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Once-Daily Omeprazole/Sodium Bicarbonate Heals Severe Refractory Reflux Esophagitis with Morning or Nighttime Dosing

Digestive Diseases and Sciences volume 60, pages 146–162 (2015)Cite this article

Abstract

Background

Morning dose or twice-daily proton pump inhibitor (PPI) use is often prescribed to heal severe reflux esophagitis.

Aim

Compare the effect of single dose morning (control arm) versus nighttime (experimental arm) omeprazole/sodium bicarbonate (Zegerid®) (IR-OME) on esophagitis and gastroesophageal reflux symptoms.

Methods

Adult outpatients with Los Angeles grade C or D esophagitis were allocated to open-label 40 mg IR-OME once a day for 8 weeks in a prospective, randomized, parallel design, single center study. Esophagogastroduodenoscopy (EGD) and validated self-report symptom questionnaires were completed at baseline and follow-up. Intention-to-treat and per-protocol analyses were performed.

Results

Ninety-two of 128 (72 %) eligible subjects participated [64 (70 %) male, mean age 58 (range 19–86), median BMI 29 (range 21–51), 58 C:34 D]. Overall, 81 (88 %) subjects healed [n = 70 (76 %)] or improved [n = 11 (12 %)] erosions. There was no significant difference (morning vs. night) in mucosal healing [81 vs. 71 %, (p = 0.44)] or symptom resolution [heartburn (77 vs. 65 %, p = 0.12), acid regurgitation (82 vs. 73 %, p = 0.28)]. Prevalence of newly identified Barrett’s esophagus was 14 % with half diagnosed only after treatment.

Conclusions

Once-daily IR-OME (taken morning or night) effectively heals severe reflux esophagitis and improves GERD symptoms. Results support the clinical practice recommendation to repeat EGD after 8 weeks PPI therapy in severe esophagitis patients to assure healing and exclude Barrett’s esophagus.

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Fig. 1
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Abbreviations

BE:

Barrett’s esophagus

BMI:

Body mass index

EGD:

Esophagogastroduodenoscopy

GERD:

Gastroesophageal reflux disease

HH:

Hiatal hernia

HRA:

Histamine receptor antagonist

IMC:

Intestinal metaplasia of the cardia

IR-OME:

Immediate release-omeprazole

ITT:

Intention-to-treat analysis

LA:

Los Angeles classification system for erosive reflux esophagitis

LSBE:

Long segment Barrett’s esophagus

MDQ-30:

Mayo Dysphagia Questionnaire–30 day

PPI:

Proton pump inhibitor

SSBE:

Short segment Barrett’s esophagus

References

  1. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles classification. Gut. 1999;45:172–180.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. Chiba N, De Gara CJ, Wilkinson JM, Hunt RH. Speed of healing and symptom relief in grade II to IV gastroesophageal reflux disease: a meta-analysis. Gastroenterology. 1997;112:1798–1810.

    CAS  PubMed  Article  Google Scholar 

  3. Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol. 2001;96:656–665.

    CAS  PubMed  Article  Google Scholar 

  4. Labenz J, Armstrong D, Lauritsen K, et al. A randomized comparative study of esomeprazole 40 mg versus pantoprazole 40 mg for healing erosive oesophagitis: the expo study. Aliment Pharmacol Ther. 2005;21:739–746.

    CAS  PubMed  Article  Google Scholar 

  5. Kinoshita Y, Hongo M. Efficacy of twice-daily rabeprazole for reflux esophagitis patients refractory to standard once-daily administration of PPI: the Japan-based TWICE Study. Am J Gastroenterol. 2012;107:522–530.

    CAS  PubMed  Article  Google Scholar 

  6. Adachi K, Fujishiro H, Katsube T, et al. Predominant nocturnal acid reflux in patients with los angeles grade c and d reflux esophagitis. J Gastroenterol Hepatol. 2001;16:1191–1196.

    CAS  PubMed  Article  Google Scholar 

  7. Campos GR, Peters JH, DeMeester TR, Öberg S, Crookes PF, Mason RJ. The pattern of esophageal acid exposure in gastroesophageal reflux disease influences the severity of the disease. Arch Surg. 1999;134:882–888.

    CAS  PubMed  Article  Google Scholar 

  8. Orr WC, Allen ML, Robinson M. The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage. Am J Gastroenterol. 1994;89:509–512.

    CAS  PubMed  Google Scholar 

  9. Frazzoni M, De Micheli E, Savarino V. Different patterns of oesophageal acid exposure distinguish complicated reflux disease from either erosive reflux oesophagitis or non-erosive reflux disease. Aliment Pharmacol Ther. 2003;18:1091–1098.

    CAS  PubMed  Article  Google Scholar 

  10. Bredenoord AJ. Mechanisms of reflux perception in gastroesophageal reflux disease: a review. Am J Gastroenterol. 2012;107:8–15.

    PubMed  Article  Google Scholar 

  11. Peura DA, Pilmer B, Hunt B, Mody R, Perez MC. The effects of increasing body mass index on heartburn severity, frequency and response to treatment with dexlansoprazole or lansoprazole. Aliment Pharmacol Ther. 2013;37:810–818.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  12. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology. 1998;115:1335–1339.

    CAS  PubMed  Article  Google Scholar 

  13. Cicala M, Emerenziani S, Guarino MP, Ribolsi M. Proton pump inhibitor resistance, the real challenge in gastro-esophageal reflux disease. World J Gastroenterol. 2013;19:6529–6535.

    PubMed Central  PubMed  Article  Google Scholar 

  14. Castell D, Bagin R, Goldlust B, Major J, Hepburn B. Comparison of the effects of immediate-release omeprazole powder for oral suspension and pantoprazole delayed-release tablets on nocturnal acid breakthrough in patients with symptomatic gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2005;21:1467–1474.

    CAS  PubMed  Article  Google Scholar 

  15. Katz PO, Koch FK, Ballard ED, et al. Comparison of the effects of immediate-release omeprazole oral suspension, delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time gerd symptoms. Aliment Pharmacol Ther. 2007;25:197–205.

    CAS  PubMed  Article  Google Scholar 

  16. Castell D. Review of immediate-release omeprazole for the treatment of gastric acid-related disorders. Expert Opin Pharmacother. 2005;6:2501–2510.

    CAS  PubMed  Article  Google Scholar 

  17. Moher D, Hopewell S, Schulz KF, et al. Consort 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol. 2010;63:e1–37.

    PubMed  Article  Google Scholar 

  18. McElhiney J, Lohse MR, Arora AS, et al. The mayo dysphagia questionnaire-30: documentation of reliability and validity of a tool for interventional trials in adults with esophageal disease. Dysphagia. 2010;25:221–230.

    PubMed  Article  Google Scholar 

  19. Sharma P, Dent J, Armstrong D, et al. The development and validation of an endoscopic grading system for Barrett’s esophagus: the Prague C & M criteria. Gastroenterology. 2006;131:1392–1399.

    PubMed  Article  Google Scholar 

  20. Lee D, Lee KJ, Kim KM, Lim SK. Prevalence of asymptomatic erosive esophagitis and factors associated with symptom presentation of erosive esophagitis. Scand J Gastroenterol. 2013;48:906–912.

    PubMed  Article  Google Scholar 

  21. Hanna S, Rastogi A, Weston AP, et al. Detection of Barrett’s esophagus after endoscopic healing of erosive esophagitis. Am J Gastroenterol. 2006;101:1416–1420.

    PubMed  Article  Google Scholar 

  22. Modiano N, Gerson LB. Risk factors for the detection of Barrett’s esophagus in patients with erosive esophagitis. Gastrointest Endosc. 2009;69:1014–1020.

    PubMed  Article  Google Scholar 

  23. Rodriguez S, Mattek N, Lieberman D, Fennerty B, Eisen G. Barrett’s esophagus on repeat endoscopy: should we look more than once? Am J Gastroenterol. 2008;103:1892–1897.

    PubMed Central  PubMed  Article  Google Scholar 

  24. Gilani N, Gerkin RD, Ramirez FC, Hakim S, Randolph AC. Prevalence of Barrett’s esophagus in patients with moderate to severe erosive esophagitis. World J Gastroenterol. 2008;14:3518–3522.

    PubMed Central  PubMed  Article  Google Scholar 

  25. Gaddam S, Maddur H, Wani S, et al. Risk factors for nocturnal reflux in a large GERD cohort. J Clin Gastroenterol. 2011;45:764–768.

    PubMed  Article  Google Scholar 

  26. Chiba H, Gunji T, Sato H, et al. A cross-sectional study on the risk factors for erosive esophagitis in young adults. Intern Med. 2012;51:1293–1299.

    PubMed  Article  Google Scholar 

  27. Egan LJ, Myhre GM, Mays DC, Dierkhising RA, Kammer PP, Murray JA. Cyp2c19 pharmacogenetics in the clinical use of proton-pump inhibitors for gastro-oesophageal reflux disease: variant alleles predict gastric acid suppression, but not oesophageal acid exposure or reflux symptoms. Aliment Pharmacol Ther. 2003;17:1521–1528.

    CAS  PubMed  Article  Google Scholar 

  28. Abdalla AA, Petersen BT, Ott BJ, et al. Impact of feedback and didactic sessions on the reporting behavior of upper endoscopic findings by physicians and nurses. Clin Gastroenterol Hepatol. 2007;5:326–330.

    PubMed  Article  Google Scholar 

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Acknowledgments

We thank Lori R. Anderson for help typing and submitting the manuscript; Kaiser Lim, M.D., Prasad Iyer, M.D., Adil A. Abdalla, M.B.B.S. and Judith McElhiney, M.D., for help recruiting subjects; Rayna M. Grothe, M.D., Joanna M. Peloquin, M.D., Shabana F. Pasha, M.D., and Darlene E. Graner, CCC-SLP, for help conceptualizing the study design; and Michael D. Van Norstrand, M.D., Ph.D., for editorial assistance. The project was supported in part by the Miles and Shirley Fiterman Center for Digestive Diseases at Mayo Clinic, Rochester, Minnesota. Yvonne Romero, M.D., was supported in part by a grant from the National Institutes of Health (NIDDK 02956) and the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program.

Conflict of interest

This study was funded in part by an Investigator-Initiated Research Award from Santarus, Inc., IRB # 07-008503. Santarus Inc. provided study medications [omeprazole/sodium bicarbonate (Zegerid®) and Gelusil™] at no charge. No assistance for manuscript preparation was received from Santarus, Inc. Unpaid academicians voluntarily wrote this paper. All data analysis was undertaken by Felicity T. Enders, Diana M. Orbelo, Nancy N. Diehl, Debra M. Geno, Yvonne Romero, David A. Katzka, Dawn L. Francis, Michael D. Crowell, Sami R. Achem, Ramona DeJesus, Vikneswaran Namasivayam, Steven C. Adamson, Amindra S. Arora, Andrew J. Majka, Jeffrey A. Alexander, Joseph A. Murray, Kee Wook Jung, Margaret S. Houston and Angela O’Neil, all of whom are or were Mayo Clinic employees at the time. Santarus Inc. provided salary support to FTE, NND, and DMG for data analysis, and DMG and MF for data collection. The Santarus study sponsors, William F. Bleker, M.D., Philip Yeung, Pharm.D., Gregg Checani, M.D., and E. David Ballard, M.D., participated in study design but did not participate in data collection, analysis or interpretation, and did not participate in drafting the manuscript or in the decision to publish the results of this trial. Study sponsors were permitted to review the manuscript prior to its submission for publication. Yvonne Romero has received research funding from Aptalis, AstraZeneca, Meritage Pharma and Takeda, has served as an ad hoc consultant for Kala, and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Dawn L. Francis has received research funding from AstraZeneca, and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Jeffrey A. Alexander has received research funding from Aptalis and Merck, serves as a consultant and has stock holdings of Meritage Pharma and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Joseph A. Murray has an ownership interest with Torax Medical Inc. and Vysera Biomedical, and receives royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day. Felicity T. Enders, Michael D. Crowell, Debra M. Geno, Matthew Lohse, Nancy N. Diehl, and Mary Fredericksen receive royalties from the licensed use of the Mayo Dysphagia Questionnaire—30 day.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Mayo Clinic, 200 First St., SW, Rochester, MN, 55905, USA

    Diana M. Orbelo

  2. Division of Biomedical Statistics and Informatics, Mayo Clinic, 200 First St., SW, Rochester, MN, 55905, USA

    Felicity T. Enders

  3. Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St., SW, Rochester, MN, 55905, USA

    Yvonne Romero, Debra M. Geno, Amindra S. Arora, Jeffrey A. Alexander, Joseph A. Murray, Mary Fredericksen & David A. Katzka

  4. Division of Gastroenterology and Hepatology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Dawn L. Francis & Sami R. Achem

  5. Department of Dermatology, Tufts Medical Center, 1615 Tremont St., Boston, MA, 02120, USA

    Tushar S. Dabade

  6. Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ, 85259, USA

    Michael D. Crowell

  7. Division of Primary Care Internal Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN, 55905, USA

    Ramona S. DeJesus

  8. Department of Gastroenterology and Hepatology, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore

    Vikneswaran Namasivayam

  9. Department of Family Medicine, Lake City Medical Center, Mayo Clinic Health System, 500 W. Grant St., Lake City, MN, 55041, USA

    Steven C. Adamson

  10. Division of General Internal Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN, 55905, USA

    Andrew J. Majka

  11. Department of Surgery, Virginia Mason Medical Center, 901 8th Ave., Seattle, WA, 98104, USA

    Matthew Lohse

  12. Division of Biostatistics, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA

    Nancy N. Diehl

  13. Department of Internal Medicine, Asan Medical Center, Seoul, Korea

    Kee Wook Jung

  14. Department of Family Medicine, Mayo Clinic, 200 First St., SW, Rochester, MN, 55905, USA

    Margaret S. Houston & Angela E. O’Neil

Authors
  1. Diana M. Orbelo
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  2. Felicity T. Enders
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  3. Yvonne Romero
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  4. Dawn L. Francis
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  5. Sami R. Achem
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  6. Tushar S. Dabade
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  7. Michael D. Crowell
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  8. Debra M. Geno
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  9. Ramona S. DeJesus
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  10. Vikneswaran Namasivayam
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  11. Steven C. Adamson
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  12. Amindra S. Arora
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  13. Andrew J. Majka
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  14. Jeffrey A. Alexander
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  15. Joseph A. Murray
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  16. Matthew Lohse
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  17. Nancy N. Diehl
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  18. Mary Fredericksen
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  19. Kee Wook Jung
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  20. Margaret S. Houston
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  21. Angela E. O’Neil
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  22. David A. Katzka
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Corresponding author

Correspondence to Diana M. Orbelo.

Additional information

ClinicalTrials.gov, Number: NCT00693225.

Appendix

Appendix

  1. 1.

    Hypotheses and aims

    • A priori hypotheses:

      • The timing of administration of omeprazole/sodium bicarbonate will impact its efficacy in healing esophagitis

      • Nighttime administration (experimental arm) will be superior in healing esophagitis compared to morning administration (control arm) prior to a meal.

    • A priori primary aim: quantify the efficacy of omeprazole/sodium bicarbonate in healing severe erosive esophagitis when used either as a morning or before bedtime dose.

    • A priori secondary aims:

      • Determine the percent of patients who improve, but did not resolve, their mucosal damage.

      • Determine the efficacy of omeprazole/sodium bicarbonate on symptom resolution in patients with erosive esophagitis

      • Assess the frequency with which a diagnosis of Barrett’s esophagus was made once the overlying severe esophagitis had healed.

    • A priori exploratory and hypothesis-generating objective: assess objective control of esophageal acid exposure as determined by ambulatory pH monitoring.

  2. 2.

    IR-OME powder instruction details

Omeprazole/sodium bicarbonate powder for oral suspension 40 mg was supplied in individual packets that are emptied into a small cup containing 15–30 ml (1–2 tablespoons) of water, one per day, for 8 weeks. They were asked to stir well and drink immediately then refill the cup with water and drink. Subjects assigned to morning dosing were instructed to take the medication on an empty stomach, immediately upon rising, 20–60 min prior to chewing a solid. Subjects assigned to nighttime dosing were instructed to keep the medication by their bedside; taking the medication in a standing or seated upright position immediately before turning off the lights with the intention to sleep. The subject was instructed to not use other liquids or foods for 20 min after taking their study medication for those allocated to morning dosing, and until the next morning for those allocated to nighttime dosing.

  1. 3.

    Endoscopic outcomes

LA classification system [1]

  • LA grade A: one or more erosions on non-confluent folds in which the longest erosion is <5 mm length

  • LA grade B: one or more erosions on non-confluent folds in which the longest erosion is ≥5 mm length

  • LA grade C: confluent erosions of more than one fold involving <75 % of the circumference.

  • LA grade D: confluent erosions involving ≥75 % of the circumference of the distal esophagus.

The endoscopic evaluation results were grouped for outcomes analysis as follows, for subjects with:

  • LA C esophagitis at baseline:

    • Healed = no erosions in the esophagus

    • Improved = LA grades A or B

    • Same or worse = C or D at follow-up

  • LA D esophagitis at baseline:

    • Healed = no erosions in the esophagus

    • Improved = LA grades A, B or C

    • Same = LA grade D at follow-up

  1. 4.

    MDQ-30 scoring details

    • Symptom analysis: GERD symptoms (absent, infrequent, frequent) at baseline and follow-up were measured by the MDQ-30.

      • Frequent: The respondent reports experiencing heartburn, (a burning pain or discomfort behind the breast bone in the chest), at least once per week, with at least one of the following: heartburn that improves with antacids, awakens them at night, or radiates to the neck. Respondents would also be categorized as having frequent GERD symptoms if they report experiencing acid regurgitation, (a bitter or sour-tasting fluid coming up from the stomach into the mouth or throat), at least once per week.

      • Absent: The respondent is completely asymptomatic; denies experiencing heartburn or acid regurgitation.

      • Infrequent: Any heartburn or acid regurgitation in those who do not meet criteria for frequent symptoms.

    • Symptom outcomes at follow-up include:

      • Complete resolution (subjects with either frequent or infrequent GERD symptoms at baseline report the absence of GERD symptoms at follow-up)

      • Partial resolution (subjects with frequent GERD symptoms at baseline meet criteria for infrequent GERD symptoms at follow-up)

      • No improvement (subjects with either frequent or infrequent GERD symptoms at baseline continue to report those symptoms at follow-up)

  1. 5.

    Per-protocol demographic results (Table 5)

    Table 5 Subject demographics at baseline, per-protocol analysis
    Full size table
  2. 6.

    Table 6 is an ITT (worst case) version of Table 2. Table 6 was not used in the body of the manuscript because there was imbalance in the subjects who completed their questionnaires. Nine subjects allocated to nighttime IR-OME dosing, compared to 3 subjects allocated to morning dosing did not fully complete their follow-up questionnaires. In the ITT analysis, we assume subjects without follow-up questionnaire information have severe symptoms at follow-up. Thus, the statistically significant findings shown in Table 6 are artifactual. Thus, we opted to show the Per-protocol results in the manuscript (see Table 2).

    Table 6 Frequency of heartburn, acid regurgitation and overall GERD symptoms in subjects allocated to morning (n = 43) versus nighttime (n = 49) dosing of omeprazole/sodium bicarbonate at entry and following 8 weeks therapy, intention-to-treat analysis (worst case)
    Full size table
  3. 7.

    Table 7 is the ITT (best case) version of Table 2. It shows the results for ITT best case scenario in which we assume subjects without follow-up questionnaire information are symptom free at 8 weeks.

    Table 7 Frequency of heartburn, acid regurgitation and overall GERD symptoms in subjects allocated to morning (n = 43) versus nighttime (n = 49) dosing of omeprazole/sodium bicarbonate at entry and following 8 weeks therapy, Intention-To-Treat analysis (best case)
    Full size table
  4. 8.

    Detailed demographic information of 13 subjects ultimately diagnosed with Barrett’s esophagus (Table 8).

    Table 8 Endoscopic features of subjects ultimately diagnosed with Barrett’s esophagus showing raw symptom, sex, age and Body Mass Index (BMI) data
    Full size table
Fig. 4
figure 4

a Frequency of heartburn before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (worst case). b Frequency of acid regurgitation before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (worst case)

Full size image
Fig. 5
figure 5

a Frequency of heartburn before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (best case). b Frequency of acid regurgitation before and after 8 weeks of omeprazole/sodium bicarbonate therapy comparing morning versus nighttime dosing. Intention-to-treat (best case)

Full size image

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Orbelo, D.M., Enders, F.T., Romero, Y. et al. Once-Daily Omeprazole/Sodium Bicarbonate Heals Severe Refractory Reflux Esophagitis with Morning or Nighttime Dosing. Dig Dis Sci 60, 146–162 (2015). https://doi.org/10.1007/s10620-013-3017-y

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Keywords

  • Gastroesophageal reflux disease
  • Esophagitis
  • Barrett’s esophagus
  • Prospective randomized controlled trial