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EINSTEIN DVT: Oral rivaroxaban versus standard therapy in the initial treatment of symptomatic deep vein thrombosis and long-term prevention of recurrent venous thromboembolism

Venous Thromboembolism




Harry Buller
  Presenter
Presenter | see Discussant report | read press release
Buller, Harry
(Netherlands)

List of Authors:

Abstract:


Background: Standard therapy for venous thromboembolism is low molecular weight heparin, followed by a vitamin K antagonist. In two dose-ranging studies of patients with symptomatic deep vein thrombosis, rivaroxaban, a direct oral factor Xa inhibitor, had efficacy and safety profiles similar to those of standard therapy. We investigated the potential use of rivaroxaban, as a replacement for standard therapy in a large and representative series of patients with deep vein thrombosis.

Methods: Rivaroxaban was compared with standard therapy in a randomized, open-label, assessor-blind, non-inferiority study involving over 3400 patients with acute symptomatic proximal deep-vein thrombosis, but without concomitant symptomatic pulmonary embolism.
Patients received either oral rivaroxaban (an intensified course of 15 mg bid for the first 3 weeks followed by 20 mg od) or bodyweight-adjusted enoxaparin (1 mg/kg bid) followed by a vitamin K antagonist (warfarin or acenocoumarol), dose adjusted to maintain a therapeutic INR (target 2.5, range 2.0-3.0) for 3, 6 or 12 months, based on the physician’s assessment at baseline. All patients assigned to rivaroxaban received a fixed dose, including those with moderate renal dysfunction (CrCl 30-50 ml/min) and high or low bodyweights.
The primary efficacy outcome was the cumulative incidence of symptomatic recurrent venous thromboembolism (non-fatal or fatal). The principal safety outcome was the composite of major and clinically relevant non-major bleeding. The study was event-driven requiring a minimum of 88 confirmed recurrent events to demonstrate non-inferiority. All outcomes were adjudicated by an independent committee blinded to treatment assignment.
The study’s aim was to include a consecutive series of patients to optimize generalizability and allow standard therapy to be administered and monitored in the local setting. Several measures were implemented to guarantee similar scrutiny for follow-up and outcome assessments.

Results: Over 3400 patients were randomized between February 2007 and August 2009 by 253 study sites in 32 countries. Maximum treatment duration was 6 months for the last randomized patients. The target of 88 events was achieved and closure of the database is expected in June 2010. Patients’ characteristics were typical for an unselected series of patients with deep vein thrombosis and comparable with contemporary studies. Final results will be presented.

Conclusions: If the Einstein-DVT study meets its goal to demonstrate non-inferiority, the single-drug approach with rivaroxaban will provide clinicians and patients with an attractive, simple, alternative regimen for the initial treatment of deep vein thrombosis as well as the long-term secondary prevention of recurrent venous thromboembolism.


Harald Darius
  Discussant
Discussant | see Presenter abstract Webcasts become available 24h after the session
Darius, Harald
(Germany)
Open presentation slides

Report:

Oral factor Xa antagonists and direct thrombin inhibitors represent a new generation of antithrombotic drugs being tested for several clinical indications requiring continued anticoagulation. In the EINSTEIN DVT study rivaroxaban, an oral factor Xa antagonist was tested in 3449 patient with acute venous thrombosis and compared to treatment with LMWH followed by vitamin K antagonist with a target INR range 2-3. The primary efficacy endpoint - First symptomatic recurrent venous thromboembolism (VTE) – showed no significant difference for the two treatment regimens albeit a clear trend in favor of rivaroxaban and a significant improved net benefit adding recurrent VTE and major bleeding complications. There were no significant differences with regard to major bleedings or clinically relevant minor bleedings.

Although the study seemed well planned and performed a number of questions remain unanswered. The duration of treatment was individualized between 6 and 12 months. Is there an identical efficacy for rivaroxaban for the early and late treatment after DVT? Is the quality of anticoagulation with vitamin K antagonists shown by INR measurements being only 57.7% within the target range (INR2-3) sufficient to accept the non-inferiority of rivaroxaban and the positive trend in favor of rivaroxaban for secondary efficacy endpoints? Is the initial treatment with subcutaneous injections of LMWH or fondaparinux in the rivaroxaban group necessary? For reasons of clinical convenience and patient’s compliance physicians would like to initiate and continue the patient on the same drug and mode of administration. How do the results of EINSTEIN DVT compare to other trials testing alternative innovative anticoagulation strategies e.g. direct thrombin inhibitors or other factor Xa antagonists ?

Despite of these multiple questions still being unanswered the author firmly believes that a new era of anticoagulation therapies is approaching for a number of clinical indications which will benefit the patients suffering from thromboembolic disease.

References


708007 - 708008

SessionTitle:

Hot Line III - Cardiovascular disease and rhythm disturbances
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.