36 – Is there a role for sequential combination VTE prophylaxis in patients undergoing orthopaedic procedures?

36 – Is there a role for sequential combination VTE prophylaxis in patients undergoing orthopaedic procedures?

James Larkin, Michael Dunbar, Emil Schemitsch.

Response/Recommendation: Based on the available evidence, sequential combination venous thromboembolism (VTE) prophylaxis has not been shown to be superior to other established treatment regimens.

Strength of Recommendation: Limited.

Rationale: Consensus has grown1 for chemoprophylaxis of VTE disease.  National guidelines such as the National Institute for Health and Care Excellence (NICE) guidelines in the UK suggest patients who had total hip arthroplasty (THA) should have 28 days of chemoprophylaxis and those who had total knee arthroplasty (TKA) should have 14 days of chemoprophylaxis2.  Evidence-based guidelines such as the American College of Chest Physicians (ACCP) have suggested a minimum 10-14 days of prophylaxis for those who have undergone hip or knee arthroplasty3.

Many different drugs have been reported to be effective4 with varying degrees of side effects, and there continues to be discussions about the agent of choice for prevention of VTE after orthopaedic procedures.  Some have advocated for a combination of pharmacological agents to attempt to increase compliance, decrease side effects, and maintain efficacy of prevention of disease.

A randomized control trial (RCT) published in 2018 by Tang et al., aimed to compare Rivaroxaban alone, enoxaparin alone, and enoxaparin followed by rivaroxaban.  There was a small sample size of 287 patients with less than 100 in each group.  There was no statistically significant difference in the rate of VTE between all groups.  They found the group that received sequential therapy had increased compliance compared to enoxaparin alone.  The rate of wound complications was higher in the rivaroxaban group.  Their conclusion was “it is speculated that the clinical application of the sequential therapy is safe, convenient, cost-effective, and efficient”.  They did not however, demonstrate a significant benefit in their primary endpoint of VTE, but instead found the effectiveness of the sequential therapy was due in part to the increased compliance and cheaper cost of therapy.  There was no multivariate analysis done regarding the compliance rates, and causes for non-compliance were multifactorial, and in some parts specific to the Chinese population5.

A double-blinded, RCT sought to determine whether there was any benefit to following 5 days of rivaroxaban with aspirin (ASA) or continuing with rivaroxaban.  A total of 3,427 patients undergoing THA or TKA were randomized.  There was no statistically significant difference in bleeding complications.  The combination of ASA and rivaroxaban was not inferior to rivaroxaban alone, but neither was it superior.6

A retrospective analysis comparing ASA alone to ASA with additional unfractionated heparin (UH) was published in 2018.  Patients either received ASA alone, ASA with a single dose of UH, and ASA with multiple doses of UH.  There were 5,350 patients who met inclusion criteria.  The cohorts were not matched.  They found an increase in perioperative blood loss and an increase in blood transfusion rates for those patients that received 1 or more doses of UH.  There was no statistically significant difference in VTE rates between groups7.

Gonzalez Della Valle et al., published a retrospective review of 257 high-risk patients over a 14 year period from 2004-2018.  These were patients who had either a deep venous thrombosis (DVT), a pulmonary embolism (PE) or both in the past.  Their chemoprophylaxis was grouped into ASA, anticoagulation other than ASA, or combined.  They were unable to draw conclusions on the efficacy of different chemoprophylaxis regimens based on the small numbers involved and the selection biases of choosing medications8.

Based on the literature available, a recommendation cannot be made for or against sequential combination VTE prophylaxis in those patients undergoing orthopaedic procedures where there is an established requirement for VTE prophylaxis.  Sequential therapy may have some advantages in improving compliance for extended VTE prophylaxis, reducing cost, and reducing the risk of wound complications.


1.         Wainwright TW, Gill M, McDonald DA, et al. Consensus statement for perioperative care in total hip replacement and total knee replacement surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations. Acta Orthop. 2020;91(1):3-19. doi:10.1080/17453674.2019.1683790

2.         National Guideline Centre (UK). Venous Thromboembolism in over 16s: Reducing the Risk of Hospital-Acquired Deep Vein Thrombosis or Pulmonary Embolism. National Institute for Health and Care Excellence (UK); 2018. Accessed August 23, 2021. http://www.ncbi.nlm.nih.gov/books/NBK493720/

3.         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(2 Suppl):e278S-e325S. doi:10.1378/chest.11-2404

4.         Nadi S, Vreugdenburg TD, Atukorale Y, Ma N, Maddern G, Rovers M. Safety and effectiveness of aspirin and enoxaparin for venous thromboembolism prophylaxis after total hip and knee arthroplasty: a systematic review. ANZ J Surg. 2019;89(10):1204-1210. doi:10.1111/ans.15122

5.         Tang Y, Wang K, Shi Z, Yang P, Dang X. A RCT study of Rivaroxaban, low-molecular-weight heparin, and sequential medication regimens for the prevention of venous thrombosis after internal fixation of hip fracture. Biomed Pharmacother. 2017;92:982-988. doi:10.1016/j.biopha.2017.05.107

6.         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. doi:10.1056/NEJMoa1712746

7.         Sobh AH, Koueiter DM, Mells A, Siljander MP, Karadsheh MS. The Role of Aspirin and Unfractionated Heparin Combination Therapy Immediately After Total Hip and Knee Arthroplasty. Orthopedics. 2018;41(3):171-176. doi:10.3928/01477447-20180320-08

8.         Gonzalez Della Valle A, Shanaghan KA, Nguyen J, et al. Multimodal prophylaxis in patients with a history of venous thromboembolism undergoing primary elective hip arthroplasty. Bone Joint J. 2020;102-B(7_Supple_B):71-77. doi:10.1302/0301-620X.102B7.BJJ-2019-1559.R1

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