July-August 2018, Volume 15, Issue 4
Ground-Breaking Trial Shows Aspirin Is As Effective As Rivaroxaban Following Hip and Knee Arthroplasty
Published on: June 19, 2018
Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med. 2018;378:699-707.k96.
Deep vein thrombosis (DVT) and pulmonary embolism (PE) are dreaded complications of hip and knee replacement surgery. Anticoagulants reduce the risk of these events, and current guidelines support their use beyond the duration of hospital stay (10 days for knee surgery, 30 days for hip surgery).1-4 However, more recently, questions have been raised about the applicability of studies performed decades ago and the lesser value placed on anticoagulant-related surgical site bleeding.
These questions, coupled with aspirin’s low cost and toxicity profile, prompted investigators to study this agent in the postoperative setting. Dr. David Anderson and colleagues reported the results of their multicenter, double-blind, randomized noninferiority clinical trial (EPCAT II) comparing extended-duration rivaroxaban (10 mg daily; 9 days for knee arthroplasty, 30 days for hip arthroplasty) with aspirin (81 mg daily) following an initial period of rivaroxaban (10 mg daily) for five days for all patients. Patients who were taking long-term aspirin were allowed to continue the regimen (at a dose less than 100 mg daily), in addition to the study drug. The primary outcome measure was symptomatic venous thromboembolism (VTE) at 90 days, and the primary safety outcome was major and clinically relevant nonmajor bleeding (CRNMB).
A total of 3,424 arthroplasty patients (1,804 hip, 1,620 knee) with a mean age of 62 years and a mean hospital length-of-stay of 3.5 days were enrolled. There was no significant difference in the rate of symptomatic VTE between the aspirin group and the extended rivaroxaban group (0.64% [11/1,707] vs. 0.70% [12/1,717], respectively; difference, 0.06 percentage points; 95% CI, –0.55-0.66]. The combination of major bleeding and CRNMB occurred in 1.29 percent of the aspirin group and 0.99 percent of the extended rivaroxaban group (p=.43). There was only one death — a fatal PE that occurred in the aspirin group 17 days after completion of aspirin prophylaxis. The authors concluded that aspirin was noninferior to rivaroxaban for extended prophylaxis following elective hip or knee arthroplasty after an initial five-day course of rivaroxaban.
For decades, the evidence from clinical trials has supported the view that a minimum of 10 days of anticoagulant therapy following elective hip and knee arthroplasty is required to reduce the risk of postoperative VTE.4 The results of the EPCAT II study seem to contradict that dogma. So, what has changed? The answer: a lot. Surgical technique, postoperative pain control, timing of mobilization, and length of hospital stay have all changed dramatically throughout the years. Furthermore, most older trials used DVT detected on screening venography as a surrogate outcome measure for symptomatic VTE. There are good arguments both for and against this approach5; however, the EPCAT II study avoided it altogether by reporting symptomatic VTE as the primary outcome measure.
Do the results of this ground-breaking trial mean that there is no role for extended duration thromboprophylaxis with anticoagulants following elective joint arthroplasty? No, that is not the case. There are still high-risk groups that were not well represented in the EPCAT II study, including patients with prior VTE, strong family history of VTE, known thrombophilia, morbid obesity, or advanced cancer . However, the results do suggest that a clinical trial comparing aspirin with a direct oral anticoagulant right from postoperative day 1 is the next natural step — an idea that would have thrown thrombosis consultants into revolt less than a decade ago (PEPPER trial comparing aspirin with rivaroxaban and warfarin from postoperative day 1; ClinicalTrials.gov NCT02810704).
Hull RD, Pineo GF, Stein PD, et al. Extended out-of-hospital low-molecular-weight heparin prophylaxis against deep venous thrombosis in patients after elective hip arthroplasty: a systematic review. Ann Intern Med. 2001;135:858-869.
Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358:9-15.
O'Donnell M, Linkins LA, Kearon C, et al. Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low-molecular-weight heparin following elective hip arthroplasty: a systematic review. Arch Intern Med. 2003;163:1362-1366.
Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e278S-e325S.
Segers AE, Prins MH, Lensing AW, et al. Is contrast venography a valid surrogate outcome measure in venous thromboembolism prevention studies?. J Thromb Haemost. 2005;3:1099-1102.
Conflict of Interests
Dr. Linkins indicated no relevant conflicts of interest.
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