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

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NSAID gastric damage: treatment time is more important than specific

drugs

Rheumawire

Jun 25, 2004 Janis

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 ls 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, " Richy

tells rheumawire.

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 meetingincluding experts in rheumatology,

gastroenterology, endocrinology, public health, and quantitative

epidemiologyselected 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.

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 rheumawire 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

NSAID Relative risk of GI complications

Indomethacin 2.25

Naproxen 1.83

Diclofenac 1.73

Piroxicam 1.66

Tenoxicam 1.43

Meloxicam 1.24

Ibuprofen 1.19

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. "

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.

" 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. "

Sources

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

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

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