BACKGROUND/RATIONALE:
This is a series of two prospective studies based on the Department of Veterans Affairs drug treatment guideline for the pharmacologic management of gastroesophageal reflux disease. Our hypothesis is that novel strategies for medical management of gastroesophageal reflux disease (GERD) can decrease resource utilization without adversely affecting patient quality of life. The strategies tested in this project included 1) step-down management, whereby patients rendered asymptomatic on proton pump inhibitors (PPIs) are treated with less expensive medication, and 2) intermittent therapy, defined as administration of medication only for recurrence of GERD symptoms. We chose to examine an intermittent strategy of PPI administration since in addition to the VA guideline requiring step-down therapy, over-the-counter PPIs administered by intermittent therapy became available for use by patients during the study period.

OBJECTIVE(S):
The objectives of this project are to determine the efficacy of step-down therapy and intermittent therapy in patients with GERD, and the impact of these strategies on direct healthcare costs and health-related quality of life (HRQOL). Additionally, we will examine patient factors predictive of non-response to these management strategies that may be alternatives to traditional continuous PPI administration.

METHODS:
Two separate studies were conducted in our population of patients with GERD symptoms (heartburn or acid regurgitation) rendered asymptomatic on PPIs. Both studies randomized subjects to an intervention strategy (Step-down or Intermittent therapy) or to a control group in which PPIs were continued on a daily basis.
Step-down therapy: Step-down subjects discontinued PPIs and were prescribed histamine2-receptor antagonists (H2RAs) for 2 weeks, and if still asymptomatic, H2RAs were discontinued. If symptoms recurred, H2RAs were reinitiated, and if still symptomatic, subjects were prescribed PPIs at the dose that initially alleviated their symptoms. Intermittent therapy: Intermittent therapy subjects discontinued daily use of PPIs and were prescribed short courses of PPI (daily for 8 weeks) for recurrence of GERD symptoms. The primary efficacy measure was the proportion of subjects remaining free of GERD symptoms while on their prescribed therapy (step-down group: no symptoms on H2RAs or no GERD medication; intermittent therapy group: no PPIs for ³2 weeks after discontinuation, and < 3 symptom recurrences requiring PPIs; control groups: no GERD symptoms on PPI). Follow up was conducted for 6 months after randomization. In addition to the primary efficacy measure, we examined total resource utilization (pharmacy and non-pharmacy), HRQOL, and potential predictors of non-response to step-down or intermittent therapy (requirement of daily PPI to control symptoms). Logistic regression and random-effects models adjusted for covariates and clustering effects.

FINDINGS/RESULTS:
Step-down therapy: 79 subjects were enrolled in this part of the study. Of the 40 subjects in whom step-down was initiated, only 7 remained free of GERD symptoms while on either H2RAs (4) or no medication (3) to treat GERD. Of the 39 control subjects, 2 withdrew from the study; all other subjects remained asymptomatic. Thus, efficacy was established in only 18% of step-down subjects compared to 95% of control subjects (p < 0.0001; Fisher exact). Intermittent therapy: 37 subjects were enrolled in this part of the study. Of the 17 subjects in whom intermittent PPI therapy was instituted, only 1 remained on intermittent therapy after 6 months follow-up, the remainder failing to achieve efficacy based on recurrence of symptoms within 2 weeks of discontinuation of PPIs (10), having 3 or more episodes of recurrent symptoms (1), refusing to remain in the study due to recurrent symptoms (3), or loss to follow-up (2). Of the 20 subjects randomized to continuous therapy, 4 did not achieve efficacy based on recurrent GERD symptoms despite PPI (1), or loss to follow-up (3) (p < 0.0001; Fisher exact).

IMPACT:
Despite VA guidelines advocating step-down therapy for GERD, this randomized controlled trial does not support the efficacy of step-down management in the veteran population. In a similar manner, despite FDA approval of over-the-counter PPI administration using intermittent therapy, it is unlikely that this dosing strategy will provide adequate symptom relief for the majority of veterans with GERD symptoms.

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External Links for this Project

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PUBLICATIONS:

Journal Articles

1. Rhee J, Scheiman J, Inadomi J. "Spontaneous" passage of a pancreatic duct stone. Gastrointestinal endoscopy. 2003 Feb 1; 57(2):278-80. [view]
2. Inadomi JM. Cost-effectiveness of colorectal cancer surveillance in ulcerative colitis. Scandinavian Journal of Gastroenterology. Supplement. 2003 Jan 1;(237):17-21. [view]
3. Rubenstein JH, Inadomi JM. Dysphagia drives doctors to diagnose a disease: pitfalls in interpreting observational studies. Gastrointestinal endoscopy. 2005 Jun 1; 61(7):809-11. [view]
4. Rubenstein JH, Inadomi JM. Empiric beta-blockers for the prophylaxis of variceal hemorrhage: cost effective or clinically applicable? Hepatology. 2003 Feb 1; 37(2):249-52. [view]
5. Inadomi JM. On-demand and intermittent therapy for gastro-oesophageal reflux disease: economic considerations. Pharmacoeconomics. 2002 Sep 1; 20(9):565-76. [view]
6. Inadomi JM, Fendrick AM. PPI use in the OTC era: who to treat, with what, and for how long? Clinical Gastroenterology and Hepatology. 2005 Mar 1; 3(3):208-15. [view]
7. El-Serag HB, Graham DY, Richardson P, Inadomi JM. Prevention of complicated ulcer disease among chronic users of nonsteroidal anti-inflammatory drugs: the use of a nomogram in cost-effectiveness analysis. Archives of internal medicine. 2002 Oct 14; 162(18):2105-10. [view]
8. Chey WD, Inadomi JM, Booher AM, Sharma VK, Fendrick AM, Howden CW. Primary-care physicians' perceptions and practices on the management of GERD: results of a national survey. The American journal of gastroenterology. 2005 Jun 1; 100(6):1237-42. [view]
9. Rubenstein JH, Davis J, Marrero JA, Inadomi JM. Relationship between diabetes mellitus and adenocarcinoma of the oesophagus and gastric cardia. Alimentary pharmacology & therapeutics. 2005 Aug 1; 22(3):267-71. [view]
10. Inadomi JM, Sampliner R, Lagergren J, Lieberman D, Fendrick AM, Vakil N. Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis. Annals of internal medicine. 2003 Feb 4; 138(3):176-86. [view]
11. Inadomi JM, McIntyre L, Bernard L, Fendrick AM. Step-down from multiple- to single-dose proton pump inhibitors (PPIs): a prospective study of patients with heartburn or acid regurgitation completely relieved with PPIs. The American journal of gastroenterology. 2003 Sep 1; 98(9):1940-4. [view]
12. Inadomi JM, Jamal R, Murata GH, Hoffman RM, Lavezo LA, Vigil JM, Swanson KM, Sonnenberg A. Step-down management of gastroesophageal reflux disease. Gastroenterology. 2001 Nov 1; 121(5):1095-100. [view]
13. Rubenstein JH, Vakil N, Inadomi JM. The cost-effectiveness of biomarkers for predicting the development of oesophageal adenocarcinoma. Alimentary pharmacology & therapeutics. 2005 Jul 15; 22(2):135-46. [view]
14. Cram P, Fendrick AM, Inadomi J, Cowen ME, Carpenter D, Vijan S. The impact of a celebrity promotional campaign on the use of colon cancer screening: the Katie Couric effect. Archives of internal medicine. 2003 Jul 14; 163(13):1601-5. [view]
15. Inadomi JM. Update on the cost-effectiveness of screening for colorectal neoplasia. Current Opinion in Gastroenterology. 2003 Jan 1; 19(1):44-50. [view]

Conference Presentations

1. Inadomi J. Outcomes Research. Paper presented at: American College of Gastroenterology Annual Meeting; 2002 Oct 22; Seattle, WA. [view]

DRA: Health Systems Science
DRE: Epidemiology, Treatment - Observational
Keywords: Chronic disease (other & unspecified), Clinical practice guidelines, Cost
MeSH Terms: none