AMSTERDAM – The growing role for the new factor Xa inhibitors in treating acute venous thromboembolism received another boost with the performance of a new drug from the class, edoxaban, in a pivotal, randomized, international trial with more than 8,000 patients.
Edoxaban showed noninferior efficacy and superior safety compared with the standard treatment, warfarin, during 12 months of follow-up, performance that closely matched prior results for the first two direct factor Xa inhibitors that were tested for treating venous thromboembolism (VTE), rivaroxaban (Xarelto) and apixaban (Eliquis). The edoxaban trial also showed an important new feature for drugs in this class, a statistically significant benefit compared with warfarin in the roughly one-third of enrolled patients with a severe pulmonary embolism causing right ventricular dysfunction.
"The most interesting observation is that the third of patients [with pulmonary embolism and] with right ventricular dysfunction were better off with edoxaban," Dr. Harry R. Büller said at the European Society of Cardiology Congress 2013.
"A criticism raised with [the pivotal rivaroxaban and apixaban trials treating acute VTE] was that the investigators were reluctant not to use low molecular weight heparin in the patients with large clots. In that group we’ve made a novel observation" in this prespecified subgroup analysis, said Dr. Büller, professor and chairman of vascular medicine at the Academic Medical Center in Amsterdam.
Dr. Harry Büller
Investigators in the edoxaban trial may have been more willing to enroll their severely ill VTE patients because the treatment regimens compared began all patients with at least 5 days of treatment with either enoxaparin or unfractionated heparin. Intravenous treatment stopped after about a week and then continued with either oral warfarin or edoxaban. This treatment strategy contrasted with the prior rivaroxaban (EINSTEIN, N. Engl. J. Med. 2012;366:1287-97 and apixaban (AMPLIFY, N. Engl. J. Med. 2013;369:799-808) pivotal studies that began acute VTE patients on the oral drugs from the start of treatment. In the edoxaban study, participating physicians enrolled "the full spectrum of VTE patients," Dr. Büller said.
Physicians "feel comfortable intervening with heparin in these patients because you have quick, intravenous treatment with an anticoagulant," commented Dr. William A. Zoghbi, professor of medicine and director of the Cardiovascular Imaging Institute at the Debakey Heart and Vascular Center at Methodist Hospital in Houston. The results showing superior efficacy of edoxaban over warfarin in the most severely affected pulmonary embolism patients "makes you more confident that in the higher-risk patients edoxaban was not only not inferior but may even have an advantage," Dr. Zoghbi said in an interview.
The Hokusai-VTE trial randomized 4,921 patients with deep-vein thrombosis and 3,319 patients with pulmonary embolism at 439 centers in 37 countries during January 2010–October 2012. Patients averaged 56 years of age, a bit more than half were men, and they received heparin for a median of 7 days.
After 1 year, the primary efficacy endpoint of recurrent VTE in all patients occurred in 3.2% of the 4,118 patients randomized to received edoxaban and in 3.5% of the 4,122 randomized to receive warfarin, results that meet the study’s criterion for noninferiority.
Among the prespecified subgroup of pulmonary embolism patients with a larger clot and inferred right-ventricular dysfunction – based on both the anatomic size of their clot and on their blood level of N-terminal pro-brain natriuretic peptide – the rate of recurrent VTE during follow-up was 3.3% in the edoxaban group and 6.2% in the warfarin group, a statistically significant difference.
The study’s primary safety outcome was the rate of clinically relevant major or nonmajor bleeds, which occurred in 8.5% of the edoxaban patients and in 10.3% of the warfarin patients, for a relative hazard reduction of 19% by edoxaban that was statistically significant for superiority, reported Dr. Büller. Concurrent with his talk at the meeting a report of the trial results was published online (N. Engl. J. Med. 2013;doi:10.1056NEJMoa1306638).
The safety data also showed that the edoxaban-treated patients had a total of 5 intracranial or retroperitoneal bleeds, compared with 22 in the patients treated with warfarin, a difference that Dr. Büller said he believed was real and due to the effect of warfarin on clotting factor VII, and is something that has also been seen in the trials testing the other new factor Xa inhibitors.
The Hokusai-VTE study is unique among the trials of oral factor Xa inhibitors by being the only study that allowed for a flexible duration of anticoagulation treatment, followed all patients for 12 months, and used imaging and biomarkers to risk-stratify patients to prove efficacy in patients with severe pulmonary embolism, commented Dr. Stavros V. Konstantinides, professor and deputy scientific director of the Center for Thrombosis and Haemostasis of Johannes Gutenberg University in Mainz, Germany.