ACC: Is rivaroxaban the new EINSTEIN for VTE?
CHICAGO—As more and more anticoagulants continue to seep into research and onto the market as alternatives to warfarin, a late-breaking clinical trial presented March 26 at the 61st annual American College of Cardiology (ACC) scientific session showed rivaroxaban to be noninferior to enoxaparin for patients with venous thromboembolism (VTE). The drug was also shown to result in less intracranial bleeds.

Rivaroxaban is currently the only anticoagulant FDA approved for the prevention of VTE.

The randomized, open-label, non-inferiority EINSTEIN-PE trial enrolled 4,833 patients to receive either rivaroxaban (Xarelto, Janssen Pharmaceuticals) or enoxaparin (combo of either warfarin or acenocoumarol) to evaluate rivaroxaban and its efficacy and safety to prevent VTE or prevent recurrence in patients when compared to standard treatment (enoxaparin).

During the study, 2,419 patients were randomized to rivaroxaban and 2,414 received enoxaparin.

EINSTEIN-PE is part of a series of other trials (EINSTEIN DVT and EINSTEIN Extension) and was conducted at 263 sites in 38 countries. Patients included had a pulmonary embolism and 25 percent in both groups had deep vein thrombosis (DVT).

The previous studies within the EINSTEIN series found that a treatment of a 15 mg twice daily dose of rivaroxaban for three weeks should be followed by a 20 mg once daily rivaroxaban for the subsequent period, said Harry R. Buller, MD, PhD, professor of vascular medicine at the Academic Medical Center, Amsterdam, Tte Netherlands, during a morning session.

Patients in the study were treated for three, six or 12 months.

Using molecular weight heparin therapy for VTE is “actually very, very effective,” said Buller. “So what we are looking for is a regimen, a treatment regimen, that is at least as good as low molecular weight heparin.”

Buller et al used an enoxaparin bid for at least five days as the comparator arm. Other patients, all with PE with or without DVT, received 15 mg of rivaroxaban at day one for three weeks, followed by a 20 mg dose of the drug at 21 days.

The researchers used the recurrence of a first episode of VTE as the study’s primary end point, but also looked at major or non-major clinically relevant bleeding events.

“Pulmonary embolism is a disease that occurs at a mean age of 58 years old,” Buller said. Additionally, the majority of patients were treated for six to 12 months, and 24 percent of the patient population had “extensive” PE.

“Twenty percent of patients in both groups had concomitant symptomatic objectively confirmed DVT,” said Buller. “This number is high when compared to other studies where it is around 10 percent.”

The researchers found that a first symptomatic recurrent VTE event occurred in 2.1 percent of patients in the rivaroxaban group compared with 1.8 percent of patients in the enoxaparin arm. Bleeding occurred in 10.3 percent of patients in the rivaroxaban arm compared with 11.4 percent of patients in the enoxaparin arm. These rates for major bleeds were 1.1 percent and 2.1 percent, respectively.

In terms of major bleeding, Buller said, “If you look at the curves they start to separate very early in the course of the treatment suggesting that the combo  (Vitamin K/warfarin)  within the first five to10 days is something we need to pay attention to.”

The researchers also found that total mortality rates were 2.4 percent in the rivaroxaban group vs. 2.1 percent in the enoxaparin arm.

“Where does the difference in these major bleedings occur?” asked Buller. To find out, he and colleagues conducted a subgroup analysis. “Is it body weight where the difference is coming from?” he asked.  Actually, the researchers found that this difference was attributed to the older population over the age of 75. The principle safety end point was shown to be consistent in all groups.

“The EINSTEIN pulmonary embolism study set out to show noninferiority and observed noninferiority,” Buller said. “There is a similar finding when you combine principal safety. There is superiority for major bleeding, there is consistency in the defined subgroups and there is no evidence for liver toxicity,” Buller summed.

“This regimen provides patients and clinicians with a simple, single drug approach for acute management of DVT," he said.

Panelist C. Michael Gibson, MD, of Beth Israel Deaconess Medical Center in Boston, called Buller et al’s strategy to switch to the lower dose of rivaroxaban after giving high doses and altering the dosing strategy during the trial clever.

“There is bleeding and there is bleeding. There is major bleeding and there is major bleeding,” said Gibson. “Major bleeding includes ICH [intracranial hemorrhage]. It includes fatal bleeding. Did you find a reduction in major bleeding for ICH?”

Buller noted that only once intracranial hemorrhage occurred in the rivaroxaban arm compared with 10 events in the comparator arm.

“This is a once-a-day drug. It's one drug, not two drugs … and then you have this reduction in bleeding and bleeds can cost up to $1,000 per episode,” Gibson said, when describing the clinical implications of the findings.

Buller said that future studies will look at the cost effectiveness of this strategy in terms of bleeds. “We now pay attention that these bleeds cause morbidity, cause costs and cause people to stop the drugs,” Buller said.