Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Satoshi Yamate; Chieko Ishiguro; Haruhisa Fukuda; Satoshi Hamai; Yasuharu Nakashima

doi:10.1371/journal.pone.0305320

. 2024 Jun 11;19(6):e0305320. doi: 10.1371/journal.pone.0305320

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Satoshi Yamate ¹, Chieko Ishiguro ², Haruhisa Fukuda ^3,⁴, Satoshi Hamai ^1,^*, Yasuharu Nakashima ¹

Editor: Mahmoud Kandeel⁵

PMCID: PMC11166339 PMID: 38861561

Abstract

Background

Rebamipide has been widely co-prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) in Japan for decades. This study aimed to evaluate the effectiveness of rebamipide in preventing upper gastrointestinal bleeding in new users of NSAIDs without risk factors of NSAID-induced ulcers other than age.

Methods

A nested case-control study was conducted using medical claims data of 1.66 million inhabitants of 17 municipalities participating in Japan’s Longevity Improvement & Fair Evidence study. The cohort entry (t₀) corresponded to a new user of NSAIDs for osteoarthritis or low back pain. Patients with risk factors of NSAID-induced ulcers other than age were excluded. Cases were defined as patients who underwent gastroscopy for upper gastrointestinal bleeding (occurrence date was defined as index date). A maximum of 10 controls were selected from non-cases at the index date of each case by matching sex, age, follow-up time, and type and dosage of NSAIDs. Exposure to rebamipide was defined as prescription status from t₀ to index date: Non-user (rebamipide was not co-prescribed during the follow-up period), Continuous-user (rebamipide was co-prescribed from t₀ with the same number of tablets as NSAIDs), and Irregular-user (neither Non-user nor Continuous-user). Conditional logistic regression analysis was conducted to estimate each category’s odds ratio compared to non-users.

Findings

Of 67,561 individuals who met the inclusion criteria, 215 cases and 1,516 controls were selected. Compared with that of Non-users, the odds ratios and 95% confidence interval were 0.65 (0.44–0.96) for Continuous-users and 2.57 (1.73–3.81) for Irregular-users.

Conclusions

Continuous co-prescription of rebamipide significantly reduced the risk of upper gastrointestinal bleeding in an Asian cohort of new users of NSAIDs with osteoarthritis or low back pain without risk factors other than age.

Introduction

Rebamipide is a peptic ulcer protective drug developed in Japan [1] and is the most popular drug used in Japan for this purpose. According to the government’s annual all-counts survey, 2.5 billion tablets (0.25 million kg) of rebamipide, marketed by 24 pharmaceutical companies, were prescribed from April 2021 to March 2022 [2]. Rebamipide promotes the synthesis of prostaglandins [3] and secretion of gastric mucus [4], thereby inhibiting the production of reactive oxygen radicals and inflammatory cytokines and suppressing the activity of leukocytes [5]. In East Asia, rebamipide is widely prescribed as a prophylaxis for non-steroidal anti-inflammatory drug (NSAID)-induced ulcers [6]. However, current guidelines in Japan [7] and abroad [8] do not describe rebamipide’s effectiveness, usage, or efficacy.

The Japanese guideline [7] recommends the co-prescription of proton-pump inhibitors (PPIs) in preventing NSAID-induced ulcers; however, Japanese insurance does not cover using PPIs as prophylaxis for NSAID-induced ulcers. The effectiveness of PPIs in preventing NSAID-induced ulcers has been reported in numerous randomized controlled trials [9–13] and is also recommended by worldwide guidelines for moderate or high-risk patients who have any of the following risk factors: age over 65 years, previous history of an uncomplicated ulcer, or concurrent use of aspirin, antiplatelet drugs, corticosteroids, or anticoagulant agents [8]. However, their effectiveness in low-risk patients without risk factors remains unclear. Recently, there have been several reports linking PPIs with adverse drug reactions, such as dementia [14], bone fractures [15], prosthetic joint infection [16], and severe clinical outcomes of coronavirus disease (COVID-19) [17]. However, it is also essential to consider potential bias in reporting these associations [18–20]. On the other hand, rebamipide prevents ulcers without affecting gastric acid secretion [1], is known to have very few adverse drug reactions [5, 21], and could be considered as an alternative to PPIs as a prophylactic agent for patients at low risk of NSAID-induced ulcers [6].

The prevention of NSAID-induced ulcers can be established from the initial prescription of NSAIDs, such as in an orthopaedic outpatient clinic; however, several of these prescriptions fail to adhere to the guidelines for preventing ulcers [22]. In our study, we focused on new users of NSAIDs with low back pain or joint pain caused by osteoarthritis, which are typical orthopaedic diseases [23–26], to evaluate the effectiveness of co-prescription of rebamipide in preventing NSAID-induced ulcers. Our investigation aimed to answer the question, “Does rebamipide contribute to preventing upper gastrointestinal bleeding in new users of NSAIDs for osteoarthritis or low back pain and who are at low risk of NSAID-induced ulcers?” We hypothesized that continuous co-prescription of rebamipide would have a preventive effect on NSAID-induced ulcers.

Materials and methods

Study design

Using routinely collected medical claims data, this observational study using a nested case-control study design [27–29] was conducted following the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines [30], RECORD (Reporting of Studies Conducted Using Observational Routinely-Collected Health Data) Statement [31], and ethical standards of the Declaration of Helsinki.

We used a nested case-control study design to account for many covariates of bleeding gastric ulcers, such as the type and dosage of NSAIDs prescribed, treatment duration, comorbidities, and co-prescribed drugs that may cause ulcers. In addition, changes in the type or dosage of NSAIDs prescribed during the study period were considered an essential confounding factor associated with the occurrence of events. Therefore, the study design, which could incorporate the information on the dosage and type of NSAIDs prescribed, was considered appropriate to assess the effect of rebamipide.

Setting

We used medical claims data for the analysis as we considered it useful for tracking patients across specialties in the real world. We reviewed the medical claims data collected from April 1, 2013, to December 31, 2020, of 1.66 million inhabitants of 17 municipalities participating in the Longevity Improvement & Fair Evidence (LIFE) Study [32–34], a research database project by Kyushu University, Fukuoka, Japan, and approved by the Kyushu University Institutional Review Board for Clinical Research (Registration number: 22114–04).

The LIFE Study collected medical claims data from two public insurance systems: Japan’s National Health Insurance System for individuals aged 0–74 years and Latter-Stage Older Persons Health Care System for individuals aged ≥75 years and those aged 65–74 years with specific diseases. The former enrolls 26.3% of all citizens aged 0 to 74, of which 68.5% of all citizens aged 65 to 74 are enrolled, and the latter is in principle enrolled by all citizens aged 75 and older, thus these two insurance policies cover the majority of the elderly in Japan [32, 35]. The claims data included recorded diagnoses based on the International Classification of Disease, Tenth Revision (ICD-10) codes, drug prescriptions, and medical treatment during clinical encounters, collected by five researchers using pre-delineated forms of LIFE Common Data Model [32].

The review board waived the requirement for informed consent due to the study’s retrospective nature and because all records were de-identified and fully anonymized before our access for analysis. The data were accessed for research purposes from May 11, 2022, to March 24, 2023. The authors did not have access to information that could identify individual participants during or after data collection.

Participants

Definition of cohort

The cohort included patients who were prescribed NSAIDs, including selective cyclooxygenase-2 (COX-2) inhibitors (S1 Table), in the calendar month when the ICD-10 codes for osteoarthritis (M16-19) and back pain (M54) were recorded. The calendar date of the first NSAID prescription was defined as t₀. Considering that insurance payers often do not allow prescriptions to exceed 90 days, therefore, the time window (T.W.) from 90 days before t₀ to 1 day before t₀ was used for defining exclusion criteria.

The exclusion criteria were as follows: (1) patients without medical records before the T.W., (2) patients who received NSAIDs without an ICD-10 diagnosis of osteoarthritis or back pain during the T.W., (3) patients with a history of upper gastrointestinal ulcers (ICD-10 codes: K25-28 and K922) or diagnosis related to Helicobacter pylori infection (ICD-10 codes: K294, K296, A048, A498, and B980), (4) patients who received drugs associated with the risk of gastric ulcer development or associated with bleeding [7] (such as anticoagulants, antiplatelet agents, steroids, or bisphosphonates) prescribed during the T.W., (5) patients with a history of upper gastrointestinal endoscopy before t₀, (6) patients with ulcer treatment or prophylaxis (rebamipide, PPI, misoprostol, H2 receptor antagonists, or other gastroprotective medicines) during the T.W., and (7) patients with ulcer treatment or prophylaxis other than rebamipide at t₀. These inclusion and exclusion criteria aimed to select patients who were prescribed NSAIDs alone or NSAIDs with rebamipide for the first time to treat joint or back pain, with no risk factors [8] other than age. We excluded cases in which rebamipide was used to treat H. pylori-associated gastritis [36–38], as our objective was to assess the effectiveness of rebamipide for the prevention and not for the treatment of gastric ulcers.

The follow-up period encompassed the prescription date with a 180-day gap and a 180-day grace period for NSAIDs. Therefore, if any NSAIDs were prescribed within 180 days of the last prescription date, it was considered as continued treatment. Patients who received high-risk drugs (anticoagulants, antiplatelet agents, steroids, or bisphosphonates) after t₀ were censored on that previous day. Therefore, only data from the period until the prescription of high-risk drugs were used for the analysis.

Definition of cases and controls

In a nested case-control study, cases within the cohort experience the event of interest selected from the follow-up period [29]. In this study, the event of interest was upper gastrointestinal bleeding. Patients were considered as cases if the following two criteria (A) and (B) were met: (A) there was a claim for gastroscopy (treatment code: 160093810) or a hemostatic procedure (treatment code: 150164850) from the day after the first NSAID prescription until 180 days after the last NSAID prescription date within the follow-up period; (B) there was a diagnosis of ‘upper gastrointestinal bleeding’ (ICD-10 codes: K250, K252, K254, K256, K260, K262, K264, K266, K290, and K922) was required in the same calendar month.

In a nested case-control study, controls are selected from the cohort members who are at risk of the event at the time of each case’s occurrence, and these controls can be chosen repeatedly or may later become cases themselves [29]. For each case, controls (maximum 10) were selected from non-cases at the index date of each case by matching (A) sex at t₀, (B) age (±5 years) at t₀, (C) follow-up (±180 days) from t₀ to the index date, (D) the total number of NSAID tablets prescribed, and the total dose of the five types of NSAIDs (loxoprofen, celecoxib, diclofenac, meloxicam, and ibuprofen).

Grouping

Patients were grouped based on the prescription status of rebamipide from t₀ to the index date: 1) Non-user, 2) Continuous-user, and 3) Irregular-user (Fig 1). Patients without rebamipide prescriptions from t₀ to the index date were grouped as Non-users. If patients were continuously prescribed rebamipide from t₀ to the index date with the same number of tablets as NSAIDs, they were grouped as Continuous-users. Patients not falling under either Continuous-user or Non-user were grouped as Irregular-users. Therefore, if a patient was prescribed NSAIDs less than three times a day but rebamipide 100 mg three times a day [4], they were classified as an irregular user because the number of tablets did not match.

Fig 1 — Non-user = Rebamipide was not co-prescribed during the follow-up period. Continuous-user = Rebamipide was co-prescribed from t₀ with the same number of tablets as NSAIDs. Irregular-user = Neither Non-user nor Continuous-user. NSAIDs, non-steroidal anti-inflammatory drugs.

Statistical analysis

Conditional logistic regression analysis considering matching factors was conducted to estimate the odds ratio (OR) for the occurrence of NSAID-induced bleeding ulcers to evaluate the association between the use of rebamipide as a prophylaxis for NSAID-induced ulcers and the incidence of upper gastrointestinal bleeding. The reference was defined as no rebamipide prescription during the entire observation period from t₀. We performed a subgroup analysis stratifying patients by age, either younger than 65 years of age (Subgroup analysis 1) or 65 years of age and older (Subgroup analysis 2), of which the latter is a risk factor for NSAID-induced ulcers [8]. In addition, we performed a subgroup analysis based on whether NSAIDs prescribed at t₀ were loxoprofen (Subgroup analysis 3) or celecoxib (Subgroup analysis 4) or diclofenac (Subgroup analysis 5). All statistical analyses were performed using R version 4.2.0 (The R Foundation, Vienna, Austria) and RStudio version 2022.02.2 (RStudio, Boston, MA, USA).

Sensitivity analyses

Considering the possibility that “low-risk” was not well defined in the main analysis [39], we performed three patterns of sensitivity analysis with additional exclusion criteria of patients with an ICD-10-based Charlson Comorbidity Index [40] of ≥1 point (Sensitivity analysis 1), ≥2 points (Sensitivity analysis 2), or ≥3 points (Sensitivity analysis 3).

Patient and public involvement

In this study, there was no direct involvement from patients or the general public in the research design, conduct, or reporting. However, we shared our study protocol with participating municipalities. In line with the aim of the LIFE Study database, the analytical results are planned to be fed back to the public through these participating municipalities [32].

Results

Of the 367,714 patients who were prescribed NSAIDs (including selective COX-2 inhibitors) and had a diagnosis of osteoarthritis or back pain in the same calendar month, 295,950 (80.5%) patients were aged 65 years or older. The most prescribed NSAIDs were loxoprofen (233,575 patients; 63.5%), followed by celecoxib (91,863 patients; 25.0%) and diclofenac (32,817 patients; 8.9%). The co-prescription rate of rebamipide was 36.1% for loxoprofen, 41.2% for celecoxib, and 26.2% for diclofenac, respectively (S2 Table).

After applying the exclusion criteria, 67,561 patients were included in the study cohort (Fig 2). From the cohort, 345 (0.5%) case candidates were identified, and their median age at cohort entry was 77 years (S3 Table). Of the 345 case candidates, 61 had claim codes for hemostatic procedures.

After matching, 215 cases and 1,516 controls were identified; there were no notable differences in patient background between cases and controls (Table 1). Total dose of NSAIDs for the cases used for the control matching factor showed a wide distribution in the quartile range for loxoprofen, celecoxib, and diclofenac. The median time to upper gastrointestinal bleeding after the first prescription of NSAIDs was 134 days (S1 Fig). Regarding the prescription status of rebamipide, 649 patients were classified as continuous-users, 265 patients as irregular-users, and 817 patients as non-users. The OR for the occurrence of upper gastrointestinal bleeding for the continuous-user group was 0.65 (95% confidence interval [CI] 0.44–0.96) compared with that of non-users and 2.57 (95% CI 1.73–3.81) for irregular-users compared with that of non-users (Table 2).

Table 1. Patient characteristics of cases and controls in this study.

Variable	Case (n = 215)	Control (n = 1,516)
Index date (range)^a	11 Sep 2013 to	11 Sep 2013 to
Index date (range)^a	11 Nov 2020	11 Nov 2020
Days from t₀ to index^a	median 134	median 159
	IQR 48–377	IQR 76–292
	range 1–1836	range 1–1656
Age at t₀^a	median 76.2	median 75.8
	IQR 69–83	IQR 69–81
	range 36.7–98.5	range 32.6–98.8
Age at t₀ (no. [%])
≤64 years	32 (14.9)	184 (12.1)
65–74 years	61 (28.4)	513 (33.8)
75–84 years	84 (39.1)	604 (39.8)
≥85 years	38 (17.7)	215 (14.2)
Sex at t₀^a (no. [%])
Male	107 (49.8)	764 (50.4)
Female	108 (50.2)	752 (49.6)
Diagnosis at t₀ (no. [%])
Osteoarthritis of hip	4 (1.9)	50 (3.3)
Osteoarthritis of knee	65 (30.2)	480 (31.7)
Osteoarthritis (Others)	17 (7.9)	118 (7.8)
Back pain	129 (60.0)	868 (57.3)
Type of NSAIDs at t₀ (no. [%])
Loxoprofen	152 (70.7)	1143 (75.4)
Celecoxib	52 (24.2)	331 (21.8)
Diclofenac	8 (3.7)	36 (2.4)
Meloxicam	2 (0.9)	5 (0.3)
Ibuprofen	1 (0.5)	1 (0.1)
Co-prescription of rebamipide at t₀ (no. [%])	95 (44.2)	713 (47.0)
Total dose of NSAIDs^a^,^b
Loxoprofen (mg)	(n = 155^c)	(n = 1,146^c)
	median 600	median 420
	IQR 330–1,260	IQR 300–840
	range 60–18,240	range 60–18,240
Celecoxib (mg)	(n = 52^c)	(n = 334^c)
	median 1,400	median 1,400
	IQR 7,00–2,800	IQR 700–2,800
	range 100–21,000	range 100–21,000
Diclofenac (mg)	(n = 10^c)	(n = 38^c)
	median 62.5	median 50
	IQR 31.25–228.12	IQR 25–50
	range 25–525	range 25–525
Meloxicam (mg)	(n = 2^c)	(n = 5^c)
	median 70	median 70
	IQR 70–70	IQR 70–70
	range 70–70	range 70–70
Ibuprofen (mg)	(n = 1^c)	(n = 1^c)
Ibuprofen (mg)	1,500	1,500
Total tablets of NSAIDs^a (median [IQR, range])	median 10	median 7
	IQR 6–23	IQR 5–14
	range 1–304	range 1–304

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NSAIDs, non-steroidal anti-inflammatory drugs; IQR, interquartile range (25^th percentile–75^th percentile).

^aVariables used for matching.

^bData are shown excluding patients with 0 mg, respectively.

^cNumber of patients included in the relevant section after excluding patients with 0 mg.

Table 2. Conditional logistic regression analysis of upper gastrointestinal bleeding.

Prescription status of rebamipide	Case (n = 215)	Control (n = 1,516)	Crude Odds Ratio (95% CI)	Adjusted Odds Ratio^a (95% CI)
Non-user	93 (43.3)	724 (47.8)	1 (Reference)	1 (Reference)
Continuous-user	52 (24.2)	597 (39.4)	0.68 (0.47–0.97)	0.65 (0.44–0.96)
Irregular-user	70 (32.6)	195 (12.9)	2.79 (1.97–3.95)	2.57 (1.73–3.81)

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^aConditional logistic regression analysis was conducted by considering matching factors: (A) sex at t₀, (B) age (± 5 years) at t₀, (C) follow-up (± 180 days) from t₀ to index date, (D) the total number of NSAID tablets prescribed, and (E) the total dose of the five types of NSAIDs (loxoprofen, celecoxib, diclofenac, meloxicam, and ibuprofen).

CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs.

For the continuous-user group, the ORs for the occurrence of upper gastrointestinal bleeding were 0.35 (95% CI 0.09–1.32) for the subgroup with patients younger than 65 years of age (S4 Table) and 0.69 (95% CI 0.46–1.04) for the subgroup with patients older than 65 years of age (S5 Table). The results of the subgroup analysis based on NSAIDs prescribed at t₀ showed ORs of 0.67 (95% CI 0.42–1.08) for loxoprofen (S6 Table) and 0.58 (95% CI 0.28–1.20) for celecoxib (S7 Table). Sensitivity analyses using the Charlson Comorbidity Index to determine the low-risk factors of NSAID-induced ulcer, other than age, also showed consistent results (S8–S10 Tables).

Discussion

We found that upper gastrointestinal bleeding significantly decreased when rebamipide was co-prescribed with the same number of tablets from the first dose of NSAID and later continuously prescribed. This result was based on real-world data in orthopaedic patients without risk factors for NSAID-induced ulcers other than age. Using rebamipide for preventing NSAID-induced ulcers, a simple co-prescription pattern for rebamipide may improve adherence in clinical practice. The co-prescription rate of rebamipide with NSAIDs was high in our LIFE database, consistent with that in previous reports [1, 5, 36, 37, 41]. Thus, the study results demonstrate rebamipide’s clinical relevance and effectiveness in real-world practice in an Asian cohort.

Our findings also revealed that for irregular-users for whom the total number of rebamipide tablets did not match that of NSAIDs, the occurrence of upper gastrointestinal bleeding was higher than that in non-users. In some cases, rebamipide may be prescribed after the initiation of NSAIDs owing to patients’ symptoms, such as stomach pain. Our findings suggest that by re-evaluating the pattern of rebamipide prescription by gastroenterology nonspecialists, early detection of gastric ulcers may be possible.

Rebamipide was comparable to misoprostol in reducing the incidence of gastric and duodenal ulcers according to a multicenter, double-blind, randomized parallel-group study by Kim et al. [42] They also found that rebamipide was associated with fewer adverse drug reactions, such as nausea and diarrhea. However, our study found that the actual number of prescriptions is approximately 1/100th of that for rebamipide; this could be because rebamipide has fewer adverse drug reactions than misoprostol [42, 43]. Recently, Lee et al. [6] reported no significant difference in the risk of serious gastrointestinal adverse drug reactions between PPI and rebamipide for preventing NSAID-induced ulcers (adjusted hazard ratio 0.69, 95% CI 0.27–1.76) using the national claims database. Even though the frequency is lower compared to other acid-related disorder treatments, prescribers should be aware of the risk of pulmonary adverse drug reactions associated with rebamipide [44], and leukopenia might occur in rare cases [5], meaning that rebamipide is not entirely risk-free.

Imai et al. [45] found that the reporting ORs for lower gastrointestinal tract injury with loxoprofen and diclofenac in combination with rebamipide were 0.50 (95% CI 0.35–0.71) using the U.S. Food and Drug Administration (FDA) database and 0.43 (95% CI 0.27–0.67) using the Pharmaceuticals and Medical Devices Agency database. Our study on upper gastrointestinal bleeding similarly supports these protective effects. Kato et al. [46] found that the combination of PPI and rebamipide is more effective than PPI alone for treating ulcers after endoscopic submucosal dissection. Mizukami et al. [47] reported that rebamipide is effective in combination therapy with PPIs to prevent low-dose aspirin-induced gastrointestinal symptoms. Therefore, co-prescription of rebamipide with PPIs may be effective in specific patients.

Our study found that >80% of NSAID users with orthopaedic conditions were older than 65 years of age. Maes et al. [14] showed that long-term PPI use in patients older than 60 years increased the incidence of fractures due to osteoporosis. Zhang et al. [48] reported PPI use may influence total hip bone mineral density via plasma metabolites involved in the sex hormone pathway. The FDA has stated that low-dose, short-term oral PPIs are not associated with fractures; moreover, fracture warnings owing to high-dose, long-term PPIs are still present in the FDA’s current safety announcement [49]. Yamashiro et al. [50] reported PPI use is associated with an increased risk of hypomagnesemia, especially in males under 60 years and those with low body-mass index. Several systematic reviews suggest that suppressing gastric acid with PPI leads to bacterial colonization and increased susceptibility to enteric infections [51, 52]. A case-cohort study by Bruin et al. [16] found that perioperative dosing of PPIs is associated with increased prosthetic joint infections. According to a multicenter, cross-sectional study conducted in 2022 in Japan, the mean age of new patients with hip osteoarthritis was 63.5 years [53], and those patients with osteoarthritis may undergo joint replacement surgery after taking NSAIDs for an extended duration [54]. However, infection and periprosthetic fractures are serious complications of joint replacement surgery [55]. Using PPIs to prevent NSAID-induced ulcers in patients at low risk should be discussed in light of these possibilities.

The CYP2C19 enzyme involved in PPI metabolism varies considerably across different racial and ethnic groups [18, 56]. Asians with low CYP2C19 levels and lower stomach acid secretion [57] than Caucasians could have an increased risk of adverse drug reactions associated with PPIs [18]. A recent study by Lee et al. using the Korean database found that PPIs were associated with severe COVID-19-related outcomes [17]. However, Nayar et al. [19] found no such association among United States veterans. In addition to the effects of unadjusted confounding factors [20], racial differences, such as Asians having an increased likelihood of experiencing adverse drug reactions from PPIs, could be related to the discrepancy in results.

Forgerini et al. [58] reported variants in the CYP2C9 gene, as the *2 and *3 alleles are responsible for the slow metabolism of NSAIDs, which increases the risk of gastrointestinal bleeding. Zhou et al. [59] reported pronounced regional differences in the distribution of the CYP2C9*2 and *3 alleles, underscoring the importance of genetic variability in the CYP2C9 gene for the efficacy and safety of drugs on a global scale. When considering the risk of NSAID-induced ulcers in the future, it is essential to consider such genetic backgrounds to enhance patient safety and tailor treatment strategies.

This study has several limitations. First, the cases in this study underwent upper gastrointestinal endoscopy and had a diagnosis of upper gastrointestinal bleeding based on ICD-10 codes. However, we did not have access to the written reports or images of the endoscopy; thus, there might have been some misclassification of cases in this study. Second, we did not assume that upper gastrointestinal bleeding was due to etiologies other than NSAID-induced ulcers. Therefore, we ensured the robustness of our findings by conducting sensitivity analyses that excluded patients with a Charlson Comorbidity Index score of 1 or higher to support the assumption that the upper gastrointestinal bleeding was not due to other causes, such as neoplasia, cirrhosis, or varicose veins. Third, this study did not adjust for confounding factors that cannot be captured by medical receipt data, such as patients’ smoking and alcohol consumption habits.

The strength of this study is in its high tracking rate. Japan has a universal health insurance system, in which most citizens visit hospitals and receive prescriptions for NSAIDs and gastroprotective medicines from their doctors. Since all individuals in this study visited a hospital and are covered by insurance, paying a maximum of 30% out-of-pocket for prescription medication, we assume that there is a low likelihood they would purchase NSAIDs at significantly higher prices by not using their insurance. Our results using medical claims data might reflect the incidence and risk across the broader population.

Conclusions

Our study showed that continuous co-prescription of rebamipide significantly reduced the risk of upper gastrointestinal bleeding in new users of NSAIDs with osteoarthritis or low back pain without risk factors other than age. This result was confirmed by a nested case-control study, which could strictly adjust the type and dosage of NSAIDs prescribed.

Supporting information

S1 Fig. Days from t₀ to upper gastrointestinal bleeding.

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S1 Table. ATC code list.

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S2 Table. Demographics of the cohort in which NSAIDs were first used for osteoarthritis or back pain.

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S3 Table. Population that received NSAIDs for the first time for osteoarthritis or low back pain and without risk factors for gastric ulcer other than age.

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S4 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients aged under 65 years (Subgroup analysis 1).

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S5 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients aged 65 years or over (Subgroup analysis 2).

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S6 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients receiving loxoprofen at t₀ (Subgroup analysis 3).

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S7 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients receiving celecoxib at t₀ (Subgroup analysis 4).

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S8 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding (Sensitivity analysis 1).

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S9 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding (Sensitivity analysis 2).

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S10 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding (Sensitivity analysis 3).

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Data Availability

The data used in this study were acquired under agreements between Kyushu University and the participating municipalities, which stipulate that the data can only be used by authorized research institutions and cannot be shared with third parties. However, research institutions that have entered into agreements with the authorized research group in Kyushu University may access the data. Please contact the Joint Research Department of Kyushu University (ijkkyoudou@jimu.kyushu-u.ac.jp) regarding data access.

Funding Statement

This work was supported by the Japan Society for the Promotion of Science KAKENHI (Grant Numbers JP19K21590 and JP20H00563) and by Japan Science and Technology Agency FOREST (Fusion Oriented REsearch for disruptive Science and Technology) program (Grant Number JPMJFR205J). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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PLoS One. doi: 10.1371/journal.pone.0305320.r001

Decision Letter 0

Mahmoud Kandeel

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23 Jan 2024

PONE-D-23-40113Rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study databasePLOS ONE

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Reviewer #1: Estimated Editor and Authors,

First, I would like to thank you for the opportunity to review this manuscript. This is a nested case-control that evaluated the effectiveness of the prescription of rebamipide for prevention of upper gastrointestinal bleeding in NSAIDs users living with orthopedic conditions. The manuscript is well written and is relevant in the scope of patient safety, considering the high morbidity and mortality related to gastrointestinal bleeding as an adverse drug event. However, methodological reporting is somewhat confusing and needs to be improved for a better understanding of the study and to be reproducible.

Follow my feedback below to help you improve the quality and clarity of your manuscript:

- Title: The authors report as if the rebamipide prevents upper gastrointestinal bleeding on any NSAIDS user, but the authors' findings only identified this protection in occasional users. Therefore, it is important to review the title so that it is harmonious with the findings of the study.

- At many times the occasional use of NSAIDS is cited, but this is not defined. It is very important to define how stratified the consumption of NSAIDS and what was considered in each stratum.

Introduction

- Page 5, Line 60: Is there no more current data on the rebamipide prescription?

- The most appropriate terminology is "adverse drug events" and not "effects".

- Important to define what was considered "low risk of NSAIDs induced ulcers".

- Page 6, lines 86 and 87 do not fit in the introduction: "We used medical claims data for the analysis we consider it a useful approach for tracking cats across specialties in the real world."

Methodology

- The methodology should follow the reporting of checklist Strobe, because in many moments this section is confused. Strobe should be used to guide the methodology report.

I understand, for example, that the methodology should start by presenting the study and setting design and not the database used to consult the data.

- Page 6, Line 103: Do two public insurance systems cover the entire country?

- How many researchers conducted data collection? Were pre-delineated forms used for this data collection?

- Why was the Time Window (T.W.) from 90 days before t0 to 1 day before t0 the exclusion criteria?

- Were the life habits of patients, such as smoking and consumption of beverages, which depending on the amount consumed may be associated with gastrointestinal problems?

- Pages 8 and 9, lines 151 - 153: This sentence is not clear. What refers to censorship in line 153?

- The definition of cases is not clear. Patients diagnosed with osteoarthritis or back pain who were prescribed from NSAIDs were follow-up until these patients undergoing endoscopy and developed upper gastrointestinal bleeding? This flow of recruitment of participants was not clear to me.

- If the patient had in his medical record the reporting of endoscopic findings such as "duodenal ulcer" or "gastric ulcer", would it be considered case? As already reported in the limitations of the study, the non-analysis of endoscopic reports consists of an important bias.

Another aspect, the intention was to evaluate upper gastrointestinal bleeding as an adverse event of the use of NSAIDS, right? Therefore, this excludes the non-variceal etiology. How was the control of the etiologies of the upper gastrointestinal bleeding? Was it possible to identify if the patient was bleeding by neoplasia, cirrhosis, varicose veins, or other conditions? This aspect needs to be better reported.

- I was also in doubt in the following excerpt "However, we assume that the fictitious disease name of "upper gastrointestinal bleeding" would be rarely assigned to a patent without any symptoms of gastrointestinal ulcer." Was it considered cases only patients with upper with gastrointestinal bleeding or just with ulcer as well? Were evaluated if these patients had signs of recent bleeding?

- Page 10, line 176: define what was considered "1) continuous user, 2) occasional user, and 3) non-user".

- Page 11, line 206: the following sentence is confusing: "the analytical results are planned to be disseminated to the public through these participating municipalities."

- One piece of information that would greatly enrich the results would be to assess the defined daily dose of NSAIDs consumed by the participants. I suggest that the authors assess the feasibility or relevance of including this data.

- Was it possible to control whether patients self-medicated with NSAIDs, in addition to the medical prescription they received? How are NSAIDs sold in Japan? In many patients, there is free access to this class.

Results

- When reporting averages or medians, I suggest including the standard deviation or quartiles, respectively.

- In table 1, the data presented in the last rows is not clear. Is it the dose of each NSAID and the respective quartiles? Why are most of the drugs set to 0? I think this form of presentation is a bit confusing. I apologize if I'm not understanding the presentation correctly.

Discussion

- As the authors cite the importance of variants in the CYP2C19 gene, which can impact the metabolism of proton pump inhibitors, it is also worth highlighting variants in the CYP2C9 gene, as the *2 and *3 alleles are responsible for the slow metabolism of NSAIDs, which increases the risk of gastrointestinal bleeding.

- The authors could further highlight the clinical implications and contributions of these findings to clinical practice and patient safety.

Reviewer #2: This is a worthwhile study as there is a paucity of clinical trial data of rebamipide for this indication.

Methods are sound. Inclusion criteria are quite narrow but this helps to avoid confusing.

The discussion about the adverse effects of PPIs compared to those of rebamipide is not equitable. More types of adverse effects have been reported with PPIs, but they have also been used more widely than rebamipide.

It is necessary to make more mention of the adverse effects of rebapimide. The labels list leukopenia and liver dysfunction as adverse effects; although rare (I checked Malaysian and Philippine labels).

The results are than continuous use of rebamipide was associated with less GI bleeding than no use, but the occasional use was associated with a higher risk than no use

The conclusion than rebamipide may be more beneficial than PPIs is unsound since the effect of PPIs has not be addressed in this study.

Some issues need to be addressed:

In the abstract, it should be specified that the patients are at low risk of NSAIDs induced ulcers.

Enteric infections and hypomagnesemia should be mentioned as adverse effects of PPI

Line 78: “[Rebamipide] and may be superior to PPIs as a prophylactic agent for patients at low risk of NSAID induced ulcers.” This statement is not supported by a reference.

Line 80 “The prevention of NSAID-induced ulcers can be achieved from the initial prescription of NSAIDs, such as in an orthopaedic outpatient clinic; however…”

This phrase is strange. From the initial prescription of NSAIDs, prevention is established, it is not yet achieved.

The methods should make it clear whether it is a calendar month or a 30-day period.

Why is ICD-10 code B98.0 (H. pylori as a cause of diseases classified in other chapters) not used as an exclusion criterion?

Line 138: Anticoagulants are associated with bleeding rather than ulcer risk.

Authors should provide unadjusted estimates of the main analysis. (STROBE item 16)

Line 162: “However, we assumed that the fictitious disease name…”

The phrase is strange. The name is not fictitious.

Line 170: the total number of NSAID tablets “prescribed” instead of “administered”.

Line 320: “the study sample was limited to low-risk patients”. This is not a limitation since the research question was about low risk patients

S2 Figure The duration of upper gastrointestinal bleeding after the first prescription of NSAIDs

Figure title is wrong. Data are days to bleeding.

**********

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Reviewer #1: Yes: Marcela Forgerini

Reviewer #2: Yes: Javier Garjon

**********

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PLoS One. 2024 Jun 11;19(6):e0305320. doi: 10.1371/journal.pone.0305320.r002

Author response to Decision Letter 0

11 Mar 2024

Journal requirements:

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Response: Thanks for the information.

We have revised the manuscript according to the PLOS ONE's style requirements.

Response: We reconfirm that we had clearly stated in the main text as follows.

Text Changes (Materials and methods, Lines 120-122):

The review board waived the requirement for informed consent due to the study’s retrospective nature and because all records were de-identified and fully anonymized before our access for analysis.

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Text Changes (Funding):

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Response: We removed the funding-related text from the manuscript.

Please revise our “Funding” section as follows.

Text Changes (Funding):

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Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

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Text Changes (Competing Interests):

Yasuharu Nakashima received research grants from Chugai Pharmaceutical Co., Ltd., AYUMI Pharmaceutical Corporation, EA Pharma Co., Ltd., KYOCERA Corporation, and Zimmer Biomet G.K. All other authors have no conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Before we proceed with your manuscript, please address the following prompts:

We will update your Data Availability statement on your behalf to reflect the information you provide.

Response: Please revise our Data Availability Statement as follows.

Text Change (Data Availability Statement):

Data Availability Statement: The data used in this study were acquired under agreements between Kyushu University and the participating municipalities, which stipulate that the data can only be used by authorized research institutions and cannot be shared with third parties. However, research institutions that have entered into agreements with the authorized research group in Kyushu University may access the data. Please contact the Joint Research Department of Kyushu University (ijkkyoudou@jimu.kyushu-u.ac.jp) regarding data access.

Response to Reviewer #1:

Reviewer #1 (1): Estimated Editor and Authors,

Follow my feedback below to help you improve the quality and clarity of your manuscript:

Response: We are grateful to Reviewer #1 for critical comments and useful suggestions that helped us to improve our paper considerably. We appreciate you pointing out that the description of our methodology was unclear. We did our best effort to revise the manuscript according to your comments.

Reviewer #1 (2):

Response:

Thank you for your valuable comment. We identified this protection in continuous users. We have revised the title to be appropriate.

Text Changes (Title):

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Reviewer #1 (3):

- At many times the occasional use of NSAIDS is cited, but this is not defined. It is very important to define how stratified the consumption of NSAIDS and what was considered in each stratum.

Response: We have modified the wording as we believe Irregular-user would be more appropriate than occasional-user. We also added a definition of grouping to Abstract. In addition, we added a figure to the main text that illustrates the definition of the grouping.

Text Changes (Abstract, Lines 36-41):

Exposure to rebamipide was defined as prescription status from t0 to index date: Non-user (rebamipide was not co-prescribed during the follow-up period), Continuous-user (rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs), and Irregular-user (neither Non-user nor Continuous-user). Conditional logistic regression analysis was conducted to estimate each category’s odds ratio compared to non-users.

Text Changes (Materials and methods, Lines 177-182):

Patients were grouped based on the prescription status of rebamipide from t0 to the index date: 1) Non-user, 2) Continuous-user, and 3) Irregular-user (Fig 1). Patients without rebamipide prescriptions from t0 to the index date were grouped as non-users. If patients were continuously prescribed rebamipide from t0 to the index date with the same number of tablets as NSAIDs, they were grouped as continuous-users. Patients not falling under either continuous-user or non-user were grouped as irregular-users.

Text Changes (Fig 1., Lines 184-188):

Fig 1. Definition of the prescription status of rebamipide. Non-user = Rebamipide was not co-prescribed during the follow-up period. Continuous-user = Rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs. Irregular-user = Neither Non-user nor Continuous-user. NSAIDs, non-steroidal anti-inflammatory drugs.

Reviewer #1 (4):

Introduction

- Page 5, Line 60: Is there no more current data on the rebamipide prescription?

Response:

We thank the reviewer for the valuable comment.

We have checked the latest data available and updated the numbers.

Text Changes (Introduction, Lines 51-53):

According to the government’s annual all-counts survey, 2.5 billion tablets (0.25 million kg) of rebamipide, marketed by 24 pharmaceutical companies, were prescribed from April 2021 to March 2022.

Reviewer #1 (5):

- The most appropriate terminology is "adverse drug events" and not "effects".

Response: We thank the reviewer for the valuable comment. We agree that the term "adverse drug events" was appropriate and have revised the relevant section.

Text Changes (Introduction, Lines 68-69):

Recently, there have been several reports linking PPIs with adverse drug events,

Text Changes (Introduction, Lines 72-73):

On the other hand, rebamipide prevents ulcers without affecting gastric acid secretion[1], is known to have very few adverse drug events,

Text Changes (Introduction, Lines 284-285):

They also found that rebamipide was associated with fewer adverse drug events,

Text Changes (Discussions, Lines 326-327):

than Caucasians could have an increased risk of adverse drug events associated with PPIs.

Text Changes (Discussions, Lines 330-331):

such as Asians having an increased likelihood of experiencing adverse drug events from PPIs,

Reviewer #1 (6):

- Important to define what was considered "low risk of NSAIDs induced ulcers".

Response: We thank the reviewer for the valuable comment. We listed the risk factors and clarified that patients without these factors were defined as low risk patients.

Text Changes (Introduction, Lines 62-68):

The effectiveness of PPIs in preventing NSAID-induced ulcers has been reported in numerous randomized controlled trials and is also recommended by worldwide guidelines for moderate or high-risk patients who have any of the following risk factors: age over 65 years, previous history of an uncomplicated ulcer, or concurrent use of aspirin, antiplatelet drugs, corticosteroids, or anticoagulant agents. However, their effectiveness in low-risk patients without risk factors remains unclear.

Reviewer #1 (7):

- Page 6, lines 86 and 87 do not fit in the introduction: "We used medical claims data for the analysis we consider it a useful approach for tracking cats across specialties in the real world."

Response: We thank the reviewer for the valuable comment. We have moved the relevant sentence from Introduction to Methods.

Text Changes (Materials and methods, Lines 103-104):

We used medical claims data for the analysis as we considered it a useful approach for tracking patients across specialties in the real world.

Reviewer #1 (8):

Methodology

- The methodology should follow the reporting of checklist Strobe, because in many moments this section is confused. Strobe should be used to guide the methodology report.

I understand, for example, that the methodology should start by presenting the study and setting design and not the database used to consult the data.

Response: We have rearranged the method headings and the order of content to follow STROBE whenever possible.

Text Changes (Materials and methods, Lines 88-100):

Study design

Text Changes (Materials and methods, Lines 102-124):

Setting

Text Changes (Materials and methods, Lines 126-187):

Participants

Reviewer #1 (9):

- Page 6, Line 103: Do two public insurance systems cover the entire country?

Response: The two public insurance programs cover the majority of the older population, however, do not cover the entire population. Therefore, we added a sentence that specifically indicates the coverage rate.

Text Changes (Materials and methods, Lines 113-116):

The forme

Attachment

Submitted filename: Response to Reviewers.docx

pone.0305320.s012.docx^{(65.7KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0305320.r003

Decision Letter 1

Mahmoud Kandeel

7 May 2024

PONE-D-23-40113R1Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study databasePLOS ONE

Dear Dr. Hamai,

Please submit your revised manuscript by Jun 21 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
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We look forward to receiving your revised manuscript.

Kind regards,

Mahmoud Kandeel

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: Dear Editor and Authors,

Firstly, I thank you for the opportunity to review again this manuscript.

The authors carried out a carefully review and attended all my suggestions. Hence, I am delighted with the revised version and have no other suggestions.

Minor comment: genes should be written in italics.

Finally, I congratulate the authors for their careful review.

Reviewer #2: Continuous-user is defined as one whom rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs. However, as dosage of rebamipide is one tablet 3 times/day and dosage of celecoxib is one tablet/day, the same number of tablets covers fewer days with rebamipide than with celecoxib. This not fit with figure 1.

In which group is someone who is prescribed more rebamipide tablets than NSAIDs (as they should be in the case of celecoxib or meloxicam for being a continuous user)? It is necessary to clarify this issue.

I am sorry, but I disagree with reviewer #1. “Adverse drug event” is not a standard term; I consider “adverse effect” or “adverse drug reaction” more accurate terms because a causal relationship between the drug and an occurrence is suspected.

Please see: European Medicines Agency and Heads of Medicines Agencies, 2017. Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 4). https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-good-pharmacovigilance-practices-annex-i-definitions-rev-4_en.pdf

Lines 292-296

There is a duplicity:

prescribers should be aware of the risk of pulmonary adverse drug events associated with rebamipide [44], and leukopenia might occur in rare cases [5], meaning that rebamipide is not entirely risk-free. However, prescribers need to be aware of the potential for pulmonary adverse events associated with rebamipide [44] and rare instances of leukopenia [5], highlighting that it is not without risks.

Line 323

"Using PPIs to prevent NSAID-induced ulcers in patients with no risks should be discussed"

“with no risk factors” or “at low risk” are better expressions.

Lines 345 346

"While we found that NSAIDs might unexpectedly cause upper gastrointestinal bleeding, this conclusion is based on studies with low-risk patients."

I do not understand the sentence. NSAIDs, expectedly, cause upper gastrointestinal bleeding even in low-risk patients. This is a finding from the present study. What studies are the authors referring to?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Marcela Forgerini

Reviewer #2: No

**********

PLoS One. 2024 Jun 11;19(6):e0305320. doi: 10.1371/journal.pone.0305320.r004

Author response to Decision Letter 1

17 May 2024

Response to Journal requirements:

Response:

Thanks for the information. We re-searched all the articles on Pubmed and confirmed that they had not been Retracted.

We have added one additional citation (Sato T, Yamate S, Utsunomiya T, Inaba U, Ike H, Kinoshita K, et al. Life Course Epidemiology of Hip Osteoarthritis in Japan: A Multicenter, Cross-Sectional Study. J Bone Joint Surg Am. 2024; Forthcoming. doi: 10.2106/JBJS.23.01044, PMID 38626018.) and have indicated accordingly at the end of this letter.

Response to Reviewer #1:

Reviewer #1: Dear Editor and Authors,

Firstly, I thank you for the opportunity to review again this manuscript.

The authors carried out a carefully review and attended all my suggestions. Hence, I am delighted with the revised version and have no other suggestions.

Minor comment: genes should be written in italics.

Finally, I congratulate the authors for their careful review.

Response:

We are grateful to Reviewer #1 for taking the time to review and provide comments to improve the quality of our paper. As commented to us, we have modified the genes to italics.

Text Changes (Discussion, Lines 338-345):

Forgerini et al. reported variants in the CYP2C9 gene, as the *2 and *3 alleles are responsible for the slow metabolism of NSAIDs, which increases the risk of gastrointestinal bleeding. Zhou et al. reported pronounced regional differences in the distribution of the CYP2C9*2 and *3 alleles, underscoring the importance of genetic variability in the CYP2C9 gene for the efficacy and safety of drugs on a global scale. When considering the risk of NSAID-induced ulcers in the future, it is essential to consider such genetic backgrounds to enhance patient safety and tailor treatment strategies.

Response to Reviewer #2:

Reviewer #2 (1):

Continuous-user is defined as one whom rebamipide was co-prescribed from t0 with the same number of tablets as NSAIDs. However, as dosage of rebamipide is one tablet 3 times/day and dosage of celecoxib is one tablet/day, the same number of tablets covers fewer days with rebamipide than with celecoxib. This not fit with figure 1.

Response:

Thank you for your comment. You are correct in noting that rebamipide is recommended to be taken three times per day, while celecoxib is usually taken twice per day in Japan. We believe that the clinical significance of our results lies in showing that a prescribing pattern where rebamipide and NSAIDs taken with the same number of tablets can be effective. This approach may enhance patient compliance in real-world settings because complex prescribing patterns may reduce patient compliance in real-world clinical practice. We have revised the manuscript to clarify this issue. Thank you for your constructive feedback.

Text Changes (Materials and methods, Lines 182-185):

Therefore, if a patient was prescribed NSAIDs less than three times a day but rebamipide three times a day [4], they were classified as an irregular user because the number of tablets did not match.

Text Changes (Discussion, Lines 275-277):

Using rebamipide for preventing NSAID-induced ulcers, a simple co-prescription pattern for rebamipide may improve adherence in clinical practice.

Reviewer #2 (2):

Response:

Thank you for the information. We have confirmed the PDFs and corrected the terminology to “adverse drug reaction”. Thank you for your careful review to improve the quality of our paper.

Text Changes (Introduction, Lines 68-71):

Recently, there have been several reports linking PPIs with adverse drug reactions, such as dementia, bone fractures, prosthetic joint infection, and severe clinical outcomes of coronavirus disease (COVID-19).

Text Changes (Introduction, Lines 72-75):

On the other hand, rebamipide prevents ulcers without affecting gastric acid secretion, is known to have very few adverse drug reactions, and could be considered as an alternative to PPIs as a prophylactic agent for patients at low risk of NSAID-induced ulcers.

Text Changes (Discussion, Lines 287-299):

Rebamipide was comparable to misoprostol in reducing the incidence of gastric and duodenal ulcers according to a multicenter, double-blind, randomized parallel-group study by Kim et al. They also found that rebamipide was associated with fewer adverse drug reactions, such as nausea and diarrhea. However, our study found that the actual number of prescriptions is approximately 1/100th of that for rebamipide; this could be because rebamipide has fewer adverse drug reactions than misoprostol. Recently, Lee et al. reported no significant difference in the risk of serious gastrointestinal adverse drug reactions between PPI and rebamipide for preventing NSAID-induced ulcers (adjusted hazard ratio 0.69, 95% CI 0.27–1.76) using the national claims database. Even though the frequency is lower compared to other acid-related disorder treatments, prescribers should be aware of the risk of pulmonary adverse drug reactions associated with rebamipide, and leukopenia might occur in rare cases, meaning that rebamipide is not entirely risk-free.

Text Changes (Discussion, Lines 330-332):

Asians with low CYP2C19 levels and lower stomach acid secretion than Caucasians could have an increased risk of adverse drug reactions associated with PPIs.

Text Changes (Discussion, Lines 334-337):

In addition to the effects of unadjusted confounding factors, racial differences, such as Asians having an increased likelihood of experiencing adverse drug reactions from PPIs, could be related to the discrepancy in results.

Reviewer #2 (3):

Lines 292-296

There is a duplicity:

Response:

We are grateful for the careful review of Reviewer #2. We have removed the duplicate sections of the latter.

Text Changes (Discussion, Lines 296-299):

Even though the frequency is lower compared to other acid-related disorder treatments, prescribers should be aware of the risk of pulmonary adverse drug reactions associated with rebamipide [44], and leukopenia might occur in rare cases [5], meaning that rebamipide is not entirely risk-free. However, prescribers need to be aware of the potential for pulmonary adverse events associated with rebamipide [44] and rare instances of leukopenia [5], highlighting that it is not without risks.

Reviewer #2 (4):

Line 323

"Using PPIs to prevent NSAID-induced ulcers in patients with no risks should be discussed"

"with no risk factors" or "at low risk" are better expressions.

Response:

Thank you for your comment. We have revised our expressions.

Text Changes (Discussion, Lines 326-328):

Using PPIs to prevent NSAID-induced ulcers in patients at low risk should be discussed in light of these possibilities.

Reviewer #2 (5):

Lines 345 346

"While we found that NSAIDs might unexpectedly cause upper gastrointestinal bleeding, this conclusion is based on studies with low-risk patients."

Response: Thank you for your comment. In response to the previous comment by Reviewer #1, our intention was not well expressed.

(Previous comment by Reviewer #1: Another aspect, the intention was to evaluate upper gastrointestinal bleeding as an adverse event of the use of NSAIDS, right? Therefore, this excludes the non-variceal etiology. How was the control of the etiologies of the upper gastrointestinal bleeding? Was it possible to identify if the patient was bleeding by neoplasia, cirrhosis, varicose veins, or other conditions? This aspect needs to be better reported.)

Text Changes (Materials and methods, Lines 350-354):

Second, we did not assume that upper gastrointestinal bleeding was due to etiologies other than NSAID-induced ulcers. Therefore, we ensured the robustness of our findings by conducting sensitivity analyses that excluded patients with a Charlson Comorbidity Index score of 1 or higher to support the assumption that the upper gastrointestinal bleeding was not due to other causes, such as neoplasia, cirrhosis, or varicose veins.

Note: We have added one additional citation.

Text Changes (Materials and methods, Lines 322-325):

According to a multicenter, cross-sectional study conducted in 2022 in Japan, the mean age of new patients with hip osteoarthritis was 63.5 years [53], and those patients with osteoarthritis may undergo joint replacement surgery after taking NSAIDs for an extended duration.

Additional Reference:

[53] Sato T, Yamate S, Utsunomiya T, Inaba U, Ike H, Kinoshita K, et al. Life Course Epidemiology of Hip Osteoarthritis in Japan: A Multicenter, Cross-Sectional Study. J Bone Joint Surg Am. 2024; Forthcoming. doi: 10.2106/JBJS.23.01044, PMID 38626018.

We thank Reviewer #1 and Reviewer #2 for the thorough review of our work, and provide comments to improve the quality of our paper.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0305320.s013.docx^{(33KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0305320.r005

Decision Letter 2

Mahmoud Kandeel

27 May 2024

PONE-D-23-40113R2Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study databasePLOS ONE

Dear Dr. Hamai,

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Comments to the Author

Reviewer #2: (No Response)

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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6. Review Comments to the Author

Reviewer #2: Line 240.

I think what is meant is “The median time to upper gastrointestinal bleeding after the first prescription of NSAIDs was 134 days (S2 Figure).”

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Reviewer #2: Yes: Javier Garjon

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PLoS One. 2024 Jun 11;19(6):e0305320. doi: 10.1371/journal.pone.0305320.r006

Author response to Decision Letter 2

27 May 2024

Response to Journal requirements:

Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Response:

Thank you for the information. We re-searched all the articles on Pubmed and confirmed that they are complete and correct, and none have been retracted.

Response to Reviewer #2:

Reviewer #2: Line 240.

I think what is meant is “The median time to upper gastrointestinal bleeding after the first prescription of NSAIDs was 134 days (S2 Figure).”

Response:

Thank you so much for pointing out the error. Your revised description is correct. We also corrected the numbering of the figure; S1 is correct, not S2.

Text Changes (Results, Lines240-242):

The median time to upper gastrointestinal bleeding after the first prescription of NSAIDs was 134 days (S1 Figure).

We thank Reviewer #1 and Reviewer #2 for the thorough review of our work, and provide comments to improve the quality of our paper.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0305320.s014.docx^{(25.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0305320.r007

Decision Letter 3

Mahmoud Kandeel

30 May 2024

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

PONE-D-23-40113R3

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PLOS ONE

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PLoS One. doi: 10.1371/journal.pone.0305320.r008

Acceptance letter

Mahmoud Kandeel

31 May 2024

PONE-D-23-40113R3

PLOS ONE

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Fig. Days from t₀ to upper gastrointestinal bleeding.

(TIF)

pone.0305320.s001.tif^{(283KB, tif)}

S1 Table. ATC code list.

(DOCX)

pone.0305320.s002.docx^{(114.4KB, docx)}

S2 Table. Demographics of the cohort in which NSAIDs were first used for osteoarthritis or back pain.

(DOCX)

pone.0305320.s003.docx^{(31.3KB, docx)}

S3 Table. Population that received NSAIDs for the first time for osteoarthritis or low back pain and without risk factors for gastric ulcer other than age.

(DOCX)

pone.0305320.s004.docx^{(28.8KB, docx)}

S4 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients aged under 65 years (Subgroup analysis 1).

(DOCX)

pone.0305320.s005.docx^{(27KB, docx)}

S5 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients aged 65 years or over (Subgroup analysis 2).

(DOCX)

pone.0305320.s006.docx^{(27.1KB, docx)}

S6 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients receiving loxoprofen at t₀ (Subgroup analysis 3).

(DOCX)

pone.0305320.s007.docx^{(26.8KB, docx)}

S7 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding in patients receiving celecoxib at t₀ (Subgroup analysis 4).

(DOCX)

pone.0305320.s008.docx^{(27KB, docx)}

S8 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding (Sensitivity analysis 1).

(DOCX)

pone.0305320.s009.docx^{(27.3KB, docx)}

S9 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding (Sensitivity analysis 2).

(DOCX)

pone.0305320.s010.docx^{(27.3KB, docx)}

S10 Table. Conditional logistic regression analysis of upper gastrointestinal bleeding (Sensitivity analysis 3).

(DOCX)

pone.0305320.s011.docx^{(27.3KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0305320.s012.docx^{(65.7KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0305320.s013.docx^{(33KB, docx)}

Attachment

Submitted filename: Response to Reviewers.docx

pone.0305320.s014.docx^{(25.1KB, docx)}

Data Availability Statement

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PERMALINK

Continuous co-prescription of rebamipide prevents upper gastrointestinal bleeding in NSAID use for orthopaedic conditions: A nested case-control study using the LIFE Study database

Satoshi Yamate

Chieko Ishiguro

Haruhisa Fukuda

Satoshi Hamai

Yasuharu Nakashima

Roles

Abstract

Background

Methods

Findings

Conclusions

Introduction

Materials and methods

Study design

Setting

Participants

Definition of cohort

Definition of cases and controls

Grouping

Fig 1. Grouping based on the prescription status of rebamipide.

Statistical analysis

Sensitivity analyses

Patient and public involvement

Results

Fig 2. STROBE diagram illustrating the workflow for patient selection.

Table 1. Patient characteristics of cases and controls in this study.

Table 2. Conditional logistic regression analysis of upper gastrointestinal bleeding.

Discussion

Conclusions

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Mahmoud Kandeel

Roles

Transfer Alert

Author response to Decision Letter 0

Decision Letter 1

Mahmoud Kandeel

Roles

Author response to Decision Letter 1

Decision Letter 2

Mahmoud Kandeel

Roles

Author response to Decision Letter 2

Decision Letter 3

Mahmoud Kandeel

Roles

Acceptance letter

Mahmoud Kandeel

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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