ReviewEvidence for Endoscopic Ulcers as Meaningful Surrogate Endpoint for Clinically Significant Upper Gastrointestinal Harm
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:
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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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2018, GastroenterologyCitation Excerpt :It should be noted that these observations relate to the pathogenesis of damage, but not necessarily the clinical adverse effects. Clinically serious gastric and small bowel ulcer events of perforation and bleeding involve separate clinical and comorbidity factors.150 Our model emphasizes the multistage complexities of the pathogenesis and numerous interactive and ongoing synergistic factors that intensify or modulate the damage.
Balancing the risk and benefits of low-dose aspirin in clinical practice
2012, Best Practice and Research: Clinical GastroenterologyCitation Excerpt :The clinical significance of these findings is unclear, since the incidence of ulcers detected is higher than actual incidence of upper GI complications in clinical practice and the correlation between mucosal lesions and symptoms is weak. Nevertheless, a review suggests that endoscopic lesions can be used as surrogate marker of more severe lesions within the biological progression of GI damage with LDA use [20]. Three recent systematic reviews have shown that LDA increased upper GI bleeding risk by two to four fold and also that the estimated average excess risk of symptomatic or complicated ulcer related to LDA is five cases per 1000 users per year [21–24].
Gastrointestinal lesions and complications of low-dose aspirin in the gastrointestinal tract
2012, Best Practice and Research: Clinical GastroenterologyCitation Excerpt :The clinical significance of these endoscopic findings is unclear, as the incidence of detected ulcers is higher that actual incidence of upper GI complications in clinical practice and the correlation between symptoms and mucosal damage is scarce. A recent review of available literature suggested, however, that endoscopic ulcers could be a possibly surrogate endpoint for upper GI harm [46]. It was generally believed that low dose ASA did not cause any small bowel damage since the drug is largely absorbed before reaching the intestine, and this would limit the topical action on the intestinal mucosa.
Intestinal Barrier Dysfunction in Inflammatory Bowel Disease: Underpinning Pathogenesis and Therapeutics
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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.