Comparison of Acid-Lowering Drugs for Endoscopy-Negative Reflux Disease

Neurogastroenterology and Motility Journal: Published: September 2022

GERD is a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. These symptoms include typical ones, such as heartburn, regurgitation, or both, angina-mimicking non-cardiac chest pain, and extra-esophageal symptoms, including chronic cough or laryngitis.

Based on the presence or absence of mucosal damage, GERD patients can be subclassified as to whether there is evidence of erosive esophagitis (EE) or not.

However, patients with EE represent only a minority of those with GERD, estimated at 30%, with the remaining 70% having endoscopy-negative reflux disease with increased esophageal acid exposure, reflux hypersensitivity, or functional heartburn.


This network meta-analysis identified 23 randomized controlled trials including 10,735 patients with endoscopy-negative reflux disease; acid-lowering medications considered were proton pump inhibitors, histamine 2 receptor antagonists, potassium-competitive acid blockers, and alginates.

The primary outcome was failure to achieve complete relief of reflux symptoms.

When compared with placebo beyond 4 weeks, the most efficacious anti-reflux therapies, from least likely to fail, were Dexlansoprazole, the alginate and omeprazole combination, alginate alone, and omeprazole alone.

Among anti-reflux therapies compared with placebo, the three most efficacious short-term (<4 weeks) therapies were omeprazole 20 mg once daily and esomeprazole at both 20 and 40 mg once daily.

In patients with endoscopy-negative reflux disease, treatments with dexlansoprazole, omeprazole, esomeprazole and alginates may be the most efficacious at eliminating symptoms.


In the short-term (<4 weeks), omeprazole 20 mg o.d. and esomeprazole 20 mg o.d. or 40 mg o.d. were the best treatments in terms of achieving complete relief of symptoms, whereas rabeprazole 10 mg o.d. performed best for adequate relief.

In the longer term (>4 weeks), Dexlansoprazole 30 mg o.d., 30 ml of alginate q.i.d. combined with omeprazole 20 mg o.d., and 30 ml of alginate t.i.d. were ranked first, second, and third in achieving complete relief of symptoms.

Dexlansoprazole 60 mg or 30 mg o.d. and Rabeprazole 20 mg o.d. were the most efficacious for adequate relief. 

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Background: The comparative efficacy and safety of medical therapies for gastro-esophageal reflux symptoms in endoscopy-negative reflux disease is unclear. We conducted a network meta-analysis to evaluate efficacy and safety of proton pump inhibitors (PPIs), histamine-2-receptor antagonists, potassium-competitive acid blockers (PCABs), and alginates in patients with endoscopy-negative reflux disease.

Methods: We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane central register of controlled trials from inception to February 1, 2022. We included randomized controlled trials (RCTs) comparing efficacy of all drugs versus each other, or versus a placebo, in adults with endoscopy-negative reflux disease. Results were reported as pooled relative risks with 95% confidence intervals to summarize effect of each comparison tested, with treatments ranked according to P-score.

Key results: We identified 23 RCTs containing 10,735 subjects with endoscopy-negative reflux disease. Based on failure to achieve complete relief of symptoms between ≥2 and <4 weeks, omeprazole 20 mg o.d. (P-score 0.94) ranked first, with esomeprazole 20 mg o.d. or 40 mg o.d. ranked second and third. In achieving adequate relief, only rabeprazole 10 mg o.d. was significantly more efficacious than placebo. For failure to achieve complete relief at ≥4 weeks, dexlansoprazole 30 mg o.d. (P-score 0.95) ranked first, with 30 ml alginate q.i.d. combined with omeprazole 20 mg o.d., and 30 ml alginate t.i.d. second and third. In terms of failure to achieve adequate relief at ≥4 weeks, dexlansoprazole 60 mg o.d. ranked first (P-score 0.90), with dexlansoprazole 30 mg o.d. and rabeprazole 20 mg o.d. second and third. All drugs were safe and well-tolerated.

Conclusions & inferences: Our results confirm superiority of PPIs compared with most other drugs in treating endoscopy-negative reflux disease. Future RCTs should aim to better classify patients with endoscopy-negative reflux disease, and to establish the role of alginates and PCABs in achieving symptom relief in both the short- and long-term.

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