EINSTEIN PE: Rivaroxaban Equals Standard Therapy, Halves Major Bleeding

March 26, 2012

March 26, 2012 (Chicago, Illinois) — The new oral anticoagulant rivaroxaban (Xarelto, Bayer) is at least as effective as the standard therapy of injected low-molecular-weight heparin (LMWH) followed by warfarin for the treatment of pulmonary embolism (PE), according to the results of the EINSTEIN PE study reported today at the American College of Cardiology 2012 Scientific Sessions and simultaneously published online in the New England Journal of Medicine [1].

And importantly, there was a "very convincing" 50% lower rate of major bleeding, "particularly in the types of bleeds we hate, which are major intracranial hemorrhage [ICH] and retroperitoneal bleeds," with rivaroxaban compared with the standard treatment, Dr Harry R Büller (Academic Medical Center, Amsterdam, the Netherlands), who presented the findings, told heartwire . One of the patient groups who particularly benefited with regard to major bleeding with rivaroxaban compared with standard therapy was those over 75, he noted.

The standard treatment is subcutaneous injections for five to 10 days with LMWH--which is now done out of the hospital much of the time--and then an oral vitamin-K antagonist, usually warfarin, which requires monitoring and "is cumbersome but very effective," says Büller. "So our primary objective was not to show that rivaroxaban was better, but that it was at least as good, and it was. The risk of getting a recurrence was completely identical between the two groups."

"We want to make life easier," he says, noting that many physicians and patients hate the monitoring that is required with warfarin and similar agents. "Pulmonary embolism is a disease that occurs in all ages, and therefore having a strategy with a pill and no monitoring is, I believe, a small revolution."

Will Rivaroxaban Cut Costs? Only Time Will Tell

EINSTEIN PE was unique in that rivaroxaban was given alone, at a slightly higher dose for the first three weeks, from the beginning of the trial: other studies looking at new anticoagulants in this indication and in venous thromboembolism (VTE) in general have kept the LMWH portion of standard treatment and effectively compared their new agent with warfarin, said Büller: "This is the first program that 'bites the bullet.' The conventional wisdom is that you have to give LMWH."

Pulmonary embolism is a disease that occurs in all ages, and therefore having a strategy with a pill and no monitoring is, I believe, a small revolution.

But he explained that prior pharmacological work with rivaroxaban had illustrated that the twice-daily dosing during the first three weeks would lead to better thrombus resolution. "I think the message is if you don't get enough silencing of the clot in the first two to three weeks, you are going to pay the price in years to come. I think in retrospect that's what we avoided."

In a panel discussion following Büller's presentation, Dr C Michael Gibson (Harvard Medical School, Boston, MA) said the strategy adopted, to alter the dose and dosing of rivaroxaban in EINSTEIN PE, "was very clever." And the 50% reduction in ICH and retroperitoneal bleeds observed was "very impressive." But he wondered about cost-effectiveness.

Büller said hospitalization for PE currently varies hugely in length around the world. In Canada, for example, the mean stay is two days, while in the US it is more in the range of six to seven days and can be longer still in many parts of the world that use unfractionated heparin, which must be given intravenously, rather than LMWH. But there is also a psychological aspect to PE, he added. "With deep vein thrombosis [DVT], people feel very confident that these patients can be treated outside the hospital, but with PE there is an interesting psychology, a little more concern, probably because the clot is closer to the heart."

The hope is that rivaroxaban will prove cost-effective, given that it will likely reduce initial hospitalization time, he said, and taking into account the reduction in major bleeding and associated costs and the fact that it will no longer be necessary for patients to visit outpatient anticoagulant clinics, as they currently do when taking vitamin-K antagonists. "The drug costs are only a minor fraction of the total costs incurred," he noted. A combined cost-effectiveness analysis of EINSTEIN PE and the earlier study of rivaroxaban in DVT, EINSTEIN DVT, is under way, he added.

Dr Patrick O'Gara (Brigham and Women's Hospital, Boston, MA) commented to heartwire : "The potential availability of an oral agent for management of patients with pulmonary emboli is a very important development in patient care. The reality of treating patients who have VTE or arterial embolic disease is that so few of them, or less than ideal numbers of them, spend time in therapeutic range [with vitamin-K antagonists]. We will look forward to additional information about cost; we will look forward to additional information about nonbleeding adverse events with medications of this type; and I think that as postmarketing experience begins to increase, rivaroxaban will find its appropriate place in the armamentarium.

"I don't think you should underestimate the potential value of being able to manage patients like this with oral medications," O'Gara added, "and I could envisage a future where length of stay would drop by more than 50% for patients admitted with this particular disease and no adverse risk factors at time of presentation."

EINSTEIN PE and EINSTEIN DVT Data Are Consistent

In EINSTEIN PE, which was an open-label trial, 4832 patients with acute symptomatic PE with or without DVT were enrolled at 263 sites in 38 countries from 2007 to 2011. Of them, 2419 were assigned to receive rivaroxaban (15 mg twice daily for three weeks, followed by 20 mg once daily) while 2413 had standard therapy (enoxaparin and a vitamin-K antagonist). Approximately 25% of patients in both groups also had DVT.

Treatment was continued for three, six, or 12 months at the discretion of the treating physician; the mean duration of therapy was nine months.

Clinical Outcomes of EINSTEIN PE

Outcome Rivaroxaban (%) Enoxaparin/vitamin-K antagonist (%) Hazard ratio p
Primary efficacy end point: First symptomatic VTE recurrence a 2.1 1.8 1.12 0.003b
Net clinical benefit: VTE plus major bleeding a 3.4 4.0 0.85 0.28
Primary safety outcome: Major or nonmajor clinically relevant bleeding 10.3 11.4 0.90 0.23
Major bleeding 1.1 2.2 0.49 0.0032

a. These were based on the intention-to-treat population of 2419 patients in the rivaroxaban group and 2413 in the standard-therapy group; all other outcomes were based on 2412 patients in the rivaroxaban group and 2405 in the standard-therapy arm.

b. p for noninferiority with a margin of 2.0; p=0.57 for superiority

During the late-breaking trial session, Büller said the efficacy and safety results were consistent irrespective of age, body weight, gender, renal function, and cancer, and there was no evidence for liver toxicity with rivaroxaban.

He also presented a pooled analysis of EINSTEIN PE and EINSTEIN DVT--representing a population of just over 4000 patients taking rivaroxaban compared with 4000 on standard therapy--which resulted in broadly similar outcomes to EINSTEIN PE. The primary end point, first symptomatic VTE recurrence, occurred in 2.1% of patients taking rivaroxaban and 2.3% of those on standard treatment (HR 0.89, p for noninferiority <0.0001), and there was a halving of major bleeding with rivaroxaban as opposed to standard care (HR 0.54; p=0.0018).

The findings show that oral rivaroxaban 15 mg twice daily for three weeks followed by 20 mg once daily "provides patients and clinicians with a simple, single-drug approach for the acute and continued treatment of both DVT and PE with a potential improvement in risk/benefit profile," Büller concluded.

Büller has consulted for, received research support from, and is on scientific advisory boards for Sanofi, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, and Thrombogenics. Disclosures for the coauthors are listed in the paper.

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