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Most patients with cancer-associated deep venous thrombosis (DVT) or pulmonary embolism (PE) in the U.S. are treated indefinitely with subcutaneous injections of low-molecular weight heparin (LMWH), like enoxaparin. LMWH has been shown to be better than warfarin at preventing DVT/PE in cancer patients, with similar rates of bleeding.
A new generation of oral anticoagulants have largely displaced warfarin as first line therapy for treatment and prevention of DVT-PE, and for non-valvular atrial fibrillation. However, the new oral agents, variably called NOACs or DOACs, haven't been well-tested in cancer patients.
In a study published in the New England Journal of Medicine, 1,050 patients with cancer and an acute DVT or PE (symptomatic or incidental) were randomized to receive either a daily injection of dalteparin (a LMWH) or oral edoxaban (a DOAC) for at least six months. The noninferiority trial was unblinded (open label), and the composite outcome was a composite of recurrent venous thromboembolism or serious bleeding at any time in the year following randomization.
There was no significant difference in the primary outcome between groups (~13% each). Numerically fewer DVT-PEs occurred in patients taking edoxaban (~8% vs. ~11%), which did not reach statistical significance. More major bleeding occurred with edoxaban (~7% vs. 4%), which was mostly concentrated in patients with gastrointestinal cancer.
The combination of bleeding with DVT-PE made the composite outcome confusing and not terribly useful clinically, which may have been the intention. From a pharmaceutical company's perspective, a successful noninferiority trial expands professionally acceptable off-label prescribing behavior for already-approved drugs. Combining the efficacy outcome with an adverse event rate would seem to increase the likelihood of finding non-inferiority, and also distills both outcomes into a simple, memorable (though muddled) surrogate for drug equivalence.
After publication of the data, authors of a widely used online expert decision support tool endorsed use of edoxaban as a first-line alternative to LMWH for treatment of DVT-PE in patients with cancer not in the gastrointestinal system.
Another noninferiority trial, CANVAS, will test direct oral anticoagulants rivaroxaban, dabigatran, edoxaban, and apixaban against LMWH among 940 patients with cancer and DVT-PE, according to clinicaltrials.gov.