Walter E. Smalley

Colorectal Cancer and Nonsteroidal Anti-inflammatory Drugs

The authors have presented a concise review of the studies which evaluate the risk of colorectal cancer among NSAID users. Animals studies have clearly documented a protective effect of NSAIDs in preventing colon cancers in a carcinogen-induced (AOM) model. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that they must be playing a role very early in the adenoma-to-carcinoma sequence of events. Several studies have indicated that treatment of FAP patients with NSAIDs causes a regression of adenomas that were already present prior to initiation of NSAID therapy. Many epidemiological studies have examined the relationship between aspirin use and colorectal cancer. Most of these studies have shown a marked decrease in the relative risk (40-50%) of colorectal cancer among continuous aspirin users. The appropriate dose and duration of aspirin treatment for optimal effects are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is their ability to inhibit cyclooxygenase. Presently, it is not clear whether inhibition of cyclooxygenase-1 or -2 effects on other signaling pathways are required for the protective effect of aspirin and other NSAIDs. The authors and others have demonstrated that COX-2 is upregulated from 2- to 50-fold in 85-90% of colorectal adenocarcinomas, which makes the COX-2 enzyme a possible target. Drugs are currently under development at several pharmaceutical companies that preferentially inhibit either COX-2 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, then these newly developed, more selective NSAIDs may play a role in future chemoprevention strategies.

American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Asymptomatic Neoplastic Pancreatic Cysts

This article has an accompanying continuing medical education activity on page e12. Learning Objective: At the conclusion of this exercise, the learner will understand the approach to counseling patients regarding the optimal method and frequency of radiologic imaging, indications for invasive tests like endoscopic ultrasonography (EUS) and surgery, select patients for follow-up after surgery, decide the duration of such follow-up, and decide when to stop surveillance for those with and without surgery.

Aspirin use and potential mechanisms for colorectal cancer prevention.

Disease prevention is receiving more attention in the United States today. This welcome trend is largely a result of two economic forces: The increased level of support for prevention research by the National Institutes of Health (Healthy People 2000), and the potential payoff of prevention research in cutting the health care costs of managing patients with end-stage diseases. Indeed, the efficacy of preventive measures for many chronic diseases (such as heart disease and cancer) are being evaluated with the full expectation that mortality and morbidity—and perhaps health care costs—will decrease. One example of recent cancer prevention research indicates that there may be a 40–50% reduction in mortality from colorectal cancer in persons who take aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) 1 on a regular basis. It is clear that an effect of this magnitude would have a significant impact on both the number of lives saved and on the health care dollars recovered. Colorectal cancer is a major cause of death in Western civilizations, claiming about 55,000 lives in the United States this year alone. Americans have a 1 in 20 lifetime risk of developing this disease, and z 1 in 10 have a family member who develops colorectal cancer. Initially, it was hoped that early detection would reduce these high numbers. However, despite recent evidence that early detection by fecal occult blood tests and flexible sigmoidoscopy can decrease the risk of colorectal cancer death by 20–30%, most people do not undergo appropriate screening. Therefore, a number of laboratories have initiated research efforts focused on understanding the molecular basis of the potential chemoprotective effects resulting from aspirin and other NSAID use. It is hoped that this approach, in conjunction with more rigorous clinical trials, will lead to a rationale design for future colorectal cancer prevention regimens. This Perspectives article considers both the clinical and the basic research efforts underway this year, the 100th anniversary of the discovery of aspirin.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS, EICOSANOIDS, AND COLORECTAL CANCER PREVENTION

A concise review of the literature that evaluates the risk of colorectal cancer among NSAID users has been presented. Animal studies document a protective effect of NSAIDs in preventing colorectal cancers in carcinogen-induced (AOM) models and in Min mice. NSAIDs are protective in the animal model, even if given 14 weeks after administration of the carcinogen, indicating that these agents must be acting early in the adenoma-to-carcinoma sequence. Treatment of FAP patients with NSAIDs causes regression of adenomas that were already present before initiation of therapy. Many epidemiologic studies have examined the relationship between aspirin use and colorectal cancer. Most show a marked decrease in the relative risk (40% to 50%) of this tumor among continuous aspirin users. The appropriate dose and duration of aspirin treatment needed for optimal results are still unknown. Future work, directed at the molecular basis for the chemoprotective effects of NSAIDs in humans, may reveal strategies for the development of better chemopreventive agents. One effect shared by all NSAIDs is inhibition of cyclooxygenase. Presently, whether inhibition of COX-1 or COX-2 is required for the protective effect of aspirin and other NSAIDs is unclear. The authors and others have demonstrated that COX-2 is up-regulated from 2 to 50 fold in 85% to 90% of colorectal adenocarcinomas, making the COX-2 enzyme a more likely target. The authors have also reported a dramatic increase in COX-2 expression in colon tumors that develop in rats after AOM treatment. Drugs are currently being developed that preferentially inhibit either COX-1 or COX-2. If COX-2 is found to be a relevant target in the prevention of colorectal cancer, these newly developed, selective NSAIDs may play a role in future chemoprevention strategies.

Outcomes With Concurrent Use of Clopidogrel and Proton-Pump Inhibitors: A Cohort Study

BACKGROUND Proton-pump inhibitors (PPIs) and clopidogrel are frequently coprescribed, although the benefits and harms of their concurrent use are unclear. OBJECTIVE To examine the association between concurrent use of PPIs and clopidogrel and the risks for hospitalizations for gastroduodenal bleeding and serious cardiovascular disease. DESIGN Retrospective cohort study using automated data to identify patients who received clopidogrel between 1999 through 2005 after hospitalization for coronary heart disease. SETTING Tennessee Medicaid program. PATIENTS 20,596 patients (including 7593 concurrent users of clopidogrel and PPIs) hospitalized for myocardial infarction, coronary artery revascularization, or unstable angina pectoris. MEASUREMENTS Baseline and follow-up drug use was assessed from automated records of dispensed prescriptions. Primary outcomes were hospitalizations for gastroduodenal bleeding and serious cardiovascular disease (fatal or nonfatal myocardial infarction or sudden cardiac death, stroke, or other cardiovascular death). RESULTS Pantoprazole and omeprazole accounted for 62% and 9% of concurrent PPI use, respectively. Adjusted incidence of hospitalization for gastroduodenal bleeding in concurrent PPI users was 50% lower than that in nonusers (hazard ratio, 0.50 [95% CI, 0.39 to 0.65]). For patients at highest risk for bleeding, PPI use was associated with an absolute reduction of 28.5 (CI, 11.7 to 36.9) hospitalizations for gastroduodenal bleeding per 1000 person-years. The hazard ratio associated with concurrent PPI use for risk for serious cardiovascular disease was 0.99 (CI, 0.82 to 1.19) for the entire cohort and 1.01 (CI, 0.76 to 1.34) for the subgroup of patients who had percutaneous coronary interventions with stenting during the qualifying hospitalization. LIMITATIONS Unmeasured confounding and misclassification of exposure (no information on adherence or over-the-counter use of drugs) and end points (not confirmed by medical record review) were possible. Because many patients entered the cohort from hospitals with relatively few cohort members, the analysis relied on the assumption that after adjustment for observed covariates, PPI users from one such hospital could be compared with nonusers from a different hospital. CONCLUSION In patients with serious coronary heart disease treated with clopidogrel, concurrent PPI use was associated with reduced incidence of hospitalizations for gastroduodenal bleeding. The corresponding point estimate for serious cardiovascular disease was not increased; however, the 95% CI included a clinically important increased risk. PRIMARY FUNDING SOURCE Agency for Healthcare Research and Quality and National Heart, Lung, and Blood Institute.

Excess costs from gastrointestinal disease associated with nonsteroidal anti-inflammatory drugs

OBJECTIVE: To quantify medical care costs for the diagnosis and treatment of gastrointestinal disorders attributable to use of nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin in elderly persons.DESIGN AND SETTING: Retrospective cohort study of 75,350 Tennessee Medicaid enrollees at least 65 years of age.MEASUREMENTS: The cohort was classified by baseline NSAID use as nonusers (no use preceding 1988), occasional users (⩾75% of days) or regular users (<75% of days). For the follow-up year (1989), we calculated annual rates of utilization of and Medicare/Medicaid payments for: medical care for NSAID-associated gastrointestinal disorders; hospitalizations/emergency department visits for peptic ulcers, gastritis/duodenitis, and gastrointestinal bleeding; outpatient upper and lower gastrointestinal tract radiologic and endoscopic examinations; and histamine2 (H2)-receptor antagonist, sucralfate, and antacid prescriptions. Rates were adjusted for demographic characteristics and baseline health care utilization.RESULTS: Among nonusers of NSAIDs, the adjusted mean annual payment for all types of medical care for study gastrointestinal disorders was

Cyclooxygenase, NSAIDs, and colorectal cancer

134. This increased to

An automated database case definition for serious bleeding related to oral anticoagulant use

180 among occasional users, an excess of

Effect of a Prior-Authorization Requirement on the Use of Nonsteroidal Antiinflammatory Drugs by Medicaid Patients

46 (p<.001); and to

THE RISKS AND COSTS OF UPPER GASTROINTESTINAL DISEASE ATTRIBUTABLE TO NSAIDS

244 among regular users, an excess of