NSAID gastric damage: treatment time is more important than specific drugs

Janis Kelly

June 25, 2004

Jun 25, 2004

Sart-Tilman, Belgium - A new World Health Organization (WHO) consensus statement on gastrointestinal (GI) complications caused by nonsteroidal anti-inflammatory drug (NSAID) use says that (apart from indomethacin) the specific drug used is less important than the duration of use. The relative risk for GI complications ranged from 1.19 with ibuprofen to 1.83 with naproxen and 2.25 with indomethacin. Dr Florent Richy (Santé Publique, Epidemiologie et Economic de la Santé, Sart-Tilman, Belgium) reports the analysis in the July 2004 issue of the Annals of the Rheumatic Diseases on behalf of the WHO Collaborating Centre for Public Health Aspects of Osteoarticular Disorders (Liége, Belgium) [ 1 ].

These results have clear implications in the long-term management of patients with osteoarticular diseases, in which gastroprotective drugs and risk factors for GI complications should be considered early.

"These results have clear implications in the long-term management of patients with osteoarticular diseases, in which gastroprotective drugs and risk factors for GI complications should be considered early," Richy tells rheuma wire .

NSAID-related GI damage seen as increasing worldwide problem

WHO embarked on this analysis because about 60 million people worldwide use OTC NSAIDs and because gastroduodenal erosions and ulcerations (known as NSAID-induced gastropathy) are estimated to affect up to half of chronic NSAID users, with major world health implications. Previous quantitative systematic reviews estimated that exposure to NSAIDs tripled the risk of perforation, ulcers, or bleeding [ 2 ].

Previous meta-analyses focused on cross-sectional and retrospective trials, which may overestimate effects compared with randomized controlled trials (RCTs) or controlled longitudinal cohort studies. To remedy this deficiency, the WHO group undertook a meta-analysis limited to high-quality RCTs and controlled cohort studies that assessed the relationship between exposure to NSAIDs and adverse GI events. The NSAIDs included were indomethacin, naproxen, diclofenac, piroxicam, tenoxicam, meloxicam, and ibuprofen. Eligible trials compared NSAIDs with an inactive control (placebo or nonexposed group), with treatment lasting at least 5 days.

A special WHO meeting -- including experts in rheumatology, gastroenterology, endocrinology, public health, and quantitative epidemiology -- selected the studies to be included, and Richy and Dr O Bruyere (Santé Publique, Epidemiologie et Economic de la Santé) performed the data extraction. Data from all RCTs were combined to produce a summary estimate, then subdivided according to drug. Individual drug estimates were regressed against the respective study durations. Sensitivity analyses explored the confounding effects of age, study purpose, dose, and outcomes. Abdominal pain, nausea, constipation, diarrhea, and dyspepsia were classed as minor GI events. Duodenal, gastric, or intestinal ulcers; bleeding; perforation; hospitalization; and related death were classed as major GI events.

Initial screening of 1893 publications (1985-2003) produced 527 candidates, which were reviewed for minimal methodological quality. The investigators next winnowed out articles dealing with tertiary prevention of NSAID-induced complications and studies with insufficient data for meta-analysis. This left 32 RCTs and 13 major cohort studies to be included in the meta-analysis.

The meta-analysis excluded trials of NSAIDs used with gastroprotective drugs such as misoprostol. "There is not sufficient data on this association to derive evidence-based medical conclusions yet," Richy says.

NSAID GI relative risk 1.54 compared with nonusers

The risk of GI complications due to NSAIDs compared with the risk for nonusers was estimated at 1.54 at a median exposure time of 28 days in the RCTs and 2.2 at a median exposure time of 365 days in the cohort studies.

Richy tells rheuma wire that the risk of a GI event in the placebo patients was about 13.8%. In data from the RCTs, indomethacin more than doubled the risk for GI complications, and substantial increased risk was also associated with the other NSAIDs.

Relative risk of GI complications associated with specific NSAIDs in RCT data, compared with nonusers

Relative risk of GI complications

The authors comment, "The classic GI side effects of NSAIDs are just as much a feature of treatment with contemporary drugs as they were with aspirin itself, and in this context it is amazing that aspirin was thought initially to be a better-tolerated drug in the stomach than the salicylic acid from which it was derived."

Indomethacin causes more problems and causes them sooner

The meta-analysis adds another layer to the pile of evidence showing that indomethacin is substantially more problematic than other NSAIDs in terms of gastric damage. "Indomethacin has become a rare treatment in Europe. We did know about its side effects but didn't know that the onset of GI side effects was so early. In this setting, our study adds evidence that indomethacin should perhaps be recommended as a last option, together with a careful follow-up of any early GI symptoms," Richy says.

Apart from indomethacin, the meta-analysis showed that risk of GI side effects depends less on the drug used than on the length of time of treatment. Indomethacin caused GI complications within 7 days, much more quickly than other NSAIDs. "The meta-regression for nonindomethacin NSAIDs, grouped together, provided a duration of treatment of 84 days as a threshold for a significant risk of GI effects," Richy reported.

Richy says that the investigators were surprised to find a nonlinear relationship between "time" and "GI-troubles incidence." More GI problems were reported in short-term studies than in longer studies. This might just reflect an artificial selection process for NSAID-tolerant patients: patients who continue to take NSAIDs long term are those who do not develop ulcers and clinical events, while more vulnerable patients stop NSAID therapy sooner. Richy et al also point out that several epidemiological studies have suggested that the risk of GI complications is higher at the onset of NSAID therapy.

Patient education seen as key to reducing NSAID-caused problems

"I would suggest, at least, a more careful use of over-the-counter NSAIDs," Richy says. "As an epidemiologist with a background in public health, I'd say that this would involve patient education rather than MD education. Also, we need studies on the sequential administration of NSAIDs to evaluate the balance between pain reduction and side effects compared with continuous administration."


1. Richy F, Bruyere O, Ethgen O, et al Time-dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach Ann Rheum Dis  2004; 63:759-766

2. Gabriel SE, Jaakkimainen L, Bombardier Risk of serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis. Ann Intern Med  1991; 115:787-795