Loren Laine

Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis

BACKGROUND Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. METHODS We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). RESULTS Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed gastrointestinal events per 100 patient-years occurred with rofecoxib, as compared with 4.5 per 100 patient-years with naproxen (relative risk, 0.5; 95 percent confidence interval, 0.3 to 0.6; P<0.001). The respective rates of complicated confirmed events (perforation, obstruction, and severe upper gastrointestinal bleeding) were 0.6 per 100 patient-years and 1.4 per 100 patient-years (relative risk, 0.4; 95 percent confidence interval, 0.2 to 0.8; P=0.005). The incidence of myocardial infarction was lower among patients in the naproxen group than among those in the rofecoxib group (0.1 percent vs. 0.4 percent; relative risk, 0.2; 95 percent confidence interval, 0.1 to 0.7); the overall mortality rate and the rate of death from cardiovascular causes were similar in the two groups. CONCLUSIONS In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.

Clopidogrel with or without Omeprazole in Coronary Artery Disease

BACKGROUND Gastrointestinal complications are an important problem of antithrombotic therapy. Proton-pump inhibitors (PPIs) are believed to decrease the risk of such complications, though no randomized trial has proved this in patients receiving dual antiplatelet therapy. Recently, concerns have been raised about the potential for PPIs to blunt the efficacy of clopidogrel. METHODS We randomly assigned patients with an indication for dual antiplatelet therapy to receive clopidogrel in combination with either omeprazole or placebo, in addition to aspirin. The primary gastrointestinal end point was a composite of overt or occult bleeding, symptomatic gastroduodenal ulcers or erosions, obstruction, or perforation. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, revascularization, or stroke. The trial was terminated prematurely when the sponsor lost financing. RESULTS We planned to enroll about 5000 patients; a total of 3873 were randomly assigned and 3761 were included in analyses. In all, 51 patients had a gastrointestinal event; the event rate was 1.1% with omeprazole and 2.9% with placebo at 180 days (hazard ratio with omeprazole, 0.34, 95% confidence interval [CI], 0.18 to 0.63; P<0.001). The rate of overt upper gastrointestinal bleeding was also reduced with omeprazole as compared with placebo (hazard ratio, 0.13; 95% CI, 0.03 to 0.56; P = 0.001). A total of 109 patients had a cardiovascular event, with event rates of 4.9% with omeprazole and 5.7% with placebo (hazard ratio with omeprazole, 0.99; 95% CI, 0.68 to 1.44; P = 0.96); high-risk subgroups did not show significant heterogeneity. The two groups did not differ significantly in the rate of serious adverse events, though the risk of diarrhea was increased with omeprazole. CONCLUSIONS Among patients receiving aspirin and clopidogrel, prophylactic use of a PPI reduced the rate of upper gastrointestinal bleeding. There was no apparent cardiovascular interaction between clopidogrel and omeprazole, but our results do not rule out a clinically meaningful difference in cardiovascular events due to use of a PPI. (Funded by Cogentus Pharmaceuticals; ClinicalTrials.gov number, NCT00557921.).

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials

Summary Background The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14–1·66; p=0·0009) or diclofenac (1·41, 1·12–1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31–2·37; p=0·0001; diclofenac 1·70, 1·19–2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10–4·48; p=0·0253), but not major vascular events (1·44, 0·89–2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69–1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56–6·41; p=0·17), but not by naproxen (1·08, 0·48–2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17–2·81, p=0·0070; diclofenac 1·89, 1·16–3·09, p=0·0106; ibuprofen 3·97, 2·22–7·10, p<0·0001; and naproxen 4·22, 2·71–6·56, p<0·0001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. Funding UK Medical Research Council and British Heart Foundation.

Endoscopic Ligation Compared with Sclerotherapy for Treatment of Esophageal Variceal Bleeding: A Meta-Analysis

Esophageal varices are the site of bleeding in as many as 30% of all patients presenting with upper gastrointestinal tract hemorrhage [1]. Patients with variceal bleeding fare poorly; they have higher rates of rebleeding, complications, and death than patients with bleeding from nonvariceal sources [2]. Early endoscopy is used to identify the source of bleeding, and, when varices are present, the use of endoscopic sclerotherapy decreases further bleeding [3-6]. Long-term treatment with repeated sessions of sclerotherapy significantly decreases rebleeding, and some reports state that it leads to improved survival [5-8]. However, rebleeding is still common in patients receiving sclerotherapy. The injection of sclerosing agents, moreover, induces various local and systemic complications [7, 9]. Ligation, which is a newer form of endoscopic treatment for variceal bleeding, was developed in an attempt to provide an endoscopic therapy that would be at least as effective as sclerotherapy but that would have fewer complications [9-11]. Endoscopic variceal ligation is based on the widely used technique of rubber-band ligation of hemorrhoids. The esophageal mucosa and submucosa, containing varices, are ensnared, causing subsequent strangulation, sloughing, and eventual fibrosis, and resulting in the obliteration of the varices [9-11]. Randomized trials comparing endoscopic variceal ligation with sclerotherapy suggest that ligation is at least as effective as sclerotherapy [12-14]. However, significant differences in favor of ligation for outcomes such as rebleeding and mortality have not been consistently documented. To critically appraise and synthesize the current evidence on endoscopic ligation for esophageal variceal bleeding, we did a meta-analysis of the results of randomized clinical trials that compared endoscopic ligation with sclerotherapy. Methods Data Identification Both of us separately did a computerized bibliographic search of research (MEDLINE, National Library of Medicine, Bethesda, Maryland) published from 1983 onward using the keywords varices and ligation; an additional search using the keywords varices and band was also done. We identified frequently cited references and used SCISEARCH (Scientific Citation Index on-line, Institute for Scientific Information, Philadelphia, Pennsylvania) to locate additional studies that cited these articles. We also scanned the reference lists of all articles obtained to identify additional research not found in the computerized bibliographic database searching. Strategies used to obtain unpublished material included searching Federal Research in Progress (National Technical Information Service, Springfield, Virginia), NTIS (National Technical Information Service, Springfield, Virginia), Conference Papers Index (Cambridge Scientific Abstracts, Bethesda, Maryland), and BIOSIS Previews (Biosciences Information Service, Philadelphia, Pennsylvania). We also communicated with the manufacturer of the ligation device (Bard Interventional Products, Tewksbury, Massachusetts) and with investigators in the field of variceal hemorrhage, and we reviewed abstracts from national meetings (1988 to May 1994) of the American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, the American College of Gastroenterology, and the American Association for the Study of Liver Diseases. Selecting Research We independently reviewed the titles and abstracts of all studies and retrieved all articles that met the following inclusion criteria: 1) The study was a randomized comparison of endoscopic ligation and sclerotherapy; 2) the target population was composed of patients with esophageal variceal bleeding; and 3) outcome measures were rebleeding, mortality, complications, or treatment sessions to obliteration. We again applied these same criteria independently to the full text of articles that had passed the first eligibility screening to make a final selection of the studies to be included in the overview. Methodologic Quality Assessment and Data Collection The criteria used to assess the methodologic quality of the primary articles are listed in Table 1. Each study received a score based on specifications of the population, intervention, and outcome measures. Total methodologic quality scores were then used to rank studies. We independently did methodologic quality assessment and data abstraction, and disagreement was resolved by consensus. We recorded data in terms of number of patients rather than number of events, and solicited missing or ambiguous data from the authors of the studies. A copy of the completed methodologic quality assessment and data abstraction forms were sent to the corresponding author of each study, who was asked to correct erroneous assessments and provide missing information. We asked authors of abstracts to provide full information about methods and updated results. Table 1. Methodologic Quality Assessment* Data Analysis The statistic with quadratic weights was used to measure agreement between coders for research selection and validity assessment [15]; the degree of agreement rather than the presence or absence of agreement is captured by this method. The odds ratio (OR) was the measure of association used in this meta-analysis. The Breslow-Day method was used to test for homogeneity under the null hypothesis that the ORs were consistent across studies, and the corrected Mantel-Haenszel chi-square test (1 degree of freedom, two-tailed) was used to test whether the ORs differed systematically from a value of 1. The software used was OR2 2 x ka (Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario). To avoid problems of biased or unstable estimators when data were sparse, a modification of the Mantel-Haenszel technique (adding 0.5 to each cell when any cell in the category contained zero) was used to estimate the common OR [16, 17]. A priori, we developed four hypotheses to identify potential differences in treatment across studies. First, we proposed that study results might be related to study quality. Hence, a separate analysis was planned to compare the effect of treatment in studies with an overall methodologic quality score of at least 8 with the effect of treatment in studies with a score of less than 8. The cutoff point of 8 was chosen as the midpoint in the scoring system. Second, we considered that patients with different causes of liver disease might derive different benefits from ligation therapy. Therefore, we planned a separate analysis for studies in which at least 75% of the patients had alcoholic cirrhosis and studies in which fewer than 75% of the patients had alcoholic liver disease. Third, we reasoned that patients might have different baseline risks for rebleeding, complications, and death based on the severity of their liver disease. Therefore, we did a separate analysis of studies in which at least 40% of patients had Child C liver disease and studies in which fewer than 40% of patients had Child C liver disease. Fourth, we questioned whether the results presented in fully published manuscripts would differ systematically from results presented only in abstract form. Hence, we also did a subgroup analysis for those studies published in full and those published only as abstracts. Results Study Selection Computerized bibliographic searches identified 158 articles. Overall, 7 randomized trials [12-14, 18-21] involving 547 patients met the inclusion criteria (Table 2). Four were published in full in peer-reviewed journals [12-14, 20], and 3 were published in abstract form [18, 19, 21]. Agreement between reviewers for the selection of relevant articles was 100%. Data from the 7 individual studies for specific outcome measures are provided in Appendix Table 1. We excluded 2 studies [22, 23] that were reported to be randomized, controlled trials comparing ligation with sclerotherapy for the treatment of esophageal varices. Hashizume and colleagues [22] randomly assigned patients who did not present with bleeding to ligation or sclerotherapy at the initial session, and then all patients received sclerotherapy at 1-week intervals. Avgerinos and coworkers [23] did sclerotherapy on all patients at the time of initial hemorrhage and then assigned patients to receive either ligation or sclerotherapy at subsequent treatment sessions. Table 2. Design of Randomized Trials Comparing Ligation and Sclerotherapy for the Treatment of Bleeding Esophageal Varices Methodologic Quality Assessment and Data Collection Chance-corrected agreement for the methodologic quality assessment yielded values of 0.8 to 0.9. Six of the seven authors (including the authors of all three abstracts) provided corroborative, corrective, or missing information [12, 13, 18-21], which was used in the analysis. Selected design details for individual trials are outlined in Table 2. Methodologic quality scores ranged from 7 to 12 on a scale of 0 to 16. Health care workers caring for the patients were blinded to treatment in only one trial [18], and the assessment of rebleeding and other variables was unblinded in all trials. The study population is described in Table 3. The mean age ranged from 46 to 56 years, and more than 99% of patients had cirrhosis [12, 13, 18-21]. The proportion of patients with alcoholic cirrhosis ranged from 23% to 100%, and the proportion with Child C liver disease ranged from 19% to 78% (Table 3). The mean follow-up period, when specified, ranged from 295 to 337 days [13, 14, 19]. In the five studies that reported having patients lost to follow-up, 7% of the ligation group and 8% of the sclerotherapy group were lost to follow-up [12, 14, 19-21]. Table 3. Patient Characteristics in Randomized Trials Comparing Sclerotherapy and Ligation for the Treatment of Bleeding Esophageal Varices Sodium tetradecyl sulfate (1% to 1.5% final dilution) was used as the primary sclerosing agent in five studies [12,

ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy.

PURPOSE We have previously shown that relative thymidylate synthase (TS) mRNA levels in primary gastric adenocarcinomas treated with fluorouracil (5-FU) and cisplatin are inversely associated with response and survival. This is a presumed function of TS as a target for 5-FU activity. We now test the hypotheses that the relative mRNA level of the excision repair cross-complementing (ERCC1) gene is inversely associated with response and survival as an independent function of cisplatin efficacy. PATIENTS AND METHODS Patients had intact, untreated, primary gastric adenocarcinoma cancer and were evaluated for eligibility on a preoperative cisplatin infusion-5-FU protocol. cDNA, derived from primary gastric tumors before chemotherapy, was used to determine ERCC1 mRNA levels, expressed as the ratio of polymerase chain reaction (PCR) product of the ERCC1 gene and the beta-actin gene. RESULTS The median ERCC1 mRNA level from 38 primary gastric cancers (33 assessable for response) was 5.8 x 10(-3) (range, 1.8 x 10(-3) to 19.5 x 10(-3)). Of 17 responding patients, 13 (76%) were less than or equal to 5.8 x 10(-3) and four were greater than 5.8 x 10(-3) (P = .003). The median survival for patients with ERCC1 mRNA levels less than or equal to 5.8 x 10(-3) has not been reached, whereas for those greater than 5.8 x 10(-3) it was 5.4 months (P = .034). The median TS mRNA level, 3.7 x 10(-3) (range, 0.9 to 18.9) also segregated responsive versus resistant tumors (P = .024). With both ERCC1 and TS mRNA levels below their medians, 11 of 13 patients (85%) responded; with both ERCC1 and TS mRNA levels above their medians, two of 10 patients (20%) responded (P = .003). CONCLUSION Considered separately, either ERCC1 or TS mRNA levels in a primary gastric adenocarcinoma has a statistically significant relationship to response. ERCC1 mRNA levels have a statistically significant association with survival; in this cohort TS mRNA levels did not reach statistically significant association with survival as in our previous publication. Whether these molecular parameters are independent of each other as predictors of outcome remains to be determined.

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

BACKGROUND & AIMS Prostaglandin production in the normal gastrointestinal tract, believed to be critical for mucosal integrity, is mediated by cyclooxygenase (COX)-1, whereas prostaglandin production at inflammatory sites seems to occur via induction of COX-2. We hypothesized that COX-2-specific inhibition with rofecoxib (25 mg once daily) in the treatment of patients with osteoarthritis would cause fewer gastroduodenal ulcers than an equally effective dose of ibuprofen (800 mg 3 times a day), a nonspecific COX inhibitor. METHODS A total of 742 osteoarthritis patients without ulcers on baseline endoscopy were randomly assigned to receive rofecoxib (25 or 50 mg once daily), ibuprofen (800 mg 3 times daily), or placebo. Endoscopy was repeated at 6, 12, and 24 weeks. At 16 weeks, by study design, 95% of the placebo group and 5% of the other groups were discontinued. RESULTS The cumulative incidence of gastroduodenal ulcers >/=3 mm with rofecoxib (25 or 50 mg once daily) was significantly (P < 0.001) lower than with ibuprofen and was statistically equivalent to placebo at week 12 (placebo, 9.9%; 25 mg rofecoxib, 4.1%; 50 mg rofecoxib, 7.3%; and ibuprofen, 27.7%). At 24 weeks, ulcer rates were 25 mg rofecoxib, 9. 6%; 50 mg rofecoxib, 14.7%; and ibuprofen, 45.8% (P < 0.001, ibuprofen vs. 25 and 50 mg rofecoxib). CONCLUSIONS Rofecoxib, at doses 2-4 times the dose demonstrated to relieve symptoms of osteoarthritis, caused significantly less gastroduodenal ulceration than ibuprofen, with ulcer rates comparable to placebo.

Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

BACKGROUND Cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials, but no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. METHODS We designed a prespecified pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). The primary hypothesis stated that etoricoxib is not inferior to diclofenac, defined as an upper boundary of less than 1.30 for the 95% CI of the hazard ratio for thrombotic cardiovascular events in the per-protocol analysis. Intention-to-treat analyses were also done to assess consistency of results. These trials are registered at http://www.clinicaltrials.gov with the numbers NCT00092703, NCT00092742, and NCT00250445. FINDINGS 34 701 patients (24 913 with osteoarthritis and 9 787 with rheumatoid arthritis) were enrolled. Average treatment duration was 18 months (SD 11.8). 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 (95% CI 0.81-1.11) for etoricoxib compared with diclofenac. Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac (0.67 vs 0.97 per 100 patient-years; hazard ratio 0.69 [0.57-0.83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0.30) and diclofenac (0.32). INTERPRETATION Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.

Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival.

PURPOSE We tested the hypothesis that polymerase chain reaction (PCR) quantitation of the enzyme thymidylate synthase (TS) within a primary adenocarcinoma of the stomach, has an inverse relationship to response and survival for patients who receive fluorouracil (5FU)-based chemotherapy. PATIENTS AND METHODS Before systemic chemotherapy, the genetic expression of TS (TSmRNA level) was determined using a PCR method. Gene expression was calculated by determining the ratio between the amount of radiolabeled PCR product with the linear amplification range of the TS gene and the beta-actin gene. Chemotherapy consisted of two cycles of protracted infusion (PI) 5FU 200 mg/m2/d administered for 3 weeks with leucovorin 20 mg/m2/w. Cisplatin 100 mg/m2 was administered on day 1. RESULTS Sixty-five patients with primary gastric cancer had a median TS mRNA level of 4.6 x 10(-3) (range, 0.9 to 20.1 x 10(-3)). Thirty-five percent of patients had measurable responses in their primary tumors. The mean gastric cancer TSmRNA level in responding and resistant patients is statistically significant (P < .001). The median survival time was 43+ months for treated patients with TSmRNA levels less than the median and 6 months for those with TS m-RNA levels greater than the median (P = .003). CONCLUSION The genetic expression of TS (TSmRNA level) influences response to 5FU-based chemotherapy and survival for a cohort of patients with primary gastric cancer. Confirmation of these data could lead to therapeutic decisions based on specific molecular properties within a tumor.

Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: A randomized, double‐blind, placebo‐controlled trial

OBJECTIVE This randomized, double-blind study tested the hypothesis that rofecoxib, a drug that specifically inhibits cyclooxygenase 2, would cause fewer gastroduodenal ulcers than ibuprofen (in a multicenter trial), and its side effects would be equivalent to those of placebo (in a prespecified analysis combining the results with another trial of identical design). METHODS Seven hundred seventy-five patients with osteoarthritis were randomized to receive rofecoxib at a dosage of 25 mg or 50 mg once daily, ibuprofen 800 mg 3 times daily, or placebo. Gastroduodenal ulceration was assessed by endoscopy at 6, 12, and (for active treatment) 24 weeks. The primary and secondary end points were the incidence of gastroduodenal ulcers at 12 and 24 weeks, respectively. RESULTS Ulcers were significantly less common (P < 0.001) following treatment with rofecoxib (25 mg or 50 mg) than with ibuprofen after 12 weeks (5.3% and 8.8% versus 29.2%, respectively) or 24 weeks (9.9% and 12.4% versus 46.8%, respectively). In the combined analysis, the 12-week ulcer incidence with 25 mg rofecoxib (4.7%) and with placebo (7.3%) satisfied prespecified criteria for equivalence. CONCLUSION At 2-4 times the therapeutically effective dose, rofecoxib caused fewer endoscopically detected ulcers than did ibuprofen. Rofecoxib at a dose of 25 mg (the highest dose recommended for osteoarthritis) satisfied prespecified criteria for equivalence to placebo.

A systematic review and meta-analysis of randomized, controlled trials of moderate sedation for routine endoscopic procedures.

BACKGROUND Numerous agents are available for moderate sedation in endoscopy. OBJECTIVE Our purpose was to compare efficacy, safety, and efficiency of agents used for moderate sedation in EGD or colonoscopy. DESIGN Systematic review of computerized bibliographic databases for randomized trials of moderate sedation that compared 2 active regimens or 1 active regimen with placebo or no sedation. PATIENTS Unselected adults undergoing EGD or colonoscopy with a goal of moderate sedation. MAIN OUTCOME MEASUREMENTS Sedation-related complications, patient assessments (satisfaction, pain, memory, willingness to repeat examination), physician assessments (satisfaction, level of sedation, patient cooperation, examination quality), and procedure-related efficiency outcomes (sedation, procedure, or recovery time). RESULTS Thirty-six studies (N = 3918 patients) were included. Sedation improved patient satisfaction (relative risk [RR] = 2.29, range 1.16-4.53) and willingness to repeat EGD (RR = 1.25, range 1.13-1.38) versus no sedation. Midazolam provided superior patient satisfaction to diazepam (RR = 1.18, range 1.07-1.29) and less frequent memory of EGD (RR = 0.57, range 0.50-0.60) versus diazepam. Adverse events and patient/physician assessments were not significantly different for midazolam (with or without narcotics) versus propofol except for slightly less patient satisfaction (RR = 0.90, range 0.83-0.97) and more frequent memory (RR = 3.00, range 1.25-7.21) with midazolam plus narcotics. Procedure times were similar, but sedation and recovery times were shorter with propofol than midazolam-based regimens. LIMITATIONS Marked variability in design, regimens tested, and outcomes assessed; relatively poor methodologic quality (Jadad score </=3 in 23/36 trials). CONCLUSIONS Moderate sedation provides a high level of physician and patient satisfaction and a low risk of serious adverse events with all currently available agents. Midazolam-based regimens have longer sedation and recovery times than does propofol.