Evidence for endoscopic ulcers as meaningful surrogate endpoint for clinically significant upper gastrointestinal harm.

BACKGROUND & AIMS: Surrogate endpoints are biomarkers intended to substitute for a clinical endpoint. Are endoscopic ulcers a useful surrogate endpoint for a biological progression to clinical endpoints of ulcer complications (perforation, ulcers, and bleeds), hospital admission, or death?

METHODS

Review of randomized trials, meta-analyses, clinical outcomes trials, and observational studies.

RESULTS

No large study examined both endoscopic and clinical endpoints. Endoscopic ulcers and clinically significant ulcer complications were affected in the same direction and to about the same extent in 4 distinct circumstances: (1) by risk factors-age, previous history of symptomatic ulcer or bleeding, Helicobacter pylori, aspirin; (2) in studies of antiulcer treatments with differing modes of action, especially in relation to nonsteroidal anti-inflammatory drug toxicity, and Helicobacter pylori infection; (3) in studies evaluating ulcer complications with Cox-2 selective drugs and nonsteroidal anti-inflammatory drugs; and (4) in studies of interventions in patients with high risk of recurrent ulcer bleed needing nonsteroidal anti-inflammatory drug therapy. All study designs showed consistent and reproducible effects on gastrointestinal ulcer complications paralleling endoscopy.

CONCLUSIONS

Consistent and plausible findings from disparate populations and designs make endoscopic ulcers a strong candidate for surrogacy, though direct progression from endoscopic ulcers to ulcer complications cannot be demonstrated. Large outcome studies are needed to establish the power of the surrogacy, absolute risk of clinical outcomes, and to identify the totality of risks and benefits of new pharmacologic therapies.