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Empirical rescue treatment of Helicobacter pylori infection in third and subsequent lines: 8-year experience in 2144 patients from the European Registry on H. pylori management (Hp-EuReg)
  1. Diego Burgos-Santamaría1,2,
  2. Olga P Nyssen3,4,5,6,
  3. Antonio Gasbarrini7,8,
  4. Dino Vaira9,
  5. Ángeles Pérez-Aisa10,11,
  6. Luís Rodrigo12,
  7. Rinaldo Pellicano13,
  8. Alma Keco-Huerga14,
  9. Manuel Pabón-Carrasco14,
  10. Manuel Castro-Fernandez14,15,
  11. Doron Boltin16,
  12. Jesus Barrio17,
  13. Perminder Phull18,
  14. Juozas Kupcinskas19,
  15. Laimas Jonaitis19,
  16. Inmaculada Ortiz-Polo20,
  17. Bojan Tepes21,
  18. Alfredo J Lucendo22,
  19. José María Huguet23,
  20. Miguel Areia24,
  21. Natasa Brglez Jurecic25,
  22. Maja Denkovski25,
  23. Luís Bujanda26,27,
  24. June Ramos-San Román26,
  25. Antonio Cuadrado-Lavín28,
  26. Judith Gomez-Camarero29,
  27. Manuel Alfonso Jiménez Moreno29,
  28. Angel Lanas30,
  29. Samuel Jesús Martinez-Dominguez30,
  30. Enrique Alfaro30,
  31. Ricardo Marcos-Pinto31,32,
  32. Vladimir Milivojevic33,34,
  33. Theodore Rokkas35,
  34. Marcis Leja36,37,
  35. Sinead Smith38,
  36. Ante Tonkić39,
  37. György Miklós Buzás40,
  38. Michael Doulberis41,42,
  39. Marino Venerito43,
  40. Frode Lerang44,
  41. Dmitry S Bordin45,46,
  42. Vincent Lamy47,
  43. Lisette G Capelle48,
  44. Wojciech Marlicz49,
  45. Daniela Dobru50,
  46. Oleksiy Gridnyev51,
  47. Ignasi Puig52,53,
  48. Francis Mégraud54,
  49. Colm O'Morain55,
  50. Javier P Gisbert3,4,5,6
  51. On behalf of the Hp-EuReg Investigators
    1. 1Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Madrid, Spain
    2. 2Enfermedades Hepáticas y Digestivas, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain
    3. 3Gastroenterology Unit, Hospital Universitario de la Princesa, Madrid, Spain
    4. 4Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Madrid, Spain
    5. 5Universidad Autónoma de Madrid (UAM), Madrid, Spain
    6. 6Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
    7. 7Internal Medicine, Gastroenterology and Liver Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
    8. 8Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy
    9. 9Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
    10. 10Department of Gastroenterology, Hospital Costa del Sol Marbella, Marbella, Spain
    11. 11Redes de Investigación Cooperativa Orientada a Resultados en Salud (RICORS), Marbella, Spain
    12. 12Department of Gastroenterology, Hospital Universitario Central de Asturias, Oviedo, Spain
    13. 13Outpatient Clinic, Molinette-SGAS Hospital, University of Turin, Turin, Italy
    14. 14Hospital Universitario Virgen de Valme, Sevilla, Spain
    15. 15Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Sevilla, Spain
    16. 16Department of Gastroenterology, Rabin Medical Center, Beilinson Campus, Tel Aviv University, Petach Tikva, Israel
    17. 17Department of Gastroenterology, Hospital Rio Hortega, Valladolid, Spain
    18. 18Aberdeen Royal Infirmary, Aberdeen, UK
    19. 19Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
    20. 20Department of Gastroenterology, Hospital Universitari i Politècnic La Fe, Valencia, Spain
    21. 21Department of Gastroenterology, AM DC Rogaska, Rogaska Slatina, Slovenia
    22. 22Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain
    23. 23Gastroenterology Unit, Consorcio Hospital General Universitario de Valencia, Valencia, Spain
    24. 24Francisco Gentil Portuguese Institute for Oncology of Coimbra, Coimbra, Portugal
    25. 25Interni oddelek Diagnostic Centre, Bled, Slovenia
    26. 26Department of Gastroenterology, Hospital Universitario de Donostia, San Sebastian, Spain
    27. 27Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), San Sebastián, Spain
    28. 28Department of Gastroenterology and Hepatology, Hospital Universitario Marques de Valdecilla, Santander, Spain
    29. 29Gastroenterology, Hospital Universitario de Burgos, Burgos, Spain
    30. 30Department of Gastroenterology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
    31. 31Department of Gastroenterology, Centro Hospitalar do Porto, Porto, Portugal
    32. 32CINTESIS, University of Porto Institute of Biomedical Sciences Abel Salazar, Porto, Portugal
    33. 33University Clinical Center of Serbia Clinic for Gastroenterology and Hepatology, Belgrade, Serbia
    34. 34School of Medicine, University of Belgrade, Belgrade, Serbia
    35. 35Department of Gastroenterology, Henry Dunant Hospital Center, Athens, Greece
    36. 36Digestive Disease Center GASTRO, Institute of Clinical and Preventive Medicine, Riga, Latvia
    37. 37University of Latvia Faculty of Medicine, Riga, Latvia
    38. 38Department of Clinical Medicine, Trinity College Dublin, Dublin, Ireland
    39. 39Department of Gastroenterology, University Hospital Center Split Križine, Split, Croatia
    40. 40Department of Gastroenterology, Ferencváros Health Centre, Budapest, Hungary
    41. 41Division of Gastroenterology and Hepatology, Kantonsspital Aarau AG, Aarau, Switzerland
    42. 42Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland
    43. 43Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
    44. 44Department of Gastroenterololgy, Ostfold Hospital, Gralum, Norway
    45. 45Department of Pancreatic, Biliary and Upper Digestive Tract disorders, AS Loginov Moscow Clinical Scientific Center, Moscow, Russian Federation
    46. 46A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russian Federation
    47. 47CHU de Charleroi, Charleroi, Belgium
    48. 48Department of Gastroenterology and Hepatology, Erasmus University Medical Centre, Rotterdam, The Netherlands
    49. 49Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
    50. 50Department of Gastroenterology, University of Medicine, Pharmacy, Science, and Technology of Târgu Mures, Târgu Mures, Romania
    51. 51National Academy of Medical Sciences of Ukraine, Kiiv, Ukraine
    52. 52Department of Digestive Diseases, Althaia, Xarxa Assistencial Universitària de Manresa, Manresa, Spain
    53. 53Universitat de Vic-Universitat Central de Catalunya (UVicUCC), Manresa, Spain
    54. 54INSERM U1312, Université de Bordeaux, Bordeaux, France
    55. 55Department of Gastroenterology, Trinity College Dublin, Dublin, Ireland
    1. Correspondence to Dr Diego Burgos-Santamaría, Department of Gastroenterology and Hepatology, Hospital Universitario Ramón y Cajal, Madrid, Madrid, Spain; diegoburgossantamaria{at}gmail.com

    Abstract

    Objective To evaluate the use, effectiveness and safety of Helicobacter pylori empirical rescue therapy in third and subsequent treatment lines in Europe.

    Design International, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociación Española de Gastroenterología-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis.

    Results Overall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed >90% of cases. Overall effectiveness remained <90% in all therapies. Optimised treatments achieved a higher eradication rate than non-optimised (78% vs 67%, p<0.0001). From 2017 to 2021, only 44% of treatments other than 10-day single-capsule therapy used high proton-pump inhibitor doses and lasted ≥14 days. Quadruple therapy containing metronidazole, tetracycline and bismuth achieved optimal eradication rates only when prescribed as third-line treatment, either as 10-day single-capsule therapy (87%) or as 14-day traditional therapy with tetracycline hydrochloride (95%). Triple amoxicillin-levofloxacin therapy achieved 90% effectiveness in Eastern Europe only or when optimised. The overall incidence of adverse events was 31%.

    Conclusion Empirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update.

    Trial registration number NCT02328131.

    • Helicobacter pylori
    • antibiotic therapy
    • drug resistance
    • proton pump inhibition
    • antibiotics

    Data availability statement

    Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information. The data supporting the conclusions of this study are not publicly available, as their content may compromise the privacy of research participants. However, previously published data from the Hp-EuReg study, or de-identified raw data referring to the current study, as well as further information on the methods used to explore the data, may be shared, with no particular time constraint. Individual participant data will not be shared.

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    Data availability statement

    Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. All data relevant to the study are included in the article or uploaded as supplementary information. The data supporting the conclusions of this study are not publicly available, as their content may compromise the privacy of research participants. However, previously published data from the Hp-EuReg study, or de-identified raw data referring to the current study, as well as further information on the methods used to explore the data, may be shared, with no particular time constraint. Individual participant data will not be shared.

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    Footnotes

    • Twitter @marlicz

    • Collaborators The Hp-EuReg Investigators: Noelia Alcaide, Benito Velayos, Luis Fernández-Salazar, Jorge Pérez Lasala, Xavier Calvet, Blas José Gómez Rodríguez, Ian L P Beales, Manuel Domínguez-Cajal, Mónica Perona, Sotirios Georgopoulos, Debora Compare, Renate Bumane, Pedro Almela, Óscar Núñez, Marinko Marusic, José María Botargues Bote, Javier Tejedor-Tejada, Miguel Fernandez-Bermejo, Irina Voynovan, Luisa Carmen de la Peña-Negro, Xavier Segarra Ortega, Jesús M González-Santiago, Deidre McNamara, Debora Compare, Ramon Pajares Villarroya, Eduardo Iyo, Bárbara Gómez, Alexander Link, Rosa Rosania, Marino Venerito, Peter Malfertheiner, Alisan Kahraman, Óscar Núñez, Matteo Ghisa, Natalia Nikolaevna Dekhnich, Marko Nikolic, Javier Alcedo, Itxaso Jiménez Iragorri, Fernando Bermejo, Alicia Algaba, Ana Campillo, Rustam Abdulkhakov, Ludmila Grigorieva, Galina Fadeenko, Joana Alves da Silva, Sergey Alekseenko, Oleg Zaytsev, Tatiana Ilchishina, Anna Pakhomova, José María Huguet-Malavés, Edurne Amorena, Liya Nikolaevna Belousova, Ekaterina Yuryevna Plotnikova, Liudmila Vologzhanina, Natalia Bakanova, Liya Nikolaevna Belousova, Tanja Novica Stovrag, Ivan Nagorni, Milica Bjelakovic.

    • Contributors DB-S: Spanish recruiter. Reviewed the quality of the database, performed the statistical analysis, synthesised the data, interpreted the data, wrote the manuscript drafts and approved the submitted manuscript. OPN: Scientific Director and member of the Scientific Committee. Planned and coordinated the study, designed and programmed the electronic case report form, performed the data extraction, the monitoring and the dataset quality check, supervised the statistical analysis and reviewed the data interpretation, critically reviewed the manuscript drafts and approved the submitted manuscript. AG, DB, PP, JK, BT, RM-P, VM, TR, ML, AT, DSB, VL, LGC, DD, OG, MD, FL, GMB, SS, MV and WM: acted as national coordinators for their country and as recruiters. Selected national recruiters, collected and helped interpret data, critically reviewed the manuscript drafts and approved the submitted manuscript. IP: Scientific Director and member of the project’s Scientific Committee. Critically reviewed the manuscript drafts and approved the submitted manuscript. FM: member of the Scientific Committee. Designed the protocol, critically reviewed the manuscript drafts and approved the submitted manuscript. CO’M: member of the Scientific Committee. Designed the protocol, collected the data, critically reviewed the manuscript drafts and approved the submitted manuscript. JPG: Principal Investigator, member of the Scientific Committee and guarantor of the study. Directed the project, obtained funding, designed the protocol, planned the study, acted as Spanish National Coordinator, recruited patients, interpreted the data, critically reviewed the manuscript drafts and approved the final submitted manuscript.

    • Funding This project was supported and funded by the European Helicobacter and Microbiota Study Group (EHMSG), the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).

    • Competing interests OPN has received research funding from Mayoly and Allergan. JPG has served as speaker, consultant and advisory member for or has received research funding from Mayoly, Allergan, Diasorin, Gebro Pharma and Richen. MC-F has received retribution from Allergan for formative actions. AP-A has received retribution from Allergan and Mylan for formative actions. Laimas Jonaitis has served as speaker for KRKA. AL has served as a consultant to Bayer.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.