Standard Fixed Enoxaparin Dosing for Venous Thromboembolism Prophylaxis Leads to Low Peak Anti-Factor Xa Levels in Both Head and Neck and Breast Free Flap Patients

Shoshana W. Ambani; Fuat Baris Bengur; Lee J. Varelas; Vu T. Nguyen; Carolyn De La Cruz; Tahsin Oguz Acarturk; Ernest K. Manders; Mark W. Kubik; Shaum Sridharan; Michael L. Gimbel; Mario G. Solari

doi:10.1055/s-0042-1749340

Journal of Reconstructive Microsurgery, Table of Contents

J Reconstr Microsurg 2022; 38(09): 749-756
DOI: 10.1055/s-0042-1749340

Original Article

Standard Fixed Enoxaparin Dosing for Venous Thromboembolism Prophylaxis Leads to Low Peak Anti-Factor Xa Levels in Both Head and Neck and Breast Free Flap Patients

Shoshana W. Ambani

¹Division of Plastic & Reconstructive Surgery, Henry Ford Jackson Health, Jackson, Michigan

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Fuat Baris Bengur

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Lee J. Varelas

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Vu T. Nguyen

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Carolyn De La Cruz

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Tahsin Oguz Acarturk

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Ernest K. Manders

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Mark W. Kubik

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

³Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Shaum Sridharan

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

³Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Michael L. Gimbel

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

,

Mario G. Solari

²Department of Plastic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania

³Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania

› Author Affiliations

Abstract

Background Venous thromboembolism (VTE) is a serious complication, particularly in cancer patients undergoing free flap reconstruction. Subcutaneous enoxaparin is the conventional prophylaxis for VTE prevention, and serum anti-factor Xa (afXa) levels are being increasingly used to monitor enoxaparin activity. In this study, free flap patients receiving standard enoxaparin prophylaxis were prospectively followed to investigate postoperative afXa levels and 90-day VTE and bleeding-related complications.

Methods Patients undergoing free tissue transfer during an 8-month period were identified and prospectively followed. Patients received standard fixed enoxaparin dosing at 30 mg twice daily in head and neck (H&N) and 40 mg daily in breast reconstructions. Target peak prophylactic afXa range was 0.2 to 0.5 IU/mL. The primary outcome was the occurrence of 90-day postoperative VTE- and bleeding-related events. Independent predictors of afXa level and VTE incidence were analyzed for patients that met the inclusion criteria.

Results Seventy-eight patients were prospectively followed. Four (5.1%) were diagnosed with VTE, and six (7.7%) experienced bleeding-related complications. The mean afXa levels in both VTE patients and bleeding patients were subprophylactic (0.13 ± 0.09 and 0.11 ± 0.07 IU/mL, respectively). Forty-six patients (21 breast, 25 H&N) had valid postoperative peak steady-state afXa levels. Among these, 15 (33%) patients achieved the target prophylactic range: 5 (33%) H&N and 10 (67%) breast patients. The mean afXa level for H&N patients was significantly lower than for breast patients (p = 0.0021). Patient total body weight was the sole negative predictor of afXa level (R ² = 0.47, p < 0.0001).

Conclusion Standard fixed enoxaparin dosing for postoperative VTE prophylaxis does not achieve target afXa levels for the majority of our free flap patients. H&N patients appear to be a particularly high-risk group that may require a more personalized and aggressive approach. Total body weight is the sole negative predictor of afXa level, supporting a role for weight-based enoxaparin dosing.

Keywords

venous thromboembolism - prophylaxis - enoxaparin - anti-factor Xa - free flap - microsurgery

Full Text

References

References
1 Agnelli G, Bolis G, Capussotti L. et al. A clinical outcome-based prospective study on venous thromboembolism after cancer surgery: the @RISTOS project. Ann Surg 2006; 243 (01) 89-95
2 Pannucci CJ, Rockwell WB, Ghanem M, Fleming KI, Momeni A, Agarwal J. Inadequate enoxaparin dosing predicts 90-day venous thromboembolism risk among plastic surgery inpatients: an examination of enoxaparin pharmacodynamics. Plast Reconstr Surg 2017; 139 (04) 1009-1020
3 Miszkiewicz K, Perreault I, Landes G. et al. Venous thromboembolism in plastic surgery: incidence, current practice and recommendations. J Plast Reconstr Aesthet Surg 2009; 62 (05) 580-588
4 Kakei Y, Akashi M, Hasegawa T, Minamikawa T, Usami S, Komori T. Incidence of venous thromboembolism after oral oncologic surgery with simultaneous reconstruction. J Oral Maxillofac Surg 2016; 74 (01) 212-217
5 Bahl V, Shuman AG, Hu HM. et al. Chemoprophylaxis for venous thromboembolism in otolaryngology. JAMA Otolaryngol Head Neck Surg 2014; 140 (11) 999-1005
6 Bergqvist D. Enoxaparin: a pharmacoeconomic review of its use in the prevention and treatment of venous thromboembolism and in acute coronary syndromes. PharmacoEconomics 2002; 20 (04) 225-243
7 Pannucci CJ, Dreszer G, Wachtman CF. et al. Postoperative enoxaparin prevents symptomatic venous thromboembolism in high-risk plastic surgery patients. Plast Reconstr Surg 2011; 128 (05) 1093-1103
8 Ong HS, Gokavarapu S, Al-Qamachi L. et al. Justification of routine venous thromboembolism prophylaxis in head and neck cancer reconstructive surgery. Head Neck 2017; 39 (12) 2450-2458
9 ENOXACAN Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg 1997; 84 (08) 1099-1103
10 Egan G, Ensom MH. Measuring anti-factor xa activity to monitor low-molecular-weight heparin in obesity: a critical review. Can J Hosp Pharm 2015; 68 (01) 33-47
11 Helviz Y, Dzigivker I, Raveh-Brawer D, Hersch M, Zevin S, Einav S. Anti-factor Xa activity of prophylactic enoxaparin regimens in critically ill patients. Isr Med Assoc J 2016; 18 (02) 108-113
12 Ko A, Harada MY, Barmparas G. et al. Association between enoxaparin dosage adjusted by anti-factor Xa trough level and clinically evident venous thromboembolism after trauma. JAMA Surg 2016; 151 (11) 1006-1013
13 Pannucci CJ, Prazak AM, Scheefer M. Utility of anti-factor Xa monitoring in surgical patients receiving prophylactic doses of enoxaparin for venous thromboembolism prophylaxis. Am J Surg 2016
14 Wei MY, Ward SM. The anti-factor Xa range for low molecular weight heparin thromboprophylaxis. Hematol Rep 2015; 7 (04) 5844
15 Tahaineh L, Edaily SM, Gharaibeh SF. Anti-factor Xa levels in obese patients receiving enoxaparin for treatment and prophylaxis indications. Clin Pharmacol 2018; 10: 63-70
16 Vandiver JW, Ritz LI, Lalama JT. Chemical prophylaxis to prevent venous thromboembolism in morbid obesity: literature review and dosing recommendations. J Thromb Thrombolysis 2016; 41 (03) 475-481
17 Malinoski D, Jafari F, Ewing T. et al. Standard prophylactic enoxaparin dosing leads to inadequate anti-Xa levels and increased deep venous thrombosis rates in critically ill trauma and surgical patients. J Trauma 2010; 68 (04) 874-880
18 Nunez JM, Becher RD, Rebo GJ. et al. Prospective evaluation of weight-based prophylactic enoxaparin dosing in critically ill trauma patients: adequacy of antiXa levels is improved. Am Surg 2015; 81 (06) 605-609
19 Rostas JW, Brevard SB, Ahmed N. et al. Standard dosing of enoxaparin for venous thromboembolism prophylaxis is not sufficient for most patients within a trauma intensive care unit. Am Surg 2015; 81 (09) 889-892
20 Lin H, Faraklas I, Saffle J, Cochran A. Enoxaparin dose adjustment is associated with low incidence of venous thromboembolic events in acute burn patients. J Trauma 2011; 71 (06) 1557-1561
21 Wall V, Fleming KI, Tonna JE. et al. Anti-factor Xa measurements in acute care surgery patients to examine enoxaparin dose. Am J Surg 2018; 216 (02) 222-229
22 Pannucci CJ, Hunt MM, Fleming KI, Prazak AM. Weight-based dosing for once-daily enoxaparin cannot provide adequate anticoagulation for venous thromboembolism prophylaxis. Plast Reconstr Surg 2017; 140 (04) 815-822
23 Pannucci CJ, Fleming KI, Holoyda K, Moulton L, Prazak AM, Varghese Jr TK. Enoxaparin 40 mg per day is inadequate for venous thromboembolism prophylaxis after thoracic surgical procedure. Ann Thorac Surg 2018; 106 (02) 404-411
24 Walker CK, Sandmann EA, Horyna TJ, Gales MA. Increased enoxaparin dosing for venous thromboembolism prophylaxis in general trauma patients. Ann Pharmacother 2017; 51 (04) 323-331
25 Pannucci CJ, Fleming KI, Bertolaccini CB, Prazak AM, Huang LC, Pickron TB. Assessment of anti-factor Xa levels of patients undergoing colorectal surgery given once-daily enoxaparin prophylaxis: a clinical study examining enoxaparin pharmacokinetics. JAMA Surg 2019; 154 (08) 697-704
26 Scrimenti A, Seabury RW, Miller CD. et al. Pharmacist recommendations for prophylactic enoxaparin monitoring and dose adjustment in trauma patients admitted to a surgical intensive care unit. Pharm Pract (Granada) 2019; 17 (04) 1541
27 Jones DL, Jones WA, Fleming KI. et al. Underdosing of prophylactic enoxaparin is common in orthopaedic trauma and predicts 90-day venous thromboembolism. J Orthop Trauma 2019; 33 (11) 570-576
28 Stier C, Koschker AC, Stier R, Sosnierz A, Chiappetta S. Are we missing treatment standards for thromboprophylaxis of the obese and super-obese patient population? A prospective systematic cohort study. Obes Surg 2020; 30 (05) 1704-1711
29 Pannucci CJ, Fleming KI, Bertolaccini C. et al. Fixed or weight-tiered enoxaparin after thoracic surgery for venous thromboembolism prevention. Ann Thorac Surg 2020; 109 (06) 1713-1721
30 Pannucci CJ, Fleming KI, Varghese Jr TK. et al. Low anti-factor Xa level predicts 90-day symptomatic venous thromboembolism in surgical patients receiving enoxaparin prophylaxis: a pooled analysis of eight clinical trials. Ann Surg 2020
31 Eley KA, Parker RJ, Watt-Smith SR. Low molecular weight heparin in patients undergoing free tissue transfer following head and neck ablative surgery: review of efficacy and associated complications. Br J Oral Maxillofac Surg 2013; 51 (07) 610-614
32 Yang G, De Staercke C, Hooper WC. The effects of obesity on venous thromboembolism: a review. Open J Prev Med 2012; 2 (04) 499-509
33 Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med 2005; 118 (09) 978-980
34 Shaikh S, Boneva D, Hai S, McKenney M, Elkbuli A. Venous thromboembolism chemoprophylaxis regimens in trauma and surgery patients with obesity: a systematic review. J Trauma Acute Care Surg 2020; 88 (04) 522-535
35 Sebaaly J, Covert K. Enoxaparin dosing at extremes of weight: literature review and dosing recommendations. Ann Pharmacother 2018; 52 (09) 898-909
36 Rodier SG, Bukur M, Moore S. et al. Weight-based enoxaparin with anti-factor Xa assay-based dose adjustment for venous thromboembolic event prophylaxis in adult trauma patients results in improved prophylactic range targeting. Eur J Trauma Emerg Surg 2021; 47 (01) 145-151
37 Pannucci CJ, Fleming KI, Bertolaccini C, Prazak AM, Stoddard GJ, Momeni A. Double-blind randomized clinical trial to examine the pharmacokinetic and clinical impacts of fixed dose versus weight-based enoxaparin prophylaxis: a methodologic description of the FIxed or Variable Enoxaparin (FIVE) Trial. Plast Reconstr Surg Glob Open 2019; 7 (04) e2185
38 Pannucci CJ, Fleming KI, Bertolaccini C. et al. Optimal dosing of prophylactic enoxaparin after surgical procedures: results of the double-blind, randomized, controlled FIxed or Variable Enoxaparin (FIVE) Trial. Plast Reconstr Surg 2021; 147 (04) 947-958
39 Bertolaccini CM, Prazak AMB, Goodwin IA. et al. Prevention of venous thromboembolism in microvascular surgery patients using weight-based unfractionated heparin infusions. J Reconstr Microsurg 2021
40 Mowery A, Light T, Clayburgh D. Venous thromboembolism incidence in head and neck surgery patients: analysis of the Veterans Affairs Surgical Quality Improvement Program (VASQIP) database. Oral Oncol 2018; 77: 22-28
41 Thai L, McCarn K, Stott W. et al. Venous thromboembolism in patients with head and neck cancer after surgery. Head Neck 2013; 35 (01) 4-9
42 Clayburgh D, Stott W, Kochanowski T. et al. Prospective study of venous thromboembolism in patients with head and neck cancer after surgery: interim analysis. JAMA Otolaryngol Head Neck Surg 2013; 139 (02) 161-167
43 Lemaine V, McCarthy C, Kaplan K. et al. Venous thromboembolism following microsurgical breast reconstruction: an objective analysis in 225 consecutive patients using low-molecular-weight heparin prophylaxis. Plast Reconstr Surg 2011; 127 (04) 1399-1406
44 Modarressi A, Schettini AV, Rüegg EM, Pittet-Cuénod B. Venous thromboembolism events after breast reconstructions with DIEP free flaps in 192 consecutive case. Ann Chir Plast Esthet 2018; 63 (01) 11-19
45 Rochlin DH, Sheckter CC, Pannucci C, Momeni A. Venous thromboembolism following microsurgical breast reconstruction: a longitudinal analysis of 12,778 patients. Plast Reconstr Surg 2020; 146 (03) 465-473
46 Hebbeler SL, Marciniak CM, Crandall S, Chen D, Nussbaum S, Mendelewski S. Daily vs twice daily enoxaparin in the prevention of venous thromboembolic disorders during rehabilitation following acute spinal cord injury. J Spinal Cord Med 2004; 27 (03) 236-240
47 Bush S, LeClaire A, Hampp C, Lottenberg L. Review of a large clinical series: once- versus twice-daily enoxaparin for venous thromboembolism prophylaxis in high-risk trauma patients. J Intensive Care Med 2011; 26 (02) 111-115
48 Riha GM, Van PY, Differding JA, Schreiber MA. Oregon Health & Science University Trauma Research Group. Incidence of deep vein thrombosis is increased with 30 mg twice daily dosing of enoxaparin compared with 40 mg daily. Am J Surg 2012; 203 (05) 598-602
49 Robinson S, Zincuk A, Larsen UL. et al. A comparative study of varying doses of enoxaparin for thromboprophylaxis in critically ill patients: a double-blinded, randomised controlled trial. Crit Care 2013; 17 (02) R75
50 Baumgartner JM, McKenzie S, Block S, Costantini TW, Lowy AM. Prophylactic enoxaparin doses may be inadequate in patients undergoing abdominal cancer surgery. J Surg Res 2018; 221: 183-189
51 Venkatesh KP, Ambani SW, Arakelians ARL, Johnson JT, Solari MG. Head and neck microsurgeon practice patterns and perceptions regarding venous thromboembolism prophylaxis. J Reconstr Microsurg 2020; 36 (08) 549-555
52 Patel H, Srinivasa DR, Volod O, Wang ED, Kim EA. Rotational thromboelastometry derivative fibrinogen-platelet ratio predicts thrombosis in microsurgery. J Reconstr Microsurg 2021; 37 (09) 774-782