Celecoxib versus diclofenac plus omeprazole in high-risk arthritis patients: Results of a randomized double-blind trial
2004; Elsevier BV; Volume: 127; Issue: 4 Linguagem: Inglês
10.1053/j.gastro.2004.07.010
ISSN1528-0012
AutoresFrancis K.L. Chan, Lawrence C.T. Hung, Bing Yee Suen, Vincent Wai‐Sun Wong, Aric J. Hui, Justin C. Y. Wu, Wai K. Leung, Yuk T. Lee, Ka‐Fai To, S. C. S. Chung, Joseph J.�Y. Sung,
Tópico(s)Synthesis of β-Lactam Compounds
ResumoBackground & Aims: The gastric safety of cyclooxgenase-2 inhibitors and prophylactic antisecretory therapy in high-risk arthritis patients is unclear. We studied the ulcer incidence and factors predicting ulcer recurrence in a prospective, double-blinded trial. Methods: We studied patients who presented with nonsteroidal anti-inflammatory drug-associated ulcer bleeding. After ulcer healing, patients who were negative for Helicobacter pylori were randomly assigned to celecoxib 200 mg twice a day plus omeprazole placebo once daily or diclofenac 75 mg twice daily plus omeprazole 20 mg once daily for 6 months. Patients underwent endoscopy if they developed recurrent bleeding. Those without recurrent events underwent endoscopy at their last follow-up visit. Results: Two hundred eighty-seven patients were enrolled; 24 had recurrent gastrointestinal complications. Among 259 patients without events, 222 underwent endoscopy (116 received celecoxib and 106 received diclofenac plus omeprazole). The probability of recurrent ulcers in 6 months was 18.7% in the celecoxib group and 25.6% in the diclofenac plus omeprazole group (difference, −6.7%; 95% CI: −17.8% to 3.9%) (P = 0.21). Combining bleeding and endoscopic ulcers, 24.1% in the celecoxib group and 32.3% in the diclofenac plus omeprazole group had recurrent ulcers in 6 months (difference, −8.2%; 95% CI: −19.5% to 2.9%) (P = 0.15). Treatment-induced significant dyspepsia (hazard ratio, 5.3; 95% CI: 2.6–10.8), age ≥75 (hazard ratio, 2.0; 95% CI: 1.1–3.5), and comorbidity (hazard ratio, 2.1; 95% CI: 1.2–3.7) independently predicted ulcer recurrence. Conclusions: Among patients with previous ulcer bleeding, neither celecoxib nor diclofenac plus omeprazole adequately prevents ulcer recurrence. Treatment-induced significant dyspepsia is an indication for endoscopic evaluation. Background & Aims: The gastric safety of cyclooxgenase-2 inhibitors and prophylactic antisecretory therapy in high-risk arthritis patients is unclear. We studied the ulcer incidence and factors predicting ulcer recurrence in a prospective, double-blinded trial. Methods: We studied patients who presented with nonsteroidal anti-inflammatory drug-associated ulcer bleeding. After ulcer healing, patients who were negative for Helicobacter pylori were randomly assigned to celecoxib 200 mg twice a day plus omeprazole placebo once daily or diclofenac 75 mg twice daily plus omeprazole 20 mg once daily for 6 months. Patients underwent endoscopy if they developed recurrent bleeding. Those without recurrent events underwent endoscopy at their last follow-up visit. Results: Two hundred eighty-seven patients were enrolled; 24 had recurrent gastrointestinal complications. Among 259 patients without events, 222 underwent endoscopy (116 received celecoxib and 106 received diclofenac plus omeprazole). The probability of recurrent ulcers in 6 months was 18.7% in the celecoxib group and 25.6% in the diclofenac plus omeprazole group (difference, −6.7%; 95% CI: −17.8% to 3.9%) (P = 0.21). Combining bleeding and endoscopic ulcers, 24.1% in the celecoxib group and 32.3% in the diclofenac plus omeprazole group had recurrent ulcers in 6 months (difference, −8.2%; 95% CI: −19.5% to 2.9%) (P = 0.15). Treatment-induced significant dyspepsia (hazard ratio, 5.3; 95% CI: 2.6–10.8), age ≥75 (hazard ratio, 2.0; 95% CI: 1.1–3.5), and comorbidity (hazard ratio, 2.1; 95% CI: 1.2–3.7) independently predicted ulcer recurrence. Conclusions: Among patients with previous ulcer bleeding, neither celecoxib nor diclofenac plus omeprazole adequately prevents ulcer recurrence. Treatment-induced significant dyspepsia is an indication for endoscopic evaluation. Gastrointestinal (GI) toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) is a global health care problem. In the United States, NSAIDs account for about 25% of all reported adverse drug reactions. The annual cost of treating NSAID-associated GI adverse events exceeds 4 billion dollars.1Fries J.F. NSAID gastropathy the second most deadly rheumatic disease? Epidemiology and risk appraisal.J Rheumatol. 1991; 18: 6-10Google Scholar, 2Singh G. Triadafilopoulus G. Epidemiology of NSAID-induced GI complications.J Rheumatol. 1999; 26: 18-24Google Scholar Current strategies of preventing NSAID-associated ulcer include prophylactic treatment with a proton pump inhibitor (PPI) or substitution of NSAIDs with cyclooxygenase (COX)-2 inhibitors. There is good evidence that these treatments effectively prevent gastroduodenal ulcers3Rostom A. Dube C. Wells G. Tugwell P. Welch V. Jolicoeur E. McGowan J. Prevention of NSAID-induced gastroduodenal ulcers.Cochrane Database Syst Rev. 2002; 4: CD002296PubMed Google Scholar, 4Laine L. Harper S. Simon T. Bath R. Johanson J. Schwartz H. Stern S. Quan H. Bolognese J. Rofecoxib Osteoarthritis Endoscopy Study GroupA randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.Gastroenterology. 1999; 117: 776-783Abstract Full Text Full Text PDF PubMed Scopus (463) Google Scholar, 5Simon L.S. Weaver A.L. Graham D.Y. Kivitz A.J. Lipsky P.E. Hubbard R.C. Isakson P.C. Verburg K.M. Yu S.S. Zhao W.W. Geis G.S. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis a randomized controlled trial.JAMA. 1999; 282: 1921-1928Crossref PubMed Scopus (831) Google Scholar and, in some studies, reduce clinical GI events.6Bombardier C. Laine L. Reicin A. Shapiro D. Burgos-Vargas R. Davis B. Day R. Ferraz M.B. Hawkey C.J. Hochberg M.C. Kvien T.K. Schnitzer T.J. VIGOR Study GroupComparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group.N Engl J Med. 2000; 343: 1520-1528Crossref PubMed Scopus (3785) Google Scholar, 7Chan F.K. Chung S.C. Suen B.Y. Lee Y.T. Leung W.K. Leung V.K. Wu J.C. Lau J.Y. Hui Y. Lai M.S. Chan H.L. Sung J.J. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen.N Engl J Med. 2001; 344: 967-973Crossref PubMed Scopus (607) Google Scholar The updated American College of Rheumatology Guidelines for the management of osteoarthritis recommends prophylactic co-therapy or COX-2 inhibitors in patients at risk for ulcer disease.8American College of Rheumatology Subcommittee on Osteoarthritis GuidelinesRecommendations for the medical management of osteoarthritis of the hip and knee 2000 update.Arthritis Rheum. 2000; 43: 1905-1915Crossref PubMed Scopus (2013) Google Scholar Patients with a history of ulcer bleeding who use NSAIDs belong to the highest risk category.9Garcia Rodriguez L.A. Jick H. Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs.Lancet. 1994; 343: 769-772Abstract PubMed Scopus (1000) Google Scholar However, whether co-therapy with a PPI or substitution for a COX-2 inhibitor can protect high-risk patients from ulcer complications is unclear. In a prospective, double-blinded, randomized comparison of celecoxib vs. diclofenac plus omeprazole in patients with a recent episode of ulcer bleeding, we previously reported that about 5% of patients in each group still had recurrent ulcer bleeding in 6 months.10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar However, 2 issues remained unresolved. First, the result of this study raises doubt about the gastric protective effect of these 2 treatments in patients with prior ulcer bleeding.11Graham D.Y. NSAIDs, Helicobacter pylori, and Pandora's Box.N Engl J Med. 2002; 347: 2162-2164Crossref PubMed Scopus (30) Google Scholar Second, factors predicting treatment failure in these high-risk patients are unknown. To evaluate further the gastric safety of COX-2 inhibitors or prophylactic PPIs in high-risk patients, we prospectively assessed the overall incidence of ulcers and factors predicting ulcer recurrence in a prospective, double-blinded study comparing celecoxib and diclofenac plus omeprazole in patients with arthritis and prior ulcer bleeding.10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar Although the previous study assessed the incidence of recurrent ulcer bleeding,10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar we performed follow-up endoscopy on patients who had no recurrent GI complications at their last visit. Endoscopic evaluation of recurrent ulcers at the termination of the study was one of the prespecified endpoints. We anticipated that the incidence of ulcers would be low if celecoxib or diclofenac plus omeprazole conferred adequate gastric protection in high-risk patients. We screened consecutive patients with arthritis who presented with ulcer bleeding while receiving NSAIDs to the Endoscopy Center of Prince of Wales Hospital at The Chinese University of Hong Kong. The inclusion criteria were ulcer healing confirmed on follow-up endoscopy, a negative test for Helicobacter pylori or successful eradication of Helicobacter pylori based on histology, and anticipated regular use of NSAIDs for the duration of the trial. The exclusion criteria were concomitant use of anticoagulants or corticosteroids, a history of gastric or duodenal surgery other than a patch repair, the presence of erosive esophagitis, gastric outlet obstruction, renal failure (defined by a serum creatinine level of more than 2.26 mg per deciliter), terminal illness, or cancer. The protocol was approved by the Clinical Trial Ethics Committee of The Chinese University of Hong Kong. All participants provided written informed consent. After ulcer healing, we randomly assigned patients who were negative for H. pylori infection to celecoxib 200 mg twice daily plus omeprazole placebo daily or diclofenac 75 mg twice daily plus omeprazole 20 mg daily for 6 months in a double-blinded fashion as previously described.10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar Randomization was carried out through the use of a computer-generated list of random numbers. Concealed allocation was achieved by an independent staff, who assigned treatments according to consecutive numbers in sealed envelopes. After randomization, the patients were contacted by telephone at month 1, and they returned to the Endoscopy Center at month 2 and every 2 months thereafter until the end of the study. At each visit, hemoglobin levels, serum biochemical values, drug compliance, efficacy, dyspeptic symptoms, and other adverse events were assessed. Dyspepsia was defined as upper abdominal pain or discomfort. We classified the severity of dyspepsia as absent, minimal (easily tolerated), or significant (interfering with normal activities). Drug compliance was assessed by pill counts. Patients were permitted to take antacids; paracetamol; non-NSAID analgesics; and disease-modifying, antirheumatic drugs. Nonstudy NSAIDs (except for low-dose aspirin up to 325 mg daily), misoprostol, histamine H2-receptor antagonists, sucralfate, and proton pump inhibitors were prohibited during the study. Patients who were suspected to have recurrent GI bleeding according to prespecified criteria underwent endoscopy.10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar Patients without recurrent GI complications within the study period were invited to undergo follow-up endoscopic evaluation at their last follow-up visit. A single endoscopist performed all endoscopic examinations in a treatment-blinded fashion to avoid between-observer variation. The end point was recurrent gastric or duodenal ulcer. An ulcer was defined as a circumscribed mucosal break that was at least 0.5 cm in diameter and had a perceptible depth. The location of ulcers was recorded according to prespecified regions of the stomach (cardia, fundus, greater curvature, lesser curvature, angular incisura, antrum, and pylorus) and the duodenum (first part, junction of first and second parts, second part, and beyond second part). Biopsy specimens were taken from the margin of gastric ulcers to exclude malignancy and from the antrum and the corpus to detect any recurrent H. pylori infection based on histology. Treatment codes remained unbroken throughout the study and an independent data review committee analyzed the results. Sample size estimation was based on the hypothesis of noninferiority between 2 treatments as previously described.10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar We used the Kaplan-Meier method to estimate the likelihood of reaching the end point of gastroduodenal ulcers within 6 months, based on the modified intention-to-treat population, defined as patients who had taken at least 1 dose of study drugs and had undergone follow-up endoscopy at their last visit. The log-rank test was used for between-treatment comparisons. A Cox proportional-hazards model with backward stepwise regression was used to identify possible covariates as significant (P < 0.05) predictors of recurrent ulcer, which included age (below or ≥75 years), treatment assignment (celecoxib or diclofenac plus omeprazole), the presence or absence of comorbidity (including ischemic heart disease, heart failure, stroke, cirrhosis, chronic obstructive airway disease, renal diseases, and diabetes with renal and vascular complications), concomitant use of low-dose aspirin, smoking, location of ulcers (stomach or duodenum), diameter of the ulcer (smaller than or ≥2 cm), and severity of treatment-induced dyspepsia (absent/minimal or significant), which may predict ulcer recurrence (SPSS 10.0, SPSS Inc., Chicago, IL). All P values and 95% CI are 2-sided. A total of 287 patients were enrolled. Twenty-four patients developed recurrent GI bleeding; 7 in the celecoxib group and 9 in the diclofenac plus omeprazole group were adjudicated to have recurrent ulcer bleeding according to prespecified criteria.10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar Among patients with recurrent ulcer bleeding, 3 used concomitant low-dose aspirin (1 in the celecoxib group and 2 in the diclofenac plus omeprazole group), and 1 who received diclofenac plus omeprazole had relapse of H. pylori infection. Eighteen patients used herbal products of unknown composition during the study period; 1 had recurrent ulcer bleeding. One patient in the celecoxib group died of lung cancer, and 1 patient in the diclofenac plus omeprazole group died of small-bowel perforation. One patient in each group was lost to follow-up.10Chan F.K. Hung L.C. Suen B.Y. Wu J.C. Lee K.C. Leung V.K. Hui A.J. To K.F. Leung W.K. Wong V.W. Chung S.C. Sung J.J. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis.N Engl J Med. 2002; 347: 2104-2110Crossref PubMed Scopus (495) Google Scholar Two hundred fifty-nine patients did not have recurrent GI complications. Two hundred twenty-two patients (86%) gave consent to follow-up endoscopy at their last visit. There was no significant difference in the baseline characteristics between those who did and those who did not allow repeat endoscopy (age: 66.6 vs. 70.7 years, P = 0.09; male sex: 47.7% vs. 37.8%, P = 0.26; dyspepsia: 3.6% vs. 0%, P = 0.61; osteoarthritis: 86.0% vs. 94.6%, P = 0.60; comorbidity: 28.8% vs. 21.6%, P = 0.37, respectively). One hundred sixteen patients in the celecoxib group and 106 in the diclofenac plus omeprazole group had repeated enodscopy. The 2 groups were comparable in terms of their baseline demographics. There was numeric imbalance in the number of patients receiving concomitant low-dose aspirin (5.2% in the celecoxib group vs. 12.3% in the diclofenac plus omeprazole group, P = 0.06) and the presence of minimal dyspepsia at baseline (4.9% in the celecoxib group vs. 0.7% in the diclofenac plus omeprazole group, P = 0.07), but the differences did not reach statistical significance (Table 1). The median follow-up was 6 months (range, 0.5–6). Twelve patients had recurrent H. pylori infection at the end of the study period: 6 (5.2%) in the celecoxib group and 6 (5.7%) in the diclofenac plus omeprazole group. Rates of early withdrawal were similar in the 2 groups: 5.1% in the celecoxib group (3.4% because of adverse events and 1.7% because of a lack of efficacy) and 6.6% in the omeprazole group because of adverse events. Ninety-four percent of patients in the 2 treatment groups took at least 70% of the study drugs.Table 1Baseline Characteristics of the PatientsCharacteristicCelecoxib group (n = 116)Diclofenac plus omeprazole group (n = 106)Male sex, no. (%)54 (46.6)52 (49.1)Age, yr65.3 (14.6)68 (12.8)Current smoking, no. (%)13 (11.2)17 (16.0)Current drinking, no. (%)13 (11.2)9 (8.4)Location of ulcers at index bleeding, no. (%)Gastric ulcer68 (58.6)55 (51.9)Duodenal ulcer43 (37.1)41 (38.7)Gastric and duodenal ulcers5 (4.3)10 (9.4)Patients with more than 1 episode of ulcer bleeding, no. (%)24 (20.7)23 (21.7)Size of ulcer, cm1.0 ± 0.81.0 ± 0.7Size of ulcer ≥2 cm, no. (%)19 (16.4)19 (17.9)Ulcers with active bleeding or nonbleeding visible vessels, no. (%)33 (28.4)25 (23.6)Transfusion required, no. (%)53 (45.7)41 (38.7)Types of arthritis, no. (%)Osteoarthritis98 (84.4)93 (87.8)Rheumatoid arthritis5 (4.3)1 (0.9)Others13 (11.2)12 (11.3)Comorbidity, no. (%)aComorbidity included ischemic heart disease, heart failure, stroke, cirrhosis, chronic obstructive airway disease, renal diseases, and diabetes with renal and vascular complications.34 (39.3)30 (28.3)Serum creatinine >1.2 mg/dL, no. (%)25 (21.6)20 (18.9)Minimal dyspepsia at baseline, no. (%)7 (4.9)1 (0.7)Concomitant use of low-dose aspirin, no. (%)6 (5.2)13 (12.3)Previous H. pylori infection, no. (%)68 (41.4)62 (58.5)NOTE. Plus-minus values are means ± SD.a Comorbidity included ischemic heart disease, heart failure, stroke, cirrhosis, chronic obstructive airway disease, renal diseases, and diabetes with renal and vascular complications. Open table in a new tab NOTE. Plus-minus values are means ± SD. Twenty patients receiving celecoxib and 26 receiving diclofenac plus omeprazole had recurrent ulcers on follow-up endoscopy (P = 0.18). The median diameter of recurrent ulcers was 0.5 cm (range, 0.5–3.0 cm) in both groups. Among the 46 patients with recurrent ulcers, 2 (4.3%) had relapse of H. pylori infection (1 received celecoxib and 1 received diclofenac plus omeprazole), and 7 (15.2%) used concomitant aspirin (3 in the celecoxib group and 4 in the diclofenac plus omeprazole group). None of the patients who used herbal products had recurrent endoscopic ulcers. The probability of recurrent ulcers in 6 months was 18.7% (95% CI: 11.3%–26.1%) in patients receiving celecoxib and 25.6% (95% CI: 17.1%–34.1%) in patients receiving diclofenac plus omeprazole (difference, −6.7%; 95% CI for the difference: −17.8%–3.9%, log-rank test, P = 0.21) (Figure 1). Using a combined end point of bleeding ulcers and endoscopic ulcers in the intention-to-treat population of 246 patients, the probability of recurrent ulcers in 6 months was 24.1% (95% CI: 16.3%–31.8%) in the celecoxib group and 32.3% (95% CI: 23.7%–40.9%) in patients receiving diclofenac plus omeprazole (difference, −8.2%; 95% CI for the difference: −19.5%–2.9%, log-rank test, P = 0.15). Of the 203 patients who did not use concomitant low-dose aspirin, 17 in the celecoxib group and 22 in the diclofenac plus omeprazole group had recurrent ulcers on follow-up endoscopy. The probability of recurrent ulcers in 6 months was 16.9% (95% CI: 9.6%–24.2%) in patients receiving celecoxib and 24.6% (95% CI: 15.7%–33.6%) in patients receiving diclofenac plus omeprazole (difference, −7.7%; 95% CI for the difference: −19.3%–3.3%, log-rank test, P = 0.17). Combining bleeding ulcers and endoscopic ulcers, the probability of recurrent ulcers in 6 months was 21.2% (95% CI: 13.5%–28.9%) in the celecoxib group and 30.8% (95% CI: 21.8%–39.9%) in patients receiving diclofenac plus omeprazole (difference, −9.6%; 95% CI for the difference: −21.1%–1.9%, log-rank test, P = 0.10). Eight patients (3.6%) had minimal dyspepsia before they started treatment; 3 (37.5%) of them compared with 43 (20.1%) of 214 patients without dyspepsia at baseline had recurrent ulcers (P = 0.37). One hundred ninety-eight patients (89%) experienced no or minimal dyspepsia during the study period (100 in the celecoxib group and 98 in the diclofenac plus omeprazole group). Among them, 35 (18%) had silent ulcers recurring in 6 months (13 in the celecoxib group and 22 in the diclofenac plus omeprazole group). Twenty-four patients (11%) developed significant dyspepsia on therapy within the study period (16 in the celecoxib group and 8 in the diclofenac plus omeprazole group); 11 of them (46%) had symptomatic ulcers recurring in 6 months (7 in the celecoxib group and 4 in the diclofenac plus omeprazole group) (Fisher exact test, P = 0.003 vs. 18% of patients with no or minimal dyspepsia had silent ulcers; odds ratio 3.9, 95% CI: 1.6–9.2). In the Cox proportional hazards model using backward stepwise regression, treatment-induced significant dyspepsia, age ≥75 years, and comorbidity were independent risk factors predicting ulcer recurrence (Table 2).Table 2Analysis of Possible Risk Factors Predicting Ulcer Recurrence Using the Cox ModelCovariatesUnivariate analysis P valueMultivariate analysisHazard ratio (95% CI)P valueTreatment-induced significant dyspepsia0.0035.3 (2.6 to 10.8)<0.001Age ≥75 yr0.0162.0 (1.1 to 3.5)0.022Comorbidity0.0182.1 (1.2 to 3.7)0.014Treatment assignment0.1811.8 (0.97 to 3.23)0.059Concomitant low-dose aspirin0.0801.5 (0.6 to 3.9)0.435Smoking0.1190.5 (0.2 to 1.8)0.300Location of ulcers (gastric ulcer)0.0111.7 (0.8 to 3.6)0.131Diameter of ulcer ≥2 cm0.0701.5 (0.8 to 3.0)0.247 Open table in a new tab We studied the overall incidence of ulcers to evaluate the gastric safety of long-term treatment with celecoxib or diclofenac plus omeprazole in very high-risk patients, i.e., those with a recent episode of ulcer bleeding. Among patients without recurrent gastrointestinal complications within the study period, the incidence of recurrent gastroduodenal ulcers was unexpectedly high: 19% of patients receiving celecoxib and 26% of patients receiving diclofenac plus omeprazole had recurrent ulcers in 6 months. Combining bleeding ulcers and endoscopic ulcers, the 6-month incidence of recurrent ulcers was 24% in the celecoxib group and 32% in the diclofenac plus omeprazole group. Neither relapse of H. pylori infection nor concomitant use of herbal products could account for the high rate of ulcer recurrence. Our findings therefore indicate that neither treatment adequately protects high-risk patients from ulcer recurrence. Treatment-induced significant dyspepsia, age ≥75 years, and coexisting medical conditions independently predict treatment failure. Endoscopic ulcer has been widely used as a surrogate for clinical events in the evaluation of different strategies for the prevention of NSAID-induced ulcers. In general, there is reasonable correlation between endoscopic and clinical outcome studies. However, results derived from average-risk subjects may not be generalized to high-risk patients. Previous endoscopic studies have repeatedly shown that prophylactic treatment with a PPI or substitution for a COX-2 inhibitor alone effectively prevents gastroduodenal ulcers. In a randomized, placebo-controlled trial of omeprazole for the prevention of NSAID-induced ulcer, 4.7% (18.8 per 100 patient-years) of patients receiving omeprazole compared with 16.7% (66.8 per 100 patient-years) of patients receiving placebo developed ulcers in 3 months.12Ekstrom P. Carling L. Wetterhus S. Wingren P.E. Anker-Hansen O. Lundegardh G. Thorhallsson E. Unge P. Prevention of peptic ulcer and dyspeptic symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy. A Nordic multicentre study.Scand J Gastroenterol. 1996; 31: 753-758Crossref PubMed Scopus (256) Google Scholar Other studies reported that COX-2 inhibitors caused minimal gastroduodenal damage that was comparable with placebo.13Laine L. Harper S. Simon T. Bath R. Johanson J. Schwartz H. Stern S. Quan H. Bolognese J. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.Gastroenterology. 1999; 117: 776-783Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, 14Simon L.S. Weaver A.L. Graham D.Y. Kivitz A.J. Lipsky P.E. Hubbard R.C. Isakson P.C. Verburg K.M. Yu S.S. Zhao W.W. Geis G.S. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis a randomized controlled trial.JAMA. 1999; 282: 1921-1928Crossref PubMed Scopus (686) Google Scholar In one study, the 12-week incidence of ulcer (≥5 mm in diameter) was 5.5% (22 per 100 patient-years) in the rofecoxib group and 8.2% (32.8 per 100 patient-years) in the placebo group.13Laine L. Harper S. Simon T. Bath R. Johanson J. Schwartz H. Stern S. Quan H. Bolognese J. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis.Gastroenterology. 1999; 117: 776-783Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar In another study, the 12-week incidence of ulcer was 4% (16 per 100 patient-years) both in celecoxib group and the placebo group.14Simon L.S. Weaver A.L. Graham D.Y. Kivitz A.J. Lipsky P.E. Hubbard R.C. Isakson P.C. Verburg K.M. Yu S.S. Zhao W.W. Geis G.S. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis a randomized controlled trial.JAMA. 1999; 282: 1921-1928Crossref PubMed Scopus (686) Google Scholar A note of caution is that the vast majority of patients in previous endoscopic studies did not have prior ulcer complications. Unlike previous studies, our finding indicates that the rate of ulcers in high-risk patients (48 to 62 per 100 patient-years) who received celecoxib or diclofenac plus omeprazole is about 3 times more frequent than that of low-risk subjects (16 to 22 per 100 patient-years). Thus, prophylactic treatment with a PPI or substitution for a COX-2 inhibitor alone effectively prevents gastroduodenal ulcers in average-risk but not high-risk patients. Another interesting observation in this study is that treatment-induced significant dyspepsia (i.e., symptoms interfering with normal activities) predicts recurrent gastroduodenal ulcers in high-risk patients. Recurrent ulcer occurred in 46% of patients with significant dyspepsia on therapy as compared with only 18% of patients with no or mild dyspepsia on therapy. Unlike high-risk patients, dyspepsia correlates poorly with the occurrence of gastroduodenal ulcers in average-risk subjects receiving NSAIDs, such that the optimal management of NSAID-associated dyspepsia remains unclear.15Wolfe M.M. Lichtenstein D.R. Singh G. Gastrointestinal toxicity of nonsteroidal anti-inflammatory drugs.N Engl J Med. 1999; 340: 1888-1899Crossref PubMed Scopus (1984) Google Scholar Our findings suggested that endoscopic evaluation is warranted in patients with a history of ulcer complications who experience significant dyspepsia while receiving COX-2 inhibitors or co-therapy with a PPI. Early detection of recurrent ulcers might prevent progression to ulcer complications in some of these high-risk patients. Our study had limitations. First, concurrent use of low-dose aspirin is known to increase the risk of ulcers in patients receiving conventional or COX-2 selective NSAIDs.16Fiorucci S. Santucci L. Wallace J.L. Sardina M. Romano M. del Soldato P. Morelli A. Interaction of a selective cyclooxygenase-2 inhibitor with aspirin and NO-releasing aspirin in the human gastric mucosa.Proc Natl Acad Sci U S A. 2003; 100: 10937-10941Crossref PubMed Scopus (114) Google Scholar, 17Eisen G. Goldstein J.L. Stenson W. Agrawal N. Kent J. Fort J.G. Lack of correlation between risk factors and clinical GI outcomes in NSAID-treated patients analysis from two large-scale, double-blind celecoxib studies.Gastroenterology. 2002; 122: A346Google Scholar In this study, concomitant low-dose aspirin was found in about 15% of all patients with recurrent ulcers. However, the number of patients using low-dose aspirin was very small so that any definite effect of low-dose aspirin on the risk of ulcer would not be apparent. Likewise, the number of smokers was too small to assess its true effect on ulcer recurrence. Alternatively, the patients in this study were already at very high risk of ulcer recurrence so that the deleterious effect of smoking might not be apparent. Second, the absolute difference between the 2 treatments was 8.2 percentage points in terms of recurrent bleeding and endoscopic ulcers. Although the difference did not reach statistical significance, the lower bound of the 95% confidence interval for the difference in ulcer rates was −19.5%. This finding suggested that there might be a nonsignificant trend in favor of celecoxib that would require a much larger study to demonstrate. In summary, among patients with prior ulcer bleeding who require long-term regular NSAIDs, treatment with celecoxib or diclofenac plus omeprazole causes a high incidence of recurrent gastroduodenal ulcers. The development of significant dyspepsia on therapy is an indication for further endoscopic evaluation. Current guidelines on the management of arthritis patients at high risk of ulcer complications need to be critically reconsidered. The authors thank Albert Cheung of the Center of Clinical Trials and Epidemiological Research at The Chinese University of Hong Kong for statistical advice, Jessica Ching and M.Y. Yung for data review, and the nursing staff of the Endoscopy Center at the Prince of Wales Hospital for their generous support.
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