Review
Evidence for Endoscopic Ulcers as Meaningful Surrogate Endpoint for Clinically Significant Upper Gastrointestinal Harm

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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.

Section snippets

Evidence

Ideally, evidence for similar effects on surrogate and clinical endpoints would come from the same trial, or set of trials. Because evidence like this is unavailable, 4 other sources of evidence have been used to assess the relationship between endoscopic ulcers and ulcer complications, where factors affecting clinical outcomes affect endoscopic outcomes, in the same direction, and to much the same extent. These are:

  • Effects of risk factors: age, previous history of symptomatic ulcer or

Age

Pooled analysis of 12 RCTs showed the incidence of endoscopic ulcers to increase linearly with age with placebo and NSAIDs.10 NSAID-induced endoscopic gastroduodenal ulcer prevalence increased from 10% in patients aged 20–29 years to 34% in those aged 70–79 years.11 Patients aged ≥75 years had increased risk of upper GI complications (odds ratio [OR] 2.5; 95% CI, 1.5–4.1).12 There was a trend toward more endoscopic ulcers and a significant increase in perforations, ulcers, and bleeds in those

Misoprostol

Misoprostol is effective in reducing endoscopic gastroduodenal ulcers in patients taking NSAIDs. In a meta-analysis, ORs for an endoscopic gastric or duodenal ulcer were 0.3 (0.2–0.4) and 0.5 (0.3–0.7) at 3–24 months with misoprostol compared with control.38 Misoprostol compared with placebo in NSAID users had a RR of 0.3 (0.27–0.41) for endoscopic ulcers and 0.6 (0.36–0.91) for serious GI events (defined as hemorrhage, recurrent upper GI bleeds, perforation, obstruction, or melena, including

Randomized Trials

Table 1 summarizes consistently lower RR rates for coxibs than NSAID comparators for endoscopic gastroduodenal, gastric, and duodenal ulcers.48 For all COX-2 selective drugs compared with all NSAIDs, the RR for gastroduodenal ulcers was 0.26 (0.23–0.30). Absolute rates of endoscopic gastric ulcers were 3.8% and 19% for coxib and NSAID, and for endoscopic duodenal ulcers 1.6% and 5.2%, respectively. For coxibs, gastroduodenal ulcers were no different from placebo.

Table 1 also summarizes RR for

Very High GI Risk Populations Requiring NSAID Therapy

There is consistent effect of protective therapies for endoscopic and bleeding ulcers in patients with a very high risk of bleeding, such as a previous GI bleed. US and UK guidelines recommend patients at risk for ulcer disease requiring treatment for arthritis receive coxib or NSAID in combination with PPI.52, 53

A single trial compared celecoxib with diclofenac plus omeprazole in similar patients with previous NSAID-induced GI bleeding.54, 55 Recurrent endoscopic ulcer incidence at 6 months

Evidence for Endoscopic Ulcers as a Surrogate Endpoint

Formal assessments of surrogacy have been made previously using systematic reviews or meta-analyses, in which surrogate and clinical endpoints have been collected in the same trials.56, 57, 58 These approaches are not applicable to endoscopic ulcers, as endoscopic ulcers and clinically significant events are not available in the same trial in large enough numbers to compare directly. An indirect approach must be used that seeks evidence that both outcomes change in the same way to the same

Conclusions

One of the most challenging aspects in designing clinical outcome trials is the choice of primary outcome measure to assess benefit. Clinically meaningful outcomes (in this case serious GI complications) are most useful, but it is increasingly unethical to have designs in which patients are unnecessarily exposed to developing such an outcome. The MEDAL program62 emphasizes that it is now not acceptable to expose patients at higher risk of GI bleed to NSAIDs without gastroprotection. Though this

Acknowledgments

Dr Julia Fawcett and colleagues at PAREXEL provided editorial support for the original review (white paper). For this paper they provided only formatting support for references.

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    Conflicts of interest The authors disclose the following: All the authors have received research grants, consulting, or lecture fees from pharmaceutical companies, charities, and government sources at various times. The authors were involved in discussions concerning a review, supported by Pfizer Inc, for the creation of a white paper for presentation to regulatory authorities. The decision to write this paper was the decision of the authors. Pfizer and its agents had no role in the interpretation of data or writing of the paper, or in the decision to publish. The authors had the absolute right to publish the results of their research regardless of any conclusions reached. No payments were received for preparing this manuscript.

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