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3 February 2010
In the RE-COVER trial (n=2,564), dabigatran etexilate▼ 150mg twice daily for six months was found to be as effective as dose-adjusted warfarin in preventing recurrent venous thromboembolism (VTE) and related deaths in patients with verified, symptomatic, acute venous thromboembolism (VTE) initially treated with parenteral anticoagulants. The risk of major bleeding and other adverse effects were similar in the two groups.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
Dabigatran etexilate is currently licensed only for prevention of VTE events in adults who have undergone elective total hip or knee replacement surgery. If it obtains a marketing authorisation for management of acute VTE then local decision-making bodies will need to consider its place in therapy with regard to warfarin, whilst noting that the results of another study are awaited to establish longer-term efficacy and safety. A NICE appraisal for this indication is planned to commence in April 2011.
What is the background to this?
Warfarin is the most commonly used oral anticoagulant in the UK. However as it can take between 48 to 72 hours for its effect to fully develop if an immediate effect is required parenteral anticoagulation is necessary. Duration of treatment will vary depending upon the individual patient and the underlying cause of the VTE.
Dabigatran etexilate is a direct thrombin inhibitor, which has the potential advantage over warfarin of not requiring blood monitoring, and may have fewer clinically important drug interactions. It is currently licensed for short-term use (maximum 35 days) in the primary prevention of venous thromboembolism in adults undergoing elective total hip or knee surgery, and is recommended by NICE as one of the options to consider in this indication.
Further information on VTE is available on the cardiovascular section of NPC.
What does this study claim?
Dabigatran etexilate is non-inferior to warfarin (when the latter is dose-adjusted to achieve and maintain an INR in the range of 2.0 to 3.0) in the prevention of recurrent thromboembolic events. Thirty patients in the dabigatran etexilate 150mg twice daily group (2.4%) and 27 (2.1%) in the dose-adjusted warfarin group experienced the primary endpoint (a composite of symptomatic VTE or death associated with VTE) after 6 months of treatment. The risk difference was 0.4 percentage points (95% confidence interval [CI] –0.8 to 1.5, P<0.001 for the pre-specified non-inferiority margin). The hazard ratio (HR) was 1.10 (95% CI 0.65 to 1.84, P<0.001).
The safety profile for dabigatran etexilate was similar to that of warfarin with major bleeding episodes occurring in 1.6% (n=20) and 1.9% (n=24) respectively of patients (HR 0.82, 95% CI 0.45 to 1.48).
How does this relate to other studies?
A further trial is in progress (the RE-MEDY trial) to look at the efficacy and safety of dabigatran etexilate and warfarin for the long-term treatment (18 months) and secondary prevention of symptomatic VTE in patients who have been successfully treated with standard doses of an approved anticoagulant for three to six months for confirmed acute symptomatic VTE.
In addition, the RE-SONATE trial is evaluating dabigatran etexilate versus placebo in the long-term prevention of recurrent symptomatic VTE in patients with symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) who have completed 6 to 18 months of treatment with a vitamin K antagonist.
We recently reviewed the RE-LY study in which dabigatran etexilate was shown to be non-inferior to adjustable dose warfarin in preventing strokes, particularly haemorrhagic strokes, in patients with atrial fibrillation who are at moderate to high risk of strokes.
So what?
Dabigatran etexilate was shown, over six months, to be at least as effective as warfarin in preventing recurrence of events in patients who had experienced acute VTE. This together with no greater risk of major bleeding suggests a possible role as an alternative to warfarin for this indication.
More patients discontinued the study due to adverse events in the dabigatran etexilate group than in those taking warfarin. There were no significant differences between the two treatment groups in the frequency of adverse events except for dyspepsia (2.9% in the dabigatran etexilate group vs. 0.6% in the warfarin group, P<0.001). Gastrointestinal symptoms were reported as reasons for discontinuation in 2.1-2.2% of patients over 2 years in the RE-LY study.
The study considered dabigatran etexilate treatment for six months and thus long-term safety is unclear. The results from the longer-term studies due to complete later this year may help to clarify the picture.
NICE guidance on the use of dabigatran etexilate for the treatment of acute VTE is planned, and it is anticipated that this will commence in April 2011 to align with regulatory expectations.
Should dabigatran etexilate receive a licence for this indication, it is likely that a new strength preparation will be added to those already available. The price of this new strength is not yet known, but whatever the cost it would be offset by not needing anticoagulant monitoring for patients on dabigatran etexilate. However, it cannot be assumed that anticoagulant monitoring clinics will be redundant in the future as some patients are likely to remain on warfarin or phenindione.
Although dabigatran etexilate interacts with a number of medicines, it currently has fewer clinically important drug and food interactions than warfarin. It has a fast onset and offset of action, and experience over time will demonstrate whether this provides clinical advantage.
Design
A randomised, double-blind non-inferiority trial with concealed allocation. A double-dummy technique was used to maintain blinding. A point-of-care coagulometer that was pre-programmed with the randomisation schedule was used to generate sham INR results for those patients on warfarin placebo.
Patients
Adults with acute VTE (symptomatic, verified, proximal DVT of the legs or PE) were included in the study. 2,564 patients were randomised but 25 did not receive any study medication. One patient assigned to dabigatran etexilate received warfarin throughout the study. This patient did not have an event and was included in the warfarin group for the safety analysis.
Intervention and comparison
Patients were initially treated with parenteral anticoagulation for a mean of 10 days. Oral dabigatran etexilate (150mg twice daily) or dose-adjusted warfarin (to achieve an INR of 2.0 to 3.0) were taken for six months.
Outcomes and results
The primary efficacy outcome was time to first occurrence of a composite of symptomatic VTE or death associated with VTE in the six months after assignment to treatment. The power calculation had indicated that 1,275 patients should be included in each arm and that a total of 46 events should be seen in order to demonstrate that dabigatran etexilate was as effective as warfarin i.e. noninferior. In practice, 1,274 patients were randomised to dabigatran etexilate and 1,265 to warfarin. 57 events were seen: 30 patients in the dabigatran etexilate group (2.4%) and 27 in the warfarin group (2.1%). The difference in risk was 0.4 percentage points (95% CI –0.8 to 1.5, P<0.001) and the hazard ratio (HR) was 1.10 (95% CI 0.65 to 1.84, P<0.001). There was no difference in deaths between the two groups.
Major bleeding episodes were seen in 1.6% of the dabigatran etexilate patients and 1.9% of the warfarin group, HR 0.82, 95% CI 0.45 to 1.48). 7.9% of the dabigatran etexilate group and 6.5% of the warfarin group experienced adverse events which led to discontinuation of study drug (HR 1.33; 95% CI 1.01 to 1.76, P=0.05). Other adverse events (such as headache, nausea and diarrhoea) were similar in each group but dyspepsia was more common in dabigatran etexilate patients (2.9% versus 0.6%). Liver function tests were similar in the two groups.
Sponsorship
Boehringer Ingelheim
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