Success Similar for Step-Up or Step-Down Treatment of Dyspepsia in Primary Care

Laurie Barclay, MD

January 21, 2009

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January 21, 2009 — Success in the primary care setting of either step-up or step-down treatment of new-onset dyspeptic symptoms is similar, but the step-up strategy is more cost effective at 6 months for initial treatment of patients with dyspepsia in primary care, according to the results of a double-blind, randomized controlled trial reported in the January 17 issue of The Lancet.

"Substantial physician workload and high costs are associated with the treatment of dyspepsia in primary health care," write Corine J. van Marrewijk, from Radboud University Nijmegen Medical Centre in Nijmegen, the Netherlands, and colleagues from the DIAMOND study. "Despite the availability of consensus statements and guidelines, the most cost-effective empirical strategy for initial management of the condition remains to be determined. We compared step-up and step-down treatment strategies for initial management of patients with new onset dyspepsia in primary care."

Between October 2003, and January 2006, a total of 664 patients 18 years and older who consulted with their family clinician for new-onset dyspepsia were enrolled and randomly assigned, with use of a computer-generated sequence with blocks of 6. One group received stepwise treatment with an antacid, a histamine2-receptor antagonist (H2RA; ranitidine 150 mg), and a proton pump inhibitor (PPI; pantoprazole 40 mg; step-up; n = 341), and the other group received these drugs in the reverse order (step-down; n = 323). Each step lasted 4 weeks, and treatment only proceeded to the next step if dyspeptic symptoms persisted or relapsed within 4 weeks.

The main endpoints of the study were relief of symptoms and cost-effectiveness of initial management, measured at 6 months. For the intent-to-treat analysis, the intent-to-treat population consisted of all patients with evaluable data for the main endpoint at 6 months (332 patients in the step-up group and 313 in the step-down group).

Loss to follow-up was the primary reason for study dropout. After 6 months, 238 patients (72%) in the step-up group and 219 patients (70%) in the step-down group had treatment success (odds ratio, 0.92; 95% confidence interval, 0.7 - 1.3). Compared with average medical costs for patients in the step-down group, those for patients in the step-up group were lower, primarily because of medication costs (€228 vs €245; P = .0008).

A similar proportion of patients in each group reported at least 1 adverse drug event (94 patients [28%] in the step-up and 93 patients [29%] in the step-down group). These were all minor adverse events, such as other dyspeptic symptoms, diarrhea, constipation, and unpleasant or dry taste.

"Although treatment success with either step-up or step-down treatment is similar, the step-up strategy is more cost effective at 6 months for initial treatment of patients with new onset dyspeptic symptoms in primary care," the study authors write. "Nonetheless, patients on initial empirical treatment with proton pump inhibitor (step-down) show an earlier response, especially in the small subgroup with predominant reflux symptoms."

Limitations of this study include differences between the study protocol and actual clinical practice, inability to determine whether selection of patients was relevant, limited generalizability because of a low number of general practitioners enrolling patients and low average number of patients enrolled per practice, actual success rate higher than the assumed success rate, and evaluation of cost-effectiveness limited to 6 months.

"The difference in cost-effectiveness declines when calculations are based on prices of generic acid-suppressive medication," the study authors conclude. "These data provide important information for management protocols of patients with new onset dyspepsia in general practice."

In an accompanying comment, Sander Veldhuyzen van Zanten, from the University of Alberta in Edmonton, Canada, writes that the data from DIAMOND are interesting but are "not likely to alter current management."

"It should be clearly established what amount of improvement the patient should expect to make the treatment clinically meaningful," Dr. van Zanten writes. "Patients should become either completely or virtually asymptomatic or, when they have severe and frequent symptoms, there should be an overall large improvement. If the patient responds, treatment should be stopped and long-term treatment given only to patients who have a relapse of symptoms."

The Netherlands Organisation for Health Research and Development funded this study. The study authors have disclosed no relevant financial relationships. Dr. van Zanten has received research support, served on advisory boards for, or received speaker fees from AstraZeneca, Abbott Laboratories, Nycomed, Janssen Ortho, and GlaxoSmithKline.

Lancet. 2009;373:187-188, 215-225.

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