Canadian investigators went beyond the EPCAT II trial (1) and presented the EPCAT III study at the Congress of the International Society on Thrombosis and Haemostasis (ISTH) 2026 in Paris. The double-blind randomized trial, simultaneously published in the New England Journal of Medicine, compared antithrombotic prophylaxis with aspirin (ASA) alone versus rivaroxaban followed by ASA after hip or knee arthroplasty (2).

The EPCAT III trial

This study enrolled 5,429 patients who were randomized to receive either ASA 85 mg or rivaroxaban 10 mg for 5 days followed by ASA 85 mg (starting on the night after surgery or postoperative day 1, according to the treating surgeon). Aspirin prophylaxis was continued for an additional nine days after knee arthroplasty and for 30 days after hip arthroplasty. Follow‑up lasted 90 days (2).

The 3‑month incidence of symptomatic proximal deep vein thrombosis or symptomatic pulmonary embolism did not differ significantly between the two groups (0.48% in the ASA‑alone group vs 0.45% in the rivaroxaban‑then‑ASA group; risk difference, 0.02 percentage points; 95% CI, −0.34 to 0.39; P<0.001 for non‑inferiority). No significant differences were observed in bleeding outcomes. Major or clinically relevant non‑major bleeding occurred in 1.66% of patients receiving ASA alone and in 2.04% of those receiving rivaroxaban for the first 5 days (risk difference, −0.38 percentage points; 95% CI, −1.11 to 0.34) (2).

It is important to note that patients enrolled in EPCAT III were all at very low risk of thrombotic complications (mean STOP‑VTE score = 1), and mobilization was extremely early, with a mean hospital stay of one day (1.1 ± 3.7 days). Furthermore, the decision to consider only symptomatic thromboembolic events has been criticized by some authors due to the possibility of undiagnosed venous thromboses leading to serious consequences after the study’s follow‑up period.

Commentary

Caution in interpreting these results—and especially in applying them clinically, as current guidelines do not yet incorporate them—is also warranted in light of contrasting findings from the Australian CRISTAL trial, published in 2022. This study was stopped early due to a significantly higher incidence of symptomatic venous thromboembolism in the aspirin‑only group (3.45%) compared with the enoxaparin group (1.82%). The trial failed to demonstrate non‑inferiority of ASA and documented the superiority of enoxaparin (p=0.007) (3).

How can these studies yield such different results? Patient selection based on thrombotic risk—both individual and procedure‑related—plays a central role.

“EPCAT III confirms that the risk of thrombotic complications after elective major orthopedic surgery (hip and knee arthroplasty) is now lower than previously reported, thanks to improved surgical techniques and mobilization beginning on the first postoperative day. As a result, more conservative prophylactic strategies may be appropriate compared with past practice”- stated Walter Ageno, President of the 34th ISTH Congress- “These data may prompt reconsideration of commonly used postoperative prophylaxis strategies, highlighting the need for stratification within these populations to define the appropriate intensity and duration of antithrombotic therapy.”

References
  1. Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. N Engl J Med. 2018;378(8):699‑707.
  2. Shivakumar S, Matino D, Zukor D, et al. Rivaroxaban Then Aspirin vs. Aspirin Alone after Total Hip or Knee Arthroplasty. N Engl J Med. Published online July 12, 2026.
  3. CRISTAL Study Group. Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial. JAMA. 2022;328(8):719–727.

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