Stephan Moll, MD writes… Today, Sept 1st, 2013, the New England Journal of Medicine published the phase 3 clinical trial of edoxaban versus warfarin in the treatment of DVT and PE [ref 1]. It showed that edoxaban was as effective as warfarin and led to less clinically relevant bleeding.
- Edoxaban is one of the new oral anti-Xa anticoagulants.
- At this point it is not FDA approved for any indication.
- It is dosed once daily.
- It reaches its peak anticoagulant plasma activity within 1 to 2 hours of oral intake.
- Its half-life is 9-11 hours.
- 35 % of the drug is cleared by the kidney.
- This is a randomized, double-blind study.
- All patients received initial therapy with open-label enoxaparin or unfractionated heparin for at least 5 days, before edoxaban or warfarin were started.
- Edoxaban was dosed 60 mg once daily. The dose was reduced to 30 mg once daily in patients with a GFR of 30-50 mL/min or a body weight less than 60 kg (132 pounds).
- Length of anticoagulation treatment: 3 to 12 months.
- A total of 8292 patients were randomized (4143 into the edoxaban treatment arm, 4149 into the warfarin arm).
- Recurrent DVT or PE: 3.2 % in the edoxaban group, 3.5 % in the warfarin group. Conclusion: edoxaban is not inferior to warfarin.
- “Clinically relevant bleeding”, which was the primary safety outcome: 8.5 % in the edoxaban group, 10.3 % in the warfarin group. Conclusion: edoxaban is superior.
- “Major bleeding”: same in both groups, 1.4 % in the edoxaban group, 1.6 % in the warfarin group. Conclusion: edoxaban is non-inferior.
- Quality of warfarin control: time in therapeutic range: 63.5 %.
The study concludes that edoxaban (a) is non-inferior to high quality standard therapy, and (b) causes less clinically relevant bleeding.
My perspective – Edoxaban compared to the other new oral anticoagulants
- This table lists the key differences of the 4 new oral anticoagulants in the treatment of VTE.
- Edoxaban is the 4th of the big new oral anticoagulants. Its development lags behind the other 3 drugs, which are, at least for the atrial fibrillation indication, already FDA-approved and on the market. For VTE treatment, only rivaroxaban (Xarelto) is FDA-approved; Xarelto is, therefore, the only one of the new oral anticoagulants I would use for VTE treatment at this time.
- The main downside of the edoxaban study design is that edoxaban was not started right off the bat once the diagnosis of VTE was made in a patient, but that patients were first treated for at least 5 days with low molecular weight heparin LMWH) or i.v. heparin before edoxaban or warfarin were started. This is similar to the dabigatran study design. The rivaroxaban and apixaban studies, on the other hand, gave the new oral anticoagulant immediately after diagnosis, without the need for initial LMWH. Thus, from a clinical-practical point of view, treatment of an acute DT or PE with edoxaban would be more cumbersome (cost of LMWH; teaching of self injections) than treatment with rivaroxaban or apixaban.
- Edoxaban is given once daily. This is more convenient for patients than a twice daily regimen, such as with dabigatran or apixaban.
- It is good to see data of VTE trials on these various drugs published and the drugs making their way through the FDA approval process and, hopefully, eventually onto the market. It is good to see data on a variety of different patients treated with these drugs as there are a number of different patient populations which we need to learn more about as to how they fare on the new oral anticoagulants: patients who are obese, have renal impairment, have cancer, have large PEs, etc. The data published in today’s NEJM are a very helpful addition to our knowledge-base.
- HOKUSAI-Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;Sept 1.
- Agnelli G et al. Oral Apixaban for the Treatment of acute venous thromboembolism. N Engl J Med, 369:799-808.
- The Einstein Investigators: Oral Rivaroxaban for symptomatic venous thromboembolism. New Engl J Med 2010;363:2499-510.
- The Einstein Investigators: Oral Rivaroxaban for the treatment of symptomatic pulmonary embolism. New Engl J Med 2012;366:1287-97.
- Schulman s et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342-52.
Disclosure: I have consulted for Janssen, Boehringer-Ingelheim and Daiichi.
Last updated: Sept 2nd, 2013