Evaluation of the Efficacy and Safety of DW1903 in Patients with Gastritis: A Randomized, Double-Blind, Noninferiority, Multicenter, Phase 3 study.

Background/Aims: H2 receptor antagonists (H2RA) have been used to treat gastritis by inhibiting gastric acid. Proton pump inhibitors (PPIs) are more potent acid suppressants than H2RA. However, the efficacy and safety of low-dose PPI for treating gastritis remain unclear. The aim was to investigate the efficacy and safety of low-dose PPI for treating gastritis. Methods: A double-blind, noninferiority, multicenter, phase 3 clinical trial randomly assigned 476 patients with endoscopic erosive gastritis to a group using esomeprazole 10 mg (DW1903) daily and a group using famotidine 20 mg (DW1903R1) daily for 2 weeks. The full-analysis set included 319 patients (DW1903, n=159; DW1903R1, n=160) and the per-protocol set included 298 patients (DW1903, n=147; DW1903R1, n=151). The primary endpoint (erosion improvement rate) and secondary endpoint (erosion and edema cure rates, improvement rates of hemorrhage, erythema, and symptoms) were assessed after the treatment. Adverse events were compared. Results: According to the full-analysis set, the erosion improvement rates in the DW1903 and DW1903R1 groups were 59.8% and 58.8%, respectively. According to the per-protocol analysis, the erosion improvement rates in the DW1903 and DW1903R1 groups were 61.9% and 59.6%, respectively. Secondary endpoints were not significantly different between two groups except that the hemorrhagic improvement rate was higher in DW1903 with statistical tendency. The number of adverse events were not statistically different. Conclusions: DW1903 of a low-dose PPI was not inferior to DW1903R1 of H2RA. Thus, lowdose PPI can be a novel option for treating gastritis (ClinicalTrials.gov Identifier: NCT05163756).

Oral famotidine reduces the plasma level of soluble P-selectin in children with sickle cell disease.

Plasma histamine levels are increased in patients with sickle cell disease (SCD), potentially promoting endothelial P-selectin expression and vaso-occlusion via histamine type 2 (H2) receptors. We conducted a prospective, non-comparative, single-centre study to determine whether famotidine, a H2 receptor antagonist, reduces P-selectin expression in SCD children. The median plasma P-selectin level was significantly reduced after 29 days of oral famotidine (53.2 ng/mL [IQR: 46.7-63.4] vs. 69.9 ng/mL [IQR: 53.6-84.2], median difference -10.2 ng/mL [IQR: -21.8 to -2.7], p = 0.005) in 28 patients. No effect was observed on other adhesion molecules, inflammation or haemolysis markers, except decreased reticulocyte count. No adverse events deemed related to famotidine were observed. Randomized controlled trials are now needed to assess the efficacy of famotidine in preventing vaso-occlusion in SCD.

Premedication strategy in cetuximab rechallenge after Grade 2 hypersensitivity reactions.

INTRODUCTION: Cetuximab, an IgG1 monoclonal antibody, is utilized in the treatment of metastatic colorectal cancer and squamous cell head and neck cancers. Due to the risk of hypersensitivity reactions, standard premedication with a histamine-1 (H-1) antagonist is recommended prior to administration, however, there is less guidance for premedication strategies to assist with rechallenge after infusion reactions. Here, we describe two cases of successful cetuximab treatment after Grade 2 reactions, in addition to risk factors and proposed premedication strategies for successful rechallenge. CASE REPORT: Two patients who experienced Grade 2 hypersensitivity reactions were both successfully rechallenged with increased premedications 1-2 weeks after initial infusions. The first patient was a 56-year-old male diagnosed with metastatic colorectal cancer receiving cetuximab as part of a clinical trial. The second patient was a 73-year-old male diagnosed with head and neck cancer receiving cetuximab as part of standard of care concurrent with radiation. MANAGEMENT AND OUTCOME: Each patient was rechallenged with an increased premedication strategy including dexamethasone, famotidine, diphenhydramine, and acetaminophen in addition to reducing the infusion rate. Both patients either continued treatment or successfully completed therapy, without any additional infusion-related reactions. DISCUSSION: We aimed to review risk factors related to cetuximab infusion reactions and propose a premedication strategy for rechallenge postreaction. Known risk factors include male sex and the accumulation of cetuximab-specific IgE. These may be mitigated by the addition of increased premedication with dexamethasone and famotidine with concurrent reduced infusion rate.

Effects of taxifolin on aspirin-induced gastric damage in rats: macroscopic and biochemical evaluation.

Taxifolin (dihydroquercetin) is a flavanonol isolated from various plants and has antioxidant effects. The aim of our study was to macroscopically and biochemically investigate the effects of taxifolin on aspirin-induced oxidative gastric damage in rats and to evaluate them by comparison with those of famotidine. Rats were divided into four drug administration groups: a healthy control group, an aspirin-only group (ASG), a taxifolin + aspirin group (TASG), and a famotidine + aspirin group (FASG). The results revealed that in light of the results that we obtained, 50 mg/kg taxifolin had anti-ulcer effects. At this dose, taxifolin was able to bring COX-1 activities to a level close to those seen in healthy rats with appropriate macroscopic, oxidant/antioxidant, and biochemical parameters. Based on these results, it can be said that taxifolin may be successfully used as a more potent alternative to famotidine, which is the currently accepted treatment for aspirin-induced ulcers.

Effectiveness of oral famotidine in reducing the hematologic complications of radiotherapy in patients with esophageal and cardia cancers: a randomized controlled trial.

BACKGROUND: Chemoradiotherapy complications has always been of great concern to both clinicians and patients during the course of treatment. The purpose of the present study was to examine the effectiveness of oral famotidine on the reduction of hematologic complications of patients with esophageal and gastric cardia cancers undergoing radiotherapy. METHODS: A single-blind controlled trial was conducted on 60 patients with esophageal and cardia cancers, who were undergoing chemoradiotherapy. Patients were randomly assigned to 2 groups with 30 patients to receive either 40 mg of oral famotidine (daily and 4 h before each session) or placebo. Complete blood count with differential, platelet counts, and hemoglobin levels were obtained weekly during treatment. The main outcome variables were lymphocytopenia, granulocytopenia, thrombocytopenia, and anemia. RESULTS: The findings indicated a significant effect of famotidine on reduction of thrombocytopenia among intervention group compared to control group (P < 0.0001). Even so, the effect of intervention was not significant for other outcome variables (All, P ≥ 0.05). The lymphocyte (P = 0.007) and platelet (P = 0.004) counts were also significantly greater in famotidine group in comparison with placebo group at the end of the study. CONCLUSION: As evidenced by the findings of the current study, famotidine might be recommended as an effective radioprotective agent among patients with esophageal and gastric cardia cancers to prevent Leukocyte and platelet reduction to some extent. Trial registration This study was prospectively registered at irct.ir (Iranian Registry of Clinical Trials) with the code IRCT20170728035349N1, 2020-08-19.

Pharmacoepidemiological Research on N-Nitrosodimethylamine-Contaminated Ranitidine Use and Long-Term Cancer Risk: A Population-Based Longitudinal Cohort Study.

N-Nitrosodimethylamine (NDMA), a carcinogenic chemical, has recently been identified in ranitidine. We conducted a population-based study to explore ranitidine use and cancer emergence over time. Using the Taiwan National Health Insurance Research Database, a population-based cohort study was conducted. A total of 55,110 eligible patients who received ranitidine between January 2000 and December 2018 were enrolled in the treated cohort. We conducted a 1:1 propensity-score-matching procedure to match the ranitidine-treated group with the ranitidine-untreated group and famotidine controls for a longitudinal study. The association of ranitidine exposure with cancer outcomes was assessed. A multivariable Cox regression analysis that compared cancer risk with the untreated groups revealed that ranitidine increased the risk of liver (hazard ratio (HR): 1.22, 95% confidence interval (CI): 1.09-1.36, p < 0.001), lung (HR: 1.17, CI: 1.05-1.31, p = 0.005), gastric (HR: 1.26, CI: 1.05-1.52, p = 0.012), and pancreatic cancers (HR 1.35, CI: 1.03-1.77, p = 0.030). Our real-world observational study strongly supports the pathogenic role of NDMA contamination, given that long-term ranitidine use is associated with a higher likelihood of liver cancer development in ranitidine users compared with the control groups of non-ranitidine users treated with famotidine or proton-pump inhibitors.

Pharmacological interventions for prevention of weight gain in people with schizophrenia.

BACKGROUND: Antipsychotic-induced weight gain is an extremely common problem in people with schizophrenia and is associated with increased morbidity and mortality. Adjunctive pharmacological interventions may be necessary to help manage antipsychotic-induced weight gain. This review splits and updates a previous Cochrane Review that focused on both pharmacological and behavioural approaches to this problem. OBJECTIVES: To determine the effectiveness of pharmacological interventions for preventing antipsychotic-induced weight gain in people with schizophrenia. SEARCH METHODS: The Cochrane Schizophrenia Information Specialist searched Cochrane Schizophrenia's Register of Trials on 10 February 2021. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that examined any adjunctive pharmacological intervention for preventing weight gain in people with schizophrenia or schizophrenia-like illnesses who use antipsychotic medications. DATA COLLECTION AND ANALYSIS: At least two review authors independently extracted data and assessed the quality of included studies. For continuous outcomes, we combined mean differences (MD) in endpoint and change data in the analysis. For dichotomous outcomes, we calculated risk ratios (RR). We assessed risk of bias for included studies and used GRADE to judge certainty of evidence and create summary of findings tables. The primary outcomes for this review were clinically important change in weight, clinically important change in body mass index (BMI), leaving the study early, compliance with treatment, and frequency of nausea. The included studies rarely reported these outcomes, so, post hoc, we added two new outcomes, average endpoint/change in weight and average endpoint/change in BMI. MAIN RESULTS: Seventeen RCTs, with a total of 1388 participants, met the inclusion criteria for the review. Five studies investigated metformin, three topiramate, three H2 antagonists, three monoamine modulators, and one each investigated monoamine modulators plus betahistine, melatonin and samidorphan. The comparator in all studies was placebo or no treatment (i.e. standard care alone). We synthesised all studies in a quantitative meta-analysis. Most studies inadequately reported their methods of allocation concealment and blinding of participants and personnel. The resulting risk of bias and often small sample sizes limited the overall certainty of the evidence. Only one reboxetine study reported the primary outcome, number of participants with clinically important change in weight. Fewer people in the treatment condition experienced weight gains of more than 5% and more than 7% of their bodyweight than those in the placebo group (> 5% weight gain RR 0.27, 95% confidence interval (CI) 0.11 to 0.65; 1 study, 43 participants; > 7% weight gain RR 0.24, 95% CI 0.07 to 0.83; 1 study, 43 participants; very low-certainty evidence). No studies reported the primary outcomes, 'clinically important change in BMI', or 'compliance with treatment'. However, several studies reported 'average endpoint/change in body weight' or 'average endpoint/change in BMI'. Metformin may be effective in preventing weight gain (MD -4.03 kg, 95% CI -5.78 to -2.28; 4 studies, 131 participants; low-certainty evidence); and BMI increase (MD -1.63 kg/m2, 95% CI -2.96 to -0.29; 5 studies, 227 participants; low-certainty evidence). Other agents that may be slightly effective in preventing weight gain include H2 antagonists such as nizatidine, famotidine and ranitidine (MD -1.32 kg, 95% CI -2.09 to -0.56; 3 studies, 248 participants; low-certainty evidence) and monoamine modulators such as reboxetine and fluoxetine (weight: MD -1.89 kg, 95% CI -3.31 to -0.47; 3 studies, 103 participants; low-certainty evidence; BMI: MD -0.66 kg/m2, 95% CI -1.05 to -0.26; 3 studies, 103 participants; low-certainty evidence). Topiramate did not appear effective in preventing weight gain (MD -4.82 kg, 95% CI -9.99 to 0.35; 3 studies, 168 participants; very low-certainty evidence). For all agents, there was no difference between groups in terms of individuals leaving the study or reports of nausea. However, the results of these outcomes are uncertain given the very low-certainty evidence. AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that metformin may be effective in preventing weight gain. Interpretation of this result and those for other agents, is limited by the small number of studies, small sample size, and short study duration. In future, we need studies that are adequately powered and with longer treatment durations to further evaluate the efficacy and safety of interventions for managing weight gain.

Gastrointestinal prophylaxis for COVID-19: an illustration of severe bias arising from inappropriate comparators in observational studies.

OBJECTIVES: We aimed to use setting-appropriate comparisons to estimate the effects of different gastrointestinal (GI) prophylaxis pharmacotherapies for patients hospitalized with COVID-19 and setting-inappropriate comparisons to illustrate how improper design choices could result in biased results. STUDY DESIGN AND SETTING: We identified 3,804 hospitalized patients aged ≥ 18 years with COVID-19 from March to November 2020. We compared the effects of different gastroprotective agents on clinical improvement of COVID-19, as measured by a published severity scale. We used propensity score-based fine-stratification for confounding adjustment. Based on guidelines, we prespecified comparisons between agents with clinical equipoise and inappropriate comparisons of users vs. nonusers of GI prophylaxis in the intensive care unit (ICU). RESULTS: No benefit was detected when comparing oral famotidine to omeprazole in patients treated in the general ward or ICUs. We also found no associations when comparing intravenous famotidine to intravenous pantoprazole. For inappropriate comparisons of users vs. nonusers in the ICU, the probability of improvement was reduced by 32%-45% in famotidine users and 21%-48% in omeprazole or pantoprazole users. CONCLUSION: We found no evidence that GI prophylaxis improved outcomes for patients hospitalized with COVID-19 in setting-appropriate comparisons. An improper comparator choice can lead to spurious associations in critically ill patients.

Effect of common maintenance drugs on the risk and severity of COVID-19 in elderly patients.

BACKGROUND: Maintenance drugs are used to treat chronic conditions. Several classes of maintenance drugs have attracted attention because of their potential to affect susceptibility to and severity of COVID-19. METHODS: Using claims data on 20% random sample of Part D Medicare enrollees from April to December 2020, we identified patients diagnosed with COVID-19. Using a nested case-control design, non-COVID-19 controls were identified by 1:5 matching on age, race, sex, dual-eligibility status, and geographical region. We identified usage of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), statins, warfarin, direct factor Xa inhibitors, P2Y12 inhibitors, famotidine and hydroxychloroquine based on Medicare prescription claims data. Using extended Cox regression models with time-varying propensity score adjustment we examined the independent effect of each study drug on contracting COVID-19. For severity of COVID-19, we performed extended Cox regressions on all COVID-19 patients, using COVID-19-related hospitalization and all-cause mortality as outcomes. Covariates included gender, age, race, geographic region, low-income indicator, and co-morbidities. To compensate for indication bias related to the use of hydroxychloroquine for the prophylaxis or treatment of COVID-19, we censored patients who only started on hydroxychloroquine in 2020. RESULTS: Up to December 2020, our sample contained 374,229 Medicare patients over 65 who were diagnosed with COVID-19. Among the COVID-19 patients, 278,912 (74.6%) were on at least one study drug. The three most common study drugs among COVID-19 patients were statins 187,374 (50.1%), ACEI 97,843 (26.2%) and ARB 83,290 (22.3%). For all three outcomes (diagnosis, hospitalization and death), current users of ACEI, ARB, statins, warfarin, direct factor Xa inhibitors and P2Y12 inhibitors were associated with reduced risks, compared to never users. Famotidine did not show consistent significant effects. Hydroxychloroquine did not show significant effects after censoring of recent starters. CONCLUSION: Maintenance use of ACEI, ARB, warfarin, statins, direct factor Xa inhibitors and P2Y12 inhibitors was associated with reduction in risk of acquiring COVID-19 and dying from it.

Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial.

OBJECTIVE: We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19. DESIGN: Randomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory). RESULTS: Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms. CONCLUSIONS: Famotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

Therapeutic Status of Famotidine in COVID-19 Patients: A Review.

The novel coronavirus, SARS-coV-2, which emerged in Wuhan in November 2019, has increasingly spread worldwide. More than 272 million cases of infection have been identified. COVID-19 has affected 223 countries and territories across the world. The principal target of the SARS-CoV-2 infection is the lower respiratory tract. Series of moderate to non-specific severe clinical signs and symptoms appear two to fourteen days after exposure to SARS-CoV-2 in patients with COVID-19 disease, including cough, breath deficiency, and at least two of these symptoms: headache, fever, chills, repeated rigor, myalgia, oropharyngitis, anosmia, and ageusia. No therapeutic agents have been validated to have substantial efficacy in the clinical care of COVID-19 patients in large-scale trials, despite worsening infected rates of COVID-19. Early clinical evidence from many sources suggests that treatment with famotidine may decrease COVID-19-related morbidity and mortality. The mechanism by which famotidine could improve the outcomes of COVID-19 is currently unknown. A more recent postulated mechanism is that the effect of famotidine is mediated by histamine-2 receptor antagonism or inverse agonism, inferring that the SARS-CoV-2, resulting in COVID-19 infection, at least partially leads to the abnormal release of histamine and perhaps dysfunction of mast cells.

The association between famotidine and in-hospital mortality of patients with COVID-19.

Famotidine has been considered to be a potential treatment for COVID-19 but the current data is conflicting. This retrospective study was conducted by utilizing data of 9565 COVID-19 hospitalized patients. Patients treated with and without famotidine were matched by propensity score using a 1:1 matching scheme. A total of 1593 patients (16.7%) received famotidine. In-hospital mortality was similar in patients treated with and without famotidine in the propensity-matched cohorts (28.3% vs. 28.2%, p = 0.97), which remains similar irrespective of severity or concomitant treatment by steroids. Famotidine treatment was not associated with a lower risk of in-hospital mortality of COVID-19 patients.

Low incidence of postoperative nausea, vomiting, regurgitation, and aspiration pneumonia in geriatric dogs receiving maropitant, famotidine, and fentanyl as part of an anesthesia protocol.

OBJECTIVE: To determine the incidence of and potential risk factors for postoperative regurgitation and vomiting (PORV), postoperative nausea and vomiting (PONV), and aspiration pneumonia in geriatric dogs using premedication with maropitant and famotidine, intraoperative fentanyl, and postoperative fentanyl as part of an anesthetic protocol. ANIMALS: 105 client-owned geriatric dogs that underwent general anesthesia for a major surgical procedure between January 2019 and March 2020. PROCEDURES: Medical records were reviewed to collect data on signalment, historical gastrointestinal signs, American Society of Anesthesiologists (ASA) score, indication for surgery, duration of anesthesia and surgery, patient position during surgery, mode of ventilation, and perioperative administration of maropitant, famotidine, anticholinergics, opioids, colloidal support, NSAID, corticosteroids, and appetite stimulants. The incidence of postoperative regurgitation, vomiting, nausea, and aspiration pneumonia was calculated, and variables were each analyzed for their association with these outcomes. RESULTS: 2 of 105 (1.9%) dogs regurgitated, 1 of 105 (1.0%) dogs developed aspiration pneumonia, 4 of 105 (3.8%) dogs exhibited nausea, and no dogs vomited. Identified possible risk factors included older age (≥ 13 years old) for postoperative regurgitation, regurgitation for postoperative aspiration pneumonia, and high ASA score (≥ 4) for both regurgitation and aspiration pneumonia. CONCLUSIONS AND CLINICAL RELEVANCE: The use of an antiemetic protocol including maropitant, famotidine, and fentanyl in geriatric dogs resulted in very low incidences of PORV, PONV, and aspiration pneumonia. Future prospective studies are warranted to further evaluate and mitigate postoperative risks.

Effect of famotidine on hospitalized patients with COVID-19: A systematic review and meta-analysis.

INTRODUCTION: Famotidine is a competitive histamine H2-receptor antagonist most commonly used for gastric acid suppression but thought to have potential efficacy in treating patients with Coronavirus disease 2019 (COVID-19). The aims of this systematic review and meta-analysis are to summarize the current literature and report clinical outcomes on the use of famotidine for treatment of hospitalized patients with COVID-19. METHODS: Five databases were searched through February 12, 2021 to identify observational studies that reported on associations of famotidine use with outcomes in COVID-19. Meta-analysis was conducted for composite primary clinical outcome (e.g. rate of death, intubation, or intensive care unit admissions) and death separately, where either aggregate odds ratio (OR) or hazard ratio (HR) was calculated. RESULTS: Four studies, reporting on 46,435 total patients and 3,110 patients treated with famotidine, were included in this meta-analysis. There was no significant association between famotidine use and composite outcomes in patients with COVID-19: HR 0.63 (95% CI: 0.35, 1.16). Across the three studies that reported mortality separated from other endpoints, there was no association between famotidine use during hospitalization and risk of death-HR 0.67 (95% CI: 0.26, 1.73) and OR 0.79 (95% CI: 0.19, 3.34). Heterogeneity ranged from 83.69% to 88.07%. CONCLUSION: Based on the existing observational studies, famotidine use is not associated with a reduced risk of mortality or combined outcome of mortality, intubation, and/or intensive care services in hospitalized individuals with COVID-19, though heterogeneity was high, and point estimates suggested a possible protective effect for the composite outcome that may not have been observed due to lack of power. Further randomized controlled trials (RCTs) may help determine the efficacy and safety of famotidine as a treatment for COVID-19 patients in various care settings of the disease.

Comparative Effectiveness of Famotidine in Hospitalized COVID-19 Patients.

INTRODUCTION: Famotidine has been posited as a potential treatment for coronavirus disease 2019 (COVID-19). We compared the incidence of COVID-19 outcomes (i.e., death and death or intensive services use) among hospitalized famotidine users vs proton pump inhibitors (PPIs) users, hydroxychloroquine users, or famotidine nonusers separately. METHODS: We constructed a retrospective cohort study using data from COVID-19 Premier Hospital electronic health records. The study population was COVID-19 hospitalized patients aged 18 years or older. Famotidine, PPI, and hydroxychloroquine exposure groups were defined as patients dispensed any medication containing 1 of the 3 drugs on the day of admission. The famotidine nonuser group was derived from the same source population with no history of exposure to any drug with famotidine as an active ingredient before or on the day of admission. Time at risk was defined based on the intention-to-treat principle starting 1 day after admission to 30 days after admission. For each study comparison group, we fit a propensity score model through large-scale regularized logistic regression. The outcome was modeled using a survival model. RESULTS: We identified 2,193 users of PPI, 5,950 users of the hydroxychloroquine, 1,816 users of famotidine, and 26,820 nonfamotidine users. After propensity score stratification, the hazard ratios (HRs) for death were as follows: famotidine vs no famotidine HR 1.03 (0.89-1.18), vs PPIs: HR 1.14 (0.94-1.39), and vs hydroxychloroquine: 1.03 (0.85-1.24). Similar results were observed for the risk of death or intensive services use. DISCUSSION: We found no evidence of a reduced risk of COVID-19 outcomes among hospitalized COVID-19 patients who used famotidine compared with those who did not or compared with PPI or hydroxychloroquine users.