Analysis of Clinical Phenotypes through Machine Learning of First-Line H. pylori Treatment in Europe during the Period 2013-2022: Data from the European Registry on H. pylori Management (Hp-EuReg)

Abstract

The segmentation of patients into homogeneous groups could help to improve eradication therapy effectiveness. Our aim was to determine the most important treatment strategies used in Europe, to evaluate first-line treatment effectiveness according to year and country. Data collection: All first-line empirical treatments registered at AEGREDCap in the European Registry on Helicobacter pylori management (Hp-EuReg) from June 2013 to November 2022. A Boruta method determined the "most important" variables related to treatment effectiveness. Data clustering was performed through multi-correspondence analysis of the resulting six most important variables for every year in the 2013-2022 period. Based on 35,852 patients, the average overall treatment effectiveness increased from 87% in 2013 to 93% in 2022. The lowest effectiveness (80%) was obtained in 2016 in cluster #3 encompassing Slovenia, Lithuania, Latvia, and Russia, treated with 7-day triple therapy with amoxicillin-clarithromycin (92% of cases). The highest effectiveness (95%) was achieved in 2022, mostly in Spain (81%), with the bismuth-quadruple therapy, including the single-capsule (64%) and the concomitant treatment with clarithromycin-amoxicillin-metronidazole/tinidazole (34%) with 10 (69%) and 14 (32%) days. Cluster analysis allowed for the identification of patients in homogeneous treatment groups assessing the effectiveness of different first-line treatments depending on therapy scheme, adherence, country, and prescription year.

Keywords: Helicobacter pylori; clustering; eradication; machine learning; phenotyping; treatment.

Figure 1

Study flowchart.

Figure 2

Random Forest variable importance based on the mean decrease in accuracy for the preselected 15 variables associated with the modified intention-to-treat effectiveness, during 2013–2022. Adverse_events, defined as the incidence of at least one adverse event, as yes/no; Age, categorised in six levels: from 18 to 30, 30 to 42, 42 to 54, 54 to 66, 66 to 78, and 78 to 90, disregarding those patients with ages under 18 and over 90; Compliance, defined as yes: >90% drug intake; no: <90% drug intake; Dose_of_PPI, defined as low-dose PPI: 4.5 to 27 mg OE b.i.d; standard dose PPI: 32 to 40 mg OE b.i.d; high-dose PPI: 54 to 128 mg OE b.i.d; Duration, as a duration of treatment of 7, 10, or 14 days; Indication, as ulcer vs. dyspepsia; None_Sympt, defined as the absence of any gastrointestinal symptoms; Heartburn, as yes/no; dyspepsia as yes/no; Other_Sympt, defined as other non-frequent gastrointestinal symptoms; Sex, as female/male.

Figure 3

Random Forest variable importance based on the mean decrease in accuracy for the first six variables (year 2022). Compliance, defined as 1: yes with >90% drug intake or 0: no with <90% drug intake; Dose of_PPI, defined as low-dose PPI: 4.5 to 27 mg OE b.i.d; standard dose PPI: 32 to 40 mg OE b.i.d; high-dose PPI: 54 to 128 mg OE b.i.d; Treatment, defined as a duration of treatment of 7, 10, or 14 days; Other_Sympt, defined as other non-frequent gastrointestinal symptoms (0: absence, 1: presence).

Figure 4

Cluster compositions in terms of variable levels in the year 2022. Red colour, high content; yellow colour, low content. A: amoxicillin; B: bismuth salts; C: clarithromycin; Conco: concomitant; M: metronidazole; Seq: sequential; T: tinidazole; Tc: tetracycline hydrochloride; MTcB was prescribed either in the classical form or as a three-in-one single capsule, marketed as Pylera^®. The treatment category “other” encompassed fewer than 10% of first-line empirical treatments in Europe and were mainly quadruple therapy with amoxicillin, metronidazole, and bismuth (both in Slovenia and Russia) and quadruple therapy with amoxicillin, clarithromycin, and josamycin (in Russia only). Compliance, defined as 1: yes with >90% drug intake or 0: no with <90% drug intake; Dose of_PPI, defined as low-dose PPI: 4.5 to 27 mg OE b.i.d; standard-dose PPI: 32 to 40 mg OE b.i.d; high-dose PPI: 54 to 128 mg OE b.i.d; Duration, as a duration of treatment of 7, 10, or 14 days; Indication, as ulcer vs. dyspepsia; mITT, defined as the modified intention-to-treat; Other_Sympt, defined as other non-frequent gastrointestinal symptoms (0: absence, 1: presence); Sex, as female/male.

Figure 5

Evolution of first-line empirical treatment effectiveness in Spain, Slovenia, Italy, and Russia from the year 2013 to 2022. A: amoxicillin; B: bismuth salts; C: clarithromycin; Conco: concomitant; M: metronidazole; Seq: sequential; T: tinidazole; Tc: tetracycline hydrochloride; MTcB was prescribed either in the classical form or as a three-in-one single capsule, marketed as Pylera^®. The treatment category “other” encompassed fewer than 10% of first-line empirical treatments in Europe and were mainly quadruple therapy with amoxicillin, metronidazole, and bismuth (both in Slovenia and Russia) and quadruple therapy with amoxicillin, clarithromycin, and josamycin (in Russia only).