Comparison of the management of Helicobacter pylori infection between the older and younger European populations

1 Vol.:(0123456789) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports Comparison of the management of Helicobacter pylori infection between the older and younger European populations Paulius Jonaitis 1, Olga P. Nyssen 2*, Ilaria Maria Saracino 3, Giulia Fiorini 3, Dino Vaira 3, Ángeles Pérez‑Aísa 4, Bojan Tepes 5, Manuel Castro‑Fernandez 6, Manuel Pabón‑Carrasco 6, Alma Keco‑Huerga 6, Irina Voynovan 7, Alfredo J. Lucendo 8, Ángel Lanas 9, Samuel J. Martínez‑Domínguez 9, Enrique Alfaro Almajano 9, Luis Rodrigo 10, Ludmila Vologzanina 11, Natasa Brglez Jurecic 12, Maja Denkovski 12, Luis Bujanda 13, Umud Mahmudov 14, Mārcis Leja 15, Frode Lerang 16, Gülüstan Babayeva 17, Dmitry S. Bordin 18,19,20, Antonio Gasbarrini 21, Juozas Kupcinskas 1, Oleksiy Gridnyev 22, Theodore Rokkas 23, Ricardo Marcos‑Pinto 24, Perminder S. Phull 25, Sinead M. Smith 26, Ante Tonkić 27, Doron Boltin 28, György Miklós Buzás 29, Štěpán Šembera 30, Halis Şimşek 31, Tamara Matysiak‑Budnik 32, Vladimir Milivojevic 33, Wojciech Marlicz 34, Marino Venerito 35, Lyudmila Boyanova 36, Michael Doulberis 37, Lisette G. Capelle 38, Anna Cano‑Català 39, Leticia Moreira 40, Francis Mégraud 41, Colm O’Morain 26, Javier P. Gisbert 2,46, Laimas Jonaitis 1,46 & Hp‑EuReg investigators * The prevalence of Helicobacter pylori remains high in the older population. Specific age‑related peculiarities may impact the outcomes of H. pylori treatment. The aim of the study was to evaluate the diagnostics and effectiveness of H. pylori eradication between the younger and older European populations. “European Registry on H. pylori Management (Hp‑EuReg)” data from 2013 to 2022 were analyzed. Patients were divided into older (≥ 60 years) and younger (18–59 years) groups. Modified intention‑to‑treat (mITT) and per‑protocol (PP) analysis was performed. 49,461 patients included of which 14,467 (29%) were older‑aged. Concomitant medications and penicillin allergy were more frequent among the older patients. Differences between younger and older populations were observed in treatment duration in first‑line treatment and in proton pump inhibitors (PPIs) doses in second‑line treatment. The overall incidence of adverse events was lower in the older adults group. The overall first‑line treatment mITT effectiveness was 88% in younger and 90% in the older patients (p < 0.05). The overall second‑line mITT treatment effectiveness was 84% in both groups. The effectiveness of the most frequent first‑ and second‑line triple therapies was suboptimal (< 90%) in both groups. Optimal efficacy (≥ 90%) was achieved by using bismuth and non‑bismuth‑based quadruple therapies. In conclusion, the approach to the diagnostics and treatment of H. pylori infection did not generally differ between younger and older patients. Main differences were reported in the concurrent medications, allergy to penicillin and adverse events both in first‑ and second‑line treatment. Optimal effectiveness rates were mostly achieved by using bismuth and non‑bismuth‑ based quadruple therapies. No clinically relevant differences in the effectiveness between the age groups were observed. OPEN 1Department of Gastroenterology, Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania. 2Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-Princesa), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad Autónoma de Madrid (UAM), Diego de León, 62, 28006 Madrid, Spain. 3Department of Surgical and Medical Sciences, IRCCS AOUBO, University of Bologna, 40138 Bologna, Italy. 4Agencia Sanitaria Costa del Sol, Red de Investigación en Servicios de Salud en Enfermedades Crónicas (REDISSEC), 29651 Marbella, Spain. 5Department of Gastroenterology, AM DC Rogaska, 3250 Rogaska Slatina, Slovenia. 6Department of 2 Vol:.(1234567890) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ Helicobacter pylori (H. pylori) is the main cause of chronic gastritis as well as one of the main etiopathogenetic factors in the development of peptic ulcer disease. It is the only bacterium that is classified as Class I (definite) carcinogen by World Health Organization (WHO) and is the main risk factor in the etiopathogenesis of gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma1–4. Despite the fact that the prevalence of H. pylori is declining, especially in the younger population5,6, it is estimated that around 50% of the world’s populations is still infected with this bacterium7. Based on a wide systematic review and meta-analysis, the prevalence of H. pylori in Western Europe is 34%8 and is significantly higher in Eastern and Southern European countries9. The prevalence of H. pylori is related to the cohort effect, meaning that it is higher among the cohorts with earlier date of birth, i.e., the older the cohort, the higher the prevalence of H. pylori. The vast majority of people acquire this bacterium in their early childhood (up to 10years of age) and the possibility of a later infection is rather low10. After the treatment of H. pylori the reinfection rate is also low11; however it might be higher in the areas with low socioeconomic status and high prevalence of H. pylori. Epidemiological studies have reported that the world’s population is shifting towards older adults (> 60years old) and the number of persons aged over 60years is expected to double in the upcoming 10 years12,13. It has been reported that the prevalence of H. pylori in older population is significantly higher compared to younger people14, resulting in higher incidence of gastric cancer, peptic ulcer disease and other H. pylori-associated conditions in this population15. Even though there is a clear lack of epidemiological research in older patients, the available studies have reported the prevalence of H. pylori ranging from 40% up to 75% in these subjects14,15. Older adults are also associated with other age-related peculiarities, such as a higher number of comorbidities and concurrent medications, lower treatment compliance, impaired renal function, changes in drug metabolism16,17 as well as other physiological changes18. Both the currently updated Maastricht VI/Florence, as well as previous Maastricht V/Florence, Consensus Reports4,19 on the management of H. pylori infection have decided not to separate the recommended treatment regimens in different age groups as it has been reported that these regimens are equally effective both in older and younger patients20. In fact, the limited available studies have reported that the standard triple therapy achieved close to optimal or, in seldom cases, optimal effectiveness and most of the quadruple therapies and sequential therapies have been reported to achieve optimal (> 90%) eradication rates in older-aged groups19–21. It has been Gastroenterology, Hospital de Valme, 41014 Seville, Spain. 7Department of Gastroenterology, A.S. Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia. 8Department of Gastroenterology, Hospital General de Tomelloso, 13700 Tomelloso, Spain. 9IIS Aragón y Facultad de Medicina de la Universidad de Zaragoza, 50009 Zaragoza, Spain. 10Gastroenterology Unit, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain. 11Department of Gastroenterology, Gastrocentre, 614068 Perm, Russia. 12Department of Gastroenterology, Interni Oddelek, Diagnostic Centre, 4260 Bled, Slovenia. 13Hospital Donostia, Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), 20018 San Sebastián, Spain. 14Modern Hospital, 1119 Baku, Azerbaijan. 15Department of Gastroenterology, Digestive Diseases Centre Gastro, Institute of Clinical and Preventive Medicine and Faculty of Medicine, University of Latvia, Riga 1079, Latvia. 16Department of Gastroenterology, Østfold Hospital Trust, 1714 Grålum, Norway. 17Memorial Klinik, 1096 Baku, Azerbaijan. 18Department of Gastroenterology, A.S. Loginov Moscow Clinical Scientific Center, 111123 Moscow, Russia. 19A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia. 20Tver State Medical University, 170100 Tver, Russia. 21Medicina Interna, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico, Università Cattolica del Sacro Cuore, 00168 Rome, Italy. 22Government Institution “L.T.Malaya Therapy National Institute of the National Academy of Medical Sciences of Ukraine”, Kyiv, Ukraine. 23Department of Gastroenterology, Henry Dunant Hospital, 115 26 Athens, Greece. 24Department of Gastroenterology, Centro Hospitalar do Porto Institute of Biomedical Sciences Abel Salazar, Centro de Investigação em Tecnologias e Serviços de Saúde, University of Porto, 4050-313 Porto, Portugal. 25Department of Gastroenterology, Aberdeen Royal Infirmary, Aberdeen AB25 2ZN, UK. 26Faculty of Health Sciences, Trinity College Dublin, Dublin D02PN40, Ireland. 27Department of Gastroenterology, University Hospital of Split, University of Split School of Medicine, 21000 Split, Croatia. 28Division of Gastroenterology, Rabin Medical Center, Sackler School of Medicine, Tel Aviv University, 49100 Tel Aviv, Israel. 29Department of Gastroenterology, Ferencváros Health Centre, 1095 Budapest, Hungary. 302nd Department of Internal Medicine and Gastroenterology, University Hospital and Charles University, Faculty of Medicine in Hradec Králové, 500 03 Hradec Králové, Czech Republic. 31Division of Gastroenterology and Hepatology, Hacettepe University School of Medicine, 06230 Ankara, Turkey. 32Department of Gastroenterology, CHRU de Nantes, Hôpital Hôtel Dieu, 44000 Nantes, France. 33Department of Gastroenterology, Clinical Center of Serbia, University of Belgrade School of Medicine, 11000 Belgrade, Serbia. 34Department of Gastroenterology, Pomeranian Medical University, 70-204 Szczecin, Poland. 35Department of Gastroenterology, Otto-Von-Guericke University, 39120 Magdeburg, Germany. 36Department of Gastroenterology, Medical Microbiology, Medical University of Sofia, 1431 Sofia, Bulgaria. 37Division of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, 5001 Aarau, Switzerland. 38Department of Gastroenterology, Meander Medical Center, 3813 TZ Amersfoort, The Netherlands. 39GOES Research Group, Althaia Xarxa Assistencial Universitària de Manresa, 08243 Manresa, Spain. 40Department of Gastroenterology, Hospital Clínic Barcelona, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBEREHD), IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, 08036 Barcelona, Spain. 41INSERM U1312, Université de Bordeaux, 33000 Bordeaux, France. 46These authors contributed equally: Javier P. Gisbert and Laimas Jonaitis. *A list of authors and their affiliations appears at the end of the paper. *email: opn.aegredcap@ aegastro.es 3 Vol.:(0123456789) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ described that H. pylori eradication prescriptions are safe and effective in older adults, although the experience is quite confined21,22. There is a scarcity of data not only regarding the H. pylori diagnostics and treatment in older patients but also comparing the results with younger subjects. The latter could evaluate more in depth both population’s characteristics and potentially help in the therapeutical tailoring in the different age groups. In fact, after performing a literature search, we could not retrieve any European studies in recent years that have compared the diagnostics and treatment of H. pylori between older and younger populations. On the other hand, it is known that H. pylori resistance rates to antibiotics are increasing worldwide. An extensive analysis reported that primary clarithromycin resistance in European countries has doubled in the last 20 years23. It is likely that older adults might have patterns of higher antimicrobial resistance due to the lifelong exposure to various antibiotics24,25. However, a population based study in China revealed that the failure rates of clarithromycin containing triple therapy were especially high in younger populations, whereas the higher cure rates were observed in the older subjects26. The aim of this study was therefore to evaluate and compare the diagnostic methods and treatment prescriptions for H. pylori infection as well as the effectiveness of the most frequent first- and second-line H. pylori eradication regimens between the older and younger adults in Europe. Methods European registry on H. pylori management (Hp‑EuReg) The Hp-EuReg is an international, multicentre, prospective, non-interventional registry that has been recording information on the management of H. pylori infection since the year 2013. The Hp-EuReg protocol27 establishes national coordinators in the selected 29 countries, where gastroenterologists have been recruited at over 300 study centres to provide input to the registry. Participants and study groups This study data was obtained from the centres of all the participating countries. The participants were patients that were included in the Hp-EuReg since the year 2013 up to the January of 2022. All of the patients were adults, who were diagnosed with H. pylori infection. The study participants were divided into two groups based on the age: younger (18–59years old) and older (≥ 60years old). The age cut-off value between the groups was selected based on the “older adults” definition by WHO and some sources from the United Nations (UN)28,29. Data collection Data were collected through an electronic Case Report Form (e-CRF), collecting the patient’s demographic information, any previous eradication attempts, and the treatments employed, as well as the outcomes of the treatment, recording details such as the compliance, the cure rate, the follow-up, etc. and the adverse events (AEs). This information was registered at the REDCap database30 managed and hosted by the "Asociación Española de Gastroenterología" (AEG; http:// www. aegas tro. es), a non-profit Scientific and Medical Society that focuses on Gastroenterology research. Data management Data were quality reviewed by evaluating whether the study selection criteria had been met, whether information was correctly registered and ultimately to ensure the study was conducted according to the highest scientific and ethical standards, in accordance with the latest revision of the ethical guidelines firstly announced in 1975 Declaration of Helsinki. Data discordances were resolved by querying the investigators and through group emailing. Variables categorization and definitions PPI doses were categorized according to the potency of acid inhibition, as low-dose (4.5–27mg of omeprazole equivalents given twice a day), standard-dose (32–40mg of omeprazole equivalents given twice a day), or highdose (54–128mg of omeprazole equivalents given twice a day)31,32. Likewise, the duration of treatment was categorized as 7, 10, or 14days to ease the interpretation. Sub-analyses were performed according to the treatment duration and PPI doses comparing both age groups (younger and older subjects). The following categories were used for the most frequently prescribed first-line treatments: Triple-CA/M (clarithromycin, amoxicillin/metronidazole), Seq CAT-CAM (clarithromycin, amoxicillin, tinidazole—clarithromycin, amoxicillin, metronidazole), Quad-CAT-CAM, Quad-Pylera® (three-in-one single-capsule containing metronidazole, tetracycline and bismuth) + Quad Bi (bismuth), Quad-CAB (clarithromycin, amoxicillin, bismuth) and other. Likewise, following categories were used for the most frequent second-line treatments: Quad Pylera® + Quad Bi, Quad-LAB (levofloxacin, amoxicillin, bismuth), Triple-AL (amoxicillin, levofloxacin), Conco- Seq (concomitant-sequential), and other. In order to calculate the effectiveness of different H. pylori eradication regimens, per-protocol (PP), intention to treat (ITT) and modified intention-to-treat (mITT) analyses were used. The ITT analysis includes all cases registered in Hp-EuReg, allowing at least a 6-month follow-up, and lost to follow-up cases were considered treatment failures. The PP analysis includes all cases that have completed follow-up (i.e., had undertaken a valid confirmatory test after the eradication treatment) and had taken at least 90% of the treatment drugs, as defined in the protocol. The mITT was designed to reach the closest results to those obtained in clinical practice, and therefore included all cases that had completed the follow-up, regardless of the compliance to treatment. All the patients, that were empirically treated (that is, without prescribing a susceptibility-guided antibiotic treatment) were included in the effectiveness analysis. 4 Vol:.(1234567890) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ AEs and compliance were evaluated through patient questioning with both open-ended questions and a predefined questionnaire, by face-to-face interview. Compliance was defined, through physician questioning, as having taken at least 90% of the prescribed drugs. AEs were classified depending on the intensity of symptoms evaluated by the corresponding physician: mild (not interfering with daily routine), moderate (affecting daily routine), intense/severe (not allowing normal daily routine), and serious (causing death, hospitalization, disability, congenital anomaly, and/or requiring intervention to prevent permanent damage). Statistical analyses Continuous variables were summarized as the mean and standard deviation, while qualitative variables were presented as the absolute relative frequencies, displayed as percentages (%) together with their 95% CIs, where applicable. The selected level of statistical significance was p < 0.05 (two-tailed). All treatments were accounted in the descriptive and univariate analyses; for the purpose of the multivariate analysis, logistic regression (LR) was performed first controlling by the most frequently prescribed first-line treatments and then by the most frequently second-line treatments. The LR used a backward modelling strategy and compared models using the log-likelihood ratio. The mITT population was the dependent variable used to evaluate the association between the treatments’ eradication rate and the following independent variables: age [ref. 18–59years old group], sex [ref. female], indication [ref. dyspepsia], compliance [ref. No, < 90% drug intake], PPI dose [ref. low dose], treatment length [ref. 7days] and prescribed eradication regimens (for the first line-treatment [ref. Triple-CA/M]; for the second-line treatment [ref. Quad Pylera® + Quad Bi] as defined earlier]. In the multivariate analysis, the effect was evaluated by calculating odds ratios (ORs) and the corresponding 95% confidence intervals (95% CIs). Ethics approval statement The study was approved by the Ethics Committee of La Princesa University Hospital (Madrid, Spain). It was registered at ClinicalTrials.gov (NCT02328131). Results Baseline characteristics Figure1 depicts the flow-chart of the study. The main results of the differences in the demographics, diagnostics, and treatment of H. pylori infection between the older and younger age groups is presented in Table1. Since the year 2013, data from 49,461 cases were included in the Hp-EuReg and used for current analysis. As already mentioned, the patients were divided into two groups based on their age: there were 14,467 (29%) older (aged 60years or older) and 34,994 (71%) younger (18–59years old) patients. There were 63% female in the older group and 59% female in the younger group (p < 0.05 between the age groups). The older adults group reported a significantly higher intake of concurrent medications (the main evaluated drug groups were PPIs, acetylsalicylic acid, non-steroidal anti-inflammatory drugs and statins) as compared to the younger subjects (55% vs. 27% respectively, p < 0.05). Older-aged group was characterized by statistically significantly higher rate of allergy to penicillin (5% in the older compared to 3% in the younger group, p < 0.05), whereas there were no differences in other evaluated drug groups, such as macrolides (0.3% in both groups) and fluoroquinolones (0.2% vs. 0.1% respectively, p > 0.05). Before H. pylori eradication dyspeptic symptoms were more frequently reported in older subjects as compared to the younger ones (77% vs. 73% respectively, p < 0.05), whereas there were no differences in the prevalence of heartburn (both groups 26%, p > 0.05). The main indications for the treatment of H. pylori infection in the older and younger age groups were dyspeptic syndrome (36% vs. 38% respectively) and peptic ulcer disease (20% vs. 15% respectively, p < 0.05). Further causes (for instance, gastroesophageal reflux disease, erosive gastritis etc.) accounted for 32% of the indications in older and 29% in younger patients groups (p < 0.05). The main H. pylori diagnostic tests used in older and younger subjects before the treatment were histological examination (47% and 38% respectively, p < 0.05), rapid urease test (RUT) (both groups 38%, p > 0.05), urea breath test (UBT) (25% and 31% respectively, p < 0.05), microbiological culture (11% and 10% respectively, p < 0.05) and serology (7% vs. 8% respectively, p < 0.05). The main diagnostic tests post-treatment in both groups were UBT (66% and 62% respectively, p < 0.05), stool antigen test (14% and 15% respectively, p < 0.05), histological examination (5% and 4% respectively, p < 0.05) and RUT (3% in both groups, p > 0.05). Prescriptions, treatment duration and PPIs In both age groups 81% of the cases were treatment-naive. In the first-line treatment, quadruple therapy was prescribed in 45% of the older and 46% of the younger subjects (p < 0.05) and triple therapy in 42% and 45% respectively (p < 0.05). In the second-line treatment quadruple therapy was prescribed in 52% of the older and 51% of the younger age cases (p < 0.05) and triple therapy in 43% and 45% respectively (p < 0.05). The overall duration of first-line treatment in older and younger adults was 7days in 14% and 12% of the cases respectively; 10days in 50% and 49% respectively; and 14days in 36% and 40% respectively (p < 0.05 in all groups). The overall duration of the second-line treatment was as follows: 7days in 4%, 10days in 56% and 14days in 40% of the cases in both age groups (p > 0.05). In the first-line treatment low PPI doses were most frequently prescribed in both groups and no significant differences in prescribed PPI doses were found between the groups. In the second-line treatment low doses of PPIs were most frequently prescribed in older adults (40% vs 36% respectively, p < 0.05) and high doses of PPIs most frequently in the younger adults (38% vs 42% respectively, p < 0.05). 5 Vol.:(0123456789) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ Treatment effectiveness The detailed analysis of the most widely used first- and second-line prescriptions in the older and younger age groups and their effectiveness (ITT, mITT and PP) comparison is presented in Table2. The graphic comparison of the mITT effectiveness of the six most frequently prescribed first- and second-line treatments between the age groups is illustrated in Figs.2 and 3, respectively. The overall first-line treatment effectiveness was 89% (95% CI 89–90%) by PP and 88% (95% CI 88–89%) by mITT in the younger and 89% (95% CI 88–89%) by PP and 90% (95% CI 89–91%) by mITT in the older groups. The effectiveness of most frequently prescribed first-line regimen, which was standard triple therapy (PPI + C + A), was 88% by PP and 87% by mITT in the older group, whereas it was 87% by PP and 86% by mITT in the younger group (p < 0.05 only comparing the mITT effectiveness), meaning it reached suboptimal (< 90%) efficacy rates in either group. The remaining triple therapies failed to reach optimal eradication rates as well. Optimal (≥ 90%) eradication rates in the first-line treatment were achieved by using quadruple therapies (quadruple PPI + C + A + B, quadruple PPI + C + A + T and single-capsule bismuth quadruple therapy) and the most frequently used sequential therapy (PPI + C + A + T) in both age groups. Statistically significant differences in the eradication effectiveness between the age groups were reported when standard triple therapy (PPI + C + A), quadruple PPI + C + A + M or sequential PPI + C + A + T therapies were used. Figure1. Study flow chart. PP per-protocol, mITT modified Intention-to-treat. 6 Vol:.(1234567890) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ Table 1. Demographics, diagnostics, and treatment prescriptions in H. pylori management between older and younger European populations. PPI—proton pump inhibitor. Significant p-values are in bold. Older (≥ 60years) Younger (18–59years) p-value Total number of patients, N (%) 14,467 (29%) 34,994 (71%) Gender, N (%) Male 5365 (37%) 14,244 (41%) < 0.05 Female 9093 (63%) 20,730 (59%) < 0.05 Average age (mean ± standard deviation) 68.1 ± 6.3 42.8 ± 10.7 < 0.05 Main treatment indications, N (%) Uninvestigated dyspepsia 5111 (36%) 13,248 (38%) < 0.05 Peptic ulcer disease 2893 (20%) 5094 (15%) < 0.05 Main symptoms, N (%) Dyspepsia 10,571 (73%) 27,070 (77%) < 0.05 Heartburn 3831 (26.3%) 9183 (26.5%) > 0.05 Concurrent medications, N (%) 7364 (55%) 8834 (27%) < 0.05 Drug allergies, N (%) 796 (6%) 1306 (4%) < 0.05 Penicillin 650 (4.5%) 1050 (3%) < 0.05 Macrolides 43 (0.3%) 92 (0.3%) > 0.05 Fluoroquinolones 27 (0.2%) 50 (0.1%) > 0.05 Main diagnostic methods pre-treatment, N (%) Histology 6840 (47%) 13,191 (38%) < 0.05 Rapid urease test 5463 (38%) 13,138 (38%) > 0.05 Urea breath test 3550 (25%) 10,702 (31%) < 0.05 Main diagnostic tests post-treatment, N (%) Urea breath test 9544 (66%) 21,755 (62%) < 0.05 Stool antigen test 1968 (13.6%) 5401 (15.4%) < 0.05 Histology 715 (5%) 1529 (4%) < 0.05 Treatment compliance, N (%) 12,938 (97%) 31,270 (97%) > 0.05 First-line prescriptions, N (%) Triple-therapy 4851 (42%) 12,492 (45%) < 0.05 Quadruple-therapy 5182 (45%) 12,641 (46%) < 0.05 Second-line prescriptions, N (%) Triple-therapy 788 (43%) 2134 (45%) < 0.05 Quadruple-therapy 956 (52%) 2393 (51%) < 0.05 PPI potency in first-line treatment, N (%) Low 5275 (46%) 12,312 (45%) > 0.05 Standard 2726 (24%) 6831 (25%) > 0.05 High 3516 (31%) 8539 (31%) > 0.05 PPI potency in second-line treatment, N (%) Low 750 (40%) 1691 (36%) < 0.05 Standard 423 (23%) 1059 (23%) > 0.05 High 705 (38%) 1983 (42%) < 0.05 First-line treatment duration, N (%) 7days 1583 (14%) 3170 (12%) < 0.05 10days 5700 (50%) 13,351 (49%) < 0.05 14days 4185 (37%) 11,019 (40%) < 0.05 Second-line treatment duration, N (%) 7days 75 (4%) 197 (4%) > 0.05 10days 1023 (56%) 2618 (56%) > 0.05 14days 744 (40%) 1881 (40%) > 0.05 Adverse events Overall, N (%) 3062 (23%) 8144 (25%) < 0.05 Treatment cessation due to AEs, % 1.5% 1.2% > 0.05 7 Vol.:(0123456789) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ The overall second-line treatment effectiveness was 84% both by PP and by mITT in the younger and older subjects. The efficacy of the most popular second-line prescription PPI + A + L was 80% by PP and by mITT in the older adults group, whereas it was 83% by PP and 82% by mITT in the younger adults group (p > 0.05 by both analyses), meaning that it also achieved only suboptimal eradication rates. Optimal eradication rates in the younger group were achieved by using triple PPI + A + Mx (moxifloxacin) or quadruple PPI + C + A + B therapies and in the older group only single-capsule bismuth quadruple therapy managed to reach optimal treatment effectiveness. Statistically significant difference between the age groups in the second-line treatment effectiveness was only reported when quadruple PPI + C + A + B therapy was used. Multivariate analysis The detailed multivariate analysis of the first- and second-line treatments is presented in Table3. After performing the multivariate analysis it has been calculated that compliance with treatment, quadruple bismuth-based prescriptions (including single-capsule bismuth quadruple therapy), longer treatment durations (14days vs. 7days; 10days vs. 7days), higher acid inhibition (high PPIs doses vs. low; medium PPIs doses vs. low), sequential CAT/CAM, quadruple CAT/CAM and quadruple CAB prescriptions as well as belonging to older adults group were the main factors associated with higher mITT cure rate in the first-line treatment. In the second-line treatment the main factors associated with higher mITT rates were longer treatment durations (14days vs. 7days; 10days treatment vs. 7days), good treatment compliance and higher PPIs doses (high PPIs doses vs. low; medium PPIs doses vs. low). Compared to quadruple bismuth-based prescriptions (including single-capsule bismuth quadruple therapy), Triple-AL and Conco-Seq prescriptions were associated with significantly lower mITT rates. Table 2. First- and second-line H. pylori treatment effectiveness in the younger and older European populations. PP—per protocol, mITT—modified Intention-To-Treat, ITT—Intention-To-Treat, 95% CI—95% confidence interval, PPI—proton pump inhibitor, C—clarithromycin, A—amoxicillin, M—metronidazole, B—bismuth, T—tinidazole, L—levofloxacin, Tc—tetracycline, Mx—moxifloxacin, R—rifabutin. 1 Pylera®: threein-one single-capsule containing metronidazole, tetracycline and bismuth. *Statistically significant differences between the age groups, p < 0.05. Treatment Younger adults (18–59years) Older adults (≥ 60years) Use, N PP % (95% CI) mITT % (95% CI) ITT % (95% CI) Use, N PP % (95% CI) mITT % (95% CI) ITT % (95% CI) Effectiveness of first-line treatment prescriptions between the younger and older populations Triple PPI + C + A 10,540 87 (86–87) 86 (85–87)* 67 (66–68)* 4065 88 (87–89) 87 (86–89)* 71 (69–72)* Triple PPI + C + M 1150 86 (84–88) 86 (83–88) 68 (65–71) 491 83 (79–86) 83 (79–86) 71 (66–75) Triple PPI + A + L 425 83 (79–87) 83 (78–86) 76 (72–80) 162 83 (75–88) 83 (76–89) 76 (69–82) Quadruple PPI + C + A + M 4199 90 (89–91)* 89 (88–90)* 86 (85–87)* 1940 91 (90–93)* 91 (90–92)* 89 (87–90)* Quadruple PPI + C + A + B 3489 92 (91–93) 92 (91–93) 76 (75–77) 1086 91 (89–93) 90 (88–92) 76 (73–79) Quadruple PPI + C + A + T 309 98 (95–99) 96 (93–98) 92 (88–95) 127 96 (89–99) 92 (85–96) 86 (78–92)  Pylera® (single capsule)13233 94 (93–95) 93 (92–94) 89 (87–90) 1519 94 (93–95) 93 (92–95) 89 (87–91) Sequential C + A + T 1291 90 (88–92)* 90 (88–91)* 80 (78–82)* 623 94 (92–96)* 94 (91–96)* 85 (81–87)* Sequential C + A + M 458 84 (80–87) 82 (78–86) 76 (72–80) 222 84 (78–89) 82 (76–87) 75 (69–81) Effectiveness of second-line treatment prescriptions between the younger and older populations Triple PPI + A + L 1422 83 (80–85) 82 (80–84) 74 (71–76) 524 80 (76–84) 80 (76–83) 73 (69–77) Triple PPI + C + A 323 78 (72–83) 78 (72–83) 60 (54–65) 102 84 (74–91) 84 (74–91) 68 (58–77) Triple PPI + A + R 105 80 (70–87) 79 (69–87) 68 (58–76) 49 82 (67–92) 82 (67–92) 74 (59–85) Triple PPI + A + Mx 105 92 (85–97) 92 (85–97) 90 (82–95) 35 87 (70–96) 87 (70–96) 77 (60–90) Quadruple PPI + A + L + B 584 89 (86–92) 89 (86–91) 73 (69–76) 225 86 (80–91) 86 (80–91) 75 (69–81) Quadruple PPI + C + A + M 234 84 (79–89) 84 (78–88) 80 (74–85) 91 86 (77–92) 86 (77–93) 83 (73–90) Quadruple PPI + M + Tc + B 224 86 (80–91) 84 (78–88) 75 (69–81) 101 87 (78–93) 88 (79–94) 77 (68–85) Quadruple PPI + C + A + B 229 91 (85–96)* 91 (85–95)* 52 (45–59) 66 79 (64–89)* 80 (66–90)* 60 (47–72)  Pylera® (single capsule)1843 89 (87–91) 89 (86–91) 83 (80–86)* 384 92 (89–95) 91 (88–94) 88 (84–91)* 8 Vol:.(1234567890) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ Figure2. Comparison of the mITT effectiveness of 6 most frequent first-line prescriptions between the younger and older adults. Figure3. Comparison of the mITT effectiveness of six most frequent second-line prescriptions between the younger and older adults. 9 Vol.:(0123456789) Scientific Reports | (2023) 13:17235 | https://doi.org/10.1038/s41598-023-43287-4 www.nature.com/scientificreports/ Compliance and safety The treatment compliance was 97% in both groups. The overall AEs rate was lower in older subjects compared to the younger adults (23%; 95% CI 24–26% vs. 25%; 95% CI 22–24% respectively, p < 0.05), however severe AEs were more frequent in older patients. The most frequent AEs in older and younger subjects were dysgeusia (7% in both groups), nausea (7% and 8% respectively), diarrhea (6% and 8% respectively) and vomiting (2% and 3% respectively). Most of the AEs were mild to moderate in intensity and lasted 7–14days. The most frequent severe AEs among the older and younger age groups were asthenia (23% and 11% respectively, p < 0.05), anorexia (16% and 10% respectively, p < 0,05) and abdominal pain (8% and 7% respectively, p > 0.05). Among the older adults 1.5% had to stop taking medications due to AEs, whereas it was 1.2% in the younger group (p > 0.05). Discussion In this study we have evaluated the differences of H. pylori diagnostics and treatment between the older and younger European populations. We would like to point out that such analysis is one of only very few available both evaluating an older-aged population and comparing it to younger subjects. Additionally, this is one of only few studies providing data on such a large number of patients from all Europe and enabling more accurate data and more reliable statistical results. Our analysis confirmed the expected epidemiological hypothesis, regarding the baseline characteristics— compared to the younger patients; more older subjects were taking concurrent medications and reported a higher rate of allergy to penicillin. Even though a higher number of concurrent medications and higher rate of drug allergies is usually associated with worse treatment compliance33,34, this was not confirmed in our study and had no influence on the efficacy of the eradication therapy. The diagnostics of H. pylori also complied with the current guidelines4,19 and the study confirmed that the invasive diagnostic methods (histology, RUT) were more frequent for the initial diagnosis of H. pylori prior to the treatment and, as anticipated, some of these methods were also more common in the older population. For the confirmation of eradication UBT was the preferred choice, followed by SAT in both age groups. Most of the performed studies35–37 have revealed that quadruple therapies were superior to triple therapies regarding the effectiveness and, in fact, our study has demonstrated that quadruple therapies were more frequently prescribed for the first- and second-line treatment, in both age groups. The most frequent treatment duration was 10–14days in both age groups, in line with the current guidelines. Seven days duration treatment is no longer recommended4,37,38 and even though there were some cases with 7days treatment duration in both age groups, these cases were registered in the early years of the registry, as reported in previous Hp-EuReg research and, also in accordance with the Maastricht V/Florence consensus report, updated in the year 2016, where 7days treatment duration was no longer recommended. We could have expected that the doses of PPI might have been lower in the older population due to the higher chance of possible AEs (e.g., diarrhea, Clostridioides difficile infection); however we did not find any significant differences between the age groups regarding the PPI dose in the first line therapy and the differences in the second-line were not clinically relevant. The multivariate analysis revealed that high doses of PPIs were associated with better mITT rate in the first- and second-line therapies; however, low doses of PPIs were prescribed Table 3. Independent variables associated with higher mITT rates in the first- and second-line treatments. OR—odds ratio, 95% CI—95% confidence interval, PPIs—proton pump inhibitors, CAT —clarithromycin, amoxicillin, tinidazole, CAM—clarithromycin, amoxicillin, metronidazole, CAB—clarithromycin, amoxicillin, bismuth salts, mITT—modified intention-to-treat. Variable OR 95% CI p-value First-line treatment Treatment compliance 7.34 6.12–8.80 < 0.005 Quadruple bismuth-based prescriptions 2.36 2.06–2.70 < 0.005 14days vs. 7days treatment duration 1.73 1.54–1.95 < 0.005 High PPIs doses vs. low PPIs doses 1.64 1.48–1.80 < 0.005 Sequential CAT/CAM prescriptions 1.52 1.30–1.77 < 0.005 Medium PPIs doses vs. low PPIs doses 1.42 1.27–1.57 < 0.005 Quadruple CAT/CAM prescriptions 1.29 1.16–1.43 < 0.005 10days vs. 7days treatment duration 1.17 1.05–1.31 < 0.005 Quadruple CAB prescription 1.17 1.02–1.35 < 0.05 Older adults group 1.13 1.05–1.12 < 0.005 Second-line treatment 14days vs. 7days treatment duration 4.45 3.21–6.17 < 0.005 10days vs. 7days treatment duration 3.76 2.80–5.04 < 0.005 Treatment compliance 3.56 2.38–5.23 < 0.005 High PPIs doses vs. low PPIs doses 2.17 1.80–2.61 < 0.005 Medium PPIs doses vs. low PPIs doses 1.52 1.25–1.83 < 0.005