Skip to main content
SpringerLink
Log in

Effectiveness of Switch to Erythropoiesis-Stimulating Agent (ESA) Biosimilars versus Maintenance of ESA Originators in the Real-Life Setting: Matched-Control Study in Hemodialysis Patients

  • Original Research Article
  • Published:
Clinical Drug Investigation Aims and scope Submit manuscript

Abstract

Background

In hemodialysis (HD), switching from erythropoiesis-stimulating agent (ESA) originators to biosimilars is associated with the need for doses approximately 10% higher, according to industry-driven studies.

Objective

The aim of this study was to evaluate the efficacy on anemia control of switching from ESA originators to biosimilars in daily clinical practice.

Methods

We retrospectively selected consecutive HD patients receiving stable intravenous ESA doses, and who had not been transfused in the previous 6 months, from 12 non-profit Italian centers. Patients switched from originators to biosimilars (n = 163) were matched with those maintained on ESA originators (n = 163) using a propensity score approach. The study duration was 24 weeks, and the primary endpoint was the mean dose difference (MDD), defined as the difference between the switch and control groups of ESA dose changes during the study (time-weighted average ESA dose minus baseline ESA dose).

Results

Age (70 ± 13 years), male sex (63%), diabetes (29%), history of cardiovascular disease (40%), body weight (68 ± 14 kg), vascular access (86% arteriovenous fistula), hemoglobin [Hb] (11.2 ± 0.9 g/dL) and ESA dose (8504 ± 6370 IU/week) were similar in the two groups. Hb remained unchanged during the study in both groups. Conversely, ESA dose remained unchanged in the control group and progressively increased in the switch group from week 8 to 24. The time-weighted average of the ESA dose was higher in the switch group than in the control group (10,503 ± 7389 vs. 7981 ± 5858 IU/week; p = 0.001), leading to a significant MDD of 2423 IU/week (95% confidence interval [CI] 1615–3321), corresponding to a 39.6% (95% CI 24.7–54.6) higher dose of biosimilars compared with originators. The time-weighted average of Hb was 0.2 g/dL lower in the switch group, with a more frequent ESA hyporesponsiveness (14.7 vs. 2.5%). Iron parameters and other resistance factors remained unchanged.

Conclusions

In stable dialysis patients, switching from ESA originators to biosimilars requires 40% higher doses to maintain anemia control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. De Nicola L, Minutolo R, Chiodini P, on behalf of the TArget Blood Pressure LEvels in Chronic Kidney Disease (TABLE in CKD) Study Group, et al. Global approach to cardiovascular risk in chronic kidney disease: reality and opportunities for intervention. Kidney Int. 2006;69:538–45.

    Article  PubMed  Google Scholar 

  2. McFarlane PA, Pisoni RL, Eichleay MA, Wald R, Port FK, Mendelssohn D. International trends in erythropoietin use and hemoglobin levels in hemodialysis patients. Kidney Int. 2010;78:215–23.

    Article  CAS  PubMed  Google Scholar 

  3. European Medicines Agency [EMA]. Biosimilar medicines. London: EMA; 2013. http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000318.jsp&mid=WC0b01ac0580281bf0. Accessed 16 Jun 2017.

  4. Mestre-Ferrandiz J, Towse A, Berdud M. Biosimilars: how can payers get long-term savings? Pharmacoeconomics. 2016;34:609–16.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ingrasciotta Y, Giorgianni F, Bolcato J, Chinellato A, Pirolo R, Tari DU, Troncone C, Fontana A, Ientile V, Gini R, Santoro D, Santarpia M, Genazzani A, Uomo I, Pastorello M, Pollina Addario WS, Scondotto S, Cananzi P, Caputi AP, Trifirò G. How much are biosimilars used in clinicalpractice? A retrospective italian population-based study of erythropoiesis-stimulating agents in the years 2009–2013. BioDrugs. 2015;29(4):275–84.

    Article  PubMed  PubMed Central  Google Scholar 

  6. D’Amore C, Da Cas R, Rossi M, Traversa G. Switching between epoetins: a practice in support of biosimilar use. BioDrugs. 2016;30(1):27–32.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Marin JG, Leung M, Lo C, Tsao NW, Martinusen DJ. Efficacy and safety data of subsequent entry biologics pertinent to nephrology practice: a systematic review. Can J Kidney Health Dis. 2014;1:34.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hörl WH, Locatelli F, Haag-Weber M, Ode M, Roth K, Epo-PASS Study Group. Prospective multicenter study of HX575 (biosimilar epoetin-α) in patients with chronic kidney disease applying a target hemoglobin of 10–12 g/dl. Clin Nephrol. 2012;78:24–32.

    Article  PubMed  Google Scholar 

  9. Wizemann V, Rutkowski B, Baldamus C, Scigalla P, Koytchev R, Epoetin Zeta Study Group. Comparison of the therapeutic effects of epoetin zeta to epoetin alfa in the maintenance phase of renal anaemia treatment. Curr Med Res Opin. 2008;24:625–37.

    Article  CAS  PubMed  Google Scholar 

  10. Palmer SC, Saglimbene V, Mavridis D, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2014;12:CD010590.

    Google Scholar 

  11. Ingrasciotta Y, Giorgianni F, Marcianò I, et al. Comparative effectiveness of biosimilar, reference product and other erythropoiesis-stimulating agents (ESAs) still covered by patent in chronic kidney disease and cancer patients: an Italian population-based study. PLoS One. 2016;11:e0155805.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hörbrand F, Bramlage P, Fischaleck J, Hasford J, Brunkhorst R. A population-based study comparing biosimilar versus originator erythropoiesis-stimulating agent consumption in 6,117 patients with renal anaemia. Eur J Clin Pharmacol. 2013;69(4):929–36.

    Article  PubMed  Google Scholar 

  13. Trotta F, Belleudi V, Fusco D, et al. Comparative effectiveness and safety of erythropoiesis-stimulating agents (biosimilars vs. originators) in clinical practice: a population-based cohort study in Italy. BMJ Open. 2017;7:e011637.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Wish JB, Charytan C, Chertow GM, et al. Introduction of Biosimilar Therapeutics Into Nephrology Practice in the United States: report of a Scientific Workshop Sponsored by the National Kidney Foundation. Am J Kidney Dis. 2016;68:843–52.

    Article  PubMed  Google Scholar 

  15. Austin PC, Grootendorst P, Anderson GM. A comparison of the ability of different propensity score models to balance measured variables between treated and untreated subjects: a Monte Carlo study. Stat Med. 2007;26(4):734–53.

    Article  PubMed  Google Scholar 

  16. Rosenbaum PR, Rubin DB. Constructing a control group using multivariate matchedsampling methods that incorporate the propensity score. Am Stat. 1985;39(1):33–8.

    Google Scholar 

  17. Austin PC. Optimal caliper widths for propensity-score matching when estimating differencesin means and differences in proportions in observational studies. Pharm Stat. 2011;10:150–61.

    Article  PubMed  Google Scholar 

  18. Matthews JN, Altman DG, Campbell MJ, Royston P. Analysis of serial measurements in medical research. BMJ. 1990;300(6719):230–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012;2:279–335.

    Article  Google Scholar 

  20. Barnett AI, Crémieux PY. Dose conversion from epoetin alfa to darbepoetin alfa for patients with chronic kidney disease receiving hemodialysis. Pharmacotherapy. 2003;23(5):690–4.

    Article  CAS  PubMed  Google Scholar 

  21. Haag-Weber M, Vetter A, Thyroff-Friesinger U, INJ Study Group. Therapeutic equivalence, long-term efficacy and safety of HX575 in the treatment of anemia in chronic renal failure patients receiving hemodialysis. Clin Nephrol. 2009;72:380–90.

    CAS  PubMed  Google Scholar 

  22. Krivoshiev S, Wizemann V, Czekalsk S, Epoetin Zeta Study Group. Therapeutic equivalence of epoetin zeta and alfa, administered subcutaneously, for maintenance treatment of renal anemia. Adv Ther. 2010;27:105–17.

    Article  CAS  PubMed  Google Scholar 

  23. Krivoshiev S, Todorov V, Manitius J, Czekalski S, Scigalla P, Koytchev R, Epoetin Zeta Study Group. Comparison of the therapeutic effects of epoetin zeta and epoetin alfa in the correction of renal anaemia. Curr Med Res Opin. 2008;24(5):1407–15.

    Article  CAS  PubMed  Google Scholar 

  24. WHO Collaborating Centre for Drug Statistics Methodology. Definition and general considerations. https://www.whocc.no/ddd/definition_and_general_considera/. Accessed 12 Oct 2016.

  25. Bailie GR, Larkina M, Goodkin DA, et al. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality. Kidney Int. 2015;87:162–8.

    Article  CAS  PubMed  Google Scholar 

  26. Bailie GR, Larkina M, Goodkin DA, et al. Variation in intravenous iron use internationally and over time: the dialysis outcomes and practice patterns study (DOPPS). Nephrol Dial Transpl. 2013;28:2570–9.

    Article  CAS  Google Scholar 

  27. Gianoncelli A, Bonini SA, Bertuzzi M, et al. An integrated approach for a structural and functionalevaluation of biosimilars: implications for erythropoietin. BioDrugs. 2015;29:285–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Halim LA, Brinks V, Jiskoot W, et al. Quality and batch-to-batch consistency of original and biosimilar epoetin products. J Pharm Sci. 2016;105:542–50.

    Article  CAS  PubMed  Google Scholar 

  29. Elliott S, Egrie J, Browne J, et al. Control of rHuEPO biological activity: the role of carbohydrate. Exp Hematol. 2004;32:1146–55.

    Article  CAS  PubMed  Google Scholar 

  30. Sörgel F, Thyroff-Friesinger U, Vetter A, Vens-Cappell B, Kinzig M. Bioequivalence of HX575(recombinant human epoetin alfa) and acomparator epoetin alfa after multiple intravenous administrations: an open-label randomized controlled trial. BMC Clin Pharmacol. 2009;9:10.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lissy M, Ode M, Roth K. Comparison of the pharmacokineticand pharmacodynamic profiles of one US-marketed and two European-marketed epoetin alfa: a randomized prospective study. Drugs R D. 2011;11:61–75.

    Article  PubMed  Google Scholar 

  32. Kirkov V, Dimitrova V, Siebert-Weigel M, et al. Evaluation of the pharmacokinetics of tworecombinant human erythropoietin preparations:epoetin zeta and epoetin alfa. 1st communication:a monocentric, open, randomized, single dose, two-period crossover trial in healthy volunteers. Arzneimittelforschung. 2008;58:215–9.

    CAS  PubMed  Google Scholar 

  33. Mikhail A, Farouk M. Epoetin biosimilars in Europe: five years on. Adv Ther. 2013;30:28–40.

    Article  PubMed  Google Scholar 

  34. Brinks V, Hawe A, Basmeleh AH, et al. Quality of original and biosimilar epoetin products. Pharm Res. 2011;28:386–93.

    Article  CAS  PubMed  Google Scholar 

  35. Arnlind MH, Fryklund L, Vitols S, Bertilsson G. Biosimilar erythropoiesis-stimulating agents and the risk of developing anti-drug antibodies: a systematic review. Eur J Clin Pharmacol. 2016;72:1161–9.

    Article  CAS  PubMed  Google Scholar 

  36. Vaziri ND. Anemia and anemia correction: surrogate markers or causes of morbidity in chronic kidney disease? Nat Clin Pract Nephrol. 2008;4(8):436–45.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell’Invecchiamento, University of Campania “Luigi Vanvitelli”, Via M. Longo 50, 80138, Naples, Italy

    Roberto Minutolo, Silvio Borrelli & Luca De Nicola

  2. ASL Cagliari, Cagliari, Italy

    Piergiorgio Bolasco

  3. Medical Statistics Unit, University of Campania, Luigi Vanvitelli, Naples, Italy

    Paolo Chiodini

  4. Apuane Hospital, Massa, Italy

    Stefano Sposini

  5. Castelli Hospital, Verbania, Italy

    Maurizio Borzumati

  6. S. Giacomo Apostolo Hospital, Castelfranco Veneto, Italy

    Cataldo Abaterusso & Alessandra A. Mele

  7. University of Messina, Messina, Italy

    Domenico Santoro & Valeria Canale

  8. L. Parodi Delfino Hospital, Colleferro, Italy

    Alberto Santoboni

  9. Sant’Andrea Hospital, Vercelli, Italy

    Oliviero Filiberti

  10. Rovigo Hospital, Rovigo, Italy

    Fulvio Fiorini

  11. Santa Maria alla Gruccia Hospital, Montevarchi, Italy

    Carlo Mura

  12. Arezzo Hospital, Arezzo, Italy

    Patrizio Imperiali

  13. University “Federico II”, Naples, Italy

    Luigi Russo & Domenico Russo

Authors
  1. Roberto Minutolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Piergiorgio Bolasco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paolo Chiodini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefano Sposini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maurizio Borzumati
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cataldo Abaterusso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alessandra A. Mele
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Domenico Santoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Valeria Canale
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alberto Santoboni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Oliviero Filiberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fulvio Fiorini
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Carlo Mura
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Patrizio Imperiali
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Silvio Borrelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Luigi Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Luca De Nicola
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Domenico Russo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Minutolo.

Ethics declarations

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Funding

None.

Conflict of interest

Roberto Minutolo has received payment for lectures from Amgen and Roche, and a travel grant from Janssen. Luca De Nicola has received payment for lectures from Janssen and Roche. Domenico Russo has received payment for lectures from Amgen, Janssen, and Kerix. Piergiorgio Bolasco, Paolo Chiodini, Stefano Sposini, Maurizio Borzumati, Cataldo Abaterusso, Alessandra A. Mele, Domenico Santoro, Valeria Canale, Alberto Santoboni, Oliviero Filiberti, Fulvio Fiorini, Carlo Mura, Patrizio Imperiali, Silvio Borrelli, and Luigi Russo have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Minutolo, R., Bolasco, P., Chiodini, P. et al. Effectiveness of Switch to Erythropoiesis-Stimulating Agent (ESA) Biosimilars versus Maintenance of ESA Originators in the Real-Life Setting: Matched-Control Study in Hemodialysis Patients. Clin Drug Investig 37, 965–973 (2017). https://doi.org/10.1007/s40261-017-0562-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40261-017-0562-8

Search

Navigation