byt från Klexane till Fragmin

Fråga: Ortopeden önskar pga ekonomiska skäl byta postoperativ trombosprofylax från Klexane till Fragmin. Finns evidens som stödjer att Fragmin är ett SÄMRE medel än Klexane mot trombos/emboli efter ortopedisk kirurgi? Vi använder samma preparat till alla operationer från fötter, till ryggar, proteser och fraktur.

Svar: Sammanfattning
Clinical guidelines for venous thromboembolism (VTE) prophylaxis in patients undergoing orthopedic surgery provide recommendations on the use of low molecular weight heparin (LMWHs) as a class. None of the guidelines recommend a specific type of LMWH.

Only a few small prospective, randomized controlled studies have compared the safety and efficacy of dalteparin (Fragmin) and enoxaparin (Klexane) in patients undergoing knee or hip replacement.

Overall, the medical literature suggests comparable efficacy and safety between the two agents, but there is a degree of uncertainty. Most data on orthopaedic surgery is available for enoxaparin (Klexane).

Svar
Clinical guidelines from the American College of Chest Physicians (ACCP), from the United Kingdom National Institute for Health and Clinical Excellence (NICE) and from the Clinical decision support resource UpTodate (1-3) for venous thromboembolism (VTE) prophylaxis in patients undergoing total hip replacement (THR), total knee replacement (TKR) or hip fracture surgery provide recommendations on the use of low molecular weight heparin (LMWHs) as a class. None of the guidelines recommend a specific type of LMWH (1-3). There is little data to support the use of one type of LMWH over another.

There are no large head-to-head randomized studies comparing dalteparin (Fragmin) and enoxaparin (Klexane) in patients undergoing major orthopedic surgeries (4). A few small prospective, randomized controlled studies have compared the safety and efficacy of dalteparin and enoxaparin in patients undergoing knee or hip replacement (5, 6) and in patients with spinal cord injury (7). These studies suggest comparable efficacy and safety between the two agents (5-12).

However, in a retrospective, cohort study by Slavik RS (10) it was found that clinically symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) rates were 1.6% with enoxaparin and 9.7% with dalteparin (p=0.103) with an absolute risk increase [ARI] of 8.1% [-0.6% to 15.6%]) for dalteparin. No differences in major bleeding (6.4% versus 6.9%) or minor bleeding (64% versus 69%), or mortality (4.8% versus 6.9%) were found.
Although the study was not sufficiently powered to make any definite conclusions, the study raises the hypothesis that dalteparin 5,000 units SC daily may not be clinically noninferior to enoxaparin 30 mg SC twice daily for VTE prophylaxis in this high-risk population of major orthopedic trauma and/or acute spinal cord injury patients [135 patients (63 enoxaparin, 72 dalteparin)]. The authors went on to recommend enoxaparin in this patient population and cautious the widespread implementation of dalteparin 5,000 units SC once daily in this high-risk critically-ill population until an adequately powered, prospective, non-inferiority trial is performed.

In general, more studies have been performed for enoxaparin than for dalteparin in populations undergoing orthopedic surgery (13).

There is an ongoing debate in the literature of whether different LMWHs are pharmacologically and clinically equivalent and if they are clinically interchangeable (14). Different LMWHs vary in their pharmacokinetic profile (6, 14). The volume of distribution, half-life, and anti-Xa and anti-IIa activity vary between dalteparin and enoxaparin (11). Dalteparin has demonstrated higher anti-II activity and might have a theoretical advantage in the prophylaxis of VTE. Conversely, enoxaparin has a better anti-Xa profile, which may challenge some of the benefit conferred by the anti-IIa activity of dalteparin (11, 14). The results of the study by Slavik RS (10) suggests that these agents at the doses used may have different clinical effects. Merli GJ (15) argued that LMWHs equivalence has not been demonstrated and that LMWHs are not clinically interchangeable according to statements by the FDA and American College of Chest Physicians, ACCP (16, 17).

1. Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, Ortel TL, Pauker SG, Colwell CW Jr. 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 Feb;141(2 Suppl):e278S-e325S.
2. https://www.nice.org.uk/guidance/ng89/chapter/Recommendations#interventions-for-people-having-orthopaedic-surgery Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism. NICE guideline NG89 Published date: March 2018 Last updated: August 2019
3. Prevention of venous thromboembolism in adult orthopedic surgical patients. Menaka Pai, James D Douketis. Literature review current through: Feb 2020. This topic last updated:Jan 17, 2020.
4. PubMed. US National Library of Medicine/National Institutes of Health sökning gjord 2020-03-12. http://www.ncbi.nlm.nih.gov/pubmed
5. No authors listed. Thromboprophylaxis in hip fracture surgery: a pilot study comparing danaparoid, enoxaparin and dalteparin. The TIFDED Study Group. Haemostasis. 1999 Nov-Dec;29(6):310-7.
6. Janni W, Bergauer F, Rjosk D, Lohscheidt K, Hagena FW. Prospective randomized study comparing the effectiveness and tolerance of various low-molecular-weight heparins in high risk patients. Zentralbl Chir. 2001 Jan;126(1):32-8. Article in German
7. Chiou-Tan FY, Garza H, Chan KT, Parsons KC, Donovan WH, Robertson CS, Holmes SA, Graves DE, Rintala DH. Comparison of dalteparin and enoxaparin for deep venous thrombosis prophylaxis in patients with spinal cord injury. Am J Phys Med Rehabil. 2003 Sep;82(9):678-85.
8. Krotenberg R, Adler U, Pomeranz B, Miller JD, Russel MW: Dalteparin vs. enoxaparin as prophylaxis for deep-vein thrombosis after total hip or knee arthroplasty: a retrospective analysis. Am J Phys Med Rehabil 2001;80:889–895.
9. Shorr AF, Kwong LM, Sarnes M, Happe L, Farrelly E, Mody-Patel N. Venous thromboembolism after orthopedic surgery: implications of the choice for prophylaxis. Thromb Res. 2007; 121(1):17-24.
10. Slavik RS, Chan E, Gorman SK, et al. Dalteparin versus enoxaparin for venous thromboembolism prophylaxis in acute spinal cord injury and major orthopedic trauma patients: ‘DETECT’ trial. J Trauma 2007;62:1075–1081.
11. Okoye OT, Gelbard R, Inaba K, Esparza M1, Belzberg H, Talving P, Teixeira PG, Chan LS, Demetriades D. Dalteparin versus Enoxaparin for the prevention of venous thromboembolic events in trauma patients. Eur J Trauma Emerg Surg. 2014 Apr;40(2):183-9.
12. Dranitsaris G, Jelincic V, Choe Y. Meta regression analysis to indirectly compare dalteparin to enoxaparin for the prevention of venous thromboembolic events following total hip replacement. Thromb J. 2011 Jan 27;9(1):3. doi: 10.1186/1477-9560-9-3.
13. Deitelzweig SB, Vanscoy GJ, Niccolai CS, Rihn TL. Venous thromboembolism prevention with LMWHs in medical and orthopedic surgery patients. Ann Pharmacother. 2003 Mar;37(3):402-11.
14. Merli GJ, Groce JB. Pharmacological and clinical differences between low-molecular-weight heparins: implications for prescribing practice and therapeutic interchange. P T. 2010 Feb;35(2):95-105.
15. Merli GJ, Vanscoy GJ, Rihn TL, et al. Applying scientific criteria to therapeutic interchange: A balanced analysis of low-molecularweight heparins. J Thromb Thrombolysis 2001;11:247–259.
16. Nightingale SL. From the Food and Drug Administration. JAMA. 1993;270:1672.
17. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest. 2008;133(6 Suppl):141S–159S.