Table 3 Overview of the evidence for each of the Hill criteria

Strength of association

There is a strong association between use of aspirin or NSAIDs and the development of both endoscopic ulcers and clinical bleeding events. Protective strategies have a large effect in preventing both events

Consistency

There is a consistent effect across a range of different risk factors and interventions

Specificity

Exposure to aspirin or NSAIDs causes a spectrum of gastrointestinal harm, but these are found without exposure. The link between aspirin and NSAIDs is specific only because of the elevation of the incidence rates

Temporal relationship

Exposure to aspirin or NSAIDs precedes harm

Biological gradient

There is a consistent dose response with aspirin and NSAIDs, with higher doses and longer use increasing the incidence rates of the harms

Plausibility

There is a biological underpinning for upper gastrointestinal harm with aspirin and NSAIDs

Coherence

The consistent effect of aspirin or NSAIDs on a broad spectrum of upper gastrointestinal harms, from symptoms, to endoscopic findings, to serious bleeding events, is evidence of coherence

Experiment

A broad range of preventative therapies (misoprostol, histamine antagonists, proton pump inhibitors, coxibs) with different mechanisms of action all demonstrate significant reduction of harm with aspirin or NSAIDs

Analogy

Detection of ulcers endoscopically in circumstances where aspirin or NSAIDs are not causative (for example where there may be infection with Helicobacter pylori) would be regarded as a marker of high risk for developing more serious ulcer disease with bleeding