EINSTEIN CHOICE: Rivaroxaban Beats Aspirin for VTE Recurrence

March 18, 2017

WASHINGTON, DC (updated with commentary) — In patients with venous thromboembolism (VTE) who had completed 6 to 12 months of anticoagulation therapy but for whom it was uncertain as to whether longer-term treatment was needed, extended therapy with rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) at either 20 mg or 10 mg was more effective than aspirin at preventing recurrent VTE without an increased risk of bleeding in the EINSTEIN CHOICE trial[1].

The trial was presented here today at the American College of Cardiology (ACC) 2017 Scientific Sessions and simultaneously published online in the New England Journal of Medicine.

According to Dr Philip S Wells (University of Ottawa, ON) in his presentation, clinicians could safely prescribe rivaroxaban for prevention of recurrent VTE without concern for increased risk of bleeding.

He explained that patients who have had a VTE are generally treated with an anticoagulant for 6 to 12 months after the event. However, some patients remain at elevated risk for recurrent VTE, as well as MI or stroke, if anticoagulant therapy is stopped.

Previous studies have suggested that extended treatment with an anticoagulant such as warfarin or rivaroxaban reduced risk for a recurrent VTE, while other studies have shown that aspirin also reduced risk for a recurrent VTE and might present a lower risk for bleeding side effects than extended treatment with an anticoagulant. This study was the first to directly compare the safety and effectiveness of rivaroxaban and aspirin in patients at risk for a recurrent VTE, Wells noted.

Commenting on the study for heartwire from Medscape, Dr Gary Raskob (University of Oklahoma Health Sciences Center, Oklahoma City ) said: "EINSTEIN CHOICE is an important advance in the field. It clarifies the role of the direct acting anticoagulants vs aspirin by showing very clearly that if it is felt that extended antithrombotic therapy is needed, a direct acting anticoagulant is better than aspirin."

He added: "It has always been felt that aspirin is safer than the new direct acting anticoagulants, but this trial shows no difference in bleeding. And aspirin is clearly less effective, so we can now dispense completely with aspirin in this situation."

Raskob was an investigator in a previous similar study—AMPLIFY EXT—using a different direct acting anticoagulant—apixaban (Eliquis, Bristol-Myers Squibb/Pfizer).

The EINSTEIN CHOICE trial included 3396 patients who had completed 6 to 12 months of anticoagulant therapy for a VTE. Patients had an average age of 59 years, and 55% were men. They were randomized to receive 10 mg of rivaroxaban, 20 mg of rivaroxaban, or 100 mg of aspirin once daily for up to 12 months.

Results showed that after a median follow-up of 351 days, recurrence of VTE (the primary end point) was significantly lower in both rivaroxaban groups than in the aspirin group. The secondary composite end point of recurrent VTE/MI/ischemic stroke/systemic embolism was also significantly reduced in the rivaroxaban groups.

EINSTEIN CHOICE: Major Efficacy Results

Outcome Rivaroxaban 20 mg (%) Rivaroxaban 10 mg (%) Aspirin (%) HR, rivaroxaban 20 mg vs aspirin HR, rivaroxaban 10 mg vs aspirin
Recurrent VTE 1.5 1.2 4.4 0.34 (0.2–0.59) 0.26 (0.14–0.47)
Recurrent VTE/MI/ischemic stroke/systemic embolism 1.7 1.6 5.0 0.34 (0.20–0.57) 0.32 (0.19–0.54)

There was no significant difference in major bleeding between the three groups, occurring in 0.5% of rivaroxaban 20-mg patients, 0.4% of rivaroxaban 10-mg patients, and 0.3% of those receiving aspirin.

In the paper, Wells and colleagues note that the number of patients who would need to be treated for up to 12 months with rivaroxaban instead of aspirin to prevent one episode of fatal or nonfatal recurrent VTE without increasing the risk of bleeding was 33 with the 20-mg dose and 30 with the 10-mg dose.

Wells and associates write that participants were younger than the typical patient with VTE, so the results may not be generalizable to older patients. Patients who were known to require extended treatment with therapeutic doses of anticoagulation (eg, rivaroxaban 20 mg) were excluded, so it remains unknown whether the 10-mg dose would be sufficient to prevent recurrence in this group. The investigators plan to conduct a follow-up study to examine whether low-dose rivaroxaban is equally effective in other patient populations, he said.

The authors also point out that the treatment was given for up to 12 months, and additional studies are needed to determine whether treatment should be continued for longer than this.

They add that the current study was not powered to show the noninferiority of the 10-mg dose of rivaroxaban to the established 20-g treatment regimen. "so any conclusions with respect to this issue are speculative."

Good Evidence for Long-term Low-Dose Rivaroxaban

In an accompanying editorial[2], Dr Mark A Crowther (McMaster University, Hamilton, ON) and Dr Adam Cuker (University of Pennsylvania, Philadelphia) say that clinicians now have good-quality evidence to support the use of long-term reduced-intensity anticoagulation therapy with rivaroxaban.

The editorialists point out that patients can have provoked or unprovoked VTE. Provoked VTE occurs in a patient with a recent transient risk factor such as surgery, trauma, or significant immobility, whereas unprovoked VTE occurs in a patient with no such transient risk factors or in patients with cancer or risk factors that remain constant.

In EINSTEIN CHOICE, recurrent VTE was reduced with both doses of rivaroxaban vs aspirin inpatients with provoked as well as unprovoked VTE.

They note that with persistent VTE and strong risk factors such as cancer, anticoagulant therapy should be continued indefinitely, and prolonged therapy is now suggested for most patients with unprovoked VTE.

They say that the current results also suggested efficacy of extended therapy with low-dose rivaroxaban in provoked VTE, and they suggest that extending treatment beyond 3 months could now be considered in such patients who are at an average risk for bleeding and who are strongly averse to having another episode of VTE.

They add that for patients who cannot afford the new direct acting oral anticoagulants such as rivaroxaban, adjusted-dose warfarin remains an acceptable alternative for long-term secondary prevention of VTE.

Two Trials Now Support the Use of New Anticoagulants at a Lower Dose

Raskob noted that the AMPLIFY-EXT study, published in 2012, included patients similar to EINSTEIN CHOICE—those who had already been treated for a VTE for 6 to 12 months. They were randomized to placebo or two different doses of apixaban (5 mg or 2.5 mg twice daily) for a further 12 months. Results showed that both doses of apixaban reduced the risk of recurrent VTE but did not increase bleeding compared with placebo.

Raskob commented: "The results of AMPLIFY-EXT and EINSTEIN CHOICE are very consistent. They both show we can reduce the dose of the direct acing anticoagulant for extended treatment without appearing to lose efficacy. We can be confident about using low doses of either apixaban or rivaroxaban for extended VTE treatment. This raises the question of whether we could actually reduce the dose further. There is still a small amount of bleeding with the lower doses, so maybe we could improve this even more."

Asked for how long treatment should be continued, Raskob said this is not known. "There are data showing that when a patient comes off anticoagulant therapy the risk of events increases. Each case needs to be looked at individually—with the cause of the original VTE and bleeding risk of the patient taken into account."

He agreed with Crowther and Cuker that for unprovoked VTE, extended treatment is probably the right course of action for most patients. "How long to continue for is decided on the ongoing risk of recurrent VTE and risk of bleeding, but many patients could be treated for life," he suggested.

For provoked VTE, it has been more common to stop treatment after a few months, but as the safety of anticoagulant treatments has improved, then more patients are becoming candidates for prolonged therapy, Raskob explained.

"While AMPLIFY-EXT included mainly unprovoked VTE patients, EINSTEIN CHOICE included 60% provoked VTE, so it gives us more information on how to treat these patients," he noted.

"Results looked similar in both provoked and unprovoked VTE. In the provoked group, the event rate was 0.9% to 1.4% while the major bleeding rate was 0.3% to 0.5%. So the rate of clot was much higher than the rate of a major bleed. This suggests to me that we can now also consider treating patients with provoked VTE longer term, in discussion with the patient, considering their individual risk factors."

On which agent to use, Raskob said that either rivaroxaban or apixaban would be appropriate, and from the data from both trials he would go for the lower doses. "Although the trials were not powered to show noninferiority of the two doses, I think now that we have similar data from two trials it would not be unreasonable to use the lower dose with confidence, except perhaps in higher-risk patients who might be better with the higher dose."

He added that cancer patients who suffer VTE were not included in the current trials, as they are viewed as a special group with a high risk of recurrent events and for whom the low-molecular heparin is the standard of care.

The study was funded by Bayer. Wells reports grant support and personal fees from Bayer Healthcare, grant support from Bristol-Myers Squibb and Pfizer, and personal fees from Itreas, Janssen Scientific Affairs, and Daiichi Sankyo outside the submitted work. Disclosures for the coauthors are listed on the journal website. Crowther reports grant support, personal fees, and nonfinancial support from Bayer; personal fees from Octapharma, Shinogi, Pfizer, and Alexion; personal fees and nonfinancial support from Portola; grant support from Leo Pharma; and personal fees from legal firms retained by Bayer for expert testimony outside the submitted work. Cuker reports grant support from Bayer/Janssen and is chair of the American Society of Hematology clinical practice guidelines on venous thromboembolism. Raskob serves as a consultant on thrombosis and antithrombotic therapy to Bayer Healthcare, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Janssen, Johnson & Johnson, Merck, Pfizer, and Portola.

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