NIHR Signal Aspirin may be a follow-on option to prevent blood clots, starting five days after hip or knee surgery

Published on 5 June 2018

In a recent trial, switching to low-dose aspirin was just as effective at preventing blood clots after joint replacement surgery as continuing the anti-clotting drug rivaroxaban. Six per 1,000 people taking aspirin experienced a blood clot, compared with seven per 1,000 taking rivaroxaban. Three to five per 1,000 patients experienced major bleeding with either drug. 

Rivaroxaban or similar drugs are usually prescribed for two or five weeks after knee or hip surgery, respectively, to reduce the risk of blood clots in the legs or lungs.

This trial included over 3,000 adults who received rivaroxaban for the first five days after surgery and then either continued with the drug as is current practice or switched to aspirin.

The findings suggest that aspirin is an equally safe and effective alternative after initial rivaroxaban prophylaxis, though the chance of a clot or bleeding was small for both strategies. Aspirin is a cheap drug, and that could reduce costs of prevention if patients are switched to it after five days, by when most are discharged. Aspirin is not licensed for this use, but NICE 2018 guidelines recommend it as an option.

It’s unclear if these results would apply to groups with a higher risk of thrombosis.

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Why was this study needed?

The UK National Joint Registry reports that there were 101,651 hip replacement procedures and 108,713 knee replacements recorded in 2016, an increase of nearly 4% on 2015. Blood clots in the legs (deep vein thrombosis [DVT]) or the lungs (pulmonary embolism) are well-recognised complications in the postoperative period that require extended preventive measures.

Anti-clotting (anticoagulant) drugs like rivaroxaban and apixaban are widely used as they are safe, effective and convenient, being taken by mouth. Several studies have suggested that aspirin may be an alternative, at least after an initial period of anticoagulation, but there have been no trials comparing it directly against anticoagulants.

The Canadian EPCAT II trial (Extended Venous Thromboembolism Prophylaxis Comparing Rivaroxaban to Aspirin Following Total Hip and Knee Arthroplasty II) meets that need.

What did this study do?

The randomised trial included 3,424 adults after total hip or knee replacement across 15 centres in Canada. All patients received rivaroxaban (10mg daily) immediately following surgery for five days. From day six they were randomised to continue rivaroxaban or switch to aspirin (81mg daily) for an additional nine days following knee surgery or 30 days following hip surgery.

The drugs were given in identical capsules, so neither patients nor researchers knew what they were taking. Randomisation was balanced according to whether patients were already taking low-dose aspirin. In this case, patients continued with their standard aspirin alongside the assigned drug. The trial included sufficient patients to be able to rule out what experts thought was a clinically important difference (1%) in the rate of DVT or pulmonary embolism between groups.

What did it find?

  • Aspirin was just as effective as rivaroxaban at preventing symptomatic DVT or pulmonary embolism. These events occurred in 0.64% (11/1,707) of patients in the aspirin group and 0.70% (12/1,717) in the rivaroxaban group (difference 0.06%, 95% confidence interval [CI] -0.55% to +0.66%).
  • There was also no difference in the rate of major bleeding, which affected 0.47% (8/1,707) of the aspirin group and 0.29% (5/1,717) of the rivaroxaban group (difference 0.18%, 95% CI -0.65% to +0.29%). Neither was there a difference when including non-major bleeding (1.29% with aspirin vs 0.99% with rivaroxaban). All events involved bleeding at the surgical site.
  • There was a single death from pulmonary embolism. This occurred in a patient assigned to aspirin after knee replacement. It happened 17 days after finishing aspirin treatment.
  • Results were similar across the different operations, and when looking at those already taking long-term aspirin or not.

What does current guidance say on this issue?

Recent NICE guidelines (2018) on reducing risk of hospital-acquired venous thromboembolism recommend aspirin as an option, though not the switching strategy from rivaroxaban.

Recommended options after hip replacement are:

  • Low molecular weight heparin (LMWH) for 10 days followed by aspirin (75 to 150mg) for 28 days; or
  • LMWH for 28 days plus compression stockings until discharge; or
  • Rivaroxaban (10mg daily) for five weeks (in line with the NICE 2009 technology appraisal).

Recommended options after knee replacement are:

  • Aspirin (75 to 150mg) for 14 days; or
  • LMWH for 14 days plus compression stockings until discharge; or
  • Rivaroxaban (10mg daily) for two weeks.

What are the implications?

Enough patients were included to demonstrate the equivalence of low-dose aspirin with rivaroxaban after knee or hip replacement. Results generally support new NICE recommendations to consider aspirin as an option and as aspirin is a low-cost drug it could save resources on prevention, though treatment of clots and complications if they occurred, would remain the same.  

The trial didn’t compare treatments started immediately post-operatively, and it is possible that much of the benefit comes from the first five days of rivaroxaban. The authors note that most bleeding events occurred in the early postoperative period too.

Questions remain about the optimal time to start aspirin and how long to continue it. It is not clear whether patient characteristics should guide treatment choice.

Citation and Funding

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.

This project was funded by the Canadian Institutes of Health Research.

Bibliography

NICE. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NG89. London: National Institute for Health and Care Excellence; 2018.

NICE. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. TA170. London: National Institute for Health and Care Excellence; 2009.

NJR. 14th annual report 2017. Hemel Hempstead: National Joint Registry; 2017.

Why was this study needed?

The UK National Joint Registry reports that there were 101,651 hip replacement procedures and 108,713 knee replacements recorded in 2016, an increase of nearly 4% on 2015. Blood clots in the legs (deep vein thrombosis [DVT]) or the lungs (pulmonary embolism) are well-recognised complications in the postoperative period that require extended preventive measures.

Anti-clotting (anticoagulant) drugs like rivaroxaban and apixaban are widely used as they are safe, effective and convenient, being taken by mouth. Several studies have suggested that aspirin may be an alternative, at least after an initial period of anticoagulation, but there have been no trials comparing it directly against anticoagulants.

The Canadian EPCAT II trial (Extended Venous Thromboembolism Prophylaxis Comparing Rivaroxaban to Aspirin Following Total Hip and Knee Arthroplasty II) meets that need.

What did this study do?

The randomised trial included 3,424 adults after total hip or knee replacement across 15 centres in Canada. All patients received rivaroxaban (10mg daily) immediately following surgery for five days. From day six they were randomised to continue rivaroxaban or switch to aspirin (81mg daily) for an additional nine days following knee surgery or 30 days following hip surgery.

The drugs were given in identical capsules, so neither patients nor researchers knew what they were taking. Randomisation was balanced according to whether patients were already taking low-dose aspirin. In this case, patients continued with their standard aspirin alongside the assigned drug. The trial included sufficient patients to be able to rule out what experts thought was a clinically important difference (1%) in the rate of DVT or pulmonary embolism between groups.

What did it find?

  • Aspirin was just as effective as rivaroxaban at preventing symptomatic DVT or pulmonary embolism. These events occurred in 0.64% (11/1,707) of patients in the aspirin group and 0.70% (12/1,717) in the rivaroxaban group (difference 0.06%, 95% confidence interval [CI] -0.55% to +0.66%).
  • There was also no difference in the rate of major bleeding, which affected 0.47% (8/1,707) of the aspirin group and 0.29% (5/1,717) of the rivaroxaban group (difference 0.18%, 95% CI -0.65% to +0.29%). Neither was there a difference when including non-major bleeding (1.29% with aspirin vs 0.99% with rivaroxaban). All events involved bleeding at the surgical site.
  • There was a single death from pulmonary embolism. This occurred in a patient assigned to aspirin after knee replacement. It happened 17 days after finishing aspirin treatment.
  • Results were similar across the different operations, and when looking at those already taking long-term aspirin or not.

What does current guidance say on this issue?

Recent NICE guidelines (2018) on reducing risk of hospital-acquired venous thromboembolism recommend aspirin as an option, though not the switching strategy from rivaroxaban.

Recommended options after hip replacement are:

  • Low molecular weight heparin (LMWH) for 10 days followed by aspirin (75 to 150mg) for 28 days; or
  • LMWH for 28 days plus compression stockings until discharge; or
  • Rivaroxaban (10mg daily) for five weeks (in line with the NICE 2009 technology appraisal).

Recommended options after knee replacement are:

  • Aspirin (75 to 150mg) for 14 days; or
  • LMWH for 14 days plus compression stockings until discharge; or
  • Rivaroxaban (10mg daily) for two weeks.

What are the implications?

Enough patients were included to demonstrate the equivalence of low-dose aspirin with rivaroxaban after knee or hip replacement. Results generally support new NICE recommendations to consider aspirin as an option and as aspirin is a low-cost drug it could save resources on prevention, though treatment of clots and complications if they occurred, would remain the same.  

The trial didn’t compare treatments started immediately post-operatively, and it is possible that much of the benefit comes from the first five days of rivaroxaban. The authors note that most bleeding events occurred in the early postoperative period too.

Questions remain about the optimal time to start aspirin and how long to continue it. It is not clear whether patient characteristics should guide treatment choice.

Citation and Funding

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.

This project was funded by the Canadian Institutes of Health Research.

Bibliography

NICE. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NG89. London: National Institute for Health and Care Excellence; 2018.

NICE. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. TA170. London: National Institute for Health and Care Excellence; 2009.

NJR. 14th annual report 2017. Hemel Hempstead: National Joint Registry; 2017.

Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty

Published on 22 February 2018

Anderson, D. R.,Dunbar, M.,Murnaghan, J.,Kahn, S. R.,Gross, P.,Forsythe, M.,Pelet, S.,Fisher, W.,Belzile, E.,Dolan, S.,Crowther, M.,Bohm, E.,MacDonald, S. J.,Gofton, W.,Kim, P.,Zukor, D.,Pleasance, S.,Andreou, P.,Doucette, S.,Theriault, C.,Abianui, A.,Carrier, M.,Kovacs, M. J.,Rodger, M. A.,Coyle, D.,Wells, P. S.,Vendittoli, P. A.

N Engl J Med Volume 378 Issue 8 , 2018

BACKGROUND: Clinical trials and meta-analyses have suggested that aspirin may be effective for the prevention of venous thromboembolism (proximal deep-vein thrombosis or pulmonary embolism) after total hip or total knee arthroplasty, but comparisons with direct oral anticoagulants are lacking for prophylaxis beyond hospital discharge. METHODS: We performed a multicenter, double-blind, randomized, controlled trial involving patients who were undergoing total hip or knee arthroplasty. All the patients received once-daily oral rivaroxaban (10 mg) until postoperative day 5 and then were randomly assigned to continue rivaroxaban or switch to aspirin (81 mg daily) for an additional 9 days after total knee arthroplasty or for 30 days after total hip arthroplasty. Patients were followed for 90 days for symptomatic venous thromboembolism (the primary effectiveness outcome) and bleeding complications, including major or clinically relevant nonmajor bleeding (the primary safety outcome). RESULTS: A total of 3424 patients (1804 undergoing total hip arthroplasty and 1620 undergoing total knee arthroplasty) were enrolled in the trial. Venous thromboembolism occurred in 11 of 1707 patients (0.64%) in the aspirin group and in 12 of 1717 patients (0.70%) in the rivaroxaban group (difference, 0.06 percentage points; 95% confidence interval [CI], -0.55 to 0.66; P<0.001 for noninferiority and P=0.84 for superiority). Major bleeding complications occurred in 8 patients (0.47%) in the aspirin group and in 5 (0.29%) in the rivaroxaban group (difference, 0.18 percentage points; 95% CI, -0.65 to 0.29; P=0.42). Clinically important bleeding occurred in 22 patients (1.29%) in the aspirin group and in 17 (0.99%) in the rivaroxaban group (difference, 0.30 percentage points; 95% CI, -1.07 to 0.47; P=0.43). CONCLUSIONS: Among patients who received 5 days of rivaroxaban prophylaxis after total hip or total knee arthroplasty, extended prophylaxis with aspirin was not significantly different from rivaroxaban in the prevention of symptomatic venous thromboembolism. (Funded by the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT01720108 .).

Expert commentary

Elective orthopaedic surgery involving total hip or total knee replacement represents a major risk for venous thromboembolism (VTE). In this randomised controlled trial all patients received a standard protocol of postoperative rivaroxaban for five post-operative days and were randomised to receive 81mg aspirin or 10mg rivaroxaban, subsequently.

Equivalent outcomes for both treatment groups with respect to the incidence of symptomatic VTE (screening for asymptomatic deep vein thrombosis was not undertaken), and bleeding complications, suggests that aspirin is as efficacious as rivaroxaban when used for prolonged post-surgical prophylaxis.

While this has potential implications for cost savings, the key message for patient’s remains: postoperative anticoagulant prophylaxis in the early postoperative period is the most important factor in attenuating risk of VTE, which is likely to be initiated at this time.

Frank CT Smith, Professor of Vascular Surgery & Surgical Education, University of Bristol

Expert commentary

Aspirin is not normally used to prevent postoperative deep vein thrombosis (DVT). This study challenges this doctrine by comparing aspirin with rivaroxaban in patients recovering from joint replacement surgery. They conclude that aspirin is no less effective than rivaroxaban, is just as safe and point out the financial benefit.

This could be a game changer in terms of how we reduce the risk of postoperative DVT because it should be significantly cheaper. The data from this trial form a baseline for future studies in this area.

When is the correct time to start aspirin? How are higher risk groups managed? Which other surgical patients could benefit from aspirin rather than rivaroxaban?

Harvey Chant, Consultant Vascular Surgeon, Royal Cornwall Hospitals