Xarelto Slashes VTE After Nonmajor Orthopedic Surgery

Rivaroxaban (Xarelto) beat low molecular weight heparin for venous thromboembolic prophylaxis after nonmajor lower limb orthopedic surgery, the PRONOMOS trial showed.

The direct oral anticoagulant slashed major venous thromboembolic events by a relative 75% compared with enoxaparin (Lovenox), albeit with a small absolute reduction to 0.2% versus 1.1% (P=0.01), reported Nadia Rosencher, MD, of Hôpital Cochin in Paris, at the virtual American College of Cardiology (ACC) meeting and online in the New England Journal of Medicine.

Bleeding was similar between groups, both for major bleeding or nonmajor clinically relevant bleeding (1.1% vs 1.0%) and major bleeding alone (0.6% vs 0.7%) in this fairly young, largely healthy group of patients who needed at least 2 weeks of immobilization due to knee ligament repair, lower limb fracture, or other event aside from total knee or hip replacement.

“This is a group of patients that clinically we recognize to have a high risk of venous thromboembolism but never gotten the attention that total knee and total hip replacement have, at least in the prophylaxis literature,” said ACC session discussant Gregory Piazza, MD, of Brigham and Women’s Hospital in Boston.

“The findings are extremely important in that they not only speak to the importance of using prophylaxis, but they speak to a direct oral anticoagulant strategy,” he told the virtual audience.

Sahil Parikh, MD, of NewYork-Presbyterian Hospital in New York City agreed on the “finite but quantifiable risk.” However, he cautioned that with such a small absolute risk reduction, the number needed to treat to prevent an event would be about 110.

“Certainly from a value proposition standpoint, being able to select the highest risk patients will be important,” he said at a virtual press conference for the late-breaking ACC clinical trial session. “In my practice going forward, we will try to better risk stratify these patients and particularly those with either prolonged immobilization or additional risk factors.”

Piazza suggested that this trial could be a key step to reigning in the wide range in practice patterns.

“It’s the Wild West almost when it comes to prophylaxis for these patients, and I think there will be some clarity after this study,” he said.

The American College of Chest Physicians gave prophylaxis a grade “2C,” suggesting it’s not needed in patients with isolated lower-leg injuries and leg immobilization. Other national or international guidelines encourage the use of prophylaxis with low molecular weight heparin, as is commonly the case in France.

“We all face this issue in hospitalized patients,” noted Mitchell Elkind, MD, MPhil, of NewYork-Presbyterian/Columbia University Medical Center in New York City and president-elect of the American Heart Association. “It’s a general problem, but every patient population is different for various reason. This question of how to prevent venous thromboembolism comes up over and over again but it requires separate trials in each population.”

However, “one of challenges in the orthopedic surgery patient population is reluctance on the surgeons’ part to provide anticoagulation because of the risk of hemarthrosis and other surgical bleeding complications,” Piazza said. “How do we get this information in the hands of the surgeons and have them use it appropriately when many other studies in the total hip and total knee replacement surgery literature have not been able to?”

Rosencher noted that the trial waited to dose rivaroxaban at least 6 hours after surgery, or until the next morning if that time fell during the night.

It included a total of 3,604 adults (median age 41) getting lower-limb nonmajor orthopedic surgery at 17 centers in Europe who were planned to receive thromboprophylaxis for at least 2 weeks due to the investigator’s judgment of being at risk for venous thromboembolism.

They were randomized double blind to either 10 mg daily of rivaroxaban or 4,000 IU subcutaneous enoxaparin daily, along with matching placebo for both groups. Randomization was stratified by expected duration of immobilization.

At the end of immobilization, all but 8% of the patients got ultrasound screening for only proximal deep vein thrombosis (DVT).

Major venous thromboembolic events encompassed four rivaroxaban-group cases (0.2% of 1,661) of symptomatic distal or proximal DVT, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal DVT at the end of treatment and 18 cases (1.1% of 1,640) in the enoxaparin group.

Enrollment was stopped early due to slow enrollment, leading to some of the study drug reaching expiration dates, with prohibitive cost to replace it. While that might have limited the precision of the trial in estimating efficacy, the researchers noted that results remained blinded at the time that the decision was made, and that the observed treatment effect was more pronounced than expected.

Last Updated March 29, 2020