Antipsychotics, glycemic disorders, and life-threatening diabetic events: a Bayesian data-mining analysis of the FDA adverse event reporting system (1968-2004).

BACKGROUND: This analysis compared diabetes-related adverse events associated with use of different antipsychotic agents. A disproportionality analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) was performed. METHODS: Data from the FDA postmarketing AERS database (1968 through first quarter 2004) were evaluated. Drugs studied included aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone. Fourteen Medical Dictionary for Regulatory Activities (MedDRA) Primary Terms (MPTs) were chosen to identify diabetes-related adverse events; 3 groupings into higher-level descriptive categories were also studied. Three methods of measuring drug-event associations were used: proportional reporting ratio, the empirical Bayes data-mining algorithm known as the Multi-Item Gamma Poisson Shrinker, and logistic regression (LR) analysis. Quantitative measures of association strength, with corresponding confidence intervals, between drugs and specified adverse events were computed and graphed. Some of the LR analyses were repeated separately for reports from patients under and over 45 years of age. Differences in association strength were declared statistically significant if the corresponding 90% confidence intervals did not overlap. RESULTS: Association with various glycemic events differed for different drugs. On average, the rankings of association strength agreed with the following ordering: low association, ziprasidone, aripiprazole, haloperidol, and risperidone; medium association, quetiapine; and strong association, clozapine and olanzapine. The median rank correlation between the above ordering and the 17 sets of LR coefficients (1 set for each glycemic event) was 93%. Many of the disproportionality measures were significantly different across drugs, and ratios of disproportionality factors of 5 or more were frequently observed. CONCLUSIONS: There are consistent and substantial differences between atypical antipsychotic drugs in the disproportionality reporting ratios relating to glycemic effects, especially life-threatening events, in the AERS database. The relative associational rankings of drugs are similar in reports from younger and older patients. These results agree with several other reports in the literature, do not support a "class effect" hypothesis, and provide a strong rationale for further studies to clarify the issue.

Part 1: Vesicoureteral reflux treatment: the past, present, and future.

The purpose of this manuscript is to provide clinicians with highlights of key findings pertaining to our current understanding and treatment of the condition of vesicoureteral reflux (VUR). This includes a review of the disease, patient characteristics, current treatment options, challenges for managed care and patients, and opportunities for improvements in care. This is not intended as a comprehensive review of VUR. This manuscript does, however, serve to introduce three additional manuscripts contained within this supplement. The first article in this series is designed to provide the clinician with real-world data pertaining to treatment patterns and outcomes in patients with VUR (Examining pediatric vesicoureteral reflux: a real-world evaluation of treatment patterns and outcomes: Hensle TW, Hyun G, Grogg AL, Eaddy M). The second article considers the efficacy of prophylactic antibiotics in reducing the likelihood of urinary tract infections (UTIs) when compared with endoscopic injection with dextranomer/hyaluronic acid (Endoscopic injection versus antibiotic prophylaxis in the reduction of urinary tract infection in patients with vesicoureteral reflux: Elder JS, Shah MB, Batiste LR, et al.). The third article explores the role medication noncompliance plays in contributing to antibiotic resistance, the consequences associated with resistance (longer lasting illness and costs), and the difficulties with resistance specific to UTI pathogens in children (Considerations regarding the medical management of VUR: what have we really learned?: Koyle MA, Caldamone A). This supplement is intended to provide the clinician with valuable information regarding the treatment patterns, the role of compliance, and the efficacy of treatments for pediatric patients with VUR.

Part 2: Examining pediatric vesicoureteral reflux: a real-world evaluation of treatment patterns and outcomes.

OBJECTIVE: Vesicoureteral reflux (VUR) occurs in 1% of infants and children. Upon diagnosis, patients are often placed on prophylactic antibiotics to prevent urinary tract infections (UTIs) and potential renal damage. The objective of this study was to assess current diagnosis and treatment patterns for patients diagnosed with VUR, focusing on compliance with antibiotic therapy and the occurrence of UTIs. METHODS: This is a retrospective study of children less than 11 years of age diagnosed with VUR. Data were obtained from a national managed care database with over 45 million lives. Patients were followed for up to 6 months prior to their diagnosis and 1 year after. All were required to be eligible for medical and pharmacy services for 1 year after diagnosis. Outcome measures included the use of and compliance with prophylactic antibiotics, rates of curative treatment (surgery and endoscopic injections), and diagnoses of UTIs. RESULTS: There were 35 450 patients meeting inclusion criteria. After being diagnosed with VUR, 76.5% of patients were placed on prophylactic antibiotics, 1.5% had open surgery, and 0.38% had an endoscopic injection with dextranomer/hyaluronic acid copolymer (Dx/HA). Only 17% of patients on prophylactic antibiotics were adherent to therapy, with mean patient compliance equaling 41.4%. Of patients on prophylactic antibiotic therapy, 58% still had a diagnosis for a UTI within 12 months of VUR diagnosis. LIMITATIONS: Adherence to VUR-related antibiotic therapy may be overestimated as the data used in the analysis represents prescriptions acquired but not necessarily consumed. This study lacked detailed clinical information, such as VUR-resolution rates and VUR grade. CONCLUSIONS: Only 17% of pediatric VUR patients on prophylactic antibiotics were compliant with therapy. Of patients on prophylactic therapy, 58% had a diagnosis of a UTI within 1 year of treatment.

A large retrospective analysis of acute urinary retention and prostate-related surgery in BPH patients treated with 5-alpha reductase inhibitors: dutasteride versus finasteride.

OBJECTIVE: The purpose of this study was to examine the rates of acute urinary retention (AUR) and surgery after initiating 5-alpha reductase inhibitor (5ARI) therapy and to compare the 2 currently available 5ARIs, dutasteride and finasteride, in a real-world, managed care setting. This study constitutes the first direct comparison of therapeutic outcome between a mono 5ARI (finasteride) and a dual 5ARI (dutasteride). METHODS: This is a retrospective descriptive and comparative analysis of the rates of AUR and prostate surgery in patients with benign prostatic hyperplasia (BPH) treated with 5ARI therapy, either dutasteride or finasteride. Data were obtained from the PharMetrics Integrated Medical and Pharmaceutical Database (PIMPD) (Watertown, Mass) during a 6-year period. The PIMPD is a large national healthcare database that represents a total of 85 managed health plans and covers more than 45 million patients. The data analysis included all patients aged 50 years or older diagnosed with BPH who were treated with 5ARIs (dutasteride 0.5 mg/day or finasteride 5 mg/day) for up to 12 months during the 6-year period of January 1, 1999, to March 1, 2005. Patients meeting the selection criteria were evaluated for a total of 12 months with regard to the likelihood of experiencing AUR or prostate-related surgery. RESULTS: After 5 months of 5ARI therapy, the rate of AUR during months 5 to 12 was found to be significantly lower in the dutasteride group compared with the finasteride group (5.3% vs 8.3%). After controlling for background covariates, dutasteride-treated patients were 49.1% less likely to experience AUR than patients treated with finasteride (P = .0207). Patients treated with dutasteride were also less likely to undergo prostate-related surgery, with 1.4% of dutasteride treated patients and 3.4% of patients receiving finasteride undergoing surgery; differences in surgery rates, however, were not statistically significant (P = .0745), even after controlling for background covariates. CONCLUSTION: Although the 2 drugs, dutasteride and finasteride, belong to the same category of 5ARIs, this large retrospective multivariate analysis potentially indicates differences in therapeutic outcomes. In this study, patients treated with dutasteride were less likely to experience AUR and demonstrated a trend toward being less likely to experience surgery than patients treated with finasteride.

Clinical and economic outcomes in patients treated for enlarged prostate.

BACKGROUND: Benign prostatic hyperplasia (BPH), also referred to as enlarged prostate, is a highly prevalent condition in men aged 50 years or older. It is a progressive disease with significant morbidity from complications. OBJECTIVE: The purpose of this study was to assess the likelihood of having acute urinary retention (AUR) and prostate surgery after initiating therapy with an alpha blocker or 5-alpha reductase inhibitor in a real-world setting. STUDY DESIGN: This was a retrospective study of patients who were treated for BPH between January 1, 2003, and November 30, 2003, in a large, national managed care claims database. Outcomes measures of interest included rate of AUR, prostate surgery, and surgical complications. RESULTS: There were 2959 patient records with a diagnosis of BPH who were taking prostate medications in the database. Eighty-nine percent of patients were receiving alpha blocker therapy, whereas 11% of patients were receiving 5-alpha reductase inhibitors. Overall, the 1-year AUR rate was 12.1%, and the prostate surgery rate was 5.8%. Patients who initiated 5-alpha reductase inhibitor therapy only were less likely to have AUR or surgery compared with patients taking alpha blockers, although surgical differences did not reach statistical significance (P = .0576). Overall, the surgical complication rate was 49.4%, and the rate of AUR within 180 days of prostate surgery was 30.6%. Rates of prostate surgery, AUR, and surgical complications all increased with age. CONCLUSION: Patients receiving 5-alpha reductase inhibitor therapy alone were less likely to have AUR compared with patients receiving alpha blockers and tended to be less likely to have surgery (P = .054).

An assessment of the diagnosed prevalence of diseases in men 50 years of age or older.

OBJECTIVE: A lack of focus on certain men's health problems has led to significant morbidity and mortality in aging men. Managed care must begin to focus on the conditions that are most prevalent in this fast-growing population in an effort to improve the quality of care. To assist in achieving this goal, a naturalistic retrospective study assessing the prevalence of the 10 leading disorders in men older than the age of 50 was conducted, with an additional focus on men eligible for Medicare. METHODS: Claims data were obtained from the Integrated Health Care Information Solutions National Managed Care Benchmark database (Waltham, Mass), that includes data from 30 health plans covering more than 25 million lives, and from the Centers for Medicare & Medicaid Services, representing men from a 5% random sample of Medicare-eligible patients. Men older than 50 years of age were included in the study. The prevalence of all diseases was determined in the 2003 calendar year for each population. Prevalence was calculated by dividing the number of diagnosed cases of a disease by the total person-time observations within the 2003 period. RESULTS: The results indicate that cardiovascular (ie, coronary artery disease [CAD], hypertension, and arrhythmias), urological (ie, enlarged prostate and prostate cancer), and musculoskeletal disorders (ie, osteoarthritis and bursitis) comprise 70% of the 10 leading diseases. CAD and hypertension ranked first and second across all age categories, whereas enlarged prostate ranked fourth. In men older than 50, diabetes ranked third, whereas cataracts ranked third in Medicare-eligible men. CONCLUSION: The diseases identified in this study have the potential to cause significant clinical and economic implications when poorly treated or undertreated. Therefore, there is a need to institute early treatment for these conditions before they progress and require more extensive and costly interventions.

Pharmacy cost evaluation of risperidone, olanzapine, and quetiapine for the treatment of schizophrenia in acute care inpatient settings.

OBJECTIVE: This study examines total pharmacy cost and usage patterns of schizophrenic patients in acute mental health inpatient settings for three atypical antipsychotics -- risperidone, olanzapine, and quetiapine. Despite the readily available unit cost information for drugs, actual pharmacy costs may deviate significantly from 'labeled costs'. Recent research findings indicate the need for more robust evaluation of such pharmacy costs. RESEARCH DESIGN AND METHODS: This study used data from non-randomized inpatient retrospective charts from three acute care inpatient mental health facilities. The final pooled sample included 327 patients, of which 120 received risperidone, 153 received olanzapine, and 54 received quetiapine. Medication cost was defined as the average wholesale price (AWP) as listed in the 2001 'Red Book'. Propensity scoring methodology and multinomial regression were employed to reduce treatment selection bias. RESULTS: The observed mean daily antipsychotic drug doses were 4.45 mg (SD 2.44) for risperidone, 14.04 mg (SD 5.55) for olanzapine, and 350.33 mg (SD 228.24) for quetiapine. The corresponding mean daily drug costs were $7.66(SD $4.20) for risperidone, $8.11 (SD $5.29) for quetiapine and, $12.10 (SD $4.79) for olanzepine. Numbers adjusted for treatment selection bias show that the average daily total pharmacy cost of risperidone was $4.35 lower than olanzapine (p < 0.001) and $1.41 lower than quetiapine (p = 0.38). The adjusted average daily pharmacy cost of olanzapine was $4.02 higher than quetiapine (p < 0.001). After statistical adjustment there were no significant differences between study drugs in terms of length of stay or patient functioning. CONCLUSION: This study provides the first US comparison of medication utilization patterns and pharmacy costs for olanzapine, risperidone, and quetiapine administered in acute mental health care inpatient settings. While this study did not estimate the full economic value of the three antipsychotics in these inpatient settings, it demonstrated that the mean daily costs for risperidone were lower than the mean daily costs for olanzapine (p < 0.001) and quetiapine although the later difference was not statistically significant (p = 0.38).

Comparative study of the development of diabetes mellitus in patients taking risperidone and olanzapine.

OBJECTIVES: A growing body of literature suggests that certain atypical antipsychotics, especially olanzapine and clozapine, may induce glucoregulatory dysfunction. We assessed the differences in risk of developing diabetes mellitus during treatment with olanzapine and risperidone by using patients treated with haloperidol and fluphenazine as control subjects in whom we would not expect to see an increased risk. METHODS: We conducted a retrospective analysis of the Veteran's Integrated Service Network 10 Veterans Affairs (VA) database. Data for patients receiving olanzapine, risperidone, haloperidol, or fluphenazine from January 1, 1997-December 31, 2000, were included. Diabetes was defined as any health system encounter associated with the International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis for diabetes (250.xx) or prescription for a hypoglycemic agent. Data of patients with markers for diabetes within 1 year before their index date, female patients, racial groups other than Caucasian or African-American, and patients receiving clozapine were not analyzed. We performed a Cox regression, with antipsychotic therapy as a time-dependent covariate. Other covariates considered for inclusion in the final model were number of days supply of antipsychotic drug, age, race, psychiatric diagnoses, substance abuse, lithium, valproic acid, and other typical or atypical antipsychotic agents. RESULTS: Data for 5837 patients were analyzed. Overall rate of developing diabetes in the study population was 6.3% (368 of 5837 patients). Olanzapine therapy was associated with a significantly higher risk of development of diabetes compared with risperidone (hazard ratio [HR] 1.37, 95% confidence interval 1.06-1.76, p=0.016) while controlling for race, age, diagnosis, substance abuse, lithium, valproic acid, and other atypical antipsychotic agents. No differences in the rate of developing diabetes were detected between fluphenazine and risperidone (HR 1.11, p=0.69), or haloperidol and risperidone (HR 0.89, p=0.41). CONCLUSIONS: Olanzapine was associated with a 37% (HR 1.37) increased risk of development of diabetes compared with risperidone in a VA population, even after adjusting for other factors associated with the development of diabetes and temporal exposure to study drug. Because of limitations associated with database research, prospective studies should be conducted to corroborate these findings.

Differential effects of risperidone, olanzapine, clozapine, and conventional antipsychotics on type 2 diabetes: findings from a large health plan database.

BACKGROUND: Case series suggest that some antipsychotics may induce or exacerbate type 2 diabetes. This study measured the association of antipsychotic treatments with diabetes at a population level. METHOD: Claims data for psychosis patients (ICD-CM-9 290.xx-299.xx) within health plans encompassing 2.5 million individuals were analyzed. Patients reporting preexisting type 2 diabetes up to 8 months prior to observation were excluded. The frequency of newly reported type 2 diabetes in untreated patients and among patients treated with antipsychotics from 5 categories (risperidone, olanzapine, clozapine, and high-potency and low-potency conventionals) was compared. Logistic regression models compared the odds of diabetes based on exposure to each of the antipsychotic categories. RESULTS: Based on 12 months of exposure, the odds of type 2 diabetes for risperidone-treated patients (odds ratio = 0.88, 95% CI = 0.372 to 2.070) was not significantly different from that for untreated patients, whereas patients receiving other antipsychotics had a significantly greater risk of diabetes than untreated patients (p < .05): olanzapine, 3.10 (95% CI = 1.620 to 5.934); clozapine, 7.44 (95% CI = 0.603 to 34.751); high-potency conventionals, 2.13 (95% CI = 1.097 to 4.134); and low-potency conventionals, 3.46 (95% CI = 1.522 to 7.785). Older age and greater use of non-antipsychotic psychotropic medications also contributed to risk of type 2 diabetes. Olanzapine also showed significantly higher (p < .01) odds of diabetes associated with increasing dose. CONCLUSION: Consistent with previously published literature, these data suggest that olanzapine, clozapine, and some conventional antipsychotics appear to increase the risk of acquiring or exacerbating type 2 diabetes and that the effect may vary by drug. In contrast to these agents, risperidone was not associated with an increased risk of type 2 diabetes.