Endoscopic ulcers as a surrogate marker of NSAID-induced mucosal damage

Abstract

The characteristic of a biomarker that makes it a useful surrogate is the ability to identify a high risk of clinically important benefits or harms occurring in the future. A number of definitions or descriptions of surrogate definition have been put forward. Most recently the Institute of Medicine of the National Academy of Sciences in the USA has put forward an evaluation scheme for biomarkers, looking at validation (assay performance), qualification (assessment of evidence), and utilisation (the context in which the surrogate is to be used). This paper examines the example of endoscopy as a surrogate marker of NSAID-induced mucosal damage using the Institute of Medicine criteria. The article finds extensive evidence that the detection of endoscopic ulcers is a valid marker. The process of qualification documents abundant evidence showing that endoscopic ulcers and serious upper gastrointestinal damage are influenced in the same direction and much the same magnitude by a variety of risk factors and interventions. Criticisms of validation and qualification for endoscopic ulcers have been examined, and dismissed. Context is the key, and in the context of serious NSAID-induced upper gastrointestinal harm, endoscopic ulcers represent a useful surrogate. Generalisability beyond this context is not considered.

Figure 1

Gastroduodenal ulcers in placebo treatment groups. Data for healthy subjects at 1, 2, or 4 weeks, and patients with osteoarthritis or rheumatoid arthritis at 6 or 12 weeks [21,23,24]. Each symbol represents a treatment arm, the diameter proportional to the number of patients or subjects (inset scale).

Figure 2

Gastroduodenal ulcers in coxib or nonsteroidal anti-inflammatory drug treatment groups in osteoarthritis/rheumatoid arthritis patients. Gastroduodenal ulcers detected endoscopically (predominantly 3 mm in largest diameter, with depth) in coxib or NSAID treatment groups at 6 or 12 weeks in patients with osteoarthritis or rheumatoid arthritis. Data from meta-analyses and randomised trials [27-32]. Each symbol represents a treatment arm, the diameter proportional to the number of patients or subjects (inset scale).

Figure 3

Event rates for gastroduodenal ulcers with nonsteroidal anti-inflammatory drug, coxib, or placebo, with low-dose aspirin. Pooled event rates for gastroduodenal ulcers detected endoscopically (predominantly 3 mm in largest diameter, with depth) at 6 or 12 weeks with NSAID, coxib, or placebo, according to use of low-dose aspirin.

Figure 4

Incidence rates for gastroduodenal ulcers in treatment arms using ≥3 mm or ≥5 mm definition. Incidence rates for gastroduodenal ulcers in treatment arms from randomised trials using the ≥3 mm or ≥5 mm definition of greatest dimension [29,31,32].

Figure 5

Recurrent upper gastrointestinal bleeding in high-risk patients with healed ulcer after a previous bleed. Recurrent upper gastrointestinal bleeding according to prespecified criteria (red) or gastroduodenal ulcers using the ≥5 mm definition of greatest dimension (pink) in four randomised trials of high-risk patients with a healed ulcer after a previous bleed and still needing to use NSAIDs [35-38]. HP, Helicobacter pylori.

Figure 6

Rate of gastroduodenal complications with nonsteroidal anti-inflammatory drugs compared with control. Rate of gastroduodenal complications (events) with NSAIDs (includes aspirin) compared with control (no NSAID, or placebo, or NSAID + mucosal protection therapy) in 15 randomised controlled trials (RCTs; squares) and three cohort studies (circles). White symbols, uncomplicated peptic, gastric or duodenal ulcer; grey symbols, ulcer bleed or perforation; black symbols, death attributable to a bleeding or perforated ulcer. Several trials reported several levels of harm; that is, several events. Death outcomes in two RCTs had a control event rate of 0%; these were set a control event rate of 0.001% for graphical purposes. Dotted line, the line of equality. From [14] with permission.

Figure 7

Spectrum of endoscopic damage. Findings on endoscopic evaluation in patients taking low-dose aspirin or clopidrogel suffering dyspepsia. Data from [39].