Severe hypoglycemia in users of sulfonylurea antidiabetic agents and antihyperlipidemics.

Drug-drug interactions causing severe hypoglycemia due to antidiabetic drugs is a major clinical and public health problem. We assessed whether sulfonylurea use with a statin or fibrate was associated with severe hypoglycemia. We conducted cohort studies of users of glyburide, glipizide, and glimepiride plus a statin or fibrate within a Medicaid population. The outcome was a validated, diagnosis-based algorithm for severe hypoglycemia. Among 592,872 persons newly exposed to a sulfonylurea+antihyperlipidemic, the incidence of severe hypoglycemia was 5.8/100 person-years. Adjusted hazard ratios (HRs) for sulfonylurea+statins were consistent with no association. Most overall HRs for sulfonylurea+fibrate were elevated, with sulfonylurea-specific adjusted HRs as large as 1.50 (95% confidence interval (CI): 1.24-1.81) for glyburide+gemfibrozil, 1.37 (95% CI: 1.11-1.69) for glipizide+gemfibrozil, and 1.63 (95% CI: 1.29-2.06) for glimepiride+fenofibrate. Concomitant therapy with a sulfonylurea and fibrate is associated with an often delayed increased rate of severe hypoglycemia.

Pharmacoepidemiologic Methods for Studying the Health Effects of Drug-Drug Interactions.

A drug-drug interaction (DDI) occurs when one or more drugs affect the pharmacokinetics (the body's effect on the drug) and/or pharmacodynamics (the drug's effect on the body) of one or more other drugs. Pharmacoepidemiologic studies are the principal way of studying the health effects of potential DDIs. This article discusses aspects of pharmacoepidemiologic research designs that are particularly salient to the design and interpretation of pharmacoepidemiologic studies of DDIs.

Minimal benefit of earlier-than-recommended repeat colonoscopy among US Medicare enrollees following a negative colonoscopy.

BACKGROUND: A large proportion of US Medicare beneficiaries undergo earlier-than-recommended follow-up colonoscopies after negative screening colonoscopy. Such practice entails substantial cost and added risk. AIMS: To compare the risk of colorectal cancer (CRC) associated with varying follow-up colonoscopy intervals following a negative colonoscopy, and to determine whether the potential benefit of a shorter colonoscopy follow-up interval would differ by gender. METHODS: We conducted a weighted cohort study using the Surveillance, Epidemiology and End Results-Medicare linked database (1991-2006) among 932,370 Medicare enrollees who are representative of the entire US elderly population. We compared the cumulative incidence of CRC among patients who underwent follow-up colonoscopies at different intervals following a negative colonoscopy. The primary outcome was incident CRC. RESULTS: The eligible study cohort (n = 480,864) included 106,924 patients who underwent ≥1 colonoscopy. Men were more likely to require polypectomy during their initial colonoscopy than women. Compared to the recommended 9-10 year follow-up colonoscopy interval, an interval of 5-6 years was associated with the largest CRC cumulative risk reduction [i.e. 0.17% (95% CI: 0.009-0.32%)]. The magnitude of risk reduction associated with shorter colonoscopy follow-up intervals was not significantly different between men and women. CONCLUSIONS: Among elderly individuals who undergo a negative colonoscopy, the magnitude of reduction in the cumulative CRC risk afforded by earlier-than-recommended follow-up colonoscopy is quite small, and probably cannot justify the risk and cost of increased colonoscopy frequency. In addition, there are insufficient differences between men and women to warrant gender-specific recommendations.

Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins.

AIMS: To examine whether initiation of fibrates or statins in sulfonylurea users is associated with hypoglycaemia, and examine in vitro inhibition of cytochrome P450 (CYP) enzymes by statins, fenofibrate and glipizide. METHODS: We used healthcare data to conduct nested case-control studies of serious hypoglycaemia (i.e. resulting in hospital admission or emergency department treatment) in persons taking glipizide or glyburide, and calculated adjusted overall and time-stratified odds ratios (ORs) and 95% confidence intervals (CIs). We also characterized the in vitro inhibition of CYP enzymes by statins, fenofibrate and glipizide using fluorometric CYP450 inhibition assays, and estimated area under the concentration-time curve ratios (AUCRs) for the drug pairs. RESULTS: We found elevated adjusted overall ORs for glyburide-fenofibrate (OR 1.84, 95% CI 1.37, 2.47) and glyburide-gemfibrozil (OR 1.57, 95% CI 1.25, 1.96). The apparent risk did decline over time as might be expected from a pharmacokinetic mechanism. Fenofibrate was a potent in vitro inhibitor of CYP2C19 (IC50 = 0.2 µm) and CYP2B6 (IC50 = 0.7 µm) and a moderate inhibitor of CYP2C9 (IC50 = 9.7 µm). The predicted CYP-based AUCRs for fenofibrate-glyburide and gemfibrozil-glyburide interactions were only 1.09 and 1.04, suggesting that CYP inhibition is unlikely to explain such an interaction. CONCLUSIONS: Use of fenofibrate or gemfibrozil together with glyburide was associated with elevated overall risks of serious hypoglycaemia. CYP inhibition seems unlikely to explain this observation. We speculate that a pharmacodynamic effect of fibrates (e.g. activate peroxisome proliferator-activator receptor alpha) may contribute to these apparent interactions.

Anti-infectives and the risk of severe hypoglycemia in users of glipizide or glyburide.

The objective of this study was to evaluate whether orally administered anti-infectives increase the risk of severe hypoglycemia in users of glipizide or glyburide. We performed two case-control studies and two case-crossover studies using US Medicaid data. All the anti-infectives examined were associated with an elevated risk of severe hypoglycemia. Using cephalexin as the reference category, in glipizide users, statistically significant associations were found with co-trimoxazole (odds ratio (OR) = 3.14; 95% confidence interval (CI): 1.83-5.37); clarithromycin (OR = 2.90; 95% CI: 1.69-4.98); fluconazole (OR = 2.53; 95% CI: 1.23-5.23); and levofloxacin (OR = 2.09; 95% CI: 1.35-3.25). In glyburide users, with cephalexin as the reference, statistically significant associations were found with clarithromycin (OR = 5.02; 95% CI: 3.35-7.54); levofloxacin (OR = 2.83; 95% CI: 1.73-4.62); co-trimoxazole (OR = 2.68; 95% CI: 1.59-4.52); fluconazole (OR = 2.20; 95% CI: 1.04-4.68); and ciprofloxacin (OR = 2.08; 95% CI: 1.23-3.52). In conclusion, exposure to all studied anti-infective agents were associated with subsequent severe hypoglycemia. Using cephalexin as the reference, drug-drug interactions were evident with ciprofloxacin (in glyburide users only), clarithromycin, co-trimoxazole, fluconazole, and levofloxacin.

Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding.

The aim of this study was to determine whether a potential pharmacokinetic interaction between warfarin and orally administered anti-infectives increases the risk of hospitalization for gastrointestinal (GI) bleeding in warfarin users. We conducted a nested case-control and case-crossover study using US Medicaid data. Logistic regression was used to determine the association between GI bleeding and prior use of ciprofloxacin, levofloxacin, gatifloxacin, co-trimoxazole, or fluconazole vs. no exposure and also vs. use of cephalexin, which would not be expected to interact with warfarin. All of the anti-infectives examined were associated with elevated odds ratios (ORs) when compared to no exposure to these drugs. With cephalexin data as the reference, the ORs for co-trimoxazole (OR: 1.68 (95% confidence interval (CI): 1.21-2.33) in the prior 6-10 days) and fluconazole (OR: 2.09 (95% CI: 1.34-3.26) in the prior 11-15 days) were significantly elevated. Warfarin users who had received an anti-infective agent showed a substantially increased risk of GI bleeding. However, a drug-drug interaction with warfarin was evident only for co-trimoxazole and fluconazole.

Dosing algorithms to predict warfarin maintenance dose in Caucasians and African Americans.

The objective of this study was to determine whether warfarin dosing algorithms developed for Caucasians and African Americans on the basis of clinical, environmental, and genetic factors will perform better than an empirical starting dose of 5 mg/day. From April 2002 through December 2005, 259 subjects (Caucasians and African Americans) who started using warfarin were prospectively followed until they reached maintenance dose. The Caucasian algorithm included 11 variables (R(2) = 0.43). This model (which predicted 51% of the doses to within 1 mg of the observed dose) performed better than 5 mg/day (which predicted 29% of the doses to within 5 +/- 1 mg). The African-American algorithm included 10 variables (R(2) = 0.28). This model predicted 37% of the doses to within 1 mg of the observed dose, representing a small improvement compared with 5 mg/day (which predicted 34% of the doses to within 1 mg of 5 mg/day). These results were similar to the results we obtained from testing other published algorithms. The dosing algorithms explained <45% of the observed variability in Caucasians, and the algorithms performed only marginally better for African Americans when compared with giving 5 mg empirically.

Apolipoprotein E genotype and warfarin dosing among Caucasians and African Americans.

Warfarin sodium is a vitamin K antagonist that is plagued by large variability in patient response, including higher dose requirements among African Americans. Polymorphisms in the gene encoding apolipoprotein E (APOE) may partly explain this variability by altering transport of vitamin K to the liver. In a prospective cohort study of 232 individuals (52.2% Caucasian and 47.8% African American) initiating warfarin therapy, the weekly maintenance dose was significantly higher for African Americans than for Caucasians (mean 42.9 versus mean 36.9 mg, P=0.018), and the epsilon4 allele was more common among African Americans (37.8 versus 26.4% for Caucasians). In multivariable analyses, the presence of the epsilon4 allele was associated with a statistically significantly higher warfarin dose among African Americans (median 45.0 mg in epsilon4 carriers versus 35.0 mg in non-epsilon4 carriers, P=0.014) but not Caucasians (38.1 versus 35.0 mg, P=0.60). In addition, warfarin maintenance dose increased among African Americans according to genotype previously associated with differential hepatic chylomicron clearance (epsilon2/epsilon2 or epsilon2/epsilon3: 30.0 mg; epsilon3/epsilon3: 35.0 mg; epsilon3/epsilon4 or epsilon4/epsilon4: 45.0 mg; P=0.012), although the epsilon4/epsilon4 genotype was rare and not clearly associated with higher doses. The association of APOE with warfarin dosing was independent of CYP2C9 and VKORC1 polymorphisms. APOE polymorphisms thus may be important determinants of warfarin maintenance dose and could explain at least some of the observed racial differences in dose requirements.

Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians.

The objective of this study was to determine whether two vitamin K epoxide reductase complex 1 (VKORC1) polymorphisms contribute to the variability in warfarin response, particularly in African Americans. The effect of the VKORC1 1173C/T and -1639G/A polymorphisms was examined in a prospective cohort study of 338 warfarin users. Subjects carrying an 1173T allele had a lower warfarin maintenance dose compared with subjects with the CC genotype in African Americans (-12.10 mg/week+/-4.93; P=0.02) and Caucasians (-14.41 mg/week+/-3.28; P<0.001). Before reaching maintenance dose, only Caucasians with the T allele had significantly increased risk of international normalized ratio >3 (odds ratio=3.10; 95% confidence interval: 1.73-5.55) compared with Caucasians with the CC genotype. Polymorphisms in the VKORC1 gene are associated with warfarin maintenance dose requirements among both African Americans and Caucasians. However, these polymorphisms may not be as useful in predicting over-anticoagulation among African Americans.

Postprandial oesophageal integrated acidity is a reliable predictor of gastro-oesophageal reflux disease.

BACKGROUND: Measurement of oesophageal acid exposure parameters postprandially has been shown to distinguish gastro-oesophageal reflux disease patients from normal individuals. AIMS: To calculate the accuracy of postprandial oesophageal integrated acidity in diagnosing gastro-oesophageal reflux disease. METHODS: Ambulatory 24-h pH studies of 626 patients were analysed retrospectively. Gastro-oesophageal reflux disease, defined as pH < 4 for > 4.2% of time, was identified in 305 subjects. Postprandial oesophageal integrated acidity was measured for 2 and 3 h after the largest meal peak as determined from gastric pH. Postprandial symptom-associated probability was calculated. RESULTS: Gastro-oesophageal reflux disease subjects had a greater postprandial oesophageal integrated acidity than non-gastro-oesophageal reflux disease subjects [median (IQR): 0.57 (0.08-2.66) vs. 0.03 (0.01-0.15) mmol*h/L]. Median postprandial oesophageal integrated acidity did not differ with gender or age in gastro-oesophageal reflux disease and non-gastro-oesophageal reflux disease subjects (P > 0.05 for all). A 3-h postprandial oesophageal integrated acidity value of 0.121 mmol*h/L had a 71.1% sensitivity and 71.7% specificity in diagnosing gastro-oesophageal reflux disease. Gastro-oesophageal reflux disease subjects with symptoms had a higher postprandial oesophageal integrated acidity than those without (P = 0.043), whereas non-gastro-oesophageal reflux disease subjects with and without symptoms did not differ (P = 0.74). The correlation between symptom-associated probability and postprandial oesophageal integrated acidity was poor (gastro-oesophageal reflux disease: r = 0.15; non-gastro-oesophageal reflux disease: r = 0.25). CONCLUSION: Postprandial oesophageal integrated acidity provides a robust estimation of oesophageal acid exposure and may predict symptoms in gastro-oesophageal reflux disease patients.

EUS predictors of long-term survival in esophageal carcinoma.

BACKGROUND: EUS is the most accurate nonsurgical modality for the staging of esophageal cancer, but the ability of EUS to predict outcomes or prognosis is unclear. Patients were examined who had EUS performed for esophageal cancer staging to determine which endosonographic features predict survival. METHOD: Data on 203 patients undergoing EUS for esophageal cancer staging were studied retrospectively. Median survival was calculated for each T-stage and N-stage and according to the presence or absence of celiac axis (CAx) lymphadenopathy as determined by EUS. Kaplan-Meier survival curves were generated for each stage and the log-rank test was used to test for significant differences in survival. Multivariate analysis was performed to test for the relative importance in predicting survival of the EUS stages, also considering age, gender, histology, and type of treatment. RESULTS: Significant differences were found in the ability of EUS-determined T-stage (p = 0.0005), N-stage (p < 0.0001), and presence of CAx nodes (p = 0.0049) to predict survival. Multivariate analysis showed N-stage to predict survival. CONCLUSIONS: Pretreatment EUS can predict survival in esophageal cancer based on initial T-stage, N-stage, and the presence of CAx nodes. The presence of lymphadenopathy at EUS is an important predictor of survival. EUS should be performed in all patients with esophageal cancer, not only for staging patients before therapy, but also as a valuable method of determining prognosis.

A prospective study of interstitial cystitis: results of longitudinal followup of the interstitial cystitis data base cohort. The Interstitial Cystitis Data Base Study Group.

PURPOSE: We present baseline characteristics and longitudinal profiles of symptoms in the Interstitial Cystitis Data Base study, a prospective cohort study of patients with interstitial cystitis. MATERIALS AND METHODS: A total of 637 eligible patients were entered into the study and followed for symptoms of pain, urgency and urinary frequency. Median followup was 31 months. RESULTS: More than 90% of patients were white women with a median age of 43 years. Using the overall pain-urgency-frequency score 7% of participants presented with mild, 44% with moderate and 49% with severe symptoms. Severe urgency in 41% of cases and severe 24-hour frequency in 41% were more common than severe pain in 29%. Of the patients 51% reported nighttime frequency of 2 or more voids. Median duration of interstitial cystitis symptoms was 8 years and 68% of participants were previously diagnosed with the condition. The 36% of patients who withdrew from study or were lost to followup were more likely to have had more severe symptoms at baseline. Patterns of change with time suggest initial symptom improvement due to regression to the mean, and an intervention effect associated with the increased followup and care of cohort participants. Although all symptoms fluctuated, there was no evidence of significant long-term change in overall disease severity. CONCLUSIONS: Our observations support the clinical observation that interstitial cystitis is a chronic disease and no current treatments have a significant impact on symptoms with time. These results provide a foundation for the design and performance of future clinical trials in interstitial cystitis using these end points in a similar patient population.

Current care of hepatitis C-positive patients by primary care physicians in an integrated delivery system.

BACKGROUND: Infection with the hepatitis C virus (HCV) is an emerging health problem in the United States. Management of this condition in asymptomatic patients remains controversial. METHODS: A questionnaire was mailed in November 1997 to all primary care physicians caring for adults (internists and family physicians) in an integrated health delivery system regarding the current approach to screening, diagnosis, and management of HCV infection. Charts of patients whose tests were positive for HCV were audited in selected practice sites to document care received by those patients. RESULTS: Most physicians (70%) reported ordering alanine aminotransferase (ALT) measurements to screen for HCV infection as part of a complete checkup. Each physician diagnosed an average of 3.1 new cases of HCV infection per year. Patients received widely divergent advice regarding prognosis, precautions to prevent transmission, and treatment. More than one half of the physicians advised their patients that the condition was serious (68%) and to abstain from alcohol (56%) and use condoms in monogamous relationships (62%). In caring for HCV-positive patients, more than three quarters of physicians reported recommending a liver biopsy to patients who had elevated ALT levels, and observing clinically, without liver biopsy, those patients who had normal ALT levels. A chart audit, however, showed less-aggressive intervention. Approximately one third of HCV-positive patients with elevated ALT levels had been seen by a gastroenterologist and had had a liver biopsy. Physicians in practice longer were less likely to recommend treatment with interferon-alpha. Of those patients whose physicians reported they would recommend biopsy and treatment with interferon-alpha, only 36% had a documented liver biopsy in their charts, and 29% had documented interferon-alpha treatment. Only 1.6% and 3.0% of patients, respectively, had received the recommended hepatitis A and hepatitis B vaccines. CONCLUSIONS: Approaches to screening, diagnosis, and management of HCV infection by primary care physicians vary greatly. There appears to be a considerable population of patients in primary care settings who continue to receive conservative management of asymptomatic HCV infection.

A morphometric analysis of the posed smile.

A fundamental goal of orthodontics is to improve the smile, but no objective criteria exist to assess the lip-teeth relationship, establish objectives of treatment or measure treatment outcome. Here we propose a method to digitally measure the smile characteristics of orthodontic patients. Specifically, the 'posed smile' is measured. By definition the posed smile is voluntary and not elicited by an emotion. It can be a learned greeting or a signal of appeasement and can be sustained. The posed smile is reliably repeatable. The multimedia computer program for smile measurement we developed was based on studies of the utility of the smile photograph and the assessment of the lip-teeth characteristics of the posed smile in treated and untreated patients. On the computer screen a grid, or smile mesh, employs horizontal and vertical lines to measure eleven attributes of a smile. Not all orthodontically 'well-treated' patients with exemplary plaster casts exhibit desirable anterior tooth display while smiling. We suggest that the photographic analysis of an unstrained posed smile might be a standard orthodontic record.

Interactive method of informing patients of the risks of intravenous contrast media.

PURPOSE: To evaluate interactive computer-based informed consent for use of contrast material versus the same information in a written format. MATERIALS AND METHODS: Patients (n = 160) referred for radiologic examination with intravenous contrast material were block randomized (sex, age, and previous exposure to contrast material) into two groups and were provided either written or computer-based (video) informed consent. RESULTS: The female patients in the video group scored better on the test than those in the group with the written consent form. Male patients attained equivalent scores with both types of consent. The video took an average of 1.6 minutes longer to complete, probably because the majority of patients chose to be informed of every risk of intravenous contrast material. CONCLUSION: This project demonstrates that a video format for informed consent before use of intravenous contrast material offers a good alternative to the written consent form.