Article Text

Original research
European Registry on Helicobacter pylori management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients
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  1. Olga P Nyssen1,
  2. Dmitry Bordin2,3,
  3. Bojan Tepes4,
  4. Ángeles Pérez-Aisa5,
  5. Dino Vaira6,
  6. Maria Caldas1,
  7. Luis Bujanda7,
  8. Manuel Castro-Fernandez8,
  9. Frode Lerang9,
  10. Marcis Leja10,
  11. Luís Rodrigo11,
  12. Theodore Rokkas12,
  13. Limas Kupcinskas13,
  14. Jorge Pérez-Lasala14,
  15. Laimas Jonaitis13,
  16. Oleg Shvets15,
  17. Antonio Gasbarrini16,
  18. Halis Simsek17,
  19. Anthony T R Axon18,
  20. György Buzás19,
  21. Jose Carlos Machado20,
  22. Yaron Niv21,
  23. Lyudmila Boyanova22,
  24. Adrian Goldis23,
  25. Vincent Lamy24,
  26. Ante Tonkic25,
  27. Krzysztof Przytulski26,
  28. Christoph Beglinger27,
  29. Marino Venerito28,
  30. Peter Bytzer29,
  31. Lisette Capelle30,
  32. Tomica Milosavljević31,
  33. Vladimir Milivojevic31,
  34. Lea Veijola32,
  35. Javier Molina-Infante33,
  36. Liudmila Vologzhanina34,
  37. Galina Fadeenko35,
  38. Ines Ariño36,
  39. Giulia Fiorini6,
  40. Ana Garre1,
  41. Jesús Garrido37,
  42. Cristina F Pérez38,
  43. Ignasi Puig39,
  44. Frederic Heluwaert40,
  45. Francis Megraud41,
  46. Colm O'Morain42,
  47. Javier P Gisbert1
  48. On behalf of the Hp-EuReg Investigators
    1. 1 Gastroenterolgy Department, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid (UAM), Centro de Investigacion Biomedica en Red de Enfermedades Hepaticas y Digestivas (CIBEREHD), Madrid, Spain
    2. 2 Department of Pancreatic, Biliary and Upper Digestive Tract Disorders, AS Loginov Moscow Clinical Scientific Center, Moscow, Russian Federation
    3. 3 A.I. Yevdokimov Moscow State University of Medicine and Dentistry, Moscow, Russian Federation
    4. 4 Gastroenterology, AM DC Rogaska, Rogaska Slatina, Slovenia
    5. 5 Gastroenterology, Agencia Sanitaria Costa del Sol, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), Marbella, Spain
    6. 6 Department of of Surgical and Medical Sciences, University of Bologna, Bologna, Italy
    7. 7 Gastroenterology, Hospital Donostia/Instituto Biodonostia, Universidad del País Vasco (UPV/EHU), CIBEREHD, San Sebastian, Spain
    8. 8 Gastroenterology, Hospital de Valme, CIBEREHD, Sevilla, Spain
    9. 9 Gastroenterololgy, Østfold Hospital Trust, Grålum, Norway
    10. 10 Digestive Diseases Centre GASTRO, Institute of Clinical and Preventive Medicine & Faculty of Medicine, University of Latvia, Riga, Latvia
    11. 11 Gastroenterology, Hospital Universitario Central de Asturias, Oviedo, Spain
    12. 12 Gastroenterology, Henry Dunant Hospital, Athens, Greece
    13. 13 Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania
    14. 14 Gastroenterology, HM Sanchinarro, Madrid, Spain
    15. 15 Internal Medicine, National Medical University named after O.O.Bogomolets, Kyiv, Ukraine
    16. 16 Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
    17. 17 Internal Medicine/Gastroenterology, Hacettepe University Faculty of Medicine, Ankara, Turkey
    18. 18 Gastroenterology, Leeds General Infirmary, Leeds, UK
    19. 19 Gastroenterology, Ferencváros Health Centre, Budapest, Hungary
    20. 20 i3S - Instituto de Investigação e Inovação em Saúde. Medical Faculty of Porto. Universidade do Porto, Porto, Portugal
    21. 21 Gastroenterology, Rabin Medical Center, Tel Aviv University, Petah Tikva, Israel
    22. 22 Medical Microbiology, Medical University of Sofia, Sofia, Bulgaria
    23. 23 Gastroenterology, Timisoara Hospital, Timisoara, Romania
    24. 24 Gastroenterology, Hepatology & Nutrition, CHU de Charleroi, Charleroi, Belgium
    25. 25 Gastroenterology, University Hospital of Split, University of Split, Split, Croatia
    26. 26 Gastroenterology, Medical Centre for Postgraduate Education, Warsaw, Poland
    27. 27 Gastroenterology, University Hospital Basel, Basel, Switzerland
    28. 28 Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
    29. 29 Clinical Medicine, Zealand University Hospital, Copenhagen University, Copenhagen, Denmark
    30. 30 Gastroenterology and Hepatology, Meander Medical Center, Amersfoort, Netherlands
    31. 31 Clinic for Gastroenterology and Hepatology, Clinical Center of Serbia and School of Medicine, University of Belgrade, Belgrade, Serbia
    32. 32 Internal Medicine, Herttoniemi Hospital, Helsinki, Finland
    33. 33 Gastroenterology, Hospital San Pedro de Alcántara, CIBEREHD, Cáceres, Spain
    34. 34 Gastroenterology, Gastrocentr, Perm, Russian Federation
    35. 35 Gastroenterology, Digestive Ukrainian Academy of Medical Sciences, Kyiv, Ukraine
    36. 36 Gastroenterology, Hospital Clinico Universitario Lozano Blesa, CIBEREHD, Zaragoza, Spain
    37. 37 Departmento de Psicología Social y Metodología, Facultad de Psicología, Universidad Autónoma de Madrid, Madrid, Spain
    38. 38 Servicio de Medicina Preventiva, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain
    39. 39 Gastroenterology, Althaia Xarxa Assistencial Universitària de Manresa and Universitat de Vic-Universitat Central de Catalunya (UVicUCC), Manresa, Spain
    40. 40 Centre Hospitalier Annecy Genevois, Pringy, France
    41. 41 Laboratoire de Bactétiologie, Hôpital Pellegrin, Bordeaux, France
    42. 42 Gastroenterology, Trinity College Dublin, Dublin, Ireland
    1. Correspondence to Dr Javier P Gisbert, Gastroenterology Department, Hospital Universitario de La Princesa, Madrid, Spain; javier.p.gisbert{at}gmail.com

    Abstract

    Objective The best approach for Helicobacter pylori management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care.

    Design International multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in H. pylori management by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed.

    Results 30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical H. pylori treatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%–90%).

    Conclusion Management of H. pylori infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness.

    • helicobacter pylori
    • helicobacter pylori - treatment
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    Significance of this study

    What is already known on this subject?

    • Helicobacter pylori affects billions of people worldwide and is the main cause of chronic gastritis, peptic ulcer disease and gastric cancer.

    • The ideal regimen to treat the infection remains unclear after more than 30 years of experience.

    What are the new findings?

    • Triple therapy prescriptions (reporting cure rates of approximately 80%) have decreased, especially in those regions with high-clarithromycin resistance.

    • Over 90% eradication was only obtained with 10-day bismuth quadruple therapies or 14-day concomitant treatment.

    • From 2013 to 2018, the observed shift to longer treatment duration, higher acid inhibition and compliance provided an increase in the effectiveness.

    How might it impact on clinical practice in the foreseeable future?

    • The results of this study indicate that the management of H. pylori infection by European gastroenterologists is heterogeneous, frequently suboptimal and discrepant with current recommendations. Consensus guideline improvements are being slowly incorporated into the daily clinical practice, which emphasises the importance of regular medical education and the need of surveillance.

    Introduction

    Helicobacter pylori (H. pylori) is a bacterial pathogen with a 50% worldwide prevalence, being the main cause of chronic gastritis, peptic ulcer disease and gastric cancer. However, the ideal strategy to manage H. pylori infection remains unclear. The diagnostic method, the use of culture and antibiotic susceptibility testing, the treatment to prescribe and the test to confirm eradication are debatable, and recommendations have changed over time.1–5 Currently, most treatments are prescribed on an empiric basis, unaware of the bacterial antibiotic resistance profile. Noteworthy, recommendations have changed over time, with a shift from triple to quadruple therapies in the last consensus conferences.5 6 Therefore, a continuous evaluation of practice outcomes using the different management options is required in order to achieve high-quality ‘evidence-based medicine’.

    It is now accepted that chronic colonisation by H. pylori is an infectious disease and should be managed as such.7 For this reason, an optimal anti-H. pylori regimen is currently defined as one that reliably offers a cure rate of at least 90%, accepted as an arbitrary threshold.8 9 Triple therapies, using clarithromycin and amoxicillin, are still the most commonly used first-line therapies in spite of their failure in ≥20%–30% of patients. Resistance to clarithromycin has been identified as one of the major factors affecting H. pylori eradication success, and the rate of resistance to this antibiotic is steadily increasing in many geographical areas.10 For this reason, non-bismuth quadruple regimen, comprising a proton pump inhibitor (PPI), amoxicillin, clarithromycin and a nitroimidazole, has more recently been used as first-line treatment,5 6 11 12 and has improved the efficacy of triple therapy,13 although its efficacy is impaired when dual metronidazole-clarithromycin resistance is present.

    Bismuth has a strong bacteriostatic effect unaffected by resistance and displays a beneficial synergy when combined with several antibiotics, allowing to overcome bacterial resistance.14 15 Thus, combinations containing bismuth may be promising options in settings where there are high, unknown or increasing H. pylori antibiotic resistance rates. Traditionally, bismuth has been prescribed in a quadruple regimen containing a PPI with tetracycline and metronidazole. However, the treatment schemes are complex, and bismuth salts and tetracycline are not available in many parts of the world; therefore, these drawbacks have caused a tendency to restrict its use to patients with penicillin allergy, or those who require rescue treatments after failure of a clarithromycin-containing first-line treatment.16 17 The latest approach to H. pylori eradication has been the addition of bismuth to the standard triple therapy containing clarithromycin and amoxicillin, and this has also achieved encouraging results.18

    Considering these treatment combinations, and all of the possible optimisations that can be added (length of treatment,19 dose of PPI,20 among others), it is hard to decide which treatment will provide good results (≥90% cure rates) aligned with current recommendations and standards. Evidence from clinical trials will always be equivocal because it is impossible to perform a single randomised trial to evaluate all existing treatments. Network meta-analyses, however, may provide an acceptable pooled approach enabling analysis of combinations of data from several treatment trials. However, evidence derived from clinical trials may not be extrapolated to clinical practice, in which there are no restrictive inclusion criteria, and where available care-time per patient and patient follow-up are more limited.21

    Finally, there is a general delay from publication of recommendations to their implementation in routine clinical practice,22 23 in which sometimes they reach full penetration after being outdated.24 Therefore, scientists recommend long-term studies evaluating practice and outcome trends, and tools able to provide real-time data from real practice (local, regional and global).25

    The European Registry on Helicobacter pylori management (Hp-EuReg) brings together information on the real clinical practice of a majority of European countries, including thousands of patients with different bacterial resistance patterns and treatment accessibility. For these reasons, our aim was to establish a large-scale long-term prospective clinical practice study providing an overview of the current situation regarding H. pylori management. The study would allow not only continuous assessment on the integration of clinical recommendations agreed on medical consensus but also monitoring of the temporal trends of management options and outcomes. These evaluations were aimed to decide on the best possible treatment strategies for improvement (globally and locally) ensuring that routine clinical practice is aligned with best standards of care.

    Methods

    European Registry on H. pylori management

    The ‘European Registry on H. pylori Management’ (Hp-EuReg) is an international multicentre prospective non-interventional registry recording information of H. pylori infection management since May 2013. Detailed information can be found in the published protocol,26 and is summarised in online supplementary file 2.

    Supplemental material

    Statistical analyses

    Continuous variables are presented as mean and SD. Qualitative variables are presented as absolute and relative frequencies with percentages (%). Graphical representations are used to show temporal trends in prescriptions. In the multivariate analysis, the effect was evaluated by calculating OR) and 95% CI. Statistical significance was considered at p<0.05.

    Effectiveness analysis

    The main outcome, which is treatment eradication rate, was studied in three sets of patients as follows: Intention-to-treat (ITT) analysis included all patients registered up to December 2017, to allow at least a 6-month follow-up, and lost to follow-up cases were considered treatment failures. Per-protocol (PP) analysis included all cases that finished follow-up and had taken at least 90% of the treatment drugs, as defined in the protocol. A modified ITT (mITT) was designed aiming to reach the closest result to those obtained in clinical practice. This mITT included for analyses all cases that had completed follow-up (ie, a confirmatory test—success or failure—was available after eradication treatment). Overall (ITT, mITT and PP) analyses were performed jointly for patients treated empirically. Additional PP effectiveness analyses were performed separately in those patients with a result of in vitro susceptibility testing.

    All 27 countries were clustered in five main regions based both on their geographical situation and the 2017 gross domestic product per capita (online supplementary file 3).

    More than 100 different treatment schemes were used as first-line treatment. They were pooled in 13 categories (online supplementary file 4).

    Similarly, PPI data were standardised using the PPI acid inhibition potency as defined by Kirchheiner27 and Graham,28 29 classified as low, standard and high dose PPI (online supplementary file 5).

    The relation between eradication rate and age, gender, diagnosis, treatment length, PPI dose and compliance was studied in the mITT population considering six treatment categories (online supplementary file 6).

    Mixed logistic regression models were used in a three-step strategy: the null model, the global mixed model with interaction between compliance and treatment and the mixed effects logistic regression for each treatment (online supplementary file 7).

    Results

    From May 2013 to June 2018, 30 394 cases were registered in the Hp-EuReg from 27 countries (distribution of patients per country is shown in online supplementary table 1). From those, 21 533 (91%) were first-line therapies included in the current analysis (figure 1). Most of them were empirically treated; however, in 11% of the cases, bacterial antibiotic resistance data were available and were evaluated separately.

    Figure 1

    Study flow chart. ITT, intention-to-treat, mITT, modified ITT; PP, per-protocol.

    Geographical analysis

    The 21 533 naïve patients were distributed in the following five geographical regions: east (3679), south-east (4299), south-west (10 118), centre (1985) and north (1452). The baseline characteristics are shown in table 1. A preliminary inspection showed high heterogeneity of practice and outcomes between European regions. For instance, 7-day treatment prescription was marginal in south-western Europe (1.7%), while it was mostly prescribed in south-eastern (60.0%) and northern (53.9%) regions. Most common treatments were also region specific: triple therapies were favoured in most of Europe (82%–88% in south-eastern and northern Europe, 67% in the east and 34% in south-west), whereas quadruple therapies were preferred in south-western and central Europe (63%–82%). Results of an additional cluster comparison performed between regions and the highest recruiting countries are presented in online supplementary table 2.

    Table 1

    Baseline characteristics of Helicobacter pylori first-line empirical treatments by region

    Baseline characteristics

    Overall baseline characteristics, regional demographics and concomitant drug use are presented in table 1.

    Diagnosis

    Methods used for diagnosis of the infection and confirmation of eradication are detailed in online supplementary file 8.

    Temporal trend analysis

    Figure 2A shows the prescription trends in Europe, where prescription shifts were region dependent: triple therapies did nearly disappear in south-western and central Europe, while they remained in the east, south-east and north. Triple therapies decreased from over 50% of prescription in 2013/2015 to less than 32% in 2017/2018. Sequential therapies were prescribed in 8% in 2013 but yearly prescriptions were reduced up to 0.5% in 2018, and concomitant therapy from 21% in 2013/2014 to 11% in 2018. Use of bismuth quadruple therapies increased from 0%–2% in 2013/2014 to 20% in 2018.

    Figure 2

    Treatment trends (2013–2018) in Europe per region. (A) Trends in the prescription of treatments. (B) Trends in the duration of treatments. A, amoxicillin; B, bismuth salts; C, clarithromycin; Conc, concomitant; D, doxycycline; L, levofloxacin; M, metronidazole; PPI, proton pump inhibitor; Seq, sequential; T, tinidazole; Tc, tetracycline.

    Figure 2B depicts the trends on treatment duration, showing an increase in mean duration of treatments from 9.6 days in 2013, to 9.7 in 2014, 10.0 in 2015, 11.0 in 2016, 11.8 in 2017 and 11.8 days in 2018, with regional differences. A major change that appeared to consistently occur throughout Europe was the discontinuation of 7-day therapies, especially in south-eastern and northern Europe, where it was still the most common therapy duration; however, 7-day therapies were scarcely used in other regions (online supplementary table 3).

    Figure 3A shows the trends in daily PPI dose (milligrams of omeprazole equivalent) by region and year, whereas figure 3B shows the temporal trends in mean daily PPI dose. The potency of acid inhibition increased from a dose equivalent of 58 mg of omeprazole in 2013 to 75 mg in 2018, showing differences between regions. Mean daily dose of PPI increased in all regions except in central Europe where it decreased in 2017–2018. High doses of PPI were mainly used in south-eastern, south-western and northern Europe (online supplementary table 3).

    Figure 3

    Trends (2013–2018) in the use of proton pump inhibitors (PPIs) in Europe per region. (A) Trends in the daily dose (low, standard and high) of PPI. (B) Trends in the mean daily dose of PPI.

    Treatment use and overall effectiveness

    Overall eradication rate increased from 2013 to 2018 independently of the population analysed:

    • ITT: 70.1% (2013), 72.6% (2014), 74.5% (2015), 76.7% (2016), 75.2% (2017), 77.3% (2018).

    • PP: 84.5% (2013), 85.1% (2014), 85.7% (2015), 87.4% (2016), 88.6% (2017), 88.1% (2018).

    • mITT: 83.9% (2013), 84.5% (2014), 85.2% (2015), 86.8% (2016), 88.3% (2017), 87.8% (2018).

    The effectiveness trends were region-specific (figure 4): Eastern Europe reported eradication rates lower than 70% in 2013 and 2014, but achieved 80% mITT in the following years. The remaining regions reported an overall treatment effectiveness higher than 80% in 2013. These rates increased in south-eastern and south-western countries, but remained constant in the centre and north.

    Figure 4

    Trends in the eradication rate (modified intention-to-treat) by region.

    The effectiveness trends also appeared to be treatment dependent in each region (table 2).

    Table 2

    Effectiveness of most common first-line empirical treatments per region

    Triple therapy with clarithromycin and amoxicillin was the most frequent treatment in all regions but its eradication rate remained below 86.6% by mITT. None of the 12 treatments considered, except the concomitant therapy with clarithromycin, amoxicillin and tinidazole in the south-east, reached 90% effectiveness by mITT, whereas quadruple treatments achieved nearly 90% eradication rate. In general, single capsule bismuth quadruple treatment was the most successful, achieving approximately 90% mITT eradication in those regions where it was prescribed.

    The effectiveness was likewise modified depending on the duration of treatment. Table 3 shows the impact of treatment duration (7, 10 or 14 days). Overall, effectiveness increased with longer treatment duration; and this was mostly marked with specific treatments, such as the triple therapy with clarithromycin and amoxicillin or when bismuth was added to this triple regimen.

    Table 3

    Effectiveness of first-line empirical treatments according to duration

    An additional univariate subanalysis was performed to evaluate the effect of standard (recommended) or high dose PPI in those 14-day treatments not reaching 90% effectiveness (table 3).

    Resistance rates

    Data on susceptibility tailored prescription of antibiotics are presented in Table 1 and supplementary file 9.

    The effect of resistance on eradication rate in the most frequent first-line treatments is reported in online supplementary table 4.

    Mixed effects logistic regression

    Null model

    A null model without explanatory variables was developed to assess the proportion of variance of the outcome explained by grouping the cases in a second level ‘centre’. There were 163 centres with an average of 89 cases per group. The variance of the intercept at centre level was 0.556 (SE 0.110) on the logit scale, and intraclass correlation coefficient (ICC) was 0.145; meaning the 14.5% of the variance of mITT effectiveness was explained by the differences between centres.

    Global mixed effects model with interaction between compliance and treatment

    The global mixed effects model showed a significant effect of compliance, with an OR of 6.8 (4.1 to 11.3), as well as an effect of treatment on mITT effectiveness. Using quadruple therapies with a PPI-clarithromycin-amoxicillin-bismuth as the reference category, ORs (95% CI) were as follows: triple with clarithromycin-amoxicillin 0.494 (0.39 to 0.622), triple with clarithromycin-metronidazole 0.220 (0.156 to 0.311), sequential with clarithromycin-amoxicillin-metronidazole/tinidazole 0.452 (0.305 to 0.669), concomitant with clarithromycin-amoxicillin-metronidazole/tinidazole 1.130 (0.879 to 1.453), and the single capsule bismuth quadruple 1.766 (1.240 to 2.516), showing significantly higher mITT eradication rates in quadruple therapies compared with triple or sequential therapies. The interaction between compliance and treatment was significant (p=0.02), showing that the difference in eradication rate between compliant and non-compliant patients changed from treatment to treatment. The interaction between compliance and treatments in terms of effectiveness is plotted in figure 5, which shows that independently of the treatment considered, in compliant patients, the rate of eradication (ranging between 80% and 95%) was always higher compared with non-compliant patients. The effect of non-compliance on the mITT eradication rate was lower in concomitant therapy with clarithromycin-amoxicillin-metronidazole/tinidazole and quadruple therapy with a PPI-clarithromycin-amoxicillin-bismuth than in the remaining treatments.

    Figure 5

    Eradication rate (and 95% CI) by treatment according to compliance. A, amoxicillin; B, bismuth salts; C, clarithromycin; Conc, concomitant; M, metronidazole; PPI, proton pump inhibitor; Seq, sequential; T, tinidazole.

    Mixed effects logistic regression by treatment

    The final mixed effects logistic regression models were different for each treatment considered. To compare treatments easily, a tabular summary was built detailing the first level independent variables, the random variance component and ICCs for each model (table 4), whereas the final models are described in online supplementary file 10.

    Table 4

    Mixed effects logistic models for each first-line empirical treatment category

    Discussion

    In the present manuscript, we analysed the changes in H. pylori treatment outcomes throughout a period of 5 years (2013–2018) across Europe. We found gastroenterologists’ management of H. pylori in Europe is extremely heterogeneous (over 100 different first-line schemes), but a set of standard treatment schemes are most widely used: two-thirds as triple therapies and a quarter as quadruple therapies, and both generally prescribed as 10-day regimens. Moreover, our data show that there are strong regional differences in practice among European gastroenterologists. In this sense, our study shows that the generally unrecommended triple therapies have been abandoned in southern Europe, and are disappearing in eastern regions; however, their use is still widespread in central and northern Europe. This finding evidences an incomplete penetration or implementation of the last consensus conferences, which recommended switching from triple to quadruple therapies.4–6 This lack of update in clinical practice causes a high rate of failures (>20% in those patients), far from the current arbitrary threshold for acceptance of a proposed treatment (≥90% eradication rate).6 8 9

    However, our trend analyses of first-line prescriptions showed that European gastroenterologists are at last adapting their practice to recommendations: some regions have dropped or are abandoning triple therapies, causing an overall drop of prescriptions from 50% to less than 20%. Furthermore, central, northern and south-western Europe are increasing PPI dose and lengthening treatment duration (7-day therapies have decreased from one-third of prescriptions to less than 1%, being currently marginal in all regions). As expected, this improvement in adherence to guidelines and recommendations has correlated with an improvement in efficacy rates, reaching in 2018 almost the proposed minimum 90% cure rate by ITT.

    This manuscript focused on the most relevant first-line treatments used according to either their popularity or their success rate. The most commonly prescribed treatment was standard triple therapy with a PPI, clarithromycin and amoxicillin, achieving lower than 90% eradication rate even when given for 14 days, as previously described in the literature.30 31 Moreover, in our study this treatment was greatly affected by clarithromycin resistance, reducing the effectiveness to below 50% in patients harbouring resistant strains. In this respect, pretreatment clarithromycin resistance in our study was 23%, quite higher than the 15% resistance threshold generally considered (although the number of patients with susceptibility testing in the Hp-EuReg was very limited). However, triple therapy could still be used in those areas with low clarithromycin resistance and proven high effectiveness.

    One of the proposed options chosen to improve triple therapy has been to combine PPI, amoxicillin, clarithromycin and metronidazole in one single scheme, the so-called ‘non-bismuth quadruple treatment’, given as either a sequential or concomitant regimen. Non-bismuth quadruple sequential treatment comprises PPI with amoxicillin combined during a first phase, and a second phase with a PPI, clarithromycin and metronidazole, respectively, each phase lasting for at least 5 days. Although it was successfully proposed and implemented in the early 2000s,32 it has been falling into disuse and it accounted for less than 10% of first-line treatments in our study. The eradication rate of the sequential therapy in our study (86%) was superior to that of triple therapies but still below 90%. Furthermore, sequential therapy is affected by single and, especially, by dual resistance to clarithromycin and metronidazole,13 scoring below 80% and 75% in single and dual resistances, respectively.

    Non-bismuth quadruple concomitant therapy includes the same drugs as sequential therapy but they are all taken together, with benefits in terms of simplicity, for both patients and physicians. The literature is clear regarding its superiority to triple therapies and, although more debatable, it is better than the quadruple sequential therapy as well.12 33–35 Our study showed that concomitant regimen during 10 days with standard acid inhibition was still unable to reach the 90% cure rate arbitrary threshold, but optimised regimens lasting 14 days and/or using high dose PPIs did achieve over 90% eradication even in clarithromycin-resistant strains.

    Another treatment that has resurfaced recently in light of increased resistance rates is bismuth quadruple therapy, which contains a PPI, bismuth salts, tetracycline and metronidazole.34 36 This combination has been available as a rather complicated multiprescription regimen scheme for many years, but recently, a three-in-one single, combination treatment has emerged.37 In the literature, both the traditional and the single capsule bismuth quadruple regimens achieve eradication rates near or superior to 90% irrespective of clarithromycin resistance, and even overcoming metronidazole resistance.37–39 In our study, they both achieved this threshold in 10-day treatments, even though the treated population was biased towards a higher prevalence of penicillin allergy, which has been proposed to be a risk factor for treatment failure.40 As in previous literature,37 metronidazole resistance did not significantly affect these bismuth quadruple regimens in our study.

    Finally, bismuth may also be combined with clarithromycin and amoxicillin to improve the efficacy of standard triple therapy. This approach has not been widely used in the literature, but a few studies have been published recently with encouraging results and have promoted a change in practice.41 42 Our results with this treatment were also promising when prescribed for 14 days, scoring over 90% eradication by mITT.

    In our mixed multilevel analysis, several factors were found to be independently associated with treatment effectiveness, especially adherence to treatment, with a global OR of approximately 7. Remarkably, compliance was excellent (97%) and was indeed the factor which was mostly associated with higher eradication rate in all treatment categories evaluated, with an OR ranging from 4 (concomitant treatment) to 50 (quadruple therapy with clarithromycin, amoxicillin and bismuth). Additionally, use of the recommended dose of PPI improved cure rates in all treatment categories, although when high instead of standard doses were used, no additional benefit was found as shown in table 4.

    Findings from the present study should be interpreted with caution on account of a number of limitations. First of all, this study is not a randomised controlled clinical trial; therefore, comparisons of treatments must be taken with care, due to unidentified allocation biases that may affect effectiveness. These include different local resistance rates, the age of treatment groups, treatment and care costs for patients and providers, and the use of the mITT analysis versus the traditional ITT (which could overestimate eradication) among others. However, these limitations are inherent to studies focused on clinical practice, which are necessary to elucidate the outcomes in routine practice.

    Another drawback is that inclusion rates and numbers varied between centres, regions and countries according to the number of H. pylori infections managed in each outpatient clinic. For example, standard clinics in regions with low infection prevalence may obviously attend a lower number of H. pylori-infected patients, thus affecting their inclusion rates. Although results may not be fully representative of the general population, it is important to mention that in those highest recruiting countries such as Spain, there was a wide variety of centre types (large hospitals vs small outpatients clinics) and therefore this could balance the distribution and the representativeness of the population. In any case, in our sensitivity analysis, we did not identify any significant bias derived from high versus low inclusion countries. In addition, even if we may think heterogeneity was inevitably present, it is important to highlight that the standard triple therapy did not reach an optimal effectiveness in any of the regions; and, by contrast, in all the regions, all quadruple regimens (concomitant, single capsule bismuth quadruple and bismuth-amoxicillin-clarithromycin quadruple therapies) achieved ≈90% eradication rates, which confers consistency to the cluster-by-cluster analysis of the data.

    Finally, our intention to study clinical practice forced us to register as many open management options as possible; this increases heterogeneity and sometimes limits the amount of data obtainable from each case. For example, individual antibacterial resistance was available in a relatively low proportion of cases, translating what happens in day-to-day clinical practice in Europe. In the future, PCR testing could ease bacterial antibiotic susceptibility evaluation if such method is shown to be reliable in faecal samples, which would avoid invasive testing such as endoscopy.

    In contrast to these limitations, we believe that this type of study has a number of strengths that compensate the weaker areas. The open inclusion criteria ensure that our data represent the real clinical practice of the participant centres, and it allow the evaluation of the widest range of therapeutic options and patient contexts. Although data are heterogeneous, the analyses showed that the measure of the effect is consistent throughout Europe. Moreover, the large number of recruiters and countries has provided, to our knowledge, the largest international prospective series on H. pylori treatment under a common research protocol. This has enabled us to perform multivariate analyses to control for confounding variables, data bias and heterogeneity, to develop regional and time-trend approaches. The inclusion of centres with different levels of experience in H. pylori gave us a wide view of real practice. Finally, a high-quality method has been used to register, store, manage and monitor the data by the use of Online Platform for Collaborative Research AEG-REDCap, which provides stability and coherence to the data with programmed and real-time quality controls, queries, reports and statistics.

    In light of these results, we may conclude that in order to obtain over 90% eradication rates consistently, to avoid retreatment and to prevent patient dropout, physicians should be encouraged to use quadruple therapies, because these are the only regimens that consistently achieve eradication rates ≥90%. Those treatments were as follows: 14-day non-bismuth quadruple concomitant therapy (PPI, amoxicillin, clarithromycin and metronidazole), 14-day standard triple plus bismuth (PPI, bismuth, amoxicillin and clarithromycin) and 10-day bismuth quadruple therapy (PPI, bismuth, tetracycline and metronidazole). If antibiotic resistance rates are high in the local geographical area, and especially if dual resistance to clarithromycin and metronidazole is greater than 15%, bismuth quadruple therapy may be the most reliable choice.

    Prescribing physicians must also take into consideration that regardless of the treatment chosen or the clinical context, compliance with treatment was the most relevant factor for achieving successful eradication, so treatment, procedures and expectations must be carefully explained to the patient.

    Although overall H. pylori cure rates in the European Registry are relatively disappointing, different regions of Europe are slowly and heterogeneously incorporating recommended practices such as prescribing quadruple therapies for 2 weeks with an increased dose of acid inhibition. The observed ongoing adaptation of real clinical practice to recommendations gives room for hope, especially considering the parallel improvement (up to 10% in some regions) in overall efficacy in Europe in only 5 years.

    Acknowledgments

    We want to thank Pau Alarcón (Barcelona, Spain) and Jorge Calvo Albinelli, who performed advanced data managing and programming for this project. We want to thank the Spanish Association of Gastroenterology (AEG) for providing the e-CRF service free of charge.

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    • Correction notice This article has been corrected since it published Online First. The second author's name has been corrected.

    • Collaborators Jen Hinojosa (Agencia Sanitaria Costa del Sol Marbella Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Inmaculada Santaella (Agencia Sanitaria Costa del Sol Marbella Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Nuria Fernandez Moreno (Agencia Sanitaria Costa del Sol Marbella Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Ilaria Maria Saracino (University of Bologna Italy Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Horacio Alonso Galán (Hospital de Donisti San Sebastian Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Almudena Durán (Hospital de la Princesa Madrid Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Jennifer Fernandez Pacheco (Hospital de la Princesa Madrid Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Miroslav Vujasinovic (Slovenj Gradec General Hospital Slovenj Gradec Slovenia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Rinaldo Pellicano Molinette (Hospital Turin Italy Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Zdenko Kikec (General Hospital Slovenj Gradec Slovenj Gradec Slovenia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Pedro-Luis Gonzalez Cordero (Hospital San Pedro de Alcantara Caceres Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Maia Donday (Hospital de la Princesa, CIBERehd, Instituto de Salud Carlos III Madrid Spain Monitored and interpreted the data, critically reviewed and approved the final manuscript); Angel Lanas (Hospital Clinico Universitario Lozano Blesa Zaragoza Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Polona Lampic (Diagnosticni center Bled Bled Slovenia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Vid Leban (Diagnosticni center Bled Bled Slovenia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Aleksander Gruncic Krajnc (Diagnosticni center Bled d.o.o. Bled Slovenia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Natasa Brglez Jurecic (Diagnosticni center Bled d.o.o. Bled Slovenia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Galyna Dmytrivna Fadieienko (Ukrainian Academy of Medical Sciences Kharkiv Ukrania Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Lorena Lee (Instituto Fundación Teófilo Hernando Madrid Spain Monitored and interpreted the data, critically reviewed and approved the final manuscript); Irene V Barbado (Instituto Fundación Teófilo Hernando Madrid Spain Monitor and interpret the data, critically reviewed and approved the final manuscript); Alfredo José Lucendo (Hospital General de Tomelloso Tomelloso Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Jesus Barrio RIo Hortega (Hospital Valladolid Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Tatiana Alekseevna Ilchishina (SM-clinic Saint-Petersburg Russia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); 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Pavlov Medical University of the Ministry of Public Health of Russian Federation (SB?IHPE RSMU of Ministry of Public Health of Russian Federation) Department of Propaedeutics of Internal Diseases Ryazan Russia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Peter Mensink (Medisch Spectrum Twente Enschede The Netherlands Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); T Tang (IJsselland Ziekenhuis Capelle aan de Ijssel The Netherlands Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Andrey Yurevich Baranovsky (North-Western State Medical University named after I.I.Mechnicov Saint-Petersburg Russia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Natalya Marchenko (North-Western State Medical University named after I.I. Mechnikov Saint-Patarsburg Russia Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Boris Bastens (CHC Liege Liege Belgium Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Lyudmila Mateva ("University Hospital St. Ivan Rilski Sofia Bulgaria Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Dominique Lamarque (Hôpital Ambroise-Paré Boulogne-Billancourt (Paris) France Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Leonardo Henry (Eusebi Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Gastroenterology and Endoscopy Unit, Policlinico S.Orsola-Malpighi Bologna Italy Acquired the data, critically reviewed the manuscript draft and approved the submitted manuscript); Mario Ribeiro (FMUP/IPATIMUP Porto Portugal Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); M ter Borg (Maxima Medisch Centrum Eindhoven The Netherlands Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Alexander C Ford (Leeds Teaching Hospitals Trust Leeds UK Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Enrique Medina (Consorcio Hospital General de Valencia Valencia Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Manuel Rodriguez-Tellez (Virgen Macarena University Hospital Sevilla Spain Acquired the data, critically reviewed the manuscript draft and approved the submitted manuscript); Francisco José Rancel (Medina Hospital Virgen del Puerto Plasencia Spain Acquired the data, critically reviewed the manuscript draft and approved the submitted manuscript); Elisa Martin (Hospital Virgen del Puerto Plasencia Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Carolina Torres Gonzalez (Hospital de la Ribera Alcira (Valencia) Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript); Lissa Maria Franco (Hospital de Cabueñes Oviedo Spain Acquired data, critically reviewed the manuscript draft and approved the submitted manuscript).

    • Contributors OPN: Scientific Director and member of the project’s Scientific Committee, planned and coordinated the study, designed and programmed the electronic case report form, analysed the data, wrote the manuscript drafts and approved the submitted manuscript. DSB, BT, FL, ML, TR, LK, OS, AG, HS, ATRA, GMB, YN, VL, AT, MV, PB, LGC, TM and VM: acted as national coordinators for their country and as recruiters. Selected national recruiters, collected and helped interpreting data, critically reviewed the manuscript drafts, and approved the submitted manuscript. JCM, AG, KP and CB: acted as non-recruiting national coordinators. Selected national recruiters, helped interpreting data, critically reviewed the manuscript drafts and approved the submitted manuscript. AP-A, DV, LB, MC, LR, JP-L, LL, GF, JM-I, LV, GF and IA: collected and helped interpreting data, critically reviewed the manuscripts’ drafts and approved the submitted manuscript. MC and AG: supervised, coordinated and monitored data collection, interpreted data, critically reviewed the manuscript drafts and approved the submitted manuscript. JG and CF: supervised, analysed and interpreted 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: French National Coordinator and Member of the project’s Scientific Committee, designed the protocol, planned the study, analysed the data, critically reviewed the manuscript drafts and approved the submitted manuscript. CO’M: Irish National Coordinator and Member of the project’s Scientific Committee, designed the protocol, planned the study, collected and analysed the data, critically reviewed the manuscript drafts, and approved the submitted manuscript. JPG: directed the project and the project’s Scientific Committee, obtained funding, designed the protocol and planned the study, acted as Spanish National Coordinator, analysed and interpreted the data, collected patients, critically reviewed the manuscript drafts and approved the final submitted manuscript.

    • Funding This project has been funded by the European Helicobacter and Microbiota Study Group (EHMSG), the Asociación Española de Gastroenterología (AEG) and the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).

    • Competing interests JPG has served as speaker, consultant and advisory member for or has received research funding from Mayoly, Allergan and Diasorin. OPN has received a research grant from Allergan. JM-I has served as a consultant for Casen Recordati and has received retribution from Allergan for formative actions. MC-F has received retribution from Allergan for formative actions. PB has served as speaker, consultant and advisory member for or has received research funding from Almirall, Allergan and Reckitt Benckiser. APA has received retribution from Allergan and Mylan for formative actions. DSB has served as lecturer for Astellas, AstraZeneca, KRKA and Abbott.

    • 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.

    • Patient consent for publication Not required.

    • Ethics approval CEIM Hospital Universitario de La Princesa. There are two approvals: Hp-EuReg 20-Dec-2012 and Hp-EuReg 15-Jan-2015.

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

    • 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.

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