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In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study

  • Ylenia IngrasciottaEmail author
  • Valeria Belleudi
  • Francesco Trotta
  • Antonio Addis
  • Andrea Fontana
  • Alessandro Chinellato
  • Valentina Ientile
  • Daniele Ugo Tari
  • Giuseppe Roberto
  • Maurizio Pastorello
  • Salvatore Scondotto
  • Pasquale Cananzi
  • Giuseppe Traversa
  • Marina Davoli
  • Mariangela Rossi
  • Gianluca Trifirò
  • On behalf of the Italian Biosimilars Network (I-BioNetwork)
Original Research Article


Background and objectives

Switching between different erythropoiesis-stimulating agents (ESAs) during the first year of therapy is frequent (15–20%), much more so toward reference products than biosimilars. The objectives of this study were to investigate the frequency and identify the potential predictors of switching between biosimilar and originator ESAs during the first year of treatment in patients with chronic kidney disease (CKD), or chemotherapy-related anemia from six large Italian geographic areas in the years 2009–2015.


A retrospective cohort study was conducted using six Italian regional claims databases (≥ 13 million inhabitants) during 2009–2015. Among incident epoetin users, the frequency of single, multiple, and backward switch during the first year of treatment was evaluated. Using frailty Cox models, potential predictors of first switch were identified. All analyses were stratified by the main indications for use.


Among 102,240 incident epoetin users, 15,853 (15.5%) switched to another epoetin during the first year of therapy; only 18% of these switched to biosimilars. Single switch was more common (62.2% of the switchers) than multiple (23.5%) or backward switch (14.3%). In cancer, the cumulative number of transfusions and iron preparations dispensed, as well as hyperparathyroidism, were predictors of switching. In CKD, the cumulative number of transfusions, number of vitamin A/D preparations dispensed, and CKD severity increased the probability of switching.


Switching between ESAs was frequent in both CKD and cancer patients. The number of cumulative transfusions and severity of disease seemed to affect the switch.



Ylenia Ingrasciotta, Valentina Ientile, Alessandro Chinellato, Michele Tari, Giuseppe Roberto, Andrea Fontana, Maurizio Pastorello, Salvatore Scondotto, Pasquale Cananzi, Giuseppe Traversa, Marina Davoli, Francesco Trotta, Valeria Belleudi, Antonio Addis, Domenico Santoro, and Gianluca Trifirò are members of the I-BioNetwork. The authors thank Achille P. Caputi, Jenny Bolcato, Rosa Gini, Roberta Pirolo, Pastorello, Ilaria Uomo, Sebastiano W. Pollina Addario, Roberto Da Cas, Mariangela Rossi, and Armando Genazzani, who are also members of the I-BioNetwork.

Author contributions

GTri, YI, VB, FT, and AA generated the study idea. YI wrote the final manuscript. VI, AF, and YI performed the data analysis. MR, VB, AC, GR, MP, SS, and GTra extracted the data and authorized their utilization. DS, GTri, and YI assisted in interpreting the results from a clinical perspective. All authors assisted interpretation of the results and manuscript revision and read and approved the final manuscript.

Compliance with Ethical Standards


This study was conducted in the context of the finalized research project “Assessment of Short and Long Term Risk–Benefit Profile of Biologics through Healthcare Database Network in Italy” (RF-2010-2320172), which was funded by the Italian Health Ministry. The financial assistance was used to access and analyze data from different partners.

Conflict of interest

Gianluca Trifirò declares his participation in advisory boards on biosimilars, organized by Sandoz and Hospira; furthermore, he coordinates a pharmacoepidemiology research team at the University of Messina, which receives research grants for projects that are not related to the topic of the paper. Ylenia Ingrasciotta, Valeria Belleudi, Francesco Trotta, Antonio Addis, Andrea Fontana, Alessandro Chinellato, Valentina Ientile, Daniele Ugo Tari, Giuseppe Roberto, Maurizio Pastorello, Salvatore Scondotto, Pasquale Cananzi, Giuseppe Traversa, Marina Davoli, and Mariangela Rossi declare that they have no conflicts of interest that might be relevant to the contents of this study.

Ethical approval

This study was conducted in the context of the “Assessment of Short and Long Term Risk–Benefit Profile of Biologics through Healthcare Database Network in Italy” project, funded by the Italian Ministry of Health. The study protocol was notified to the Ethical Committee of the Academic Hospital of Messina [31], according to the current national law. The manuscript does not contain clinical studies or patient data. For this type of study formal consent is not required.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ylenia Ingrasciotta
    • 1
    Email author
  • Valeria Belleudi
    • 2
  • Francesco Trotta
    • 3
  • Antonio Addis
    • 2
  • Andrea Fontana
    • 4
  • Alessandro Chinellato
    • 5
  • Valentina Ientile
    • 1
  • Daniele Ugo Tari
    • 6
  • Giuseppe Roberto
    • 7
  • Maurizio Pastorello
    • 8
  • Salvatore Scondotto
    • 9
  • Pasquale Cananzi
    • 10
  • Giuseppe Traversa
    • 11
  • Marina Davoli
    • 2
  • Mariangela Rossi
    • 12
  • Gianluca Trifirò
    • 1
    • 13
  • On behalf of the Italian Biosimilars Network (I-BioNetwork)
  1. 1.Department of Biomedical and Dental Sciences and Morphofunctional ImagingUniversity of MessinaMessinaItaly
  2. 2.Department of EpidemiologyLazio Regional Health ServiceRomeItaly
  3. 3.Italian Medicines AgencyRomeItaly
  4. 4.Unit of BiostatisticsCasa Sollievo della SofferenzaSan Giovanni RotondoItaly
  5. 5.Pharmaceutical ServiceLocal Health Authority (ULSS9)TrevisoItaly
  6. 6.Caserta-1 Local Health ServiceCasertaItaly
  7. 7.Epidemiology UnitRegional Agency for Healthcare Services of TuscanyFlorenceItaly
  8. 8.Department of PharmacyPalermo Local Health UnitPalermoItaly
  9. 9.Department of Epidemiologic ObservatoryHealth Department of SicilyPalermoItaly
  10. 10.Sicilian Regional Centre of Pharmacovigilance, Servizio 7-FarmaceuticaHealth Department of SicilyPalermoItaly
  11. 11.Pharmacoepidemiology Unit, National Centre for EpidemiologyItalian National Institute of HealthRomeItaly
  12. 12.Health-Unit for Pharmaceutical GovernancePerugiaItaly
  13. 13.Unit of Clinical PharmacologyA.O.U. Policlinico “G. Martino”MessinaItaly

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