Radoičić Dragan, Harmen B. Ettema.
Response/Recommendation: The optimal timing for the initiation of low-molecular-weight heparin (LMWH) for venous thromboembolism (VTE) prophylaxis in patients undergoing orthopaedic procedures is 12-24 hours after surgery. Although high-quality evidence is lacking, several studies have identified an increased risk of postoperative bleeding of beginning LMWH preoperatively or immediately postoperatively. Concerns also exist for earlier initiation of LMWH in patients undergoing neuraxial anesthesia as well. There seems to be no benefit in starting LWMH preoperatively vs (>12 hours) postoperatively.
The exact timing for a specific procedure, particularly trauma patients or those at risk for VTE, should be in accordance with the chosen LMWH pharmacokinetics, surgeons/anesthesiologists’ procedure preferences, and patient comorbidities.
Strength of Recommendation: Limited.
Rationale: The LMWH was first introduced in 1976 and has had almost five decades of a successful track record for VTE prophylaxis in orthopaedic surgery1. The optimal timing for the first dose of LMWH prophylaxis, however, remains disputed. The risk of bleeding complications is closely linked to the timing of thromboprophylaxis. Studies evaluating the use of drains show that most blood loss occurs during the first 6 hours following surgery2. The most commonly used timing is initiation of LMWH at least 12 hours preoperatively, perioperatively (2-6 hours), and postoperatively (12-24 hours)3.
The ‘‘ideal’’ time for the initiation of thromboprophylaxis should balance the optimal efficacy of the antithrombotic agent with the associated risk of bleeding4. The first recommendations for the timing of prophylaxis were 2 hours preoperatively in the 1970s5 with low-dose unfractionated heparin in general surgical patients. The research has shown that the timing of the start of giving anticoagulants influences the results6, but the ideal timings, as well as dosages and ideal anti-Xa ranges for LMWH prophylaxis, have yet to be established. In the 1990s and 2000s, the timing recommendations even provoked a longstanding controversy between surgeons in North America and Europe. LMWH prophylaxis is generally initiated up to 12 hours preoperatively (40 mg once daily) in some parts of Europe, to optimize antithrombotic effectiveness, whereas in North America it is mostly initiated 12 to 24 hours (30 mg twice daily) after surgery to allow hemostasis of the surgical wound7.
In elective orthopaedic patients, concerns exist regarding preoperative LMWH prophylaxis due to the increased risk of compressive spinal hematoma if regional or neuraxial anesthetic techniques were used8,9, similar to some concerns published with early LMWH initiation in selected spine surgery patients10.
There are studies that support administering an LMWH for peak efficacy between 2 hours before and 8 hours after surgery7. Kulshrestha et al.,11 opted for half of the recommended prophylactic dose of LMWH starting 8 h after surgery and switching to full prophylactic dose on the first postoperative day (enoxaparin 40 mg). Bjørnarå et al.,12 recommend subcutaneous dalteparin (5,000 IU) or enoxaparin (40 mg) administered 12 hours before surgery in elective hip and knee cases and shortly after admission in emergencies and thereafter once daily.
Published data does not exclude the possibility that VTE will occur in some patients despite the use of prophylaxis, either because of inappropriate doses, or as a result of delayed first dose13.
Regarding the beginning of LMWH, in femoral neck fracture (FNF), if surgery is performed on an emergency basis (within 24 h), LMWH may be used (starting 12 h before or 12 h after). In total hip arthroplasty (THA) and total knee arthroplasty (TKA), no significant difference in efficacy and safety has been reported in the literature between preoperative and post-operative initiation of LMWH5,14,15 so the choice must be based on evidence reported in published studies as well as on what is indicated on LMWH labels, which per example in Italy require initiation of prophylaxis 12 h before surgery16.
Additionally, we cross-matched the results of our literature search with a recent review3 and the most recent American Society of Hematology (ASH) guideline17. In one randomized trial published in the year 2000, the relative efficacy and safety of two regimens of dalteparin given in close proximity to surgery was evaluated. The results showed lower rates of VTE with both preoperative and postoperative dalteparin compared with vitamin K antagonists (VKA) (10.7% and 13.1% vs 24.0%, respectively; p ≤.001 for both comparisons). However, the rate of major bleeding was significantly higher with preoperative dalteparin18. Another systematic review found that perioperative initiation of LMWH resulted in major bleeding rates of 5-7%, whereas rates were in the 1-3% range with preoperative and postoperative administration. The authors concluded that starting prophylaxis more than 12 hours before surgery is not more effective in preventing deep venous thrombosis (DVT) than starting 12-24 hours postoperatively and that despite slightly lower VTE rates associated with perioperative initiation, the increased risk of major bleeding outweighed any potential benefit15. One more recent randomized trial evaluated the use of 40mg enoxaparin started either 12 or 24 hours following TKA. In 210 patients they found significantly less major bleeding (8% vs 2% p< 0,045) and reduced calculated blood loss (435ml vs 387ml, p<0.01) when enoxaparin was started after 24 hours, with comparably high symptomatic VTE rates (5% vs 7%)19.
In a registry-based study of 45,913 hip fractures reported to the Norwegian Hip Fracture Register, mortality (relative risk [RR] =1.01, 95% confidence interval [CI] 0.97–1.06) and risk of reoperation (RR =0.99, CI 0.90–1.08) were similar comparing preoperative and postoperative start of LMWH. Postoperative start reduced the risk of intraoperative bleeding complications compared with preoperative start. The authors conclude that the initiation of LMWH did not influence the mortality or the risk of reoperation in hip fracture patients treated with osteosynthesis. Postoperative start of LMWH could possibly decrease the risk of intraoperative bleeding20.
Based upon the limited evidence available, there is no clinical advantage in starting LMWH (>12 hours) preoperatively vs (>12 hours) postoperatively. Data does show that initiating LMWH in close proximity to surgery might increase the risk of bleeding complications, particularly in orthopaedic surgery patients receiving neuraxial anesthesia.
Unfortunately, there are currently no recent randomized studies to help provide updated recommendations on the timing of LMWH for specific orthopaedic surgical procedures. Even in orthopaedic trauma, besides hip fractures, there is little literature to unequivocally guide the timing of initiation of VTE prophylaxis for specific injuries in these patients in a hypercoagulable state. The timing of LMWH in these patients should be determined on a case-by-case basis depending on the patient’s injuries, mobility, medical comorbidities, type of surgery, and anesthesia.
For patients undergoing elective orthopaedic surgery who would be a candidate for LMWH thromboprophylaxis, 12-24 hours postoperatively seems the optimal time to administer the first dose of LWWH.
1. Hemker HC. A century of heparin: past, present and future. J Thromb Haemost JTH. 2016;14(12):2329-2338. doi:10.1111/jth.13555
2. Wood GC, Kapoor A, Javed A. Autologous drains in arthroplasty a randomized control trial. J Arthroplasty. 2008;23(6):808-813. doi:10.1016/j.arth.2007.07.006
3. Paikin JS, Hirsh J, Chan NC, Ginsberg JS, Weitz JI, Eikelboom JW. Timing the First Postoperative Dose of Anticoagulants: Lessons Learned From Clinical Trials. Chest. 2015;148(3):587-595. doi:10.1378/chest.14-2710
4. Warwick D, Rosencher N. The “‘critical thrombosis period’” in major orthopedic surgery: when to start and when to stop prophylaxis. Clin Appl Thromb Off J Int Acad Clin Appl Thromb. 2010;16(4):394-405. doi:10.1177/1076029609355151
5. Raskob GE, Hirsh J. Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest. 2003;124(6 Suppl):379S-385S. doi:10.1378/chest.124.6_suppl.379s
6. Salazar CA, Malaga G, Malasquez G. Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement. Cochrane Database Syst Rev. 2010;(4):CD005981. doi:10.1002/14651858.CD005981.pub2
7. Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med. 2001;161(16):1952-1960. doi:10.1001/archinte.161.16.1952
8. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med. 2003;28(3):172-197. doi:10.1053/rapm.2003.50046
9. Rosencher N, Bonnet M-P, Sessler DI. Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: management strategies. Anaesthesia. 2007;62(11):1154-1160. doi:10.1111/j.1365-2044.2007.05195.x
10. Kepler CK, McKenzie J, Kreitz T, Vaccaro A. Venous Thromboembolism Prophylaxis in Spine Surgery. J Am Acad Orthop Surg. 2018;26(14):489-500. doi:10.5435/JAAOS-D-17-00561
11. Kulshrestha V, Kumar S. DVT prophylaxis after TKA: routine anticoagulation vs risk screening approach – a randomized study. J Arthroplasty. 2013;28(10):1868-1873. doi:10.1016/j.arth.2013.05.025
12. Bjørnarå BT, Gudmundsen TE, Dahl OE. Frequency and timing of clinical venous thromboembolism after major joint surgery. J Bone Joint Surg Br. 2006;88(3):386-391. doi:10.1302/0301-620X.88B3.17207
13. Warwick D, Friedman RJ, Agnelli G, et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry. J Bone Joint Surg Br. 2007;89(6):799-807. doi:10.1302/0301-620X.89B6.18844
14. 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
15. Strebel N, Prins M, Agnelli G, Büller HR. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med. 2002;162(13):1451-1456. doi:10.1001/archinte.162.13.1451
16. Prisco D, Cenci C, Silvestri E, Emmi G, Ciucciarelli L. Pharmacological prevention of venous thromboembolism in orthopaedic surgery. Clin Cases Miner Bone Metab Off J Ital Soc Osteoporos Miner Metab Skelet Dis. 2014;11(3):192-195.
17. Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-3944. doi:10.1182/bloodadvances.2019000975
18. Hull RD, Pineo GF, Francis C, et al. Low-Molecular-Weight Heparin Prophylaxis Using Dalteparin Extended Out-of-Hospital vs In-Hospital Warfarin/Out-of-Hospital Placebo in Hip Arthroplasty Patients: A Double-blind, Randomized Comparison. Arch Intern Med. 2000;160(14):2208-2215. doi:10.1001/archinte.160.14.2208
19. Liu F, Chu X, Huang J, Tian K, Hua J, Tong P. Administration of enoxaparin 24 h after total knee arthroplasty: safer for bleeding and equally effective for deep venous thrombosis prevention. Arch Orthop Trauma Surg. 2014;134(5):679-683. doi:10.1007/s00402-014-1939-2
20. Leer-Salvesen S, Dybvik E, Engesaeter LB, Dahl OE, Gjertsen J-E. Low-molecular-weight heparin for hip fracture patients treated with osteosynthesis: should thromboprophylaxis start before or after surgery? An observational study of 45,913 hip fractures reported to the Norwegian Hip Fracture Register. Acta Orthop. 2018;89(6):615-621. doi:10.1080/17453674.2018.1519101