during anticoagulation with dabigatran compared with warfarin.

Methods

Post‐hoc analysis of the pooled RE‐COVER studies and the RE‐MEDY trial. Incidences of AUB, based on a defined preferred terms search for adverse events, in female patients aged 18–50 years treated with dabigatran, were compared with those in women treated with warfarin.

Results

Of the 2964 women included in the above‐mentioned trials, 1280 women were in the relevant age category (18–50 years) and included in the current analysis. A total of 643 patients were randomized to treatment with dabigatran and 637 to treatment with warfarin. The overall rate of AUB was 8.1%, 5.9% for the women treated with dabigatran and 9.6% in those treated with warfarin, for an odds ratio for dabigatran‐treated patients of 0.59 (95% confidence interval [CI], 0.39–0.90; P = 0.015). In the dabigatran‐treated patients, three (0.5%) suffered major bleeding (MB) vs. five (0.8%) in the warfarin‐treated patients (HR, 0.65; 95% CI, 0.15–2.72). MB or non‐major relevant bleeding occurred in 30 (4.7%) patients randomized to receive dabigatran and 57 (8.9%) randomized to receive warfarin (HR, 0.53; 95% CI, 0.34–0.83). None of the bleeding events was fatal.

Conclusion

Dabigatran treatment was associated with a significantly (41%) lower risk of AUB than warfarin. Future studies in daily practice are needed to corroborate these findings.

     

Long-term outcome in patients with non-valvular atrial fibrillation on dabigatran: a prospective cohort study

ABSTRACT

Introduction: Most studies on thromboembolic and bleeding risk in patients with non-valvular atrial fibrillation (NVAF) exposed to non-vitamin K oral anticoagulants stem from interrogation of insurance databases.

Areas covered: We studied 742 consecutive patients with NVAF who started treatment with dabigatran in three hospitals in Italy. Average follow-up was 1.80 years.

Mean age was 76.2 years. CHA₂DS₂VASc score was 0–1 in 37 (5%), 2 in 97 (13%) and ≥ 3 in 604 (82%) patients. NVAF was permanent in 349 (48%). Overall, 76% of patients remained on treatment over the entire follow-up period. Among 180 patients who discontinued permanently, the most frequent reasons were dyspepsia (33.9%), bleeding (17.8%), and renal worsening (12.1%). About 48% and 74% of permanent discontinuations occurred during the first 6 and 12 months of treatment, respectively. Rates of major events (per 100 patient-years) were 0.75 for stroke, 0.31 for myocardial infarction, 1.50 for all-cause death, and 1.80 for major bleedings. The rate of intracranial bleedings was 0.45 and that of major gastrointestinal bleedings was 0.75.

Expert opinion: This prospective cohort study confirms the low incidence of stroke, major bleeding and intracranial bleeding, and a 76% persistence with treatment, in patients with NVAF treated with dabigatran over about 2 years.     

Imputabilité d’une mise en jeu du pronostic vital à un inhibiteur spécifique de la thrombine

We present the case of a 73-year-old man, operated on for paralyzing sciatica, who displayed acute postoperative respiratory distress and intra-alveolar haemorrhage following the administration of dabigatran etexilate, a new oral antithrombin used in the prevention of venous thromboembolism. This serious incident occurred in a patient who had a 20-year history of chronic thrombocytopenia (platelet level at 100 G/l) and a heparin-induced thrombocytopenia and in whom no other aetiology was found (tuberculosis, pneumorenal syndrome, etc.). The postoperative prevention of thromboembolic events in a patient with high risk bleeding requires intensive monitoring, notably, when prescribing new drugs such as new anticoagulant agents.