INTRODUCTION

Acid suppressants, also known as anti-secretory drugs, are primarily used in the treatment of conditions mediated by gastric acid [1]. The global prevalence of gastroesophageal reflux disease (GERD), the most common acid-related condition, is estimated to exceed 13% and is rising due to changes in diet and the growing obesity epidemic [2]. This increasing trend underscores the importance of effective acid suppression therapy to mitigate the disease burden.

The introduction of cimetidine, a first-generation histamine H2 receptor antagonist (H2RA), into clinical practice in 1976 marked a milestone in the history of acid suppressants [3]. This development represented a major advancement in the treatment of acid-related diseases, providing a more effective option than the previous management strategies, which relied on antacids, anticholinergics, and adjuvant therapies. Although second-generation H2RAs were later developed, their limited efficacy prompted a search for more potent agents. These efforts led to the introduction of the first proton pump inhibitor (PPI), omeprazole, in 1988 [4]. Since their introduction, PPIs have become the standard treatment for acid-related diseases. More recently, potassium-competitive acid blockers (P-CABs) have emerged, addressing many of the limitations associated with PPIs and garnering interest as a new class of acid suppressants [5].

Acid suppressants are generally recognized as relatively safe and are extensively used around the world. However, questions persist regarding the appropriateness of their use, with several studies suggesting overuse [6]. Specific concerns are focused on the potential adverse effects of acid suppressants, particularly when used at high doses over long periods. These adverse reactions include Clostridium difficile and other enteric infections [7], nutrient malabsorption [8], fracture [9], and nephrotoxicity [8,10]. Risks of these consequences may be especially high in Asian populations due to a higher prevalence of homozygous CYP2C19 mutations, which can affect PPI metabolism and prolong the inhibitory effect [11]. Similar caution is advised with H2RAs, as many adverse events have been associated with long-term acid suppression [12]. Nonetheless, the general consensus is that the benefits of acid suppressants typically outweigh the risks, although their safety profile remains a subject of debate, with conflicting reports [8,13].

In 2019, ranitidine was withdrawn from the global market after the detection of the probable carcinogen N-nitrosodimethylamine (NDMA). Developed in 1981, ranitidine is a second-generation H2RA that was widely used in clinical practice due to its superior efficacy and fewer side effects compared to first-generation H2RAs [14]. In 2017, the global market size for ranitidine was valued at approximately 412.4 million US dollars [15]. Although growth was expected to continue, this trajectory was halted by product recalls. Concerns about NDMA contamination have also prompted recalls of another H2RA, nizatidine [16]. Despite some recent studies challenging the link between ranitidine and cancer [17,18], the recall likely had a meaningful impact on the use of acid suppressants, especially considering the dominant market share of ranitidine [16,19]. Studies examining the impact of the recall have been limited to the switch from ranitidine to other medications or have focused solely on the total number of prescriptions or costs. Thus, it has been challenging to assess the overall change in drug usage following the recall [16,19–21].

H2RAs and PPIs are widely prescribed in Korea, with their usage on the rise [22]. Thus, it is essential to quantitatively assess the shifts in acid suppressant use following the withdrawal of ranitidine and to identify current trends, particularly given the potential of these drugs for harm. This study sought to examine the utilization patterns of H2RAs and PPIs in Korea before and after the recall of ranitidine, thus laying the groundwork for long-term drug safety surveillance.

METHODS

Data Source and Investigated Drugs

The study utilized claims data from the Health Insurance Review & Assessment Service (HIRA) database, spanning from January 1, 2016 to May 31, 2023. The HIRA database includes extensive claims data from nearly all medical institutions in Korea and details prescriptions from inpatient and outpatient care settings for all drugs covered by the National Health Insurance Service (NHIS) [23]. Prescriptions for acid suppressants were extracted from these claims data, which included information from National Health Insurance beneficiaries, Medical Aid beneficiaries, and veterans.

The target drugs were selected by identifying those corresponding to H2RAs and PPIs from the list of medications covered by the NHIS during the study period. These included both combination drugs containing H2RA or PPI components and single-agent drugs. Drugs that did not fall under the “alimentary tract and metabolism” main group in the Anatomical Therapeutic Chemical (ATC) classification, as well as those not classified as gastrointestinal agents by the Ministry of Food and Drug Safety, were excluded, even if they contained H2RA or PPI components. Intravenous medications were also excluded due to their limited approved indications for reimbursement. To ensure that the prescriptions were intended for acid-related conditions and to exclude off-label use, only those prescriptions with corresponding diagnostic codes in the insurance claims were extracted. The specific International Statistical Classification of Diseases and Related Health Problems, 10th revision codes defining the inclusion criteria are provided in Supplemental Material 1.

Study Design

An interrupted time series design was used to examine changes in utilization trends following the withdrawal of ranitidine. The breakpoint was established as September 26, 2019, which is the date on which ranitidine was withdrawn from the national market. Employing a quasi-experimental approach, the impact of this intervention was evaluated by comparing the observed drug usage with the predicted usage based on the trend before the breakpoint [24].

Measurement of Drug Utilization

Drug utilization was quantified using the defined daily dose (DDD) per 100 000 inhabitants per day. When DDD values were not available, dosages were determined according to domestic approval standards. Monthly usage for each drug was recorded, with the start of use defined as the date of the hospital visit for outpatient prescriptions and the beginning of hospital admission for inpatient prescriptions. To reduce the potential for underestimation due to the absence of previous prescriptions, the first 2 months of the study period were excluded from the analysis. Furthermore, the number of claims submitted for each medication was aggregated to gain insight into the patterns of drug use. Information about the study drugs and their respective dosage units can be found in Supplemental Material 2.

Statistical Analysis

The demographic characteristics of patients who were prescribed acid suppressants were summarized using means and standard deviations for continuous variables and frequencies and percentages for categorical variables. To evaluate the impact of ranitidine’s withdrawal on utilization trends, a segmented linear regression model with a generalized least squares method was applied. This model included monthly drug usage as the outcome variable and included terms for the intercept, slope change (to represent sustained effects), and level change (to indicate immediate effects). In addition to the segmented regression analysis, the pre-intervention and post-intervention periods were compared using an autoregressive integrated moving average (ARIMA) model. This model was chosen to control for any seasonality and autocorrelation present in the data [25]. To ensure that the residuals conformed to a normal distribution, we examined the residual plots of the differenced data, which are provided in Supplemental Material 3.

Statistical analyses were performed using R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria).

Ethics Statement

The Institutional Review Board of Seoul National University Hospital exempted the review process for this study, as only de-identified data were used (IRB No. 2401-019-1499).

RESULTS

From January 2016 to May 2023, a total of 483 556 858 prescriptions for H2RAs and 246 929 250 prescriptions for PPIs were issued with a diagnosis of one or more acid-related diseases. The demographic characteristics associated with these prescriptions did not differ markedly between the periods before and after the recall. The mean age of patients prescribed H2RAs was 53.11 years, while those prescribed PPIs had a mean age of 58.17 years. Both groups had a higher proportion of females than males. After the withdrawal of ranitidine, a notable shift was observed in the distribution of comorbid acid-related conditions. Before the recall, the most common diagnosis for H2RA prescriptions was gastritis and/or duodenitis (84.3%), followed by GERD (15.8%). After the recall, the percentage of gastritis and/or duodenitis diagnoses decreased to 78.5%, while GERD diagnoses rose significantly to 29.3%. For PPI prescriptions, GERD remained an associated diagnosis for over 90% of cases both before and after the recall, with gastritis and/or duodenitis listed in approximately 54% of cases (Table 1).

In terms of drug utilization, measured as DDD per 100 000 inhabitants per day, H2RA usage stood at 2601 in 2016 and continued to rise until 2018. However, a sharp decline was observed after 2019, with usage subsequently rising to reach the most recent value of 2329. Ranitidine was the predominant H2RA until 2019, after which its usage dropped to zero, leading to an increased use of other H2RAs, particularly famotidine and lafutidine. PPI usage exhibited a marked increase, nearly doubling from 2061 in 2016 to 3929 in 2023. Since 2019, esomeprazole and rabeprazole have accounted for the largest share of both PPIs and acid suppressants in general (Table 2).

Based on the observed pattern of acid suppressant use, ranitidine was largely responsible for the increase in H2RA usage prior to its withdrawal. Concurrently, among PPIs, esomeprazole and rabeprazole exhibited notable increases. After ranitidine was discontinued, the use of famotidine and lafutidine increased sharply, and nizatidine usage exhibited a sustained rise, with gradual stabilization in recent years. Meanwhile, esomeprazole and rabeprazole—already on an upward trajectory—registered an even more substantial increase in use following the withdrawal of ranitidine. This increasing trend has continued up to the present (Figure 1).

A comparison of predicted drug usage following the withdrawal of ranitidine with observed volumes using the ARIMA model revealed deviations from the pre-intervention trend for both H2RAs and PPIs. For H2RAs, we noted an immediate decline in utilization, followed by a steeper increase (relative to pre-recall trends) after March 2020. Segmented linear regression analysis indicated a monthly increase in utilization of 6.9 (95% confidence interval [CI], 4.7 to 9.0) before the intervention, followed by a sharp decrease of −1041.7 (95% CI, −1115.8 to −967.7) immediately after the withdrawal of ranitidine. Subsequently, a further increase of 6.6 (95% CI, 3.7 to 9.6) per month was noted on top of the preceding trend. This recovery pattern was especially pronounced for famotidine and lafutidine, with immediate increases of 483.9 (95% CI, 442.4 to 525.5) and 297.0 (95% CI, 276.0 to 318.0), respectively, and additional monthly increases of 8.9 (95% CI, 7.2 to 10.5) and 3.1 (95% CI, 2.2 to 3.9), respectively (Figure 2, Table 3).

For PPIs, the ARIMA model revealed a surge in utilization following the withdrawal of ranitidine, with a subsequent rise that was steeper than the previous upward trend. Before the intervention, PPI utilization exhibited a monthly increase of 19.3 (95% CI, 16.9 to 21.8), with a surge of 235.2 (95% CI, 149.1 to 321.3) immediately after ranitidine was withdrawn. Thereafter, we observed an additional monthly increase of 4.1 (95% CI, 0.7 to 7.6) relative to the pre-withdrawal trend. Most of this pattern was attributed to esomeprazole and rabeprazole, which promptly increased by 151.3 (95% CI, 113.6 to 189.0) and 50.8 (95% CI, 26.4 to 75.2), respectively, following the ranitidine recall. This change was succeeded by further monthly increases of 1.9 (95% CI, 0.4 to 3.4) for esomeprazole and 5.6 (95% CI, 4.6 to 6.6) for rabeprazole, relative to the pre-recall trend.

DISCUSSION

From January 2016 to May 2023, we observed a consistent increase in the use of acid suppressants, with a temporary decline following the withdrawal of ranitidine from the market. This event precipitated an immediate and sharp decrease in the use of H2RAs and a notable increase in the use of PPIs. However, long-term trends indicate that the utilization of both types of acid suppressants has risen more steeply than previously observed. Over approximately 7.5 years, the volume of PPI use nearly doubled, an increase primarily driven by esomeprazole and rabeprazole.

Esomeprazole and rabeprazole are early formulations of second-generation PPIs [26], with several generic versions available on the Korean market due to the expiration of patents. These drugs absorbed much of the decrease in ranitidine usage, likely due to their superior efficacy and the availability of multiple products. In contrast, first-generation PPIs such as omeprazole, pantoprazole, and lansoprazole, as well as second-generation agents like dexlansoprazole and ilaprazole—which are still under patent protection—showed low overall utilization. The modest immediate increases in the usage of most of these drugs following the withdrawal of ranitidine appear to represent temporary responses to the recall. The subsequent long-term decline in their use potentially resulted from the growing dominance of esomeprazole and rabeprazole in the market.

Among H2RAs, cimetidine experienced a notable decline, coinciding with its natural withdrawal from the national market during the study period [21]. However, following the withdrawal of ranitidine, the use of most other agents increased. As a result, total H2RA utilization initially showed a temporary decrease, but this was followed by a more pronounced rise compared to the previous upward trend, partially offsetting the absence of ranitidine.

The utilization of acid suppressants has been explored in several studies, particularly concerning the overuse of PPIs. Globally, PPI use has clearly been increasing, driven by the rising prevalence of acid-related diseases, prophylactic co-prescription of PPIs with non-steroidal anti-inflammatory drugs or antiplatelets to prevent gastrointestinal complications, and aging populations [6]. Despite clinical guidelines advocating for the minimal effective dose and shortest duration of treatment [27–29], actual usage patterns often deviate from these recommendations. In France, 29.8% of adults were reported to have used PPIs in 2015, with 4.1% of new users receiving continuous therapy for at least 6 months. This figure was even higher, at 10.2%, among individuals aged 65 years or older. Moreover, 32.4% of new PPI users had no clear indication for the medication, suggesting potential misuse or overuse [30]. A 13-year study of outpatient prescriptions in Iceland revealed that the annual prevalence of PPI use climbed from 8.5 to 15.5 per 100 people, while the number of new users remained relatively stable, indicating a trend toward longer and possibly higher-dose treatments [31]. Similarly, in Germany, long-term PPI prescriptions often lacked documented indications; however, the overall number of prescriptions has declined since 2016, which may reflect increased awareness of potential adverse effects and the implementation of targets to limit overprescribing [32]. The economic impact of widespread PPI use is also substantial. In Korea, where PPIs are not available over the counter, reimbursement costs for drugs under the ATC code A02B (which includes medications for peptic ulcers and gastroesophageal reflux disease) surpassed 1 trillion Korean won—approximately 830 million US dollars—in 2022 [33,34].

Due to the dominant market share of ranitidine, several studies investigated the impact of its recall on the utilization of acid suppressants. In North America, the use of non-ranitidine H2RAs noticeably increased after the recall, while PPI usage did not change significantly [16]. Conversely, in Europe, the patients who had previously been prescribed ranitidine most commonly shifted to PPIs [19]. In Korea, approximately two-thirds of patients who had been taking ranitidine for gastrointestinal conditions were found to have switched to alternative medications post-recall [20]. The lower-than-expected transition to PPIs has been suggested to be due to relatively high out-of-pocket costs and differences in pharmacodynamic properties [21]. These variations in drug utilization changes following the withdrawal of ranitidine across different countries are likely influenced by demographic characteristics, cultural factors, and healthcare policies [34]. Our analysis of patients prescribed ranitidine in September 2019, with a follow-up period of 3 months (until December 2019), revealed that 26.5% of patients switched to non-ranitidine H2RAs, 16.9% to PPIs, and 1.4% to P-CABs, while 55.2% did not switch to any of these 3 acid-suppressive agents (Supplemental Material 4).

The global withdrawal of ranitidine has caused concern regarding its previous users. Some individuals may have discontinued acid suppressive therapy entirely, either because their need for medication was minimal or due to heightened concerns about potential adverse effects. This may explain the lack of full compensation by other acid suppressants following the suspension of ranitidine. Although a large-scale multinational study found no significant association between ranitidine use and the development of cancer, research focusing on Korean and Asian populations has yielded conflicting results, complicating the task of dismissing a potential link [18]. Thus, continuous monitoring is required to evaluate long-term changes in prescribing patterns.

Despite ongoing safety concerns with conventional therapy, this study revealed a continued increase in PPI usage, with the rate of increase accelerating after the withdrawal of ranitidine from the market. Notably, we observed a prominent increase in the amount of usage relative to the number of claims (data not shown), suggesting growing high-dose or long-term use. Although substantial evidence supports on-demand PPI therapy, long-term prescribing remains common worldwide [35]. Moreover, concerns about long-term PPI use have been raised, regarding not only safety but also cost-effectiveness, medical necessity, and treatment adherence [36]. Addressing many of the limitations associated with PPIs, P-CABs have been introduced as a new generation of acid suppressants; however, their approved formulations remain limited [5]. Therefore, major changes in market uptake are expected to take time. While the overall utilization of PPIs continues to rise, further investigation is required to determine whether this reflects overuse within the examined population. Such research should include a case-by-case evaluation of the appropriateness of prescribing, analyze PPI dosages taken over specific periods, and examine the duration of use. In addition, follow-up studies are necessary to fully understand the public health implications of increased PPI utilization in this population.

This study quantified the utilization patterns of acid suppressants and assessed changes following the withdrawal of ranitidine. Considering the potential adverse effects and high healthcare costs associated with long-term acid suppressant therapy, evaluating the current utilization patterns of these medications is crucial. In Korea, all H2RAs and PPIs are covered by healthcare benefits, enabling a thorough analysis of their overall utilization using claims data that include these medications. Furthermore, the impact of the ranitidine recall was examined, incorporating the autocorrelation of time series data and the seasonal variations in acid suppressant prescriptions [37,38].

Due to several limitations, the results of this study should be interpreted with caution. First, the study did not fully capture all prescriptions related to acid-related diseases. The pharmacological management of these conditions includes a range of therapeutic options, such as acid suppressants, antacids, prokinetics, and other gastroprotective agents. Furthermore, the varying reimbursement criteria for each type of acid suppressant limited our ability to comprehensively identify cases involving prescriptions for acid-related diseases. Although the study focused on prescriptions associated with common diagnoses required for reimbursement for most acid suppressants, the exclusion of indications like esophagitis, Helicobacter pylori infection, and dyspepsia may have prompted an underestimation of their utilization. Second, we could not determine the exact timing of patients’ medication intake. Drug utilization was calculated based on the date of the hospital visit for outpatient prescriptions, with the assumption of complete adherence to the prescribed regimen. However, actual compliance over the specified duration could not be verified using claims data, which is particularly challenging in cases of hospitalization where even prescription dates were not available. Nevertheless, this issue likely had a minimal impact, since most acid suppressant prescriptions are dispensed in outpatient settings. Third, external events may have influenced the prescription of acid suppressants. As an interrupted time series study is designed to examine changes before and after an intervention, this analysis is vulnerable to unmeasured time-dependent factors that could have affected the outcomes [39]. Here, for instance, the introduction of P-CABs might have competed with existing agents, influencing their market uptake. Changes in insurance policies or effects of the coronavirus disease 2019 pandemic during the study period could also have impacted drug utilization [21]. The use of a control group not subject to the intervention of interest would have enabled adjustment for these time-varying confounders [39]. However, because the recall of ranitidine was nationwide, a comparison with a control group was not feasible. Finally, the impact of the intervention may not be fully explained by the level change and slope change following the intervention. More complex changes in utilization, such as a temporary slope change leading to a level change [40], present challenges for evaluation using a linear model. Furthermore, our estimates should be interpreted with caution to account for baseline seasonal variation.

The withdrawal of ranitidine from the market resulted in a significant increase in the use of other acid-suppressive agents. This event amplified the already increasing trend in PPI utilization, with recent figures showing a usage rate of 3929 DDDs per 100 000 inhabitants per day in Korea. Given the potential risks associated with long-term PPI therapy, further research on the public health implications of this shift is necessary to inform strategies that promote medication safety.

Supplemental Materials

Notes

Conflict of Interest

The authors have no conflicts of interest associated with the material presented in this paper.

Funding

None.

Author Contributions

Conceptualization: Lee J. Data curation: Kim MS, Choi JP. Formal analysis: Choi JP, Kim S. Funding acquisition: None. Methodology: Lee J, Kim MS, Choi JP, Kim S. Project administration: Lee J. Visualization: Choi JP, Lee J. Writing – original draft: Choi JP. Writing – review & editing: Choi JP, Kim S, Park JS, Kim MS, Choi NK, Shin CM, Lee J.

Acknowledgements

Figure 1

Trends in the utilization of acid suppressants. (A) H2 receptor antagonists (H2RA) and (B) proton pump inhibitors (PPI).DDD, defined daily dose.

Figure 2

Changes in the utilization of (A) H2 receptor antagonists (H2RA) and (B) proton pump inhibitors (PPI) after the withdrawal of ranitidine. The dark sky blue areas represents the 80% confidence intervals (CIs), and the light sky blue areas represent the 95% CIs. DDD, defined daily dose.

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