Prof. Stavros V. Konstantinides
Prof. Harry Buller
By Harry BullerAcademic Medical Centre, Amsterdam, the NetherlandsBackground:Acute venous thromboembolism (VTE) requires therapy that is rapidly effective, well tolerated with a long lasting effect. Edoxaban is the newest oral Factor Xa inhibitor, with once daily (OD) dosing. Methods:Hokusai VTE is a randomized, double-blind trial in acute, symptomatic VTE patients which evaluates the effects of edoxaban 60 mg OD compared to warfarin (target INR of 2-3) following an initial course of heparin on the recurrence of symptomatic VTE. Eligible patients were stratified by presenting diagnosis (PE vs. DVT), baseline risk factors (temporary VTE risk factors only vs. all others), and edoxaban dose adjustment (low body weight, lower creatinine clearance and/or use of strong P-gp inhibitors). The study design allowed flexible treatment duration of 3, 6 or 12 months to reflect usual clinical practice. Nevertheless all patients were followed up for 12 months. The primary efficacy outcome was the composite of symptomatic recurrent DVT, non-fatal and fatal PE. The principal safety outcome was clinically relevant bleeding (major or clinically relevant non-major bleeding). A blinded committee adjudicated all suspected efficacy and safety outcome events. Primary analysis will be based on the modified Intention-To -Treat population for time to the first event using a Cox’s proportional hazard model. Additional analyses will evaluate the impact of treatment duration (3, 6 or 12 months), index event (DVT or PE) and PE severity. Results:From January 2010 to September 2012, a total of 8292 patients were randomized in 39 countries at 453 clinical sites. The baseline characteristics and risk factors of the study population are comparable to earlier published studies. Median exposure was approximately 7 months, last follow-up visits occurred in April 2013; Already 230 primary outcome events have been accrued, ensuring adequate power to test the study hypothesis. Database lock is planned for June 2013 with final data to be presented. Conclusions: The Hokusai VTE Study results will address the efficacy, safety and tolerability of edoxaban relative to those of warfarin for the treatment and long term prophylaxis of recurrent VTE in patients with acute, symptomatic VTE.
Stavros V. Konstantinides, MDCentre for Thrombosis and HaemostasisUniversity of Mainz Medical Centre55131 Mainz, GermanyHOKUSAI-VTE is the most recent of the megatrials which compared a total of four new oral anticoagulants (NOACs) with standard treatment in patients with acute symptomatic venous thromboembolism (VTE). The first agent to be tested was the thrombin inhibitor dabigatran in the RECOVER trial four years ago (1), followed by two factor Xa inhibitors: rivaroxaban in EINSTEIN-DVT (2) and EINSTEIN-PE (3), and, most recently, apixaban in the AMPLIFY study (4). HOKUSAI-VTE is the largest of all these trials, having randomised a total of 8240 patients. Its results can be summarised as follows:1) following initial heparin anticoagulation, edoxaban was non-inferior to warfarin in preventing symptomatic or fatal recurrent VTE;2) non-inferiority for efficacy was established both throughout the 12-month follow-up study period and during the variable on-treatment period;3) edoxaban was superior to the vitamin K antagonist (VKA) warfarin with regard to the composite primary safety outcome of major or clinically relevant non-major bleeding during the on-treatment period;4) the efficacy and safety of edoxaban were similar in patients receiving the full dose (60 mg once daily) and the reduced dose (30 mg once daily) of edoxaban, the latter being given to patients with body weight <60 kg or reduced creatinine clearance (CrCl ≥30 and ≤50 ml/min);5) the efficacy of edoxaban appeared to be superior to that of warfarin in the prespecified subpopulation of patients with “severe” PE.Although HOKUSAI-VTE largely shares most of the inclusion/exclusion criteria and the outcome definitions with the other NOAC trials in VTE, some unique characteristics of its design and patient population deserve particular attention: 1) this was the only study in which a flexible (between 3 and 12 months) duration of anticoagulation was permitted in order to simulate “real-life” conditions;2) all patients, regardless of the actual treatment duration, were followed for 12 months (much longer than in most of the other trials) and included in the (modified) ITT analysis;3) the time in therapeutic range (TTR) in the warfarin arm was centrally tracked for each participating centre and feedback was provided to the investigators in a blinded manner to ensure high quality of warfarin treatment; and4) this was the first study to explicitly use imaging and biomarker tools to risk stratify the patients with acute PE and also test the efficacy of edoxaban in the prespecified subgroup of “severe” PE.How are the results of HOKUSAI-VTE to be interpreted and put into perspective in comparison to those of RECOVER, EINSTEIN, and AMPLIFY? With regard to efficacy, all NOACs are non-inferior (but also non-superior) to standard treatment consisting of low molecular weight heparin followed by VKA. They are also non-inferior, and probably superior, to conventional treatment in terms of safety (bleeding complications), with apixaban having shown the best safety profile so far. Unlike rivaroxaban or apixaban (but similar to dabigatran), edoxaban was not given as single oral drug from the beginning but followed “conventional” initial parenteral (subcutaneous or intravenous) heparin treatment.This regimen may be less handy in patients with DVT or “non-severe” PE, especially if immediate or early discharge and outpatient treatment is considered. On the other hand, trials on home treatment of DVT or PE have also successfully applied the switching from heparin to VKA treatment in the past. Moreover, physicians having concerns about administering a new drug to their patients right away, in the first critical hours, may feel comfortable to start with low molecular weight heparin, and then switch to the NOAC as soon as the situation is fully under control. This may particularly be the case if the physician is not certain about the patient’s haemodynamic stability during the first hours or days after admission.HOKUSAI-VTE concludes the megatrial programme on the treatment of acute VTE with NOACs. Overall, more than 27 000 patients have been included, almost 14 times as many as those included in the low molecular weight heparin trials 15 years ago. The trials were successful, and these drugs have passed the first test of efficacy and safety. The second tough test, that of their value in “real life” and their testing in specific clinical settings, has just begun for the approved agent rivaroxaban, and will probably begin in a few months for the other three agents as well, since their approval is also anticipated. Besides confirming their efficacy and safety under everyday conditions, the NOACs will have to justify their (very high) cost by showing, in focused cohort studies and management trials, an improvement in the patients’ treatment satisfaction and quality of life and, hopefully, a parallel reduction in health care costs related to shorter durations of hospital stay and a lower number of rehospitalisations for major beeding complications.
1 - Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361(24):2342-2352.2 - Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363(26):2499-2510.3 - Buller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366(14):1287-1297.4 - Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med 2013.
Session Title: Treatment of venous thromboembolism, the Hokusai VTE study - 706
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