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Background & AimsSurrogate 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? MethodsReview of randomized trials, meta-analyses, clinical outcomes trials, and observational studies. ResultsNo 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. ConclusionsConsistent 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. Abbreviations used in this paper: CI, confidence interval, COX-1, cyclooxygenase-1, COX-2, cyclooxygenase-2, GI, gastrointestinal, H2RAs, histamine-2 receptor antagonists, NSAIDs, traditional nonsteroidal anti-inflammatory drugs, OR, odds ratio, PPI, proton pump inhibitor, RCT, randomized controlled trial, RR, relative risk ⁎ Pain Research and Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom ‡ Department of Medicine, King's College Hospital, Denmark Hill, London, United Kingdom § Medical Service, Department of Veterans Affairs Medical Center, Dallas, Texas ∥ Spanish Centre for Pharmacoepidemiological Research (CEIFE), Madrid, Spain ¶ Uniformed Services University of Health Sciences, School of Medicine, Bethesda, Maryland # Department of Gastroenterology, University Hospital, Institute of Health Sciences of Aragon, Zaragoza, Spain ⁎⁎ Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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. PII: S1542-3565(09)00316-4 doi:10.1016/j.cgh.2009.03.032 © 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
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ABSTRACT
Evidence for Endoscopic Ulcers as Meaningful Surrogate Endpoint for Clinically Significant Upper Gastrointestinal Harm