45 – Is intraoperative heparin effective and safe to prevent postoperative VTE in patients undergoing orthopaedic procedures?

Sam Schulman, Alfreda Smailys, Nigel Sharrock.

Response/Recommendation: Intravenous (IV) administration of intraoperative heparin to patients undergoing total hip arthroplasty (THA) has been investigated and found to be safe and effective in prevention of postoperative venous thromboembolism (VTE). Further studies are needed to evaluate the efficacy of this modality in other orthopaedic procedures.

Strength of Recommendation: Moderate (for hip).

Rationale: There is an increased risk of VTE after major orthopaedic surgery, such as THA, total knee arthroplasty (TKA), or spine surgery¹. The initial stimulus for thrombus formation occurs during surgery but most regimens for VTE prophylaxis start postoperatively². In a randomized controlled trial (RCT) comparing low-molecular-weight heparin (LMWH) started within 2 hr. before surgery vs. 4 hr. after surgery vs. warfarin for THA, the risk of bleeding was highest in patients started on preoperative LMWH³. During surgery, particularly THA, there is activation of coagulation, measured as increased levels of thrombin-antithrombin complex, prothrombin fragment 1 + 2, fibrinogen peptide A and D-dimer after reaming of the femur during the insertion of the femoral component of the prosthesis⁴. These findings led to the evaluation of administration of intraoperative heparin to reduce the thrombus formation in the early stage. Unfractionated heparin (UFH) was used because there was experience from intravenous administration of heparin during cardiac bypass surgery. Furthermore, UFH can be effectively reversed with protamine in case of increased bleeding.

Three RCT have been published, comparing intraoperative IV UFH with placebo; two in THA^5,6, and one in total knee arthroplasty (TKA)⁷. In the THA trials, all patients received aspirin 650 mg daily for 11 – 30 days postoperatively, which could have attenuated the effect of intraoperative heparin. The UFH regimens differed. In the study by Sharrock et al., 1,000 units UFH before surgery plus 500 units every 30 min during surgery was administered⁵. In the study by Westrich et al., 15 units/kg of UFH was administered at the end of acetabular reconstruction⁶, and in the study by Giachino et al., 100 units/kg of UFH was administered before tourniquet inflation during TKA and the UFH was reversed later with protamine⁷. In the study by Sharrock et al., there was a reduction of the composite of deep venous thrombosis (DVT) detected on screening with venography and pulmonary embolism (PE) in the UFH group but also increased intraoperative blood loss⁵. In the study by Westrich et al., there were similar outcome in the two groups regarding VTE, intraoperative blood loss, and postoperative drainage⁶. The study by Giachino et al., evaluated embolic material, interpreted as mainly fat emboli, in the right atrium after release of the tourniquet without detecting any difference between the groups⁷. One additional study included 26 patients undergoing THA who were randomized into two groups (one group receiving UFH and another group receiving none), and found that the level of D-dimer and other coagulation parameters were reduced in the group receiving UFH⁸.

Several prospective cohort studies have been performed, comparing different regimens of intraoperative UFH for THA⁹, or comparing two small cohorts with or without UFH intraoperatively for THA¹⁰, or for TKA¹¹ without any difference in outcome, or comparing with historical studies that did not use intraoperative UFH but without any clear difference in symptomatic VTE¹². The exception is for one of the cohorts (adjusted dose heparin) in the study by Huo et al., for which in comparison with a historical control group there was a reduction in VTE (p = 0.37)⁹. Another prospective study in TKA was a single-arm cohort without any comparator¹³. A prospective cohort study in patients with lumbar spine surgery compared UFH 50 – 75 units/kg with control without any difference in VTE or blood loss (after adjustments for confounders)¹⁴.

A retrospective chart review of two very large cohorts with THA and TKA receiving 1,000 iu of UFH at skin incision and 500 units intraoperatively did not find significant differences in the incidence of fatal PE versus historical controls¹⁵. Finally, a retrospective review of patients with a history of VTE and undergoing THA with UFH 10 units/kg before preparation of the femoral canal had inconclusive results, since there was no comparator and postoperatively different antithrombotic regimens were used¹⁶.

Regarding safety, with the exception of the study by Sharrock et al.⁹, there was no study that showed significantly increased bleeding with intraoperative heparin (after adjustments, when applicable), and the aforementioned study used repeated doses of 500 units of heparin every 30 minutes during surgery, which added up to more heparin than any subsequent regimen.

It should be noted that almost all studies in patients with THA used regional anesthesia, which contributes to a reduction in the VTE incidence and may have been a confounding variable.

Despite the demonstration of activated coagulation during major orthopaedic surgery, there is no high-quality clinical evidence to support the benefit of intraoperative UFH for all orthopaedic procedures. The only potential benefit of intraoperative administration of UFH may be in patients undergoing THA.

References:

1.         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-325S.

2.         Strebel N, Prins M, Agnelli G, et al. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2002;162:1451-1456.

3.         Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000;160:2199-2207.

4.         Sharrock NE, Go G, Harpel PC, et al. The John Charnley Award. Thrombogenesis during total hip arthroplasty. Clin Orthop Relat Res 1995:16-27.

5.         Sharrock NE, Brien WW, Salvati EA, et al. The effect of intravenous fixed-dose heparin during total hip arthroplasty on the incidence of deep-vein thrombosis. A randomized, double-blind trial in patients operated on with epidural anesthesia and controlled hypotension. J Bone Joint Surg Am 1990;72:1456-1461.

6.         Westrich GH, Salvati EA, Sharrock N, et al. The effect of intraoperative heparin administered during total hip arthroplasty on the incidence of proximal deep vein thrombosis assessed by magnetic resonance venography. J Arthroplasty 2005;20:42-50.

7.         Giachino AA, Rody K, Turek MA, et al. Systemic fat and thrombus embolization in patients undergoing total knee arthroplasty with regional heparinization. J Arthroplasty 2001;16:288-292.

8.         Tomita M, Motokawa S. Intraoperative heparin injection reduced D-dimer and TAT levels after total hip arthroplasty. Acta Medica Nagasakiensia 2008;53:9-13.

9.         Huo MH, Salvati EA, Sharrock NE, et al. Intraoperative heparin thromboembolic prophylaxis in primary total hip arthroplasty. A prospective, randomized, controlled, clinical trial. Clin Orthop Relat Res 1992:35-46.

10.       Maezawa K, Nozawa M, Aritomi K, et al. Changes of D-dimer after total hip arthroplasty in patients with and without intraoperative heparin. Arch Orthop Trauma Surg 2008;128:37-40.

11.       Westrich GH, Menezes A, Sharrock N, et al. Thromboembolic disease prophylaxis in total knee arthroplasty using intraoperative heparin and postoperative pneumatic foot compression. J Arthroplasty 1999;14:651-656.

12.       Gonzalez Della Valle A, Serota A, Go G, et al. Venous thromboembolism is rare with a multimodal prophylaxis protocol after total hip arthroplasty. Clin Orthop Relat Res 2006;444:146-153.

13.       Mant MJ, Russell DB, Johnston DW, et al. Intraoperative heparin in addition to postoperative low-molecular-weight heparin for thromboprophylaxis in total knee replacement. J Bone Joint Surg Br 2000;82:48-49.

14.       Sim EM, Claydon MH, Parker RM, et al. Brief intraoperative heparinization and blood loss in anterior lumbar spine surgery. J Neurosurg Spine 2015;23:309-313.

15.       Nassif JM, Ritter MA, Meding JB, et al. The effect of intraoperative intravenous fixed-dose heparin during total joint arthroplasty on the incidence of fatal pulmonary emboli. J Arthroplasty 2000;15:16-21.

16.       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:71-77.