PRONOMOS: Rivaroxaban Bests Enoxaparin for VTE Prophylaxis

Susan Jeffrey

March 29, 2020

Rivaroxaban (Xarelto, Bayer/Janssen) was superior to enoxaparin in preventing venous thromboembolism (VTE) in patients immobilized by nonmajor orthopedic surgical procedures, in a new randomized trial.

Results showed a significantly lower risk for VTE events, including deep venous thrombosis and pulmonary embolism, among patients receiving oral rivaroxaban vs those receiving subcutaneous treatment with enoxaparin, without an increase in major or minor bleeding.

In this young population with a moderate risk for VTE after orthopedic surgery and who require immobilization for at least 2 weeks, "rivaroxaban should replace low-molecular-weight heparin in this case," said Nadia Rosencher, MD, from the Department of Anesthesia and Critical Care, Groupe Hospitalo-Universitaire Assistance Publique-Hospitaux de Paris Centre, Universite de Paris, Hopital Cochin, Paris, France.

Results from the Prophylaxis in Nonmajor Orthopedic Surgery (PRONOMOS) trial were presented during the virtual late breaker sessions of the American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC) and published online March 29 in the New England Journal of Medicine.

This was designed to be a noninferiority trial, but the results showing superiority were "very striking," lead author C. Marc Samama, MD, from the same institution, said in an interview.

They had actually anticipated more bleeding in the rivaroxaban group, but the increase didn't materialize, he told theheart.org | Medscape Cardiology. The only limitation is that because this population was young, with a median age of 41 years, it's not clear that the results can be generalized to older patients, Samama noted.

"So it is a major step forward for DOACs [direct oral anticoagulants], and we have the power to say that," he said.

"Wild West"

Commenting on the results, Gregory Piazza, MD, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, congratulated the investigators for a "wonderful study" and "having the foresight to study this area."

"Briefly," he explained, "this is a group of patients that clinically we recognize to have a high risk of venous thromboembolism but have never received the attention that total hip and total knee replacement have, at least in the prophylaxis literature."

"So this was a very important study and I think will be one of the most important steps in breaking up some of the heterogeneity in how we treat patients who are undergoing nontotal hip and nontotal knee surgery," Piazza said.

"Right now, there's a wide spread on how these patients are treated. Some receive no prophylaxis based on some of the guideline recommendations, others receive aspirin, warfarin, some receive DOACs, some receive injectable," he added. "But 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."

In their report, the researchers allude to this heterogeneity in practice. In the United States, for example, routine nonpharmacologic and pharmacologic prophylaxis is not required "because the U.S. guidelines assert that the risk of venous thromboembolism after such surgery is low," they write.  

"European guidelines, however, recommend a personalized strategy of prophylaxis with low-molecular-weight heparin in patients who have one or more risk factors and whose risk of a thrombotic event exceeds that of a bleeding event," the authors write. "Consequently, thromboprophylaxis after nonmajor orthopedic surgery remains a standard of care in many European countries."

Rivaroxaban replaced enoxaparin for VTE prophylaxis in total hip and knee replacements after it was shown to lower the risk for symptomatic VTE and death from any cause in those settings. The current trial then aimed to look at this oral anticoagulant in the setting of nonmajor orthopedic surgery.

The PRONOMOS trial included 3604 patients who were undergoing nonmajor orthopedic surgery of the lower limbs, including such procedures as Achilles tendon repair, knee surgery, tibial or ankle fractures, and any other procedures necessitating thromboprophylaxis for more than 2 weeks, but excluding knee and hip replacements, or hip fracture surgery where anticoagulation is recommended by clinical guidelines.

Patients were randomly assigned to receive 10 mg of rivaroxaban and a subcutaneous placebo injection (n = 1809), or an injection of enoxaparin in a dose of 40 mg (4000 IU of anti–factor Xa activity) in 0.4 mL of diluent and an oral placebo (n = 1795), both given once daily.

Randomization was stratified by center and by the intended treatment duration — 2 to 4 weeks, 4 to 8 weeks, and more than 8 weeks — based on physician assessment of individual risk and the planned duration of immobilization, which is affected by factors such as whether the patient has a plaster cast or a weight-bearing recommendation.   

The primary endpoint of major VTE was a composite of symptomatic distal or proximal deep venous thrombosis, pulmonary embolism, or VTE-related death during the treatment period, or asymptomatic proximal deep venous thrombosis at the end of treatment.

If rivaroxaban proved to be noninferior to enoxaparin, the researchers planned a test for superiority, they note. Multiple imputation was done at the end of the study to account for missing data, Rosencher said.

Between September 2015 and April 2018, 3604 patients underwent randomization at 200 sites in 10 countries.

However, slower than expected recruitment led to reaching the expiration dates of the study drugs, with "prohibitively high replacement costs." The steering committee and sponsor, "unaware of any study result — I insist, unaware — decided to stop the recruitment," in April 2018, Rosencher said.  

Results showed that major VTE event occurred in 4 of 1661 patients (0.2%) on rivaroxaban, and 18 of 1640 patients (1.1%) on enoxaparin (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 - 0.75; P < .001 for noninferiority, P = .01 for superiority).

The incidence of bleeding did not differ between the groups, the authors note. Major bleeding, defined as fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention, or nonmajor clinically relevant bleeding, was seen in 1.1% of rivaroxaban recipients and 1.0% of enoxaparin recipients.

Major bleeding occurred in 0.6% and 0.7% of rivaroxaban and enoxaparin recipients, respectively.

"Thus, the net clinical benefit is in favor of rivaroxaban, with a risk ratio of 0.48," Rosencher said.

After the presentation, Piazza asked about the choice of enoxaparin for this study. "The reason I ask is that is that enoxaparin is not used that frequently outside of the EU [European Union] for prophylaxis."

The researchers pointed to two reasons: that the dose of 4000 IU is proven to be effective and  that enoxaparin is widely used in Europe for such patients.   

Piazza further wondered how to get the message to the orthopedic surgeons.

"One of the challenges in the orthopedic surgery population is reluctance on the surgeons' parts to provide anticoagulation because of the risk of hemarthrosis and other surgical bleeding complications," he said. "How do we — and this is more of a theoretical question — but 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 literature have not been able to do so?"

Rosencher pointed out that the first dose of prophylaxis is not usually given until 6 to 10 hours after surgery after hemostasis is established, and even the next morning after surgery if it could not be given before 10 pm. "So we have a long time between the end of surgery and the first anticoagulant."

Another commenter, Craig J. Beavers, PharmD, University of Kentucky College of Pharmacy, Lexington, agreed with the characterization of geographic variation in how VTE prophylaxis is approached as the "Wild West" and called this an important study.

He asked about adherence to the subcutaneous injections of enoxaparin vs the oral treatment with rivaroxaban. Samama noted that a very small number, and roughly the same number of patients in each group, withdrew from the study, "but as we have been using the multiple imputation statistical method, it still shows a huge benefit for rivaroxaban."

The study was supported by the Centre Hospitalier Universitaire de Saint-Etienne and Bayer. Rosencher and Samama report personal fees from PSN Research (a contract research organization) during the conduct of the study. Piazza reports consultant fees/honoraria from Optum, Pfizer, Thrombolex; serving on a data safety and monitoring board for Syntactx; and research/research grants from Bayer, BMS, Daiichi, EKOS, Janssen Pharmaceuticals, and Portola. Beavers reports nothing to disclose.

American College of Cardiology 2020 Scientific Session (ACC.20)/World Congress of Cardiology (WCC). Abstract 406-11. Presented March 30, 2020.

N Engl J Med. Published online March 29, 2020. Abstract  

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