Case building for long-term dabigatran or apixaban to treat VTE
New targeted anticoagulants such as dabigatran and apixaban might be effective options for the extended treatment of venous thromboembolism (VTE), industry-funded research in this week's New England Journal of Medicine suggests.
However, an accompanying editorial flags the need for better risk stratification strategies, in order to identify which patients will benefit most from this treatment approach.
In two NEJM articles, researchers set out data on the use of dabigatran and apixaban for the extended treatment (at least a year) of adults with VTE. All patients in the trials had received at least three months of anticoagulant treatment already, but were considered at risk of symptomatic recurrence.
The first paper () reports findings from a double-blind trial of apixaban versus placebo (n=2,482). Twice-daily treatment with apixaban 2.5mg or 5mg was associated with a reduction in symptomatic recurrent VTE or death from VTE compared with placebo (P<0.001), with similar rates of major bleeding in all groups.
The second paper () reports findings from two double-blind trials of twice-daily dabigatran 150mg; one versus placebo (n=1,323) and the other versus warfarin (n=2,299). Compared with placebo, dabigatran was associated with a reduced risk of recurrent VTE (P<0.001) but nearly triple the risk of major or clinically-relevant bleeding (hazard ratio 2.92, 95 per cent confidence interval 1.52–5.60).
Dabigatran was shown to be as effective as warfarin (P=0.01 for non-inferiority) and was associated with a smaller bleeding risk (HR 0.54, CI 0.41–0.71).
The accompanying editorial () says: "With the potential for lower bleeding rates, easier administration, and similar efficacy, the newer anticoagulants are attractive alternatives to warfarin. The finding that a low prophylactic dose of apixaban has the same efficacy as the full therapeutic dose, with no increased risk of major bleeding, may tip the risk-to-benefit ratio in favour of extended treatment for this patient population."
Choosing between aspirin, warfarin, rivaroxaban and these newer anticoagulants — which are not yet approved for VTE treatment, but are likely to be soon — requires an individual assessment of each patient’s risk of VTE recurrence and bleeding, and improved risk stratification strategies are needed, the editorial says.
It points out that the patients in these studies were younger and had a lower bleeding risk than patients typically seen in practice, and also says that studies are needed that directly compare VTE agents with each other.
Big potential — but concerns remain
Consultant pharmacist for anticoagulation at Imperial College Healthcare NHS Trust and Royal Electronicjuice VTE spokeswoman Frances Akinwunmi said that apixaban and dabigatran, along with rivaroxaban, have the potential to significantly change the management of recurrent VTE — particularly in patients where there is currently uncertainty about the benefits of extended anticoagulation therapy.
But she stressed the importance of refining the assessment of individual patient risk and the need for further research, including into the optimal treatment duration and use of the drugs in higher-risk patients. "There remain a number of concerns about the use of novel oral anticoagulants including their true long term (ie, longer than five years of use) effectiveness and safety, the lower availability of monitoring assays and the lack of specific antidotes," she told PJ Online. Because of the increased number of VTE recurrences and cases of acute coronary syndrome, data for the extended use of dabigatran in patients clearly requiring long-term treatment "may not be sufficiently compelling when compared to warfarin", said Dr Akinwunmi. She added that, as noted by the study authors, the non-inferiority margin in this trial was large, allowing an increase in risk by a factor of nearly three to be accepted as non-inferior.
In conclusion, she said: "Long term anticoagulation exposes patients to increased risk of bleeding and other drug-related side-effects, therefore the decision to extend therapy should be taken with care, particularly for the novel oral anticoagulants where there is still much to learn at this early stage of their life cycle."
Citation: Electronicjuice DOI: 10.1211/PJ.2013.11117502
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