Gurkirpal Singh

Recent Considerations in Nonsteroidal Anti-Inflammatory Drug Gastropathy

Conservative calculations estimate that approximately 107,000 patients are hospitalized annually for nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) complications and at least 16,500 NSAID-related deaths occur each year among arthritis patients alone. The figures for all NSAID users would be overwhelming, yet the scope of this problem is generally under-appreciated. The Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) Post-Marketing Surveillance Program (PMS) has prospectively followed patient status and outcomes, drug side effects, and the economic impact of illness for >11,000 arthritis patients at 8 participating institutions in the United States and Canada. Analysis of these data indicates that: (1) osteoarthritis (OA) and rheumatoid arthritis (RA) patients are 2.5-5.5 times more likely than the general population to be hospitalized for NSAID-related GI events; (2) the absolute risk for serious NSAID-related GI toxicity remains constant and the cumulative risk increases over time; (3) there are no reliable warning signals- >80% of patients with serious GI complications had no prior GI symptoms; (4) independent risk factors for serious GI events were age, prednisone use, NSAID dose, disability level, and previous NSAID-induced GI symptoms; and (5) antacids and H2 antagonists do not prevent NSAID-induced gastric ulcers, and high-risk NSAID users who take gastro-protective drugs are more likely to have serious GI complications than patients not taking such medications. Currently, limiting NSAID use is the only way to decrease the risk of NSAID-related GI events. Ongoing ARAMIS research is aimed at developing a simple point-score system for estimating individual risks of developing serious NSAID-related GI complications.

Risk of perforation from a colonoscopy in adults: a large population-based study.

BACKGROUND Previous studies that reported the incidence of perforation from a colonoscopy are limited by small sample sizes, restricted age groups, or single-center data. OBJECTIVE To determine the incidence and risk factors of colonic perforation from a colonoscopy in a large population cohort. DESIGN Retrospective, population-based, cohort study, followed by a nested case-control study. SETTING California Medicaid program claims database. PATIENTS A total of 277,434 patients (aged 18 years and older) who underwent a colonoscopy during 1995 to 2005, age, sex, and time matched to 4 unique general-population controls. MAIN OUTCOME MEASUREMENTS Perforation incidence in the 7 days after colonoscopy (or matched index date for controls) with odds ratio (OR); multivariate logistic regression to calculate adjusted ORs for subsequent analysis of risk factors. RESULTS A total of 228 perforations were diagnosed after 277,434 colonoscopies, which corresponded to a cumulative 7-day incidence of 0.082%. The OR of getting a perforation from a colonoscopy compared with matched controls (n = 1,072,723) who did not undergo a colonoscopy was 27.6 (95% CI, 19.04-39.92), P < .001. On multivariate analysis, when comparing the group that had a perforation after a colonoscopy (n = 216) with those who did not (n = 269,496), increasing age, significant comorbidity, obstruction as an indication for the colonoscopy, and performance of invasive interventions during colonoscopy were significant positive predictors. Performance of biopsy or polypectomy did not affect the perforation risk. The rate of perforation did not change significantly over time. LIMITATIONS Validity of coding and capturing of all perforation diagnoses may possibly be deficient. CONCLUSION The risk of perforation from a colonoscopy is low, but, despite increased experience with the procedure, it remains unchanged over time.

Epidemiology of Alcohol-Related Liver and Pancreatic Disease in the United States

BACKGROUND The epidemiology of acute alcoholic pancreatitis (AP), chronic alcoholic pancreatitis (CP), acute alcoholic hepatitis (AH), and chronic alcoholic hepatitis with cirrhosis (CH) alone or in combination is not well described. To better understand alcohol-related liver and pancreas effects on and associations with different ethnic groups and sexes, we analyzed the trends of AP, CP, AH, CH, AP plus AH, and CP plus CH in the United States. METHODS We examined discharge records from the Nationwide Inpatient Sample, the largest representative sample of US hospitals. Hospital discharges, case-fatality, and sex and race contributions were calculated from patients with discharge diagnoses of AP, CP, AH, CH, AP plus AH, or CP plus CH between 1988 and 2004. RESULTS The distribution of overall hospital discharges per 100 000 persons between 1988 and 2004 was as follows: AP, 49.2; CP, 8.1; AH, 4.5; and CH, 13.7. Overall hospital discharges per 100 000 persons for AP plus AH were 1.8; and for CP plus CH, 0.32. There were higher male to female ratios for AH and CH, and less so for AP and CP. A markedly higher frequency of AP (63.5) and CP (11.3) was seen among blacks than among whites (AP, 29.6 and CP, 5.1), Hispanics (AP, 27.1 and CP, 3.7), Asians (AP, 12.8 and CP, 1.4), and American Indians (AP, 15.5 and CP, 2.3). This higher frequency remained stable between 1994 and 2004. Overall case fatality steadily decreased in all categories, but remains highest in CH (13.6%) with similar racial distributions. CONCLUSIONS In the United States, AP is the most common discharge diagnosis among alcohol-related liver or pancreas complications, while CH has the highest case fatality rate and male to female ratio. Blacks have the highest frequency of alcohol-related pancreatic disease.

Obesity, Abdominal Obesity, Physical Activity, and Caloric Intake in US Adults: 1988 to 2010

BACKGROUND Obesity and abdominal obesity are associated independently with morbidity and mortality. Physical activity attenuates these risks. We examined trends in obesity, abdominal obesity, physical activity, and caloric intake in US adults from 1988 to 2010. METHODS Univariate and multivariate analyses were performed using National Health and Nutrition Examination Survey data. RESULTS Average body mass index (BMI) increased by 0.37% (95% confidence interval [CI], 0.30-0.44) per year in both women and men. Average waist circumference increased by 0.37% (95% CI, 0.30-0.43) and 0.27% (95% CI, 0.22-0.32) per year in women and men, respectively. The prevalence of obesity and abdominal obesity increased substantially, as did the prevalence of abdominal obesity among overweight adults. Younger women experienced the greatest increases. The proportion of adults who reported no leisure-time physical activity increased from 19.1% (95% CI, 17.3-21.0) to 51.7% (95% CI, 48.9-54.5) in women, and from 11.4% (95% CI, 10.0-12.8) to 43.5% (95% CI, 40.7-46.3) in men. Average daily caloric intake did not change significantly. BMI and waist circumference trends were associated with physical activity level but not caloric intake. The associated changes in adjusted BMIs were 8.3% (95% CI, 6.9-9.6) higher among women and 1.7% (95% CI, 0.68-2.8) higher among men with no leisure-time physical activity compared with those with an ideal level of leisure-time physical activity. CONCLUSIONS Our analyses highlight important dimensions of the public health problem of obesity, including trends in younger women and in abdominal obesity, and lend support to the emphasis placed on physical activity by the Institute of Medicine.

Declines in Mortality From Acute Myocardial Infarction in Successive Incidence and Birth Cohorts of Patients With Rheumatoid Arthritis

Background—Patients with rheumatoid arthritis are at high risk for acute myocardial infarction (AMI). The treatment of rheumatoid arthritis has become more intensive over the past 2 decades, resulting in tighter control of inflammation and lower levels of disability. The impact of this on atherosclerotic cardiovascular diseases is not known. Methods and Results—Death rates from AMI in a cohort of 3862 patients with rheumatoid arthritis followed up from 1980 to 1997 were studied. Time trends in AMI mortality among successive incidence and birth cohorts were examined by use of multivariable Poisson regression models and by comparing standardized mortality ratios. The mean age was 56 years in this predominantly female cohort (76%), and median disease duration was 6.5 years. During the period of observation, the use of methotrexate increased substantially, whereas that of prednisone was relatively stable. Over the 22 209 person-years of observation, there were 157 deaths as a result of AMI, with a death rate of 7.06 per 1000 person-years. Mortality rates were higher in older age groups and in men. After adjustment for age, sex, race, and disease duration, the risk of AMI declined in successive incidence years (relative risk, 0.94; 95% CI, 0.92 to 0.96). Patients with rheumatoid arthritis incident after 1990 did not have excess AMI mortality compared with general population. Declines in mortality trends were observed in successive birth cohorts as well. Conclusions—Mortality as a result of AMI among patients with rheumatoid arthritis has declined over time.

Long‐term morbidity, mortality, and economics of rheumatoid arthritis

OBJECTIVE To estimate the morbidity, mortality, and lifetime costs of care for rheumatoid arthritis (RA). METHODS We developed a Markov model based on the Arthritis, Rheumatism, and Aging Medical Information System Post-Marketing Surveillance Program cohort, involving 4,258 consecutively enrolled RA patients who were followed up for 17,085 patient-years. Markov states of health were based on drug treatment and Health Assessment Questionnaire scores. Costs were based on resource utilization, and utilities were based on visual analog scale-based general health scores. RESULTS The cohort had a mean age of 57 years, 76.4% were women, and the mean duration of disease was 11.8 years. Compared with a life expectancy of 22.0 years for the general population, this cohort had a life expectancy of 18.6 years and 11.3 quality-adjusted life years. Lifetime direct medical care costs were estimated to be

Mortality and cause of death in Japanese patients with rheumatoid arthritis based on a large observational cohort, IORRA

93,296. Higher costs were associated with higher disability scores. CONCLUSION A Markov model can be used to estimate lifelong morbidity, mortality, and costs associated with RA, providing a context in which to consider the potential value of new therapies for the disease.

Risk of acute myocardial infarction with nonselective non-steroidal anti-inflammatory drugs: a meta-analysis

Objectives: To investigate mortality, cause of death, and risk factors related to mortality in Japanese patients with rheumatoid arthritis (RA). Methods: The IORRA cohort is a large observational cohort established in 2000 at the Institute of Rheumatology, Tokyo Womens Medical University. Essentially, all RA patients were registered and clinical parameters were assessed biannually. For patients who failed to participate in subsequent surveys, simple queries were mailed to confirm survival. Standardized mortality ratios (SMRs) were calculated and mortality risk factors were analysed using a Cox proportional hazard model. Results: We analysed 7926 patients (81.9% females; mean age 56.3 ± 13.1 years; mean disease duration 8.5 ± 8.3 years) with RA who enrolled in IORRA from October 2000 to April 2007. During the observational period (35 443.0 person-years), 289 deaths were reported. Major causes of death included malignancies (24.2%), respiratory involvement (24.2%) including pneumonia (12.1%) and interstitial lung disease (ILD) (11.1%), cerebrovascular disease (8.0%), and myocardial infarction (7.6%). As death was not confirmed in all patients, the SMR was deduced to be between 1.46 [95% confidence interval (CI) 1.32–1.60] and 1.90 (95% CI 1.75–2.07) for all patients, between 1.45 (95% CI 1.22–1.70) and 1.70 (95% CI 1.45–1.97) for men, and between 1.46 (95% CI, 1.29–1.65) and 2.02 (95% CI 1.82–2.24) for women. Factors associated with increased mortality included male gender, older age, worse physical disability, positive rheumatoid factor (RF), corticosteroid use, and presence of ILD. Conclusion: The mortality of Japanese RA patients is comparable to that in previous reports from western countries, even though the causes of death were significantly different.

A Novel Composite Endpoint to Evaluate the Gastrointestinal (GI) Effects of Nonsteroidal Antiinflammatory Drugs Through the Entire GI Tract

The use of cyclo-oxygenase 2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased risk of acute myocardial infarction (AMI). The association between the risks of AMI with nonselective NSAIDs is less clear. We reviewed the published evidence and assessed the risk of AMI with nonselective NSAIDs. We performed a meta-analysis of all studies containing data from population databases that compared the risk of AMI in NSAID users with that in non-users or remote NSAID users. The primary outcome was objectively confirmed AMI. Fourteen studies met predefined criteria for inclusion in the meta-analysis. Nonselective NSAIDs as a class was associated with increased AMI risk (relative AMI risk 1.19, 95% confidence interval [CI] 1.08 to 1.31). Similar findings were found with diclofenac (relative AMI risk 1.38, 95% CI 1.22–1.57) and ibuprofen (relative AMI risk 1.11, 95% CI 1.06 to 1.17). However, this effect was not observed with naproxen (relative AMI risk 0.99, 95% CI 0.88–1.11). In conclusion, based on current evidence, there is a general direction of effect, which suggests that at least some nonselective NSAIDs increase AMI risk. Analysis based on the limited data available for individual NSAIDs, including diclofenac and ibuprofen, supported this finding; however, this was not the case for naproxen. Nonselective NSAIDs are frequently prescribed, and so further investigation into the risk of AMI is warranted because the potential for harm can be substantial.

Comparative toxicity of non-steroidal anti-inflammatory agents

Objective. Nonsteroidal antiinflammatory drugs (NSAID) not only cause damage to the upper gastrointestinal (GI) tract but also affect the lower GI tract. To date, there is no endpoint that evaluates serious GI events in the entire GI tract. The objective of this report is to introduce a novel composite endpoint that measures damage to the entire GI tract — clinically significant upper and lower GI events (CSULGIE) — in patients with NSAID-induced GI damage. Methods. We reviewed the data from largescale, multicenter, randomized, clinical trials on lower GI toxicity associated with NSAID use. The rationale for using CSULGIE as a primary endpoint in 2 ongoing trials — the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial and the Gastrointestinal Randomized Events and Safety Open-Label NSAID Study (GI-REASONS) — is also discussed. Results. Previous randomized trials focused primarily on damage to the upper GI tract and often neglected the lower GI tract. The CSULGIE endpoint extends the traditional “perforation, obstruction, and bleeding” assessment of upper GI complications by including events in the lower GI tract (small/large bowel) such as perforation, bleeding, and clinically significant anemia. Conclusion. By providing clinicians with a new, descriptive language for adverse events through the entire GI tract, the CSULGIE endpoint has the potential to become a standard tool for evaluating the GI effects of a range of therapies.