Gastroprotective therapy and risk of gastrointestinal ulcers: risk reduction by COX-2 therapy.
OBJECTIVE
Proton pump inhibitors (PPI) and misoprostol decrease the risk of development of nonsteroidal antiinflammatory drug induced gastric ulcers and aid healing of upper gastrointestinal (GI) ulcers. H2 receptor antagonists (H2RA) are less effective for this task, but are widely used by patients and physicians for the treatment of GI symptoms and duodenal ulcers. Sucralfate is a weaker agent that is sometimes used for prophylaxis or treatment of upper GI ulcers. We investigated the effect of GI drugs and selective and nonselective NSAID on the incidence of GI ulcer development in a cohort of patients immediately after the release of celecoxib and rofecoxib to investigate the effect of confounding by indication when effective GI agents and cyclooxygenase 2 (COX-2)-specific inhibitors are prescribed to a high risk population.


METHODS
During a 6 month period of observation 8547 NSAID users were evaluated by mailed questionnaire concerning NSAID drug use and ulcer development. In the first half of 1999, patients took 12,177 separate NSAID courses. GI therapy that followed the development of upper GI ulcers was excluded from analysis. Ulcer reports were confirmed by followup validation.


RESULTS
GI drugs were used concomitantly in this population by 42% of patients using an NSAID. GI drugs were associated with an increased risk of ulcer. But this risk was confined to PPI (OR 4.1, 95% CI 2.95, 5.69), and not to other GI drugs. Overall, patients using nonselective NSAID compared to those taking COX-2-specific inhibitors had an increased risk of upper GI ulcers (OR 2.12, 95% CI 1.43, 3.34). Patients taking nonselective NSAID plus PPI were also at increased risk for upper GI ulcers compared to those taking nonselective NSAID alone (OR 5.09. 95% CI 3.88, 6.67). Similarly, the risk of upper GI ulcers was increased in the nonselective NSAID plus PPI group (OR 3.83, 95% CI 2.32, 6.31) compared to the COX-2 plus PPI group.


CONCLUSIONS
PPI use, but not other GI drug use, is a marker for increased susceptibility to ulcers among NSAID users. This risk of upper GI ulcers is increased in PPI users regardless of which NSAID is used (nonselective or COX-2-specific inhibitor). Although COX-2 use is associated with greater risk factors for upper GI ulcers due to channeling bias, COX-2 users have significantly fewer ulcers than equivalent nonselective NSAID users regardless of concomitant PPI utilization.
Wolfe
Frederick
F
National Data Bank for Rheumatic Diseases-Arthritis Research Center Foundation and University of Kansas School of Medicine, Wichita 67214, USA. fwolfe@arthritis-research.org
Anderson
Janice
J
Burke
Thomas A
TA
Arguelles
Lester M
LM
Pettitt
Dan
D
D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D004347:Drug Interactions; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects*; D006635:Histamine H2 Antagonists / Q000009:adverse effects; D006801:Humans; D015994:Incidence; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D010437:Peptic Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000453:epidemiology*; D011451:Prostaglandin-Endoperoxide Synthases; D054328:Proton Pump Inhibitors; D012216:Rheumatic Diseases / Q000188:drug therapy; D012307:Risk Factors; D011795:Surveys and Questionnaires
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005765:Gastrointestinal Agents; D006635:Histamine H2 Antagonists; D007527:Isoenzymes; D008565:Membrane Proteins; D054328:Proton Pump Inhibitors; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases