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Serious lower gastrointestinal clinical events with nonselective NSAID or coxib use
GASTROENTEROLOGY 2003;124:288 –292
CLINICAL–ALIMENTARY TRACT Serious Lower Gastrointestinal Clinical Events With Nonselective NSAID or Coxib Use LOREN LAINE,* LAURINE G. CONNORS,‡ ALISE REICIN,‡ CHRISTOPHER J. HAWKEY,§ RUBEN BURGOS–VARGAS,㛳 THOMAS J. SCHNITZER,¶ QINFEN YU,‡ and CLAIRE BOMBARDIER# *University of Southern California School of Medicine, Los Angeles, California; ‡Merck & Co., Whitehouse Station, New Jersey; §University of Nottingham, Nottingham, United Kingdom; 㛳Hospital General de Me´xico, Mexico City, Mexico; ¶Northwestern University, Chicago, Illinois; and #University of Toronto, Toronto, Ontario, Canada
Background & Aims: Epidemiologic studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for lower gastrointestinal (GI) clinical events, but data from prospective trials are lacking. Cyclooxygenase (COX)-2–selective inhibitors decrease upper GI clinical events but the effect on lower GI events has not been determined. We performed a post hoc analysis of serious lower GI clinical events with a nonselective NSAID and a COX-2–selective agent in a prospective, doubleblind, randomized GI outcomes trial. Methods: A total of 8076 rheumatoid arthritis patients 50 years or older (or 40 years or older on corticosteroid therapy) expected to require NSAIDs for 1 year or greater were randomly assigned to naproxen 500 mg twice daily or rofecoxib 50 mg daily. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, was determined. Results: The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22– 0.93; P ⴝ 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib. Conclusions: Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.
onsteroidal anti-inflammatory drugs (NSAIDs) are well documented to increase the risk for upper gastrointestinal (GI) adverse events, such as ulcers, bleeding, perforation, and obstruction.1 Epidemiologic studies suggest that NSAIDs also may increase the risk for lower GI adverse events, including bleeding, perforation, obstruction, ulcerations, and symptomatic diverticular dis-
N
ease.2–11 However, no prospective trials have assessed lower GI clinical events in patients taking NSAIDs to provide estimates of the risk for such events. Furthermore, use of selective cyclooxygenase (COX)-2 inhibitors has been shown recently to decrease the rate of upper GI clinical events.12 However, information on the effect of COX-2 inhibitors on lower GI events is not available. We therefore assessed serious lower GI clinical events in a post hoc analysis of a prospective, double-blind outcomes study of naproxen vs. rofecoxib in 8076 patients.12
Materials and Methods Rheumatoid arthritis patients 50 years or older (or 40 years or older and receiving corticosteroid therapy) and who were expected to require NSAIDs for 1 year or more were eligible. Exclusion criteria included use of aspirin or other antiplatelet agents, anticoagulants, misoprostol, sucralfate, proton pump inhibitors, or prescription-strength histamine2receptor antagonists (lower doses were allowed: cimetidine 400 mg daily, ranitidine 150 mg daily, famotidine 20 mg daily, nizatidine 150 mg daily), and inflammatory bowel disease. The study was conducted at 301 centers in 22 countries. The institutional review board or ethics review committee at each center approved the protocol and all patients gave written informed consent. Financial and logistical support for this study was provided by Merck & Co. An independent steering committee oversaw the study design, conduct of the trial, analyses of data, and drafting of all reports. Patients were randomly assigned to receive rofecoxib 50 mg daily or naproxen 500 mg twice daily, and allocation was concealed. A matching placebo was used for each study medication to maintain blinding. Patients returned at 6 weeks, 4 months, and every 4 months thereafter. They were contacted Abbreviations used in this paper: CI, confidence interval; COX, cyclooxygenase; GI, gastrointestinal. © 2003 by the American Gastroenterological Association 0016-5085/03/$35.00 doi:10.1053/gast.2003.50054
February 2003
by phone at week 10 and every 4 months thereafter. Patients were contacted 14 days after discontinuation of study medication, and events that occurred during this period were included in the analysis. Patients were otherwise treated according to the standard practice of the physician caring for them. Evaluation of suspected events was performed at the discretion of the physician, based on the clinical situation. The prespecified primary endpoint for the study was clinical upper GI events (bleeding, perforation, obstruction, and symptomatic ulcers identified on a clinically indicated work-up) and the prespecified secondary endpoint was complicated upper GI events (perforation, obstruction, major bleeding).12 Patients with confirmed upper GI events were discontinued from the study. For the current analyses, a list of serious lower GI events and criteria for the events were developed post hoc in a blinded manner. The term lower GI referred to the small intestine (beyond the duodenum) and the colon, and serious lower GI events were defined as follows: bleeding: gross rectal bleeding (other than melena) associated with a hemoglobin decrease of greater than 2 g/dL or hospitalization, or positive test for fecal occult blood associated with hemoglobin decrease of greater than 2 g/dL and negative upper endoscopy; hospitalization for intestinal perforation, obstruction, ulceration, or diverticulitis. All patients in the study were then assessed for any reported signs, symptoms, diagnoses, or data potentially consistent with a lower GI event. Clinical information for each of these patients was reviewed and those meeting the criteria for lower GI events were selected and independently confirmed by 2 authors (L.L. and A.R.). All review of data was performed blinded to treatment allocation. All patients randomized were included in the analysis and the rates are presented per 100 patient-years. Survival analytic methods were used to assess the time to lower GI clinical event during the entire study period. A Cox proportional hazards model was used to evaluate the effects of rofecoxib relative to naproxen for serious lower GI clinical events. Relative risk estimates, associated 95% confidence intervals (CIs), and P values were obtained by using the Cox model. Treatment was included in the Cox model as the main factor, whereas a prior history of upper GI clinical events was included in the model as a stratification variable. Statistical tests were 2 sided.
Results From January 1999 to July 1999, 8076 patients were enrolled: 4029 in the naproxen group and 4047 in the rofecoxib group. Baseline characteristics were similar in the 2 treatment groups: 80% were women, 26% were 65 years of age or older, 56% took corticosteroids, and 83% took disease-modifying agents. Patients in each treatment group were followed up for a median of 9 months (range, 0.5–13 months). Rates of discontinuation over the 13 months of the study were similar in the 2 study groups: 28.5% in the naproxen group (16.1% for adverse events, 6.5% for lack of efficacy, and 5.9% for other reasons) and 29.3% in the rofecoxib group (16.4%
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for adverse events, 6.3% for lack of efficacy, and 6.6% for other reasons).12 Ninety-nine percent of patients in each group took their study medications on 75% of study days or more. Thirty-five patients had serious lower GI events: 24 with naproxen and 11 with rofecoxib. Twenty-seven patients had serious lower GI bleeding, 2 had obstruction, 2 had diverticular perforation, 3 had diverticulitis without gross perforation (based on clinical plus computed tomographic evidence in each case), and 1 had colonic ulceration (2 additional patients in the bleeding group had colonic ulcers diagnosed). Twenty-four patients were hospitalized (16 in the naproxen group, 8 in the rofecoxib group). Among the 27 patients with bleeding, 23 had a hemoglobin level drop of greater than 2 g/dL, 16 were hospitalized, and 7 received blood transfusions. Six of the 27 patients diagnosed with lower GI bleeding had positive tests for fecal occult blood rather than gross rectal bleeding; 4 of these 6 required hospitalization because of a large drop in hemoglobin level (2 received blood transfusions) and a fifth developed congestive heart failure caused by their decrease in hemoglobin level. Four patients with gross rectal bleeding had no GI evaluation to rule out an upper GI source: 3 had a hemoglobin level drop of greater than 2 g/dL without hospitalization and without hemodynamic instability noted, while 1 was hospitalized but did not have a hemoglobin level drop that was greater than 2 g/dL. Although rectal bleeding occasionally can be a manifestation of a very large acute upper GI hemorrhage, these patients did not have the requisite clinical features consistent with an upper GI source and were considered to have bled from beyond the upper GI tract. Two patients with hemoglobin level decreases greater than 2 g/dL had their rectal bleeding ascribed to hemorrhoids when endoscopic evaluation revealed no sources of bleeding other than internal hemorrhoids. The etiologies of lower GI bleeding episodes as diagnosed by investigators are shown in Table 1. Figure 1 shows the time to serious lower GI clinical event for the treatment groups. The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen. The relative risk for serious lower GI events for rofecoxib vs. naproxen from the Cox model was 0.46 (95% CI, 0.22– 0.93; P ⫽ 0.032). The unadjusted (non–model based) relative risk was 0.46 (95% CI, 0.20 – 0.97; P ⫽ 0.041). The absolute risk difference (per 100 patient-years) was ⫺0.48 (95% CI, ⫺0.91 to ⫺0.05) with a number-needed-to-treat of 208. Although the number of events likely is too small to allow meaningful conclusions from subgroup analysis,
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Table 1. Investigator-Reported Diagnoses for the 27 Patients With Serious Lower Gl Bleeding Number of patients Diagnosis Diverticula Colonic ulcer Colitis Vascular ectasia Hemorrhoids Bleeding polyp Rectal tear Negative upper endoscopy and colonoscopy Negative upper endoscopy No Gl work-up
Naproxen (N ⫽ 18) Rofecoxib (N ⫽ 9) 4 2 0 1 2 1 1
2 0 2 1 0 0 0
1 3 3
3 0 1
we examined the rates of serious lower GI events related to use of corticosteroid therapy because this is a risk factor for upper GI events in NSAID users. The rate of lower GI events in those using corticosteroid therapy compared with those not taking corticosteroids was not significantly different in the naproxen group (0.99 vs. 0.76; relative risk, 1.29; 95% CI 0.57–2.96) or in the rofecoxib group (0.26 vs. 0.59; relative risk, 0.45; 95% CI 0.13–1.53). Only 1 of the 35 patients with a serious lower GI event also had an upper GI clinical event during the study: a patient on rofecoxib with lower GI bleeding and upper GI bleeding from vascular ectasias. However, all patients with confirmed upper GI events were discontinued from the study per the protocol, and, in most cases (63%), patients with serious lower GI events also had their study medication discontinued. The previously reported rates per 100 patient-years of complicated upper GI events were 1.4 with naproxen and 0.6 with rofecoxib.12 The rates of all serious GI events (complicated upper GI event and serious lower GI event) were 0.96 for rofecoxib and 2.26 per 100 patient-years for naproxen (relative risk, 0.43; 95%CI, 0.27– 0.67; P ⬍ 0.001; number-needed-to-treat, 77). Among patients taking naproxen, serious lower GI events accounted for 39.4% of all serious GI events (0.89 for serious lower GI events/2.26 for all serious GI events). Among patients taking rofecoxib, the proportion was 42.7%.
events occurred at an annualized incidence of 1.4% with naproxen in this study, whereas the incidence of any upper GI clinical event, including uncomplicated ulcers associated with pain or discomfort, was 4.5%.12 Therefore, serious lower GI events may account for a large proportion of GI tract complications in patients taking a nonselective NSAID. The use of the selective COX-2 inhibitor rofecoxib was associated with a 54% relative risk reduction in serious lower GI events. Case control and cohort studies suggest that the use of NSAIDs increases the risk for lower GI complications such as bleeding, perforation, and complicated diverticular disease.2–11 NSAIDs may cause ulcers of the small or large intestine, which occasionally bleed or perforate4 –7; intestinal strictures, which may cause obstruction2; colitis, which may present clinically as bloody diarrhea2; and an enteropathy, which may cause mild chronic blood loss.2 However, lower GI events associated with NSAID use appear more commonly to represent complications of pre-existing diseases such as diverticula, vascular ectasias, and cancer.5–7,9,10 In the large Arthritis, Rheumatism, and Aging Medical Information System data bank of arthritis patients, 32% of all GI hospitalizations in osteoarthritis patients were for lower GI diagnoses, whereas 13% of GI hospitalizations in rheumatoid arthritis patients were for lower GI diagnoses.13 Our prospective study provides support for the concept that lower GI events are relatively common among NSAID users. Lower GI events accounted for approximately 40% of all serious GI events that occurred. Although the rate of lower GI events may be less than the rate of upper GI events, several case-control studies
Discussion This post hoc analysis of a large prospective outcomes study showed that serious lower GI events occurred at an annualized incidence of 0.9% in rheumatoid arthritis patients taking the nonselective NSAID naproxen. By way of comparison, complicated upper GI
Figure 1. Time to serious lower GI clinical events in the naproxen and rofecoxib treatment group. (Incidence expressed as rate of events per 100 patient-years.)
February 2003
suggest that the magnitude of the increase in risk owing to NSAID use is similar for lower GI complications and upper GI complications. Data reported by Lanas et al.5 indicate odds ratios for use of NSAIDs in patients with upper GI bleeding and lower GI bleeding were 10.7 (95% CI, 4.5–26.0) and 18.4 (95% CI, 4.7–51.4), respectively, whereas Wilcox et al.7 reported odds ratios of 3.2 (95% CI, 2.6 – 4.0) for upper GI bleeding and 2.6 (95% CI, 1.7–3.9) for lower GI bleeding. In a study of NSAID use and GI perforation, the odds ratios for upper GI and lower GI perforations were 6.3 (95% CI, 3.1– 12.9) and 8.1 (95% CI, 2.3–31.9), respectively.6 The pathogenesis of NSAID-induced lower GI events is uncertain. Although NSAID enteropathy has been suggested to develop via direct effects of NSAIDs on enterocytes,2 it seems likely that clinical lower GI events occur owing to inhibition of COX-1 and prostaglandin synthesis in the GI tract and platelets. Mucosal injury owing to inhibition of intestinal prostaglandin production could lead to the development of lower GI disease de novo (e.g., ulcers) or could worsen pre-existing GI lesions. The antiplatelet effects of NSAIDs such as naproxen, owing to COX-1 inhibition, also must be considered in the pathogenesis of intestinal bleeding. Inhibition of platelet aggregation could lead to bleeding from GI lesions that are already present or to bleeding from lesions caused by the NSAID. If COX-1 inhibition in the intestine is responsible for mucosal injury, then COX-2 selective inhibitors would be expected to cause less injury than nonselective NSAIDs. In addition, because thromboxane synthesis in platelets is solely COX-1 mediated, COX-2–selective inhibitors such as rofecoxib, which do not inhibit platelet thromboxane synthesis or platelet aggregation,14 should not induce bleeding from GI lesions owing to platelet dysfunction. Previous studies provide support for the concept that inhibition of COX-1 and COX-1–mediated prostaglandin synthesis plays a role in NSAID-induced intestinal injury. Treatment with the prostaglandin analog misoprostol in patients with iron-deficiency anemia caused by NSAID enteropathy (small intestinal ulcers, erosions, or red spots) led to a significant improvement in hemoglobin level,15 and nonselective NSAIDs, but not COX-2– selective agents, significantly increase intestinal permeability.16 The results of our trial along with the results of a placebo-controlled double-blind trial in healthy subjects, which showed that ibuprofen but not rofecoxib significantly increased fecal blood loss,17 also suggest that inhibition of COX-1–mediated prostaglandin production in the intestine and/or platelets is responsible, at
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least in part, for lower GI clinical events in patients taking nonselective NSAIDs. Our data extend only to the 14-day period after the end of NSAID or COX-2 inhibitor therapy. Therefore, we cannot comment on whether the difference in favor of rofecoxib would continue beyond the treatment period. In addition, this was a post hoc analysis of a prospective double-blind trial; the trial was not designed specifically to evaluate lower GI events. For this reason, a large prospective outcomes study designed to examine lower GI events will be required to confirm our findings. In summary, serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib. Based on these results, 208 patients would need to be treated with rofecoxib instead of naproxen to avert a serious lower GI event, and the number-needed-to-treat to avert a serious upper or lower GI event is 77.
References 1. Laine L. Approaches to NSAID use in the high-risk patient. Gastroenterology 2001;120:594 – 606. 2. Bjarnason I, Hayllar H, Macpherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993;104:1832–1847. 3. Langman MJS, Morgan L, Worrall A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. Br Med J 1985;290:347–349. 4. Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. N Engl J Med 1992;327:749 –754. 5. Lanas A, Ssekar MC, Hirschowitz BI. Objective evidence of aspirin use in both ulcer and nonulcer upper and lower gastrointestinal bleeding. Gastroenterology 1992;103:862– 869. 6. Lanas A, Serrano P, Bajador E, Esteva F, Benito R, Sainz R. Evidence of aspirin use in both upper and lower gastrointestinal perforation. Gastroenterology 1997;112:683– 689. 7. Wilcox CM, Alexander LN, Cotsonis GA, Clark WS. Nonsteroidal anti-inflammatory drugs are associated with both upper and lower gastrointestinal bleeding. Dig Dis Sci 1997;42:990 –997. 8. Holt S, Rigoglioso V, Sidhu M, Irshad M, Howden CW, Mainero M. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal bleeding. Dig Dis Sci 1993;38:1619 –1623. 9. Wilson RG, Smith AN, Macintyre IMC. Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study. Br J Surg 1990;77:1103–1104. 10. Campbell K, Steele RJC. Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a case-control study. Br J Surg 1991;78:190 –191. 11. Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998;7:255–260. 12. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Bosi Ferraz M, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520 –1528.
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13. Singh G, Ramey DR. NSAID induced gastrointestinal complications: the ARAMIS perspective—1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol 1998; 25(Suppl 51):8 –16. 14. Matheson AJ, Figgitt DP. Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs 2001;61:833– 865. 15. Morris AJ, Murray L, Sturrock RD, Madhok R, Capell HA, Mackenzie JF. Short report: the effect of misoprostol on the anaemia of NSAID enteropathy. Aliment Pharmacol Ther 1994;8:343–346. 16. Sigthorsson G, Crane R, Simon T, Hoover M, Quan H, Bolognese J, Bjarnason I. COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 2000;47:527–532. 17. Hunt RH, Bowen B, Mortensen ER, Simon TJ, James C, Cagliola A, Quan H, Bolognese JA. A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects. Am J Med 2000;109:201–206.
Received September 24, 2002. Accepted November 7, 2002. Address requests for reprints to: Loren Laine, M.D., GI Division, Department of Medicine, University of Southern California School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. e-mail: [email protected]; fax: (323) 226-7573. Supported by Merck & Co., Whitehouse Station, New Jersey. Dr. Laine received research support from Merck, and is a consultant for Merck, Pharmacia, Novartis, and Pfizer. Dr. Hawkey has received research funding from AstraZeneca, Alizyme, Boehringer Ingelheim, GlaxoSmithKline, Merck, NicOx, Novartis, and Pfizer. Dr. Schnitzer is a consultant for AstraZeneca, GlaxoSmithKline, McNeil Consumer, Merck, and Novartis, and has received research support from AstraZeneca, Merck, and Novartis. Dr. Bombardier is a consultant for Merck Research Laboratories, Schering Canada, and Wyeth Ayerst Research, has received research grants from Abbott Laboratories (formerly Knoll Pharmaceutical Company), Aventis Pharmaceuticals, and Merck Research Laboratories, and is a member of the Advisory Board for Abbot Laboratories, Bristol-Myers Squibb Company, and Merck Frosst Canada.
Murphy of Murphy’s Sign John Benjamin Murphy (1857–1916) was born in Appleton, Wisconsin, the son of Irish immigrant pioneers. Awarded his M.D. degree by the Rush Medical College in 1879, his scholastic record entitled him to a coveted internship at the Cook County Hospital. A 2-year sojourn in Europe included study with the famed Viennese surgeon Theodor Billroth (1829 –1894). On his return to Chicago, he served on the surgical faculties of his alma mater and at Northwestern University. Acknowledged as a brilliant surgeon and innovator, his flamboyant character occasionally embroiled him in controversy. He was among the first to advocate early operation for acute appendicitis, as well as surgical collapse of the lung in cases of unilateral pulmonary tuberculosis. Tenderness below the right costal margin on inspiration as an indication of acute cholecystitis is known as Murphy’s sign. The Murphy button was a double, circular clip for end-to-end intestinal anastomosis; controversial in its day, it later led to development of devices that obviated certain risks of conventional suture technique. —Contributed by WILLIAM S. HAUBRICH, M.D. Scripps Clinic and Research Foundation, La Jolla, California
Copyright holder unknown. Photo obtained from the National Library of Medicine Website (http://www.nlm.nih.gov).
CLINICAL–ALIMENTARY TRACT Serious Lower Gastrointestinal Clinical Events With Nonselective NSAID or Coxib Use LOREN LAINE,* LAURINE G. CONNORS,‡ ALISE REICIN,‡ CHRISTOPHER J. HAWKEY,§ RUBEN BURGOS–VARGAS,㛳 THOMAS J. SCHNITZER,¶ QINFEN YU,‡ and CLAIRE BOMBARDIER# *University of Southern California School of Medicine, Los Angeles, California; ‡Merck & Co., Whitehouse Station, New Jersey; §University of Nottingham, Nottingham, United Kingdom; 㛳Hospital General de Me´xico, Mexico City, Mexico; ¶Northwestern University, Chicago, Illinois; and #University of Toronto, Toronto, Ontario, Canada
Background & Aims: Epidemiologic studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for lower gastrointestinal (GI) clinical events, but data from prospective trials are lacking. Cyclooxygenase (COX)-2–selective inhibitors decrease upper GI clinical events but the effect on lower GI events has not been determined. We performed a post hoc analysis of serious lower GI clinical events with a nonselective NSAID and a COX-2–selective agent in a prospective, doubleblind, randomized GI outcomes trial. Methods: A total of 8076 rheumatoid arthritis patients 50 years or older (or 40 years or older on corticosteroid therapy) expected to require NSAIDs for 1 year or greater were randomly assigned to naproxen 500 mg twice daily or rofecoxib 50 mg daily. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, was determined. Results: The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22– 0.93; P ⴝ 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib. Conclusions: Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.
onsteroidal anti-inflammatory drugs (NSAIDs) are well documented to increase the risk for upper gastrointestinal (GI) adverse events, such as ulcers, bleeding, perforation, and obstruction.1 Epidemiologic studies suggest that NSAIDs also may increase the risk for lower GI adverse events, including bleeding, perforation, obstruction, ulcerations, and symptomatic diverticular dis-
N
ease.2–11 However, no prospective trials have assessed lower GI clinical events in patients taking NSAIDs to provide estimates of the risk for such events. Furthermore, use of selective cyclooxygenase (COX)-2 inhibitors has been shown recently to decrease the rate of upper GI clinical events.12 However, information on the effect of COX-2 inhibitors on lower GI events is not available. We therefore assessed serious lower GI clinical events in a post hoc analysis of a prospective, double-blind outcomes study of naproxen vs. rofecoxib in 8076 patients.12
Materials and Methods Rheumatoid arthritis patients 50 years or older (or 40 years or older and receiving corticosteroid therapy) and who were expected to require NSAIDs for 1 year or more were eligible. Exclusion criteria included use of aspirin or other antiplatelet agents, anticoagulants, misoprostol, sucralfate, proton pump inhibitors, or prescription-strength histamine2receptor antagonists (lower doses were allowed: cimetidine 400 mg daily, ranitidine 150 mg daily, famotidine 20 mg daily, nizatidine 150 mg daily), and inflammatory bowel disease. The study was conducted at 301 centers in 22 countries. The institutional review board or ethics review committee at each center approved the protocol and all patients gave written informed consent. Financial and logistical support for this study was provided by Merck & Co. An independent steering committee oversaw the study design, conduct of the trial, analyses of data, and drafting of all reports. Patients were randomly assigned to receive rofecoxib 50 mg daily or naproxen 500 mg twice daily, and allocation was concealed. A matching placebo was used for each study medication to maintain blinding. Patients returned at 6 weeks, 4 months, and every 4 months thereafter. They were contacted Abbreviations used in this paper: CI, confidence interval; COX, cyclooxygenase; GI, gastrointestinal. © 2003 by the American Gastroenterological Association 0016-5085/03/$35.00 doi:10.1053/gast.2003.50054
February 2003
by phone at week 10 and every 4 months thereafter. Patients were contacted 14 days after discontinuation of study medication, and events that occurred during this period were included in the analysis. Patients were otherwise treated according to the standard practice of the physician caring for them. Evaluation of suspected events was performed at the discretion of the physician, based on the clinical situation. The prespecified primary endpoint for the study was clinical upper GI events (bleeding, perforation, obstruction, and symptomatic ulcers identified on a clinically indicated work-up) and the prespecified secondary endpoint was complicated upper GI events (perforation, obstruction, major bleeding).12 Patients with confirmed upper GI events were discontinued from the study. For the current analyses, a list of serious lower GI events and criteria for the events were developed post hoc in a blinded manner. The term lower GI referred to the small intestine (beyond the duodenum) and the colon, and serious lower GI events were defined as follows: bleeding: gross rectal bleeding (other than melena) associated with a hemoglobin decrease of greater than 2 g/dL or hospitalization, or positive test for fecal occult blood associated with hemoglobin decrease of greater than 2 g/dL and negative upper endoscopy; hospitalization for intestinal perforation, obstruction, ulceration, or diverticulitis. All patients in the study were then assessed for any reported signs, symptoms, diagnoses, or data potentially consistent with a lower GI event. Clinical information for each of these patients was reviewed and those meeting the criteria for lower GI events were selected and independently confirmed by 2 authors (L.L. and A.R.). All review of data was performed blinded to treatment allocation. All patients randomized were included in the analysis and the rates are presented per 100 patient-years. Survival analytic methods were used to assess the time to lower GI clinical event during the entire study period. A Cox proportional hazards model was used to evaluate the effects of rofecoxib relative to naproxen for serious lower GI clinical events. Relative risk estimates, associated 95% confidence intervals (CIs), and P values were obtained by using the Cox model. Treatment was included in the Cox model as the main factor, whereas a prior history of upper GI clinical events was included in the model as a stratification variable. Statistical tests were 2 sided.
Results From January 1999 to July 1999, 8076 patients were enrolled: 4029 in the naproxen group and 4047 in the rofecoxib group. Baseline characteristics were similar in the 2 treatment groups: 80% were women, 26% were 65 years of age or older, 56% took corticosteroids, and 83% took disease-modifying agents. Patients in each treatment group were followed up for a median of 9 months (range, 0.5–13 months). Rates of discontinuation over the 13 months of the study were similar in the 2 study groups: 28.5% in the naproxen group (16.1% for adverse events, 6.5% for lack of efficacy, and 5.9% for other reasons) and 29.3% in the rofecoxib group (16.4%
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for adverse events, 6.3% for lack of efficacy, and 6.6% for other reasons).12 Ninety-nine percent of patients in each group took their study medications on 75% of study days or more. Thirty-five patients had serious lower GI events: 24 with naproxen and 11 with rofecoxib. Twenty-seven patients had serious lower GI bleeding, 2 had obstruction, 2 had diverticular perforation, 3 had diverticulitis without gross perforation (based on clinical plus computed tomographic evidence in each case), and 1 had colonic ulceration (2 additional patients in the bleeding group had colonic ulcers diagnosed). Twenty-four patients were hospitalized (16 in the naproxen group, 8 in the rofecoxib group). Among the 27 patients with bleeding, 23 had a hemoglobin level drop of greater than 2 g/dL, 16 were hospitalized, and 7 received blood transfusions. Six of the 27 patients diagnosed with lower GI bleeding had positive tests for fecal occult blood rather than gross rectal bleeding; 4 of these 6 required hospitalization because of a large drop in hemoglobin level (2 received blood transfusions) and a fifth developed congestive heart failure caused by their decrease in hemoglobin level. Four patients with gross rectal bleeding had no GI evaluation to rule out an upper GI source: 3 had a hemoglobin level drop of greater than 2 g/dL without hospitalization and without hemodynamic instability noted, while 1 was hospitalized but did not have a hemoglobin level drop that was greater than 2 g/dL. Although rectal bleeding occasionally can be a manifestation of a very large acute upper GI hemorrhage, these patients did not have the requisite clinical features consistent with an upper GI source and were considered to have bled from beyond the upper GI tract. Two patients with hemoglobin level decreases greater than 2 g/dL had their rectal bleeding ascribed to hemorrhoids when endoscopic evaluation revealed no sources of bleeding other than internal hemorrhoids. The etiologies of lower GI bleeding episodes as diagnosed by investigators are shown in Table 1. Figure 1 shows the time to serious lower GI clinical event for the treatment groups. The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen. The relative risk for serious lower GI events for rofecoxib vs. naproxen from the Cox model was 0.46 (95% CI, 0.22– 0.93; P ⫽ 0.032). The unadjusted (non–model based) relative risk was 0.46 (95% CI, 0.20 – 0.97; P ⫽ 0.041). The absolute risk difference (per 100 patient-years) was ⫺0.48 (95% CI, ⫺0.91 to ⫺0.05) with a number-needed-to-treat of 208. Although the number of events likely is too small to allow meaningful conclusions from subgroup analysis,
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Table 1. Investigator-Reported Diagnoses for the 27 Patients With Serious Lower Gl Bleeding Number of patients Diagnosis Diverticula Colonic ulcer Colitis Vascular ectasia Hemorrhoids Bleeding polyp Rectal tear Negative upper endoscopy and colonoscopy Negative upper endoscopy No Gl work-up
Naproxen (N ⫽ 18) Rofecoxib (N ⫽ 9) 4 2 0 1 2 1 1
2 0 2 1 0 0 0
1 3 3
3 0 1
we examined the rates of serious lower GI events related to use of corticosteroid therapy because this is a risk factor for upper GI events in NSAID users. The rate of lower GI events in those using corticosteroid therapy compared with those not taking corticosteroids was not significantly different in the naproxen group (0.99 vs. 0.76; relative risk, 1.29; 95% CI 0.57–2.96) or in the rofecoxib group (0.26 vs. 0.59; relative risk, 0.45; 95% CI 0.13–1.53). Only 1 of the 35 patients with a serious lower GI event also had an upper GI clinical event during the study: a patient on rofecoxib with lower GI bleeding and upper GI bleeding from vascular ectasias. However, all patients with confirmed upper GI events were discontinued from the study per the protocol, and, in most cases (63%), patients with serious lower GI events also had their study medication discontinued. The previously reported rates per 100 patient-years of complicated upper GI events were 1.4 with naproxen and 0.6 with rofecoxib.12 The rates of all serious GI events (complicated upper GI event and serious lower GI event) were 0.96 for rofecoxib and 2.26 per 100 patient-years for naproxen (relative risk, 0.43; 95%CI, 0.27– 0.67; P ⬍ 0.001; number-needed-to-treat, 77). Among patients taking naproxen, serious lower GI events accounted for 39.4% of all serious GI events (0.89 for serious lower GI events/2.26 for all serious GI events). Among patients taking rofecoxib, the proportion was 42.7%.
events occurred at an annualized incidence of 1.4% with naproxen in this study, whereas the incidence of any upper GI clinical event, including uncomplicated ulcers associated with pain or discomfort, was 4.5%.12 Therefore, serious lower GI events may account for a large proportion of GI tract complications in patients taking a nonselective NSAID. The use of the selective COX-2 inhibitor rofecoxib was associated with a 54% relative risk reduction in serious lower GI events. Case control and cohort studies suggest that the use of NSAIDs increases the risk for lower GI complications such as bleeding, perforation, and complicated diverticular disease.2–11 NSAIDs may cause ulcers of the small or large intestine, which occasionally bleed or perforate4 –7; intestinal strictures, which may cause obstruction2; colitis, which may present clinically as bloody diarrhea2; and an enteropathy, which may cause mild chronic blood loss.2 However, lower GI events associated with NSAID use appear more commonly to represent complications of pre-existing diseases such as diverticula, vascular ectasias, and cancer.5–7,9,10 In the large Arthritis, Rheumatism, and Aging Medical Information System data bank of arthritis patients, 32% of all GI hospitalizations in osteoarthritis patients were for lower GI diagnoses, whereas 13% of GI hospitalizations in rheumatoid arthritis patients were for lower GI diagnoses.13 Our prospective study provides support for the concept that lower GI events are relatively common among NSAID users. Lower GI events accounted for approximately 40% of all serious GI events that occurred. Although the rate of lower GI events may be less than the rate of upper GI events, several case-control studies
Discussion This post hoc analysis of a large prospective outcomes study showed that serious lower GI events occurred at an annualized incidence of 0.9% in rheumatoid arthritis patients taking the nonselective NSAID naproxen. By way of comparison, complicated upper GI
Figure 1. Time to serious lower GI clinical events in the naproxen and rofecoxib treatment group. (Incidence expressed as rate of events per 100 patient-years.)
February 2003
suggest that the magnitude of the increase in risk owing to NSAID use is similar for lower GI complications and upper GI complications. Data reported by Lanas et al.5 indicate odds ratios for use of NSAIDs in patients with upper GI bleeding and lower GI bleeding were 10.7 (95% CI, 4.5–26.0) and 18.4 (95% CI, 4.7–51.4), respectively, whereas Wilcox et al.7 reported odds ratios of 3.2 (95% CI, 2.6 – 4.0) for upper GI bleeding and 2.6 (95% CI, 1.7–3.9) for lower GI bleeding. In a study of NSAID use and GI perforation, the odds ratios for upper GI and lower GI perforations were 6.3 (95% CI, 3.1– 12.9) and 8.1 (95% CI, 2.3–31.9), respectively.6 The pathogenesis of NSAID-induced lower GI events is uncertain. Although NSAID enteropathy has been suggested to develop via direct effects of NSAIDs on enterocytes,2 it seems likely that clinical lower GI events occur owing to inhibition of COX-1 and prostaglandin synthesis in the GI tract and platelets. Mucosal injury owing to inhibition of intestinal prostaglandin production could lead to the development of lower GI disease de novo (e.g., ulcers) or could worsen pre-existing GI lesions. The antiplatelet effects of NSAIDs such as naproxen, owing to COX-1 inhibition, also must be considered in the pathogenesis of intestinal bleeding. Inhibition of platelet aggregation could lead to bleeding from GI lesions that are already present or to bleeding from lesions caused by the NSAID. If COX-1 inhibition in the intestine is responsible for mucosal injury, then COX-2 selective inhibitors would be expected to cause less injury than nonselective NSAIDs. In addition, because thromboxane synthesis in platelets is solely COX-1 mediated, COX-2–selective inhibitors such as rofecoxib, which do not inhibit platelet thromboxane synthesis or platelet aggregation,14 should not induce bleeding from GI lesions owing to platelet dysfunction. Previous studies provide support for the concept that inhibition of COX-1 and COX-1–mediated prostaglandin synthesis plays a role in NSAID-induced intestinal injury. Treatment with the prostaglandin analog misoprostol in patients with iron-deficiency anemia caused by NSAID enteropathy (small intestinal ulcers, erosions, or red spots) led to a significant improvement in hemoglobin level,15 and nonselective NSAIDs, but not COX-2– selective agents, significantly increase intestinal permeability.16 The results of our trial along with the results of a placebo-controlled double-blind trial in healthy subjects, which showed that ibuprofen but not rofecoxib significantly increased fecal blood loss,17 also suggest that inhibition of COX-1–mediated prostaglandin production in the intestine and/or platelets is responsible, at
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least in part, for lower GI clinical events in patients taking nonselective NSAIDs. Our data extend only to the 14-day period after the end of NSAID or COX-2 inhibitor therapy. Therefore, we cannot comment on whether the difference in favor of rofecoxib would continue beyond the treatment period. In addition, this was a post hoc analysis of a prospective double-blind trial; the trial was not designed specifically to evaluate lower GI events. For this reason, a large prospective outcomes study designed to examine lower GI events will be required to confirm our findings. In summary, serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib. Based on these results, 208 patients would need to be treated with rofecoxib instead of naproxen to avert a serious lower GI event, and the number-needed-to-treat to avert a serious upper or lower GI event is 77.
References 1. Laine L. Approaches to NSAID use in the high-risk patient. Gastroenterology 2001;120:594 – 606. 2. Bjarnason I, Hayllar H, Macpherson AJ, Russell AS. Side effects of nonsteroidal anti-inflammatory drugs on the small and large intestine in humans. Gastroenterology 1993;104:1832–1847. 3. Langman MJS, Morgan L, Worrall A. Use of anti-inflammatory drugs by patients admitted with small or large bowel perforations and haemorrhage. Br Med J 1985;290:347–349. 4. Allison MC, Howatson AG, Torrance CJ, Lee FD, Russell RI. Gastrointestinal damage associated with the use of nonsteroidal anti-inflammatory drugs. N Engl J Med 1992;327:749 –754. 5. Lanas A, Ssekar MC, Hirschowitz BI. Objective evidence of aspirin use in both ulcer and nonulcer upper and lower gastrointestinal bleeding. Gastroenterology 1992;103:862– 869. 6. Lanas A, Serrano P, Bajador E, Esteva F, Benito R, Sainz R. Evidence of aspirin use in both upper and lower gastrointestinal perforation. Gastroenterology 1997;112:683– 689. 7. Wilcox CM, Alexander LN, Cotsonis GA, Clark WS. Nonsteroidal anti-inflammatory drugs are associated with both upper and lower gastrointestinal bleeding. Dig Dis Sci 1997;42:990 –997. 8. Holt S, Rigoglioso V, Sidhu M, Irshad M, Howden CW, Mainero M. Nonsteroidal anti-inflammatory drugs and lower gastrointestinal bleeding. Dig Dis Sci 1993;38:1619 –1623. 9. Wilson RG, Smith AN, Macintyre IMC. Complications of diverticular disease and non-steroidal anti-inflammatory drugs: a prospective study. Br J Surg 1990;77:1103–1104. 10. Campbell K, Steele RJC. Non-steroidal anti-inflammatory drugs and complicated diverticular disease: a case-control study. Br J Surg 1991;78:190 –191. 11. Aldoori WH, Giovannucci EL, Rimm EB, Wing AL, Willett WC. Use of acetaminophen and nonsteroidal anti-inflammatory drugs: a prospective study and the risk of symptomatic diverticular disease in men. Arch Fam Med 1998;7:255–260. 12. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Bosi Ferraz M, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;343:1520 –1528.
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13. Singh G, Ramey DR. NSAID induced gastrointestinal complications: the ARAMIS perspective—1997. Arthritis, Rheumatism, and Aging Medical Information System. J Rheumatol 1998; 25(Suppl 51):8 –16. 14. Matheson AJ, Figgitt DP. Rofecoxib: a review of its use in the management of osteoarthritis, acute pain and rheumatoid arthritis. Drugs 2001;61:833– 865. 15. Morris AJ, Murray L, Sturrock RD, Madhok R, Capell HA, Mackenzie JF. Short report: the effect of misoprostol on the anaemia of NSAID enteropathy. Aliment Pharmacol Ther 1994;8:343–346. 16. Sigthorsson G, Crane R, Simon T, Hoover M, Quan H, Bolognese J, Bjarnason I. COX-2 inhibition with rofecoxib does not increase intestinal permeability in healthy subjects: a double blind crossover study comparing rofecoxib with placebo and indomethacin. Gut 2000;47:527–532. 17. Hunt RH, Bowen B, Mortensen ER, Simon TJ, James C, Cagliola A, Quan H, Bolognese JA. A randomized trial measuring fecal blood loss after treatment with rofecoxib, ibuprofen, or placebo in healthy subjects. Am J Med 2000;109:201–206.
Received September 24, 2002. Accepted November 7, 2002. Address requests for reprints to: Loren Laine, M.D., GI Division, Department of Medicine, University of Southern California School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033. e-mail: [email protected]; fax: (323) 226-7573. Supported by Merck & Co., Whitehouse Station, New Jersey. Dr. Laine received research support from Merck, and is a consultant for Merck, Pharmacia, Novartis, and Pfizer. Dr. Hawkey has received research funding from AstraZeneca, Alizyme, Boehringer Ingelheim, GlaxoSmithKline, Merck, NicOx, Novartis, and Pfizer. Dr. Schnitzer is a consultant for AstraZeneca, GlaxoSmithKline, McNeil Consumer, Merck, and Novartis, and has received research support from AstraZeneca, Merck, and Novartis. Dr. Bombardier is a consultant for Merck Research Laboratories, Schering Canada, and Wyeth Ayerst Research, has received research grants from Abbott Laboratories (formerly Knoll Pharmaceutical Company), Aventis Pharmaceuticals, and Merck Research Laboratories, and is a member of the Advisory Board for Abbot Laboratories, Bristol-Myers Squibb Company, and Merck Frosst Canada.
Murphy of Murphy’s Sign John Benjamin Murphy (1857–1916) was born in Appleton, Wisconsin, the son of Irish immigrant pioneers. Awarded his M.D. degree by the Rush Medical College in 1879, his scholastic record entitled him to a coveted internship at the Cook County Hospital. A 2-year sojourn in Europe included study with the famed Viennese surgeon Theodor Billroth (1829 –1894). On his return to Chicago, he served on the surgical faculties of his alma mater and at Northwestern University. Acknowledged as a brilliant surgeon and innovator, his flamboyant character occasionally embroiled him in controversy. He was among the first to advocate early operation for acute appendicitis, as well as surgical collapse of the lung in cases of unilateral pulmonary tuberculosis. Tenderness below the right costal margin on inspiration as an indication of acute cholecystitis is known as Murphy’s sign. The Murphy button was a double, circular clip for end-to-end intestinal anastomosis; controversial in its day, it later led to development of devices that obviated certain risks of conventional suture technique. —Contributed by WILLIAM S. HAUBRICH, M.D. Scripps Clinic and Research Foundation, La Jolla, California
Copyright holder unknown. Photo obtained from the National Library of Medicine Website (http://www.nlm.nih.gov).