“I do not like to state an opinion on a matter unless I know the precise facts.”
– Albert Einstein, quoted in The New York Times, August 12, 1945.
Well, Professor, the facts are these: Venous thromboembolism (VTE) is a common and potentially fatal problem. Once clinicians have overcome the hurdle of accurate diagnosis and acute treatment, they’re often faced with a cumbersome transition from parenteral heparin to oral vitamin K antagonists. What’s more, the ideal duration of anticoagulation remains uncertain. Is there something that might make this whole mess simpler?
The EINSTEIN Investigators think so. Bauersachs and colleagues report on two trials examining the use of the oral factor Xa inhibitor rivaroxaban in the treatment of symptomatic venous thromboembolism.
The EINSTEIN-DVT study is an open-label non-inferiority study that randomized 3449 patients with objectively demonstrated symptomatic deep venous thrombosis (DVT) either to oral rivaroxaban or to a sequence of initial subcutaneous enoxaparin followed by vitamin K antagonist. Treatment duration was determined by the treating physician, and had to be between 3 and 12 months. Rivaroxaban was non-inferior to the enoxaparin-vitamin K antagonist sequence for the primary efficacy outcome of recurrent venous thromboembolism (36 events [2.1%] vs. 51 events [3.0%]; HR 0.68, 95%CI 0.44-1.04; p<0.001 for non-inferiority). When it came to the principal safety outcome, the two treatments had equivalent rates of composite major and clinically-relevant non-major bleeding (8.1% in both groups).
The EINSTEIN-Extension study is a double-blind superiority study in which enrolled patients had already completed 6 to 12 months of anticoagulation for VTE, but for whom there was clinical equipoise about the need to extend the duration of anticoagulation beyond this initial course of therapy. In all, 1196 such patients were randomized to oral rivaroxaban or placebo for 6 to 12 months after enrollment (this duration of extension was again determined by the treating physician). In an analysis stratified for pre-enrollment treatment duration, rivaroxaban had superior efficacy when compared to placebo (8 events [1.3%] vs. 42 events [7.1%]; HR 0.18, 95%CI 0.09 to 0.39, p<0.001 for superiority), with no significant increase in major bleeding (0.7% vs. none, p=0.11).
Oral, fixed-dose anticoagulants that don’t require ongoing laboratory monitoring have long been a goal of pharmaceutical innovation, and they’ve recently been the source of other encouraging results: NEJM recently published the RE-COVER Study, a double-blind, double-dummy, randomized trial of dabigatran, an orally-available direct thrombin inhibitor that can be administered in fixed dose. Other orally administered direct thrombin inhibitors (such as the as-yet-unnamed AZD0837) and oral factor Xa inhibitors (such as apixaban, betrixaban, TAK-442, and edoxaban) star in recently completed or ongoing trials examining thromboembolic stroke prevention in atrial fibrillation and the prevention and treatment of venous thromboembolism. Is anticoagulation about to enter an era of simplicity and convenience?
“The encouraging results of recent oral anticoagulant trials have given patients requiring anticoagulation a reason to hope their treatment might become simpler in the near future,” says NEJM executive editor Dr. Greg Curfman. “However, it’s important to remember that many of them, including the EINSTEIN-DVT study, are designed as non-inferiority trials. That means that in many cases, they haven’t been demonstrated to be superior in terms of efficacy. Will their higher costs be worth the increase in convenience and difference in adverse event rates? Will novel adverse effects emerge as more trials are completed? How should these new agents be used in patients with mild hepatic and renal dysfunction?”
That’s one thing with which the late Professor Einstein would almost certainly agree: “The important thing is to not stop questioning.”