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Influence of Helicobacter pylori on low dose aspirin (ASA)-induced gastric mucosal injury. A placebo-controlled, double-blind, randomized trial
April 2000
AGAA249
1450
1452
PROPHYLAXIS OF GASTRODUODENAL LESIONS WITH OMEPRAZOLE 20 MG IN PATIENTS TREATED WITH NSAIDS : SHOULD WE ERADICATE HELICOBACTER PYLORI INFEC· TION? Bernard Bannwarth, Etienne Dorval, Agnes Caekaert, Philippe Barthelemy, CHU, Bordeaux, France; CHU, Tours, France; AstraZeneca, Rueil-Malmaison, France. The aims of this prospective multicenter study were: 1) to assess the impact of Helicobacter pylori (H. pylori) eradication on the incidence of complications and clinical events associated with NSAlDs in infected patients treated preventively with omeprazole 20 mg ; 2) to assess the influence of H. pylori status on this same criterion. Methods: 919 patients (age 57+1-14 years) requiring NSAlD treatment for 5 to 8 weeks were included. H. pylori (Hp) status was assessed at inclusion via a rapid serological test based on a capillary blood sample (QuickView®). Patients infected with H. pylori were randomised in 2 groups: 1)"Hp positive+Eradication" group: eradication by omeprazole 20 mg bid + amoxicillin 19 bid + clarithromycin 500 mg bid for 7 days, followed by preventive treatment with omeprazole 20 mg od ; 2) "Hp positive" group: preventive treatment with omeprazole 20 mg od without eradication treatment. Patients not infected with H. pylori ("Hp negative" group) received preventive treatment with omeprazole 20 mg od. Dyspeptic symptoms were assessed at inclusion and after 4 and 8 weeks. Failure was defined as the occurrence of a gastroduodenal complication (ulcer, Gl-bleeding, perforation), and/or dyspeptic symptoms requiring discontinuation of NSAID or an unscheduled consultation or performance of upper Gl-endoscopy. Intent to treat analysis included 904 patients treated at least one day with NSAlDs who took at least one dose of study drugs. Results: Failure occurred in 22 patients: Hp positive + Eradication: 9/294 (3.06%), Hp positive: 8/219 (3.65%), Hp negative: 51391 (1.28%). Causes offailure were in each group respectively: Gl-bleeding (0;0;1), dyspeptic symptoms requiring discontinuation of NSAlD (7;6;5) or an unscheduled consultation (4;4;1) or performance of upper GI-endoscopy (1;1;1). No gastroduodenal ulcers or perforations were observed. The number of failures was 17/513 in patients infected with H. pylori (3.31%) versus 51391 in non-infected patients (1.28%) (% difference [95%CI]: 2.04 [1.27;3.94]). Conclusion: Our study showed that in patients receiving short-term NSAlD treatment and primary prophylaxis with orneprazole 20 mg : 1) eradication treatment had no influence on the incidence of failure in H. pylori infected patients; 2) the incidence of complications and clinical events was lower in non-infected patients.
NON-STEROIDAL ANTI·INFLAMMATORY DRUGS (NSDAIDS) AS A RISK FACTOR OF ACUTE DIARRHEA: AN EPIDEMIO· LOGIC CASE·CROSSOVER STUDY. Isabelle Etienney, Laurent Beaugerie, Cecile Viboud, Antoine Flahault, Epidemiology Research Unit U444, Paris, France; Hosp Rothschild, Paris, France. Background and Aim: NSAlD-induced lesions of the gastrointestinal tract and NSAlD-related ileal chronic enteropathy are well-known. Several cases of acute NSAlD-induced colitis have been reported but the general role of NSAlD recent intake as a risk factor for acute diarrhea has not been studied so far. The aim of our study was to determine whether the risk of acute diarrhea is increased by NSAlDs in a prospective series of cases of acute diarrhea seen by general pratitioners in France and serious enough to require a stool culture. Patients and Methods: Two hundred and eighty-five consecutive patients with acute diarrhea seen by Sentinelles practitioners between December 1998 and July 1999 were enrolled in the study. Information about exposure to NSAlDs within the 4-month period preceding the onset of diarrhea was collected by the pratitioners. The relative risk of NSAlD-related acute diarrhea was estimated using the case-crossover design (in which each case is its own control) by comparing the NSAlD exposition within the risk period preceding the onset of diarrhea with the NSAlD exposition within the first part of the 4-month observation period. Three risk periods (1, 3 or 6 days preceding the onset of diarrhea) were considered. Results: The relative risk of acute diarrhea related to recent NSAlD intake was increased for all three risk periods. The relative risk and its confidence interval was 2.9 [1.4 - 6.1] for the one-day risk period, 2.7 [1.4 - 5.1] for the 3-day risk period, and 3.3 [2.0 - 5.4] for the 6-day risk period. Conclusion: Our results first demonstrate that recent NSAlD intake increases the risk for acute diarrhea. We suggest that acute diarrhea seen in general practice and not only acute colitis seen by gastroenterologists should be considered as a potential complication of recent NSAlD intake.
1451 INFLUENCE OF HEUCOBACTER PYWRI ON LOW DOSE ASPI· RIN (ASA)-INDUCED GASTRIC MUCOSAL INJURY. A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED TRIAL. Byron Cryer, Damien Mallat, Mark Feldman, Dallas VAMC, Dallas, TX; Univ of Miami Sch of Medicine, Miami, FL. Background: Although a number of studies have assessed a potential enhanced gastric mucosal toxicity of NSAlDs in patients infected with H. pylori, data from previous studies have been conflicting. ASA is the most common NSAlD used worldwide, yet there has been very little prior prospective investigation on the interaction between ASA and H. pylori with respect to gastric mucosal toxicity. Purpose: To prospectively assess the effect of H. pylori (Hp) on gastric mucosal injury in subjects exposed to low doses of ASA. Methods: 61 healthy men and women (30 Hp+/31 Hp-) were administered by random allocation ASA 81 mg q D [n=23 (12 Hp+111 Hp-)], ASA 325 mg q 3'd D [n=23 (11 Hp+112 Hp-) or placebo [n=15 (7 Hp+/8 Hp-j]. After 1.5 months of study meds, gastric mucosal injury was endoscopically-scored using a standardized mucosal injury scale. Results: As seen in the Table, Hp+ subjects had significantly more ASA-induced gastric mucosal injury in the antrum and body than Hpsubjects. Hp did not influence gastric injury in subjects not taking ASA. In Hp+ and Hp- groups, ASA 81 mg ~ D tended to cause greater antral mucosal injury than ASA 325 mg q 3' D (p=O.1).Two Hp+ (but no Hp-) subjects developed ASA-induced gastric ulcers (9%). Conclusions: Hp gastritis significantly worsens gastric mucosal injury in subjects chronically taking low dose ASA. Hp appears to be a risk factor for low-dose ASA-induced gastric ulcers.
1453 DEVELOPMENT OF A SCORING SYSTEM FOR PREDICTING UPPER GASTROINTESTINAL DISTRESS. Jay L. Goldstein, William G. Bensen, Naurang M. Agrawal, Thomas A. Burke, Richard A. Zabinski, Daniel Pettitt, Margaret M. Cary, Univ of Illinois at Chicago, Chicago, IL; McMaster Univ, Hamilton, ON, Canada; Duke Univ, Durham, NC; Searle, Skokie, IL; Pfizer Inc, New York, NY. Introduction: Several multivariate equations exist predicting the 1iklihood of serious upper gastrointestinal (GI) events requiring hospitalization. However, no predictive tools have been developed to identify patients more likely to manifest non-hospitalized GI events, which ate likely to consume significant healthcare resources in an outpatient setting. Objective: To develop a scoring algorithm for predicting the incidence of upper GI distress in arthritis patients. Methods: Data were pooled from five, 12week, placebo and active (naproxen) controlled ce1ecoxib studies (n=4490). A Weibull parametric survival model was developed for the composite endpoint of self-reported upper GI distress (moderate-to-severe abdominal pain/nausea/dyspepsia), which was chosen as a proxy for events likely to require medical intervention in an outpatient setting. Predictors were identified based on clinical relevance and univariate association with the endpoint. Significant predictors were chosen for the final model using backwards-stepwise selection with a p-value<0.10. Results: The final model included the following predictors of GI distress and associated GI scores (in parentheses): history of ulcer (No(O)/Yes(64»; history of previous NSAlD GI intolerance (No(O)/Yes(lOO»; exposure to aspirin (No(O)1 Yes(40»; gender (Male(0)/Female(41»; and assigned treatment (naproxen (43)/celecoxib (0». When the values of the individual predictors were summed, patient GI scores ranged from 0 to 288. The table below summarizes the 90-day cumulative incidence of GI distress associated with a particular score. Similar predictive factors and GI scores were observed when alternative models (e.g., Cox or Log-Logistic) were considered. Conclusions: Several clinical indicators can be used to predict the incidence of upper GI distress. These results indicate celecoxib does not increase the incidence of upper GI distress. This scoring system has applicability to clinical practice for the treatment of arthritis. Scoring System forPredicting Upper GIDistress
9O-day event rate
Total GI Score Mean ± SEM Gastric Mucosal Injury Score
Group Hp -I Placebo Hp +I Placebo Hp·/ASA' Hp+/ASA'
Antrum
Body
O±O O±O
O±O O±O
0.39 ± 0.16 1.65 ± 0.60 t
0.13±0.10 0.48±0.18 t
• ASA 81 mg q Dand 325 mg q 3'"Dgroups combined t p<0.05 vs. Hp -I ASA and both placebo groups
(n=8) (n=7) (n=23) (n=23)
5%
10%
15%
20%
25'10
30%
35%
40%
45%
50%
5
73
113
143
167
187
205
221
236
250
AGAA249
1450
1452
PROPHYLAXIS OF GASTRODUODENAL LESIONS WITH OMEPRAZOLE 20 MG IN PATIENTS TREATED WITH NSAIDS : SHOULD WE ERADICATE HELICOBACTER PYLORI INFEC· TION? Bernard Bannwarth, Etienne Dorval, Agnes Caekaert, Philippe Barthelemy, CHU, Bordeaux, France; CHU, Tours, France; AstraZeneca, Rueil-Malmaison, France. The aims of this prospective multicenter study were: 1) to assess the impact of Helicobacter pylori (H. pylori) eradication on the incidence of complications and clinical events associated with NSAlDs in infected patients treated preventively with omeprazole 20 mg ; 2) to assess the influence of H. pylori status on this same criterion. Methods: 919 patients (age 57+1-14 years) requiring NSAlD treatment for 5 to 8 weeks were included. H. pylori (Hp) status was assessed at inclusion via a rapid serological test based on a capillary blood sample (QuickView®). Patients infected with H. pylori were randomised in 2 groups: 1)"Hp positive+Eradication" group: eradication by omeprazole 20 mg bid + amoxicillin 19 bid + clarithromycin 500 mg bid for 7 days, followed by preventive treatment with omeprazole 20 mg od ; 2) "Hp positive" group: preventive treatment with omeprazole 20 mg od without eradication treatment. Patients not infected with H. pylori ("Hp negative" group) received preventive treatment with omeprazole 20 mg od. Dyspeptic symptoms were assessed at inclusion and after 4 and 8 weeks. Failure was defined as the occurrence of a gastroduodenal complication (ulcer, Gl-bleeding, perforation), and/or dyspeptic symptoms requiring discontinuation of NSAID or an unscheduled consultation or performance of upper Gl-endoscopy. Intent to treat analysis included 904 patients treated at least one day with NSAlDs who took at least one dose of study drugs. Results: Failure occurred in 22 patients: Hp positive + Eradication: 9/294 (3.06%), Hp positive: 8/219 (3.65%), Hp negative: 51391 (1.28%). Causes offailure were in each group respectively: Gl-bleeding (0;0;1), dyspeptic symptoms requiring discontinuation of NSAlD (7;6;5) or an unscheduled consultation (4;4;1) or performance of upper GI-endoscopy (1;1;1). No gastroduodenal ulcers or perforations were observed. The number of failures was 17/513 in patients infected with H. pylori (3.31%) versus 51391 in non-infected patients (1.28%) (% difference [95%CI]: 2.04 [1.27;3.94]). Conclusion: Our study showed that in patients receiving short-term NSAlD treatment and primary prophylaxis with orneprazole 20 mg : 1) eradication treatment had no influence on the incidence of failure in H. pylori infected patients; 2) the incidence of complications and clinical events was lower in non-infected patients.
NON-STEROIDAL ANTI·INFLAMMATORY DRUGS (NSDAIDS) AS A RISK FACTOR OF ACUTE DIARRHEA: AN EPIDEMIO· LOGIC CASE·CROSSOVER STUDY. Isabelle Etienney, Laurent Beaugerie, Cecile Viboud, Antoine Flahault, Epidemiology Research Unit U444, Paris, France; Hosp Rothschild, Paris, France. Background and Aim: NSAlD-induced lesions of the gastrointestinal tract and NSAlD-related ileal chronic enteropathy are well-known. Several cases of acute NSAlD-induced colitis have been reported but the general role of NSAlD recent intake as a risk factor for acute diarrhea has not been studied so far. The aim of our study was to determine whether the risk of acute diarrhea is increased by NSAlDs in a prospective series of cases of acute diarrhea seen by general pratitioners in France and serious enough to require a stool culture. Patients and Methods: Two hundred and eighty-five consecutive patients with acute diarrhea seen by Sentinelles practitioners between December 1998 and July 1999 were enrolled in the study. Information about exposure to NSAlDs within the 4-month period preceding the onset of diarrhea was collected by the pratitioners. The relative risk of NSAlD-related acute diarrhea was estimated using the case-crossover design (in which each case is its own control) by comparing the NSAlD exposition within the risk period preceding the onset of diarrhea with the NSAlD exposition within the first part of the 4-month observation period. Three risk periods (1, 3 or 6 days preceding the onset of diarrhea) were considered. Results: The relative risk of acute diarrhea related to recent NSAlD intake was increased for all three risk periods. The relative risk and its confidence interval was 2.9 [1.4 - 6.1] for the one-day risk period, 2.7 [1.4 - 5.1] for the 3-day risk period, and 3.3 [2.0 - 5.4] for the 6-day risk period. Conclusion: Our results first demonstrate that recent NSAlD intake increases the risk for acute diarrhea. We suggest that acute diarrhea seen in general practice and not only acute colitis seen by gastroenterologists should be considered as a potential complication of recent NSAlD intake.
1451 INFLUENCE OF HEUCOBACTER PYWRI ON LOW DOSE ASPI· RIN (ASA)-INDUCED GASTRIC MUCOSAL INJURY. A PLACEBO-CONTROLLED, DOUBLE-BLIND, RANDOMIZED TRIAL. Byron Cryer, Damien Mallat, Mark Feldman, Dallas VAMC, Dallas, TX; Univ of Miami Sch of Medicine, Miami, FL. Background: Although a number of studies have assessed a potential enhanced gastric mucosal toxicity of NSAlDs in patients infected with H. pylori, data from previous studies have been conflicting. ASA is the most common NSAlD used worldwide, yet there has been very little prior prospective investigation on the interaction between ASA and H. pylori with respect to gastric mucosal toxicity. Purpose: To prospectively assess the effect of H. pylori (Hp) on gastric mucosal injury in subjects exposed to low doses of ASA. Methods: 61 healthy men and women (30 Hp+/31 Hp-) were administered by random allocation ASA 81 mg q D [n=23 (12 Hp+111 Hp-)], ASA 325 mg q 3'd D [n=23 (11 Hp+112 Hp-) or placebo [n=15 (7 Hp+/8 Hp-j]. After 1.5 months of study meds, gastric mucosal injury was endoscopically-scored using a standardized mucosal injury scale. Results: As seen in the Table, Hp+ subjects had significantly more ASA-induced gastric mucosal injury in the antrum and body than Hpsubjects. Hp did not influence gastric injury in subjects not taking ASA. In Hp+ and Hp- groups, ASA 81 mg ~ D tended to cause greater antral mucosal injury than ASA 325 mg q 3' D (p=O.1).Two Hp+ (but no Hp-) subjects developed ASA-induced gastric ulcers (9%). Conclusions: Hp gastritis significantly worsens gastric mucosal injury in subjects chronically taking low dose ASA. Hp appears to be a risk factor for low-dose ASA-induced gastric ulcers.
1453 DEVELOPMENT OF A SCORING SYSTEM FOR PREDICTING UPPER GASTROINTESTINAL DISTRESS. Jay L. Goldstein, William G. Bensen, Naurang M. Agrawal, Thomas A. Burke, Richard A. Zabinski, Daniel Pettitt, Margaret M. Cary, Univ of Illinois at Chicago, Chicago, IL; McMaster Univ, Hamilton, ON, Canada; Duke Univ, Durham, NC; Searle, Skokie, IL; Pfizer Inc, New York, NY. Introduction: Several multivariate equations exist predicting the 1iklihood of serious upper gastrointestinal (GI) events requiring hospitalization. However, no predictive tools have been developed to identify patients more likely to manifest non-hospitalized GI events, which ate likely to consume significant healthcare resources in an outpatient setting. Objective: To develop a scoring algorithm for predicting the incidence of upper GI distress in arthritis patients. Methods: Data were pooled from five, 12week, placebo and active (naproxen) controlled ce1ecoxib studies (n=4490). A Weibull parametric survival model was developed for the composite endpoint of self-reported upper GI distress (moderate-to-severe abdominal pain/nausea/dyspepsia), which was chosen as a proxy for events likely to require medical intervention in an outpatient setting. Predictors were identified based on clinical relevance and univariate association with the endpoint. Significant predictors were chosen for the final model using backwards-stepwise selection with a p-value<0.10. Results: The final model included the following predictors of GI distress and associated GI scores (in parentheses): history of ulcer (No(O)/Yes(64»; history of previous NSAlD GI intolerance (No(O)/Yes(lOO»; exposure to aspirin (No(O)1 Yes(40»; gender (Male(0)/Female(41»; and assigned treatment (naproxen (43)/celecoxib (0». When the values of the individual predictors were summed, patient GI scores ranged from 0 to 288. The table below summarizes the 90-day cumulative incidence of GI distress associated with a particular score. Similar predictive factors and GI scores were observed when alternative models (e.g., Cox or Log-Logistic) were considered. Conclusions: Several clinical indicators can be used to predict the incidence of upper GI distress. These results indicate celecoxib does not increase the incidence of upper GI distress. This scoring system has applicability to clinical practice for the treatment of arthritis. Scoring System forPredicting Upper GIDistress
9O-day event rate
Total GI Score Mean ± SEM Gastric Mucosal Injury Score
Group Hp -I Placebo Hp +I Placebo Hp·/ASA' Hp+/ASA'
Antrum
Body
O±O O±O
O±O O±O
0.39 ± 0.16 1.65 ± 0.60 t
0.13±0.10 0.48±0.18 t
• ASA 81 mg q Dand 325 mg q 3'"Dgroups combined t p<0.05 vs. Hp -I ASA and both placebo groups
(n=8) (n=7) (n=23) (n=23)
5%
10%
15%
20%
25'10
30%
35%
40%
45%
50%
5
73
113
143
167
187
205
221
236
250