A total of 45,456,150 persons were observed during the study period. There were 304,968 ranitidine users in the pre-referral period, 38,691 in the in-referral period, and 14,614 in the post-referral period (Supplemental Table 1; see the electronic supplementary material). The demographic characteristics of ranitidine users by database and referral periods are presented in Supplemental Table 3. Across databases, ranitidine users were mostly females and individuals aged 18–74 years. The duration of ranitidine use was comparable across the referral periods; however, there were some database-specific differences. In DA Germany, a high proportion (45% in the pre-referral period to 68% in the post-referral period) of patients used ranitidine for 31–100 days, but this was lower (11–56% across referral periods) in the other databases. In all databases, the majority of individuals received ranitidine in accordance with the WHO’s recommended dose (i.e. PDD/DDD of 1). Parenteral ranitidine use was low in all databases (< 5% of total ranitidine use). Although the indications for ranitidine use were missing for nearly 85% of new users, available data showed that ranitidine was mostly prescribed for GERD or gastritis without H. pylori (Supplemental Table 4). There were no differences in the type of indication between periods. However, there were differences in the type of indications between databases, with LPD Belgium, LPD France, DA Germany, and IMRD (UK) having the highest proportions for treatment of gastritis without H. pylori, and SIDIAP (Spain) and IPCI (the Netherlands) having the highest proportion for treatment of GERD (Supplemental Table 4).

3.1 Incidence of Ranitidine and Alternative Medicines Use

The incidence of the use of ranitidine, other H2RAs, PPIs, and antacids is presented in Table 1. In the pre-referral period, ranitidine was one of the most commonly prescribed H2-receptor antagonists, with incidence rates ranging from 0.8 to 9.0/1000 PY. There were notable variations in the incidence rates across databases. LPD Belgium (9.9/1000 PY) and IMRD (UK) (8.2/1000 PY) had relatively higher rates compared to LPD France (1.1/1000 PY) and DA Germany (0.7/1000 PY). In the referral period, there was a steep decrease of incident rate to 0.3–3.8/1000 PY, eventually dropping to 0.0–0.4/1000 PY in the post-referral period. In general, the incident use of ranitidine decreased over time (referral period and calendar year), as depicted in Fig. 1 and Supplemental Tables 5 and 6 (see the electronic supplementary material).

Table 1 Incidence rate of ranitidine and alternative medicines use by referral periodFig. 1

Incidence rate trends of ranitidine use by calendar year. Vertical dashed lines indicate referral initiation and finalisation. DA Disease Analyser, IMRD IQVIA Medical Research Data, IPCI Integrated Primary Care Information, LPD Longitudinal Patient Database, py person years, SIDIAP Information System for Research in Primary Care

In comparison to ranitidine, the use of other H2RAs such as cimetidine and famotidine was small and increased over time, with demonstrable trends in the IPCI (the Netherlands), SIDIAP (Spain), and IMRD (UK) databases (Fig. 2 and Supplemental Tables 5 and 6). PPIs, particularly omeprazole and pantoprazole, were the most commonly prescribed alternative medicine, with incidence rates ranging from 22.0 to 56.6/1000 PY in the pre-referral period, 27.2 to 70.0/1000 PY during referral, and 28.1 to 63.2/1000 PY in the post-referral period (Table 1 and Supplemental Table 5). The incident use of PPIs increased over time in LPD France, LPD Belgium, and DA Germany, but remained stable in the other databases (Fig. 3 and Supplemental Table 6). The incidence rates of antacids ranged from 0.3 to 13.3/1000 PY throughout the observation periods, with the lowest rates in DA Germany (0.3–0.8/1000 PY) and highest rates in IMRD (UK) (12.0–13.0/1000 PY) (Supplemental Table 6). The use of antacids was stable or decreased in IPCI (the Netherlands) and IMRD (UK), but increased in LPD Belgium, DA France, SIDIAP (Spain), and DA Germany (Table 1, Supplemental Figure 1, and Supplemental Table 6). In addition, the use of prostaglandins, combination therapy for H. pylori eradication, and other drugs for the treatment of peptic ulcers or GERD in all databases was low (i.e. incident drug use of ≤ 5.0/1000 PY) (Supplemental Tables 5 and 6).

Fig. 2

Incidence rate patterns of other H2RA use by referral period. DA Disease Analyser, H2RA histamine H2-receptor antagonist, IMRD IQVIA Medical Research Data, IPCI Integrated Primary Care Information, LPD Longitudinal Patient Database, py person years, SIDIAP Information System for Research in Primary Care

Fig. 3

Incidence rate patterns of PPI use by referral period. DA Disease Analyser, IMRD IQVIA Medical Research Data, IPCI Integrated Primary Care Information, LPD Longitudinal Patient Database, PPI proton-pump inhibitor, py person years, SIDIAP Information System for Research in Primary Care

3.1.1 Switching from Ranitidine to Proton-Pump Inhibitors (PPIs)

The trend of early switching from ranitidine to PPIs demonstrated a gradual rise from 2017 to 2019, with rates ranging from 80 (SIDIAP) to 289 (IPCI) per 1000 ranitidine users (Fig. 4). This upward trajectory peaked in 2020, with rates ranging from 234 (SIDIAP) to 684 (IPCI) per 1000 ranitidine users. However, there was a decline in early switching in 2021–2022, with rates ranging from 0 (SIDIAP) to 336 (IPCI) per 1000 ranitidine users. An intriguing exception was observed in the IMRD (UK), which displayed a consistent and gradual increase in switching throughout the study period (177 per 1000 ranitidine users in 2017 to 609–686 per 1000 ranitidine users in 2021/2022).

Fig. 4

Incidence rate patterns of early switching (within 90 days) from ranitidine use to alternative medicine use. Vertical dashed lines indicate referral initiation and finalisation. DA Disease Analyser, GERD gastro-oesophageal reflux disease, H2-receptor antagonists (excluding Ranitidine), IMRD IQVIA Medical Research Data, IPCI Integrated Primary Care Information, LPD Longitudinal Patient Database, PPI proton-pump inhibitor, SIDIAP Information System for Research in Primary Care

A similar increasing trend was observed for late switching from ranitidine to PPIs across various databases between 2017 and 2019, with rates ranging from 141 (LPD Belgium) to 400 (SIDIAP) per 1000 ranitidine users. This upward trend reached its peak in 2020/2021, with rates ranging from 446/408 (LPD France/IPCI) to 950/1826 (SIDIAP/LPD Belgium) per 1000 ranitidine users. However, a subsequent decline occurred in 2022, with rates ranging from 140 (LPD Belgium) to 532 (LPD France) per 1000 ranitidine users.

Overall, the incidence of late switching to PPIs exceeded that of early switching, nearly reaching 100% in LPD Belgium and SIDIAP in 2021 (Supplemental Figure 2; see the electronic supplementary material). After 2021, the frequency of switching decreased or remained stable.

3.1.2 Switching from Ranitidine to Histamine H2-Receptor Antagonists (H2RAs)

The frequency of individuals switching from ranitidine to other H2RAs was less evident or minimal between 2017 and 2018 (≤ 1 per 1000 ranitidine users) (Fig. 4). In 2019, switching rates saw a slight uptick across various databases, ranging from 7 (UK IMRD) to 34 (IPCI) per 1000 ranitidine users. Subsequently, a substantial surge occurred in 2020 and 2021, ranging from 31 (LPD France) to 148 (UK IMRD) per 1000 ranitidine users. However, a steep decline was observed in 2022, with rates ranging from 0 (SIDIAP/LPD France) to 56 (IPCI) per 1000 ranitidine users. A remarkable trend emerged in the IMRD (UK), showing a consistent and gradual rise in switching from 1 per 1000 ranitidine users in 2017/2018 to 112–148 per 1000 ranitidine users in 2021/2022.

3.1.3 Switching from Ranitidine to Other Alternative Medications

Early switching from ranitidine to alternative medicines increased over time, peaking between 2019 and 2020 before declining (Fig. 4). Notably, switching to antacids was most common in IPCI (the Netherlands) and IMRD (UK), albeit at a much lower rate compared to switching to PPIs. Late switching to alternative medicines, aside from PPIs, occurred in less than 30% of ranitidine users and mainly consisted of antacids, other H2RAs, and other drugs for peptic ulcer or GERD treatment.

3.2 Incidence of Discontinuation in Individuals Treated with Ranitidine

Except for SIDIAP, which showed a sharp increase in the incidence of discontinuation from 2018 onwards, the rate of discontinuation of ranitidine therapy remained relatively stable between 2017 and 2018, fluctuated from 2019 to 2020, and then decreased from 2021 onwards (Fig. 5). The incidence of ranitidine discontinuation was comparable in 2017 for LPD Belgium, LPD France, DA Germany, and IPCI (the Netherlands), ranging from 450 to 627/1000 users, except for IMRD (UK), which had the lowest incidence in that period (i.e. 308/1000 users).

Fig. 5

Incidence rate patterns of discontinuation of ranitidine use (gap of more than 90 days). Vertical dashed lines indicate referral initiation and finalisation. DA Disease Analyser, IMRD IQVIA Medical Research Data, IPCI Integrated Primary Care Information, LPD Longitudinal Patient Database, SIDIAP Information System for Research in Primary Care

3.3 Ranitidine and Alternative Medicines Prescription Rates by Indication

The incidence of medication use in individuals with new indications for ranitidine or alternative medicines use are listed in Supplemental Table 7 (see the electronic supplementary material). In all databases, PPIs were primarily prescribed to newly diagnosed patients with any of the conditions of interest, with incidence rates ranging from 346.0–809.0/1000 PY in 2017 to 126.0–525.0/1000 PY in 2022. Ranitidine was prescribed at much lower rates in 2017 (19.0–195.0/1000 PY), with incidence rates dropping nearly to zero in 2022. The use of other drugs, such as antacids, prostaglandins, and drugs used to eradicate H. pylori, was much lower. The incidence rate patterns of ranitidine prescription in individuals newly diagnosed with conditions for which ranitidine or alternative drugs are indicated are demonstrated in Fig. 6.

Fig. 6

Incidence rate patterns of ranitidine prescription in individuals newly diagnosed with conditions for which ranitidine or alternative drugs are indicated. Vertical dashed lines indicate referral initiation and finalisation. DA Disease Analyser, IMRD IQVIA Medical Research Data, IPCI Integrated Primary Care Information, LPD Longitudinal Patient Database, SIDIAP Information System for Research in Primary Care