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Increased major bleeding risk in patients with kidney dysfunction receiving enoxaparin: a meta-analysis

  • Pharmacoepidemiology and Prescription
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Abstract

Purpose

The elimination half-life and consequently the accumulation of enoxaparin increase as glomerular filtration rate (GFR) decreases. A dose adjustment for patients with a GFR <30 ml/min is recommended and considered relatively safe. Our intention was to identify whether the use of enoxaparin is safe and to determine what impact an enoxaparin dose adjustment has on patients with a GFR <60 ml/min.

Methods

A PubMed search and meta-analysis of literature were performed. Studies were analyzed to compare enoxaparin versus other heparins/heparinoids and investigate enoxaparin at different stages of kidney dysfunction. Only controlled trials were considered, and the enoxaparin dose had to be specified. The clinical endpoint was defined as apparent major bleeding.

Results

Out of 1,027 publications, 20 studies met the criteria and were analyzed. Our meta-analysis shows that enoxaparin major bleeding complications at a GFR <60 ml/min increase significantly, with a relative risk (RR) of 1.67 [95% confidence interval (CI) 1.12–2.50) compared with other anticoagulants (p = 0.01). RR for patients on enoxaparin therapy increases exponentially with each stage of chronic kidney disease (CKD stage 1–5) [RR = 0.585 x exp(0.524 x CKD)]. Despite dose adjustment, the major bleeding risk is still significantly increased in patients with a GFR <60 ml/min versus those with a GFR >60 ml/min.

Conclusion

Only patients with a GFR >60 ml/min can be safely treated with enoxaparin.

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References

  1. Barras MA, Duffull SB, Atherton JJ, Green B (2009) Modelling the occurrence and severity of enoxaparin-induced bleeding and bruising events. Br J Clin Pharmacol 68(5):700–711

    Article  PubMed  CAS  Google Scholar 

  2. Bazinet A, Almanric K, Brunet C, Turcotte I, Martineau J, Caron S, Blais N, Lalonde L (2005) Dosage of enoxaparin among obese and renal impairment patients. Thromb Res 116(1):41–50

    Article  PubMed  CAS  Google Scholar 

  3. Becker RC, Spencer FA, Gibson M, Rush JE, Sanderink G, Murphy SA, Ball SP, Antman EM (2002) Influence of patient characteristics and renal function on factor Xa inhibition pharmacokinetics and pharmacodynamics after enoxaparin administration in non-ST-segment elevation acute coronary syndromes. Am Heart J 143(5):753–759

    Article  PubMed  CAS  Google Scholar 

  4. Bruno R, Baille P, Retout S, Vivier N, Veyrat-Follet C, Sanderink GJ, Becker R, Antman EM (2003) Population pharmacokinetics and pharmacodynamics of enoxaparin in unstable angina and non-ST-segment elevation myocardial infarction. Br J Clin Pharmacol 56(4):407–414

    Article  PubMed  CAS  Google Scholar 

  5. Buller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, Prins MH, Raskob G, Segers AE, Cariou R, Leeuwenkamp O, Lensing AW (2004) Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 140(11):867–873

    PubMed  Google Scholar 

  6. Chow SL, Zammit K, West K, Dannenhoffer M, Lopez-Candales A (2003) Correlation of antifactor Xa concentrations with renal function in patients on enoxaparin. J Clin Pharmacol 43(6):586–590

    PubMed  CAS  Google Scholar 

  7. Clark N (2008) Low-molecular-weight heparin use in the obese, elderly, and in renal insufficiency. Thromb Res 123(1):58–61

    Article  Google Scholar 

  8. Collet JP, Montalescot G, Choussat R, Lison L, Ankri A (2001) Enoxaparin in unstable angina patients with renal failure. Int J Cardiol 80(1):81–82

    Article  PubMed  CAS  Google Scholar 

  9. Collet JP, Montalescot G, Fine E, Golmard JL, Dalby M, Choussat R, Ankri A, Dumaine R, Lesty C, Vignolles N, Thomas D (2003) Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials. J Am Coll Cardiol 41(1):8–14

    Article  PubMed  CAS  Google Scholar 

  10. Collet JP, Montalescot G, Agnelli G, Van de Werf F, Gurfinkel EP, Lopez-Sendon J, Laufenberg CV, Klutman M, Gowda N, Gulba D (2005) Non-ST-segment elevation acute coronary syndrome in patients with renal dysfunction: benefit of low-molecular-weight heparin alone or with glycoprotein IIb/IIIa inhibitors on outcomes. The Global Registry of Acute Coronary Events. Eur Heart J 26(21):2285–2293

    Article  PubMed  Google Scholar 

  11. Despotovic N, Erceg P, Nikolic-Despotovic M, Milosevic DP, Davidovic M (2007) Bleeding during enoxaparin treatment more common with age over 75 years and severe renal insufficiency. Drugs Aging 24(9):777–779

    Article  PubMed  CAS  Google Scholar 

  12. Feng Y, Green B, Duffull SB, Kane-Gill SL, Bobek MB, Bies RR (2006) Development of a dosage strategy in patients receiving enoxaparin by continuous intravenous infusion using modelling and simulation. Br J Clin Pharmacol 62(2):165–176

    Article  PubMed  CAS  Google Scholar 

  13. Fillastre JP, Leroy A, Baudoin C, Humbert G, Swabb EA, Vertucci C, Godin M (1985) Pharmacokinetics of aztreonam in patients with chronic renal failure. Clin Pharmacokinet 10(1):91–100

    Article  PubMed  CAS  Google Scholar 

  14. Fox KA, Antman EM, Montalescot G, Agewall S, SomaRaju B, Verheugt FW, Lopez-Sendon J, Hod H, Murphy SA, Braunwald E (2007) The impact of renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol 49(23):2249–2255

    Article  PubMed  CAS  Google Scholar 

  15. Fox KA, Bassand JP, Mehta SR, Wallentin L, Theroux P, Piegas LS, Valentin V, Moccetti T, Chrolavicius S, Afzal R, Yusuf S (2007) Influence of renal function on the efficacy and safety of fondaparinux relative to enoxaparin in non ST-segment elevation acute coronary syndromes. Ann Intern Med 147(5):304–310

    PubMed  Google Scholar 

  16. Green B, Greenwood M, Saltissi D, Westhuyzen J, Kluver L, Rowell J, Atherton J (2005) Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes. Br J Clin Pharmacol 59(3):281–290

    Article  PubMed  CAS  Google Scholar 

  17. Hammerstingl C, Omran H (2009) Bridging of oral anticoagulation with low-molecular-weight heparin: experience in 373 patients with renal insufficiency undergoing invasive procedures. Thromb Haemost 101(6):1085–1090

    PubMed  CAS  Google Scholar 

  18. Hammerstingl C, Tripp C, Schmidt H, von der Recke G, Omran H (2007) Periprocedural bridging therapy with low-molecular-weight heparin in chronically anticoagulated patients with prosthetic mechanical heart valves: experience in 116 patients from the prospective BRAVE registry. J Heart Valve Dis 16(3):285–292

    PubMed  Google Scholar 

  19. Hammerstingl C, Omran H, Tripp C, Poetzsch B (2009) How useful is determination of anti-factor Xa activity to guide bridging therapy with enoxaparin? A pilot study. Thromb Haemost 101(2):325–332

    PubMed  CAS  Google Scholar 

  20. Khazan M, Scheuering S, Adamson R, Mathis AS (2003) Prescribing patterns and outcomes of enoxaparin for anticoagulation of atrial fibrillation. Pharmacotherapy 23(5):651–658

    Article  PubMed  Google Scholar 

  21. Kruse MW, Lee JJ (2004) Retrospective evaluation of a pharmacokinetic program for adjusting enoxaparin in renal impairment. Am Heart J 148(4):582–589

    Article  PubMed  CAS  Google Scholar 

  22. Lim W (2008) Low-molecular-weight heparin in patients with chronic renal insufficiency. Intern Emerg Med 3(4):319–323

    Article  PubMed  Google Scholar 

  23. Macie C, Forbes L, Foster GA, Douketis JD (2004) Dosing practices and risk factors for bleeding in patients receiving enoxaparin for the treatment of an acute coronary syndrome. Chest 125(5):1616–1621

    Article  PubMed  Google Scholar 

  24. Mahe I, Aghassarian M, Drouet L, Bal Dit-Sollier C, Lacut K, Heilmann JJ, Mottier D, Bergmann JF (2007) Tinzaparin and enoxaparin given at prophylactic dose for eight days in medical elderly patients with impaired renal function: a comparative pharmacokinetic study. Thromb Haemost 97(4):581–586

    PubMed  CAS  Google Scholar 

  25. Mahe I, Gouin-Thibault I, Drouet L, Simoneau G, Di Castillo H, Siguret V, Bergmann JF, Pautas E (2007) Elderly medical patients treated with prophylactic dosages of enoxaparin: influence of renal function on anti-Xa activity level. Drugs Aging 24(1):63–71

    Article  PubMed  CAS  Google Scholar 

  26. McKeage K, Lyseng-Williamson KA (2010) Fondaparinux: a pharmacoeconomic review of its use in the management of non-ST-segment elevation acute coronary syndrome. Pharmacoeconomics 28(8):687–698

    Article  PubMed  Google Scholar 

  27. Montalescot G, Collet JP, Tanguy ML, Ankri A, Payot L, Dumaine R, Choussat R, Beygui F, Gallois V, Thomas D (2004) Anti-Xa activity relates to survival and efficacy in unselected acute coronary syndrome patients treated with enoxaparin. Circulation 110(4):392–398

    Article  PubMed  CAS  Google Scholar 

  28. Nutescu EA, Spinler SA, Wittkowsky A, Dager WE (2009) Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 43(6):1064–1083

    Article  PubMed  CAS  Google Scholar 

  29. Sanderink GJ, Guimart CG, Ozoux ML, Jariwala NU, Shukla UA, Boutouyrie BX (2002) Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 105(3):225–231

    Article  PubMed  CAS  Google Scholar 

  30. Schmid P, Fischer AG, Wuillemin WA (2009) Low-molecular-weight heparin in patients with renal insufficiency. Swiss Med Wkly 139(31–32):438–452

    PubMed  CAS  Google Scholar 

  31. Spinler SA, Inverso SM, Cohen M, Goodman SG, Stringer KA, Antman EM (2003) Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J 146(1):33–41

    Article  PubMed  CAS  Google Scholar 

  32. Spinler SA, Mahaffey KW, Gallup D, Levine GN, Ferguson JJ, 3 rd, Rao S V, Gallo R, Ducas J, Goodman SG, Antman E, White HD, Biasucci L, Becker RC, Col JJ, Cohen M, Harrington RA, and Califf RM (2009) Relationship between renal function and outcomes in high-risk patients with non-ST-segment elevation acute coronary syndromes: Results from SYNERGY. Int J Cardiol [Epub ahead of print]

  33. Thorevska N, Amoateng-Adjepong Y, Sabahi R, Schiopescu I, Salloum A, Muralidharan V, Manthous CA (2004) Anticoagulation in hospitalized patients with renal insufficiency: a comparison of bleeding rates with unfractionated heparin vs enoxaparin. Chest 125(3):856–863

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Nephrology, Medical Clinic, Ulm University, Ulm, Germany

    Philipp Hoffmann & Frieder Keller

  2. Nephrology, Center for Internal Medicine, University Hospital, Albert Einstein Allee 23, 89070, Ulm, Germany

    Philipp Hoffmann & Frieder Keller

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  1. Philipp Hoffmann
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  2. Frieder Keller
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Correspondence to Frieder Keller.

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Hoffmann, P., Keller, F. Increased major bleeding risk in patients with kidney dysfunction receiving enoxaparin: a meta-analysis. Eur J Clin Pharmacol 68, 757–765 (2012). https://doi.org/10.1007/s00228-011-1149-6

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  • DOI: https://doi.org/10.1007/s00228-011-1149-6

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