Gastrointestinal Outcomes Research Articles

Selective Cyclooxygenase-2 Inhibitors Development in Cardiovascular Medicine

At the end of September 2004, Merck & Co announced the voluntary withdrawal of rofecoxib (Vioxx) worldwide because of an increased risk of cardiovascular events. Since its approval in 1999, Vioxx, a selective cyclooxygenase-2 (COX-2) inhibitor, has been Merck & Co’s leading drug for control of acute pain and chronic pain associated with osteoarthritis, rheumatoid arthritis, and menstruation. Last year, worldwide sales of rofecoxib reached US $2.5 billion, and it is estimated that the drug was prescribed ≈10 million times per month in the United States.1 Thus, given the number of patients involved and the serious nature of the side effects, the withdrawal raised serious concerns about the safety of other selective COX-2 inhibitors, collectively called coxibs, that are on the market and those currently under development. Celecoxib (Celebrex) and rofecoxib were the first 2 coxibs approved by the US Food and Drug Administration (FDA) and launched in 1999 by Pfizer and Merck & Co, respectively. Since then, a second generation of these drugs has emerged onto the market. Valdecoxib (Bextra) was approved by the FDA and launched in 2002. In that same year, the European regulatory authority approved 2 other coxibs: etoricoxib (Arcoxia) and parecoxib sodium (Dynastat), the prodrug of valdecoxib. Today, etoricoxib and a fifth coxib, lumiracoxib (Prexige), are under consideration for FDA approval. In view of the rapid development in this area, the main concern is whether the reported cardiovascular effects of rofecoxib are a class effect applicable to all coxibs that were initially designed to reduce the gastric toxicity of nonselective COX inhibitors. Although most of the data accumulated so far would suggest a class effect related to the general mode of action of all coxibs and the physiological role of COX-2, recent in vitro data would theoretically support the hypothesis that the cardiovascular side …

238 Gastrointestinal Outcomes in a Randomised Controlled Trial of Pre-Emptive Morphine Analgesia in Preterm Infants

Objectives: To study the gastrointestinal (GI) side-effects of morphine and the epidemiology of feeding and GI morbidity in preterm infants.Background: Morphine slows gut motility, a key to the advancement of enteral feeds in preterm infants. Morphine may thus increase the risk of meconium inspissation and necrotising enterocolitis, and of complications related to parenteral feeding.Methods: A post-hoc analysis was done of babies in the NEOPAIN trial, a double-blind. randomised controlled trial of pre-emptive morphine (M) or placebo (Pl) in ventilated preterm infants. A loading dose (100μg/kg of morphine) was followed by an infusion for up to 14 days at a gestation-dependent dose (10–30μg/kg/hr). Open-label morphine bolus (A) could be given if clinically indicated.Subjects: There were 449 babies in each group. The gestations in weeks (median, range) were: 27, 23–32 for both groups. Birthweights in grams (median, range) were: M 984, 452-2030; Pl 985, 420-2440. The number of babies receiving A (no., %): M 201, 45; Pl 242, 55.Results: Group M was later at starting feeds [S] (median, quartiles): M 5, 3–8; Pl 4, 2–7; P=0.02, and attaining full feeds [F]: M 20, 13–29; Pl 17, 12–26; P=0.003. There was a weak correlation between total dose of morphine (TDM) and these outcomes: For S rsq.=0.12, P<0.001; for F rsq.=0.07, P<0.001. There was no relationship between morphine and GI complications (necrotising enterocolitis or intestinal obstruction): M 9/449, Pl 8/449; Chi sq. P=0.81. On multivariate analysis, S was independently associated with centre (P=0.03), the use of an umbilical venous catheter (P<0.001) and TDM (P<0.001), and F with birthweight (P=0.005), hypotension (P=0.04), Neonatal Medical Index (a morbidity score, P=0.001), and TDM (P=0.001).Conclusions: Morphine delays the attainment of full enteral feeds, but does not increase GI complications. Ages of starting and full feeds are associated with morphine dose, but are influenced by several other factors.

FDA’s drug safety initiative: Resolutions or more questions?

The storm of controversy surrounding the safety of antidepressants and nonsteroidal antiinflammatory drugs (NSAIDs) is part of a normal cycle that hits FDA every few years, Steven K. Galson, acting director of the Center for Drug Evaluation and Research (CDER), told agency employees, industry stakeholders, and news reporters during a May 20 webcast. Galson and other top FDA officials defended the agency’s actions in dealing with postmarketing reports of cardiovascular events associated with the use of cyclooxygenase-2 (COX-2)-selective NSAIDs, specifically Merck’s rofecoxib, or Vioxx, and Pfizer’s valdecoxib, sold as Bextra—both no longer on the market—and an increased risk of suicidal thoughts and behavior in pediatric patients using antidepressants. A cloud of controversy has loomed over FDA throughout the past year after lawmakers and other critics condemned the agency for being too slow to warn the public about risks linked to NSAIDs and antidepressants. John K. Jenkins, director of FDA’s Office of New Drugs, maintained that regulators in 2002 “thought we were going through the process of making sure that the public was aware” of the risks of using rofecoxib after FDA asked Merck to add information to the drug’s labeling reflecting the findings of the Vioxx Gastrointestinal Outcomes Research study, which found an increased risk of serious cardiovascular events.

Valdecoxib Withdrawal Leaves Pain Relief Treatment Gap

Valdecoxib Withdrawal Leaves Pain Relief Treatment Gap

Analysis of influence of age on acute and chronic radiotherapy toxicity in treatment of prostate cancer

Objectives To provide a single-institution analysis of the influence of age on acute and late genitourinary (GU) and gastrointestinal (GI) toxicity after radiotherapy (RT) administered in different prostate cancer scenarios. Improved understanding of the influence of age on toxicity outcome after RT for prostate cancer can assist in treatment decision-making. Methods The records of 527 consecutive nonmetastatic patients receiving RT at a single institution and for whom demographic, disease, treatment, and follow-up information were available were reviewed. The cohort was divided into four major categories as a function of age: younger than 60 years, 60 to 69 years, 70 to 74 years, and 75 years and older. The toxicity rates in each of these categories were tabulated according to the Radiation Therapy Oncology Group toxicity scales and compared using the chi-square test. Additionally, an ordered logit regression analysis was performed for each of these categories using all major patient, disease, and treatment factors. Results The toxicity rates were not significantly different as a function of age for either acute GU ( P = 0.10) or acute GI ( P = 0.19) toxicity or for either late GU ( P = 0.22) or late GI ( P = 0.09) toxicity. The ordered logit regression analysis showed that age was not a factor that correlated with toxicity in any setting (acute GU, P = 0.44; acute GI, P = 0.55; late GU, P = 0.65; late GI, P = 0.14). Conclusions Patient age did not independently influence GI or GU toxicity after RT for nonmetastatic prostate cancer and should not be used as an independent factor in treatment decision-making or in patient counseling with regard to GI and GU toxicity outcomes after RT.

Celecoxib associated with lower rate of renal dysfunction compared to nonspecific inhibitor NSAIDs

Both the COX-1 and COX-2 isoforms are expressed by the human kidney and vasculature. Therefore, it is important to evaluate the renovascular effects of COX-2 specific inhibitors and NSAIDs, particularly in patients with preexisting renal dysfunction. The Celecoxib Long-term Arthritis Safety Study (CLASS) assessed gastrointestinal outcomes associated with supratherapeutic doses of the COX-2 specific inhibitor celecoxib (400mg bid), and standard doses of NSAIDs, ibuprofen (800mg tid) and diclofenac (75mg bid), in patients with rheumatoid arthritis (RA) or osteoarthritis (OA). The trial's full database provided a large cardiorenal database for studying renal-related adverse events associated with nonspecific NSAIDs and celecoxib. Complete methods and gastrointestinal and cardiovascular results are published elsewhere. Enrolled patients had a serum creatinine ≤1.5mg/dL reflecting normal renal function. Renal function was assessed in all patients including those with mild prerenal azotemia defined by a baseline blood urea nitrogen (BUN) level of >20mg/dL. The renovascular effects measured in these patients were clinically important reductions in renal function (defined as an increase in serum creatinine >0.5mg/dL from baseline) and mean serum creatinine/estimated creatinine clearance. In patients with mild prerenal azotemia significantly fewer patients taking celecoxib exhibited clinically important reductions in renal function (3.4%) compared with either diclofenac (8.3%;P ≤0.05) or ibuprofen (7.7%;P ≤0.05). In patients with mild renal compromise, celecoxib was associated with a significantly lower rate of renal dysfunction at supratherapeutic doses compared with diclofenac and ibuprofen at standard doses. These data suggest that celecoxib may be a more suitable alternative to treat chronic pain and inflammation than nonspecific NSAIDs in patients with compromised renovascular function. (See Table) *P ≤ 0.05; ANCOVA, Fisher's exact test *P ≤ 0.05; ANCOVA, Fisher's exact test

ICES Report: The Changing Landscape for COX-2 Inhibitors: A Summary of Recent Events

The announcement on September 30, 2004 of the withdrawal of Merck & Co.’s Vioxx® (rofecoxib) from the international market sent shock waves throughout the medical community and instigated a public outcry over the current regulatory approach to monitoring drug safety (Horton 2004). The events leading up to the largest drug withdrawal in history certainly warrant discussion. Vioxx® belongs to a relatively new type of non-steroidal anti inflammatory drugs (NSAIDs) known as cyclooxygenase (COX)-2 inhibitors. NSAIDs are commonly used to manage pain and inflammation associated with acute conditions, such as sports injuries, and chronic conditions, such as arthritis. Approximately one in four elderly people use these drugs. While COX-2 inhibitors offer similar levels of pain relief relative to older, traditional NSAIDs, they are marketed as possessing lower rates of adverse gastrointestinal effects. The publication of a large randomized controlled trial in November 2000 convincingly demonstrated a favourable gastrointestinal adverse event profile associated with Vioxx® compared to a commonly used traditional NSAID, Naprosyn® (naproxen). A 50% relative risk reduction in serious gastrointestinal outcomes was observed among Vioxx® users relative to Naprosyn (Bombardier et al. 2000). However, in a secondary analysis of general safety, the same clinical trial also suggested a five fold increased risk of heart attack associated with Vioxx® relative to Naprosyn. Consequently, this prompted numerous systematic reviews and observational studies, the results of which further supported a possible adverse cardiovascular effect of Vioxx®, and were published long before Vioxx’s® withdrawal from the market. Despite this mounting evidence, Vioxx® was not withdrawn until the interim results of a second large randomized controlled trial demonstrated an associated increased cardiovascular risk with the drug; this withdrawal of Vioxx® occurred about four years after the first clinical trial suggested cardiovascular risk. Allegations that the cardiovascular risks associated with Vioxx® were suspected by Merck scientists well before the launch of Vioxx® – as early as 1996 (Lenzer 2004) – have cast serious doubts on the ethical conduct of the pharmaceutical industry and its relationship with the Food and Drug Administration (FDA) of the United States, the federal drug regulatory body. The Vioxx® withdrawal created a common state of confusion about alternative treatments for frustrated patients and prescribing physicians. At this point, the evidence supporting the use of alternative treatments to Vioxx® varies significantly. Alternatives to Vioxx® include treatment with other drugs marketed as COX-2 inhibitors in Canada, such as Celebrex® (celecoxib), BextraTM (valdecoxib) and Mobic® (meloxicam); traditional NSAIDs, such as Naprosyn® and Advil® (ibuprofen); topical NSAIDs, such as Pennsaid® (topical diclofenac) for limited joint pain; alternative therapies, such as Lakota®; and non-drug therapies, such as weight-bearing exercise, knee taping and acupuncture. A first choice for many physicians was to switch patients to Celebrex®, as the overwhelming majority of evidence from large comparative studies suggested no excess cardiovascular risk with exposure to commonly used doses.

Risk of cardiovascular events and rofecoxib: Cumulative meta-analysis

Summary Background The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. Methods We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. Findings We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2·30 (95% CI 1·22–4·33, p=0·010), and 1 year later (64 events, 21432 patients) it was 2·24 (1·24–4·02, p=0·007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0·41) or trial duration (p=0·82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0·86 [95% CI 0·75–0·99]) and could not have explained the findings of the VIGOR trial. Interpretation Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.

COX-2 Inhibitors — Lessons in Drug Safety

Approximately six years after the cyclooxygenase-2 (COX-2) inhibitors were approved for use in the United States, the results of three randomized, placebo-controlled trials provide new evidence about the cardiovascular risks of rofecoxib, celecoxib, and valdecoxib.13 The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial, a study of patients with a history of colorectal adenomas, was stopped early because rofecoxib doubled the risk of major cardiovascular events (relative risk, 1.92; 95 percent confidence interval, 1.19 to 3.11). These findings confirmed the increased risk of myocardial infarction previously seen in the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial4 and some observational studies.5 The . . .

Cardiovascular Risks of Cyclooxygenase-2 Inhibitors: Where We Stand Now

The authors believe that cyclooxygenase-2 (COX-2) inhibitors, in particular at higher dosages and for longer-term use, should not be a first-line therapy for patients who can tolerate alternative t...

Are All COX-2 Inhibitors Created Equal?

Prostaglandins (PGs) are biologically active lipids derived from the cyclooxygenase (COX)-mediated metabolism of arachidonic acid. They are constitutively produced in certain tissues (eg, brain, gut, and kidney), and their synthesis is increased at sites of inflammation. Prostanoids function as important mediators of inflammation and modulate a variety of physiological processes, including maintenance of gastric mucosal integrity, renal hemodynamic regulation, renin synthesis and release, and tubular reabsorption of salt and water.1 Cyclooxygenase, or PG synthase G2/H2, is the rate-limiting enzyme responsible for the initial conversion of arachidonic acid to PGG2 and subsequently to PGH2. PGH2 is then metabolized by tissue-specific isomerases to produce prostaglandins and thromboxanes. There are 2 distinct isoforms of cyclooxygenase, COX-1 and COX-2, which share 66% homology in amino acid sequence 2–4 but have different patterns of expression and regulation. COX-1, traditionally termed the “constitutive” enzyme, is widely distributed in tissues, and its level of activity is not dynamically regulated. COX-2, the glucocorticoid-sensitive “inducible” enzyme, is more restricted in its basal expression and is upregulated in response to inflammation, resulting in increased prostanoid production at the site of inflammation. NSAIDs, which block both isoforms COX-1 and COX-2, have been widely used in the treatment of inflammatory conditions. However, the adverse effects of NSAIDs, especially gastrointestinal toxicity, have limited their long-term use in clinical settings. The hypothesis that NSAID-induced gastrointestinal toxicity was related to the inhibition of gastric COX-1, whereas the anti-inflammatory properties caused by COX-2 inhibition5 led to the development of the new antiinflammatory agents, the coxibs, which were designed to inhibit COX-2 selectively. It was anticipated that these selective COX-2 inhibitors would be as effective as the nonselective NSAIDs in the treatment of inflammatory diseases but would be better-tolerated with fewer gastrointestinal side effects. Rofecoxib (Vioxx) and celecoxib (Celebrex) were the first COX-2–selective inhibitors to be marketed as effective antiinflammatory agents without serious gastrointestinal toxicity, based on the results of the VIoxx Gastrointestinal Outcomes Research (VIGOR) trial6 and the Celecoxib Long term Arthritis Safety Study (CLASS) trial, 7 respectively. The VIGOR trial reported that patients with rheumatoid arthritis receiving rofecoxib (50 mg daily) had fewer gastrointestinal events compared with those taking naproxen (500 mg twice daily) (2.1% versus 4.5%; P0.001), but there was similar efficacy between the drugs. However, the incidence of myocardial infarction was increased by a factor of 5 in the rofecoxib-treated group compared with the naproxen group. In the CLASS trial, celecoxib (400 mg twice daily) was compared with ibuprofen (800 mg thrice daily) or diclofenac (75 mg twice daily) in patients with osteoarthritis or rheumatoid arthritis. Celecoxib had a lower gastrointestinal side effect profile compared with other NSAIDs, and there was no difference in the incidence of cardiovascular events between celecoxib and NSAIDs regardless of aspirin use. Questions regarding the cardiovascular risk of the various coxibs remained, and on September 30, 2004 rofecoxib was withdrawn from the market based on the data from the Adenomatous Polyp PRevention On Vioxx (APPROVe) study. 8 This trial was prematurely discontinued after it was discovered that 3.5% of the patients treated with rofecoxib (25 mg once daily) had serious thromboembolic adverse events compared with 1.9% of patients in the placebo group (P0.001).8,9 The

Risk of cardiovascular events and rofecoxib: cumulative meta-analysis

The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2.30 (95% CI 1.22-4.33, p=0.010), and 1 year later (64 events, 21432 patients) it was 2.24 (1.24-4.02, p=0.007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0.41) or trial duration (p=0.82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0.86 [95% CI 0.75-0.99]) and could not have explained the findings of the VIGOR trial. Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.

Relationship of work schedules to gastrointestinal diagnoses, symptoms, and medication use in auto factory workers

Gastrointestinal (GI) complaints are common in shift workers. This study examines the relationship between work schedules and GI symptoms, medications, and diagnoses. In a cross-sectional survey of 343 US auto factory workers, four work schedule variables were examined: assigned shift, number of hours worked, number of night hours, and schedule variability. Multiple regression tested the relationship between GI outcomes and work schedule variables while controlling for covariates. The evening shift was associated with more GI symptoms and GI diagnoses. Unexpectedly, more consistent work times were associated with having a GI diagnosis. As schedule variability increased the probability of GI medication use increased in low noise exposure. Findings suggest that evening shift and widely varying work start and end times may increase risks for GI disturbances.

Early predictors of severe lower gastrointestinal bleeding and adverse outcomes: A prospective study

Background & Aims: Unlike in upper tract bleeding, prognostic factors for ongoing or recurrent bleeding from the lower gastrointestinal tract have not been well-defined. The aim of this study was to identify risk factors for severe lower gastrointestinal bleeding and for significant adverse outcomes. Methods: All patients seeking attention at a university emergency department for gastrointestinal bleeding were prospectively identified during a 3-year period. Ninety-four of 448 (21%) admitted patients had lower gastrointestinal bleeding. Clinical predictors available in the first hour of evaluation were recorded. The primary outcome, severe lower gastrointestinal bleeding, was defined as gross blood per rectum after leaving the emergency department associated with either abnormal vital signs (systolic blood pressure < 100 mm Hg or heart rate > 100/min) or more than a 2-unit blood transfusion during the hospitalization. Significant adverse outcomes, including death, were tabulated. Results: Thirty-seven patients (39%) had severe lower gastrointestinal bleeding. Independent risk factors for severe lower gastrointestinal bleeding were initial hematocrit ≤35% (odds ratio [OR], 6.3; 95% confidence interval [CI], 2.2–16.7); presence of abnormal vital signs (systolic blood pressure < 100 mm Hg or heart rate > 100/min) 1 hour after initial medical evaluation (OR, 4.3; 95% CI, 1.4–12.5); and gross blood on initial rectal examination (OR, 3.9; 95% CI, 1.2–13.2). Nineteen patients (20%) experienced a significant adverse outcome, including 3 deaths. The main independent predictor of adverse outcomes was severe lower gastrointestinal bleeding (OR, 5.3; 95% CI, 1.7–16.5). Conclusions: Risk factors are available in the first hour of evaluation in the emergency department to identify patients at risk for severe lower gastrointestinal bleeding. Severe lower gastrointestinal bleeding is a significant risk factor for global adverse outcomes.

P0970 CORROSIVE INJURY OF GASTROINTESTINAL TRACT IN CHILDREN: CLINICAL MANIFESTATIONS AND RISK FACTORS FOR ESOPHAGEAL STRICTURE

Introduction: GI corrosive injury will result in severe complications in children. Esophageal stricture is the most common one. This study is to investigate the clinical manifestations of children with gastrointestinal corrosive injury and the risk factors for esophageal stricture formation. Methods: During a 10-year period (July, 1993–June, 2003), thirty-eight children with gastrointestinal corrosive injury were admitted to our hospital. There were 25 males and 13 females with age ranged from 9 months to 18 years old. We reviewed their medical records, and focused on the gastrointestinal manifestations, complications and outcomes. Chi-square test was used to analyse the risk factors for esophageal stricture and p-value <0.05 was considered as significant. Results: There were 33 patients with alkali and 5 acid ingestion. The age distribution was biphasic: 21 (55.3%) under 5 years and 14 (36.8%) above 15 years old. The common symptoms were vomting ( 2 9 cases, 76.3 %); and followed by hyperthermia (>380C)(15 cases, 39.5%) and abdominal pain (10cases, 18.9%). Marked leukocytosis(> 15000/cumm) was found in 12(31.6%) and hyperglycemia(>120mg/dl) in 7(18.4%) patients. Electrolyte imbalance was noted in only 3(7.9%) of them. 22 patients were irrigated with nasogastric tube initially. Antibiotics and corticosteroid were used in 19 and 16 patients individually. Moderate to severe esophageal burn was diagnosed in 24(63.2%) by panendoscopy and 8(21%) of them had stricture formation within two months. Under chi-square analysis, hyperthermia, hyperglycemia, marked leukocytosis and severity of burn injury were significantly correlated with stricture formation(p<0.05) Malnutrition was not found in all the patients during 6-months follow up visit at clinic. A 2-year-old female resulted in mortality due to bowel obstruction and sepsis. Conclusion: In our result, hyperthermia, hyperglycemia, marked leukocytosis and burn injury are the risk factors for esophageal stricture formation. The role of antibiotic or corticosteroid treatment in children under GI corrosive injury is necessary to be further investigated.

Effects of rofecoxib and naproxen on life expectancy among patients with rheumatoid arthritis: a decision analysis

Background The VIOXX Gastrointestinal Outcomes Research (VIGOR) trial showed a 53% decrease in the risk of upper gastrointestinal toxicity and a fivefold increase in the risk of myocardial infarction for rofecoxib (a selective cyclooxygenase–2 inhibitor) compared with naproxen. We examined the effects of these competing adverse events on life expectancy in patients with rheumatoid arthritis. Methods We used decision analysis to compare the life expectancy of a cohort of rheumatoid arthritis patients taking naproxen versus a similar cohort taking rofecoxib, using data from the VIGOR trial. We incorporated the competing risks of upper gastrointestinal toxicity and myocardial infarction, as well as their long-term health consequences, on the basis of population-based studies. Results For 58-year-old women with rheumatoid arthritis (i.e., typical of participants in the VIGOR trial), naproxen was associated with a longer life expectancy than was rofecoxib (difference = 4.4 months). This difference was larger among 58-year-old men (7.8 months). The probability that naproxen is associated with a longer life expectancy than rofecoxib among 58-year-old patients was 92% for women and 98% for men. Life expectancy became the same between the two treatments when the risk of upper gastrointestinal toxicity was 70% higher or the risk of myocardial infarction was 40% lower than that of the base case among women, and when the risk of upper gastrointestinal toxicity was 4.4-fold higher or the risk of myocardial infarction was 70% lower among men. Conclusion Our analysis suggests that the competing risks of upper gastrointestinal toxicity and myocardial infarction shown in the VIGOR trial would project a longer life expectancy with naproxen than rofecoxib among patients with rheumatoid arthritis, except in those at low risk of myocardial infarction or at high risk of upper gastrointestinal toxicity.

Microbial contamination of drinking water and disease outcomes in developing regions.

Drinking water is a major source of microbial pathogens in developing regions, although poor sanitation and food sources are integral to enteric pathogen exposure. Gastrointestinal disease outcomes are also more severe, due to under-nutrition and lack of intervention strategies in these regions. Poor water quality, sanitation and hygiene account for some 1.7 million deaths a year world-wide (3.1% of all deaths and 3.7% of all DALY’s), mainly through infectious diarrhoea. Nine out of 10 such deaths are in children and virtually all of the deaths are in developing countries. Major enteric pathogens in these children include: rotavirus, Campylobacter jejuni, enterotoxigenic Escherichia coli, Shigella spp. and Vibrio cholerae O1, and possibly enteropathogenic E. coli, Aeromonas spp. V. cholerae O139, enterotoxigenic Bacteroides fragilis, Clostridium difficile and Cryptosporidium parvum. All except the latter are easily control by chlorination of water, but recontamination of treated water is a huge problem. Emerging environmental pathogens, such as Helicobacter pylori and Burkholderia pseudomallei, may well be of significance in some regions. In adults, much less is understood of various sequellae such as myocarditis, diabetes, reactive arthritis and cancers some months–years after initial infections. So in addition to the traditional pathogens (helminths, Entamoeba histolytica, Giardia lamblia hepatitis A and E) various enteroviruses, C. jejuni and H. pylori are emerging issues in adults.

Inhibiteurs sélectifs de COX-2 : quelle toxicité gastro-duodénale ?

Endoscopic studies have shown that cyclo-oxygenase-1 sparing non steroidal anti-inflammatory drugs (NSAIDs) of the coxib family did not produce more gastroduodenal ulcers than placebo in patients who were free of ulcer at baseline. However, the clinical relevance of these data is disputable. Only celecoxib and rofecoxib have been subject to large scale gastrointestinal outcome studies. Both have been shown to reduce the risk of symptomatic ulcers and ulcer complications (perforation, gastric outlet obstruction, bleeding) by about 50% compared to classical NSAIDs used at their maximum therapeutic doses. However, coxibs appear to retain some residual risk, especially in patients at high risk of developing serious gastrointestinal adverse events. This is the case in patients requiring low dose aspirin for cardiovascular purposes. Whether coxibs are still less toxic to the gastroduodenal tract that non-selective NSAIDs in these patients is controversial. Although coxibs have a superior upper gastrointestinal tolerability relative to traditional NSAIDs, dyspepsia, abdominal pain and nausea remain the major factor limiting their use.

Do some inhibitors of COX-2 increase the risk of thromboembolic events?: Linking pharmacology with pharmacoepidemiology.

Inhibitors of the cyclo-oxygenase (COX)-2 isoenzyme were developed with the expectation that their use would be accompanied by a reduction in adverse reactions thought to be mediated through COX-1 compared with conventional nonselective NSAIDs. However, the results of some clinical studies and other evidence have led to the hypothesis that use of COX-2 inhibitors may contribute to an increased risk of adverse thromboembolic (TE) events. In this review, we have evaluated the evidence from small-scale in vitro and in vivo pharmacological studies, clinical trials and large-scale pharmacoepidemiological studies and commented on the relationship between the pharmacological characteristics related to thromboembolic events and the clinical effects in large-scale clinical trials and pharmacoepidemiological studies. Overall, the pharmacological evidence suggests that a prothrombotic effect of COX-2 selective inhibitors is plausible. To date, despite the results from the Vioxx Gastrointestinal Outcome Research (VIGOR) study from which the clinical concern regarding cardiovascular TE risk arose, the published data from other randomised controlled trials (RCTs), retrospective observational studies and spontaneous reporting schemes provide a conflicting body of evidence on the TE risk with COX-2 inhibitors. Concerns that COX-2 inhibitors may be associated with prothrombotic effects remain and these need to be addressed in large scale, RCTs designed specifically to investigate the possibility of an excess of adverse cardiovascular outcomes in users of some or all selective COX-2 inhibitors, both with and without concomitant low-dose aspirin (acetylsalicylic acid). Consideration must also be given to other pathophysiological mechanisms for potential cardiovascular risk linked with inhibition of COX-2. In view of the evidence reviewed, it is recommended that selective COX-2 inhibitors should be prescribed with caution, only in patients with conditions for which these drugs have proven efficacy and with careful monitoring of outcomes and adverse events. This is particularly important in the elderly, in patients with cardiovascular/renal disease and in patients with other risk factors that might predispose them to adverse events.

The role of cyclooxygenase selective inhibitors in the gastrointestinal tract.

This article reviews the gastrointestinal manifestations of traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and the improved gastrointestinal safety profile of cyclooxygenase selective (COX)-2 inhibitors. By inhibiting the COX enzyme, NSAIDs provide effective analgesia and suppress inflammation in a variety of conditions. Most NSAIDs (nonselective or traditional) not only inhibit prostaglandins at sites of inflammation but also inhibit prostaglandins that have important normal functions in other parts of the body. This may be harmful when normal gastrointestinal mucosal function is impaired and mucosal damage occurs. Although such damage is often trivial and usually not symptomatic, gastrointestinal ulceration may produce pain and, more ominously, lead to bleeding, perforation, or obstruction. A new approach to the gastrointestinal complications of NSAIDs became feasible with the discovery of two isoforms of COX, COX-1 and COX-2, with COX-1 expressed mainly in the gastrointestinal tract. The development of NSAIDs that preferentially inhibit COX-2 offers the promise of relieving pain and inflammation without the side effects attendant to COX-1 blockade. In prospective studies evaluating gastrointestinal ulceration with COX-2-specific NSAIDs, rates of endoscopic ulceration have been equivalent to those with placebo and much lower than those with nonselective NSAIDs. In the recently released studies of gastrointestinal outcomes (perforated, painful, or bleeding ulcers), incidence of clinically relevant ulceration with COX-2 NSAIDs is much lower than that of traditional NSAIDs.