By Eleanor McDermid
Extended thromboprophylaxis with the direct factor Xa inhibitor betrixaban just fails to show superiority to standard treatment with enoxaparin in acutely ill medical patients.
Indeed, the randomised trial published in The New England Journal of Medicine shows significant results for the overall cohort, but this was prespecified as only an exploratory analysis in the event of a negative result in patients of primary interest: those with elevated ᴅ-dimer levels.
Among these patients, there was a numerical but not statistically significant difference in the primary outcome of asymptomatic proximal deep-vein thrombosis or symptomatic venous thromboembolism. This occurred at a rate of 6.9% in 1914 patients who received subcutaneous placebo for around 10 days plus oral betrixaban (80 mg/day) for 35 to 42 days, and of 8.5% in 1956 who received subcutaneous enoxaparin (40 mg/day) plus oral placebo.
This gave a nonsignificant relative risk of 0.81 in favour of betrixaban, with a confidence interval of 0.65 to 1.00 and a p value of 0.054.
The researchers, Alexander Cohen (Guy's and St Thomas' Hospitals, London, UK) and colleagues, anticipated the best chance of a significant treatment effect among the highest-risk patients with elevated ᴅ-dimer levels. Because this did not occur, further analyses, although prespecified, were classed as exploratory.
The first of these analyses extended the population to include patients who were aged at least 75 years. Event rates in this cohort were 5.6% in the 2842 patients given betrixaban versus 7.1% in the 2893 given enoxaparin, equating to a significant relative risk of 0.80 (p=0.03).
And in the overall population, which also included patients with neither elevated ᴅ-dimer nor old age, the rates were 5.3% in the 3112 patients given betrixaban versus 7.0% in the 3174 given enoxaparin, again equating to a significant relative risk of 0.76 (p=0.006).
The primary safety endpoint, of major bleeding, was no more common in the betrixaban than enoxaparin groups, at 0.7% versus 0.6% in the overall population, but clinically relevant non-major bleeding was significantly more common, at 2.5% versus 1.0%.
However, Cohen et al say that these safety results set betrixaban apart from other previously tested drugs, which caused significantly increased major bleeding when used for extended thromboprophylaxis. They note that use of preventive treatment "hinges on the safety of the intervention."
The researchers say that their results overall provide "evidence suggesting a benefit for betrixaban."
They comment that the current trend towards shorter hospital stays may lead to patients receiving inadequate duration of thromboprophylaxis and that being able to extend this with oral treatment "would benefit public health."
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N Engl J Med 2016; Advance online publication