John D. Seeger

Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide.

ABSTRACT Objective: To estimate risk and relative risk (RR) of acute pancreatitis among patients using incretin-based diabetes therapies (exenatide or sitagliptin) compared to patients treated with agents with established safety profiles (metformin or glyburide). Research design and methods: The study population was derived from a large US commercial health insurance transaction database using an active drug safety surveillance system (i3 Aperio*). This analysis is based on data from June 2005 through June 2008. Cohorts of exenatide and sitagliptin initiators were each matched to an equal number of metformin or glyburide (met/gly) initiators using propensity scores to reduce confounding in the comparison of outcomes during follow-up. Patients with claims suggesting pancreatic disease in the 6 months prior to cohort entry were excluded. * i3 Drug Safety, Waltham, MA 02451, USA, www.i3aperio.com Main outcome measure: Claims for hospitalizations associated with a primary diagnosis of acute pancreatitis (ICD-9 577.0). Results: There were 27 996 exenatide initiators and 16 276 sitagliptin initiators and approximately equal numbers of matched comparators. During follow-up of up to 1 year, acute pancreatitis occurred among 0.13% of patients treated with exenatide and 0.12% of patients treated with sitagliptin. The risk of acute pancreatitis was comparable for initiators of exenatide (RR 1.0; 95% confidence interval (CI) 0.6–1.7) and sitagliptin (RR 1.0; 95% CI 0.5–2.0) relative to the comparison cohorts. Conclusions: These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database.

Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

BACKGROUND Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating evidence suggests that this practice increases mortality. METHODS Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized patients with operating-room charges for the use of aprotinin (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated the numbers of patients with a hospital-discharge status of death and performed three types of analyses: a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed 50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis of data from patients whose surgeons showed a strong preference for one of the two study drugs. RESULTS In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score-matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid. CONCLUSIONS Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding.

Botulinum toxin A versus fixed cast stretching for dynamic calf tightness in cerebral palsy.

Objective: To compare botulinum toxin A injections with fixed plaster cast stretching in the management of cerebral palsied children with dynamic (i.e. non‐fixed) calf tightness.

Long-Term Effectiveness of Highly Active Antiretroviral Therapy on the Survival of Children and Adolescents with HIV Infection: A 10-Year Follow-Up Study

BACKGROUND Previous observational studies found highly active antiretroviral therapy (HAART) to be associated with improved survival among human immunodeficiency virus (HIV)-infected children and adolescents. However, these studies had limited follow-up of HIV-infected children undergoing HAART. Given that HIV infection is chronic and that exposure to HAART is likely to be life-long, there is a need to evaluate the long-term effect of HAART on survival in this population. METHODS The study included 1236 children and adolescents who were perinatally infected with HIV, who were on study or enrolled after January 1996 in a United States-based multicenter prospective cohort study (Pediatric AIDS Clinical Trials Group 219/219C), and who were not receiving HAART at baseline; subjects were observed for a maximum of 10 years through June 2006. A weighted Cox regression model was used to estimate the effect of HAART on survival, appropriately adjusted for time-varying confounding by severity. RESULTS At the end of the 10-year follow-up period (median duration of follow-up, 6.3 years; interquartile range, 4.3-9.8 years), 70% of participants had initiated HAART. Lower CD4 cell percentages, total lymphocyte counts, and albumin levels were associated with an increased probability of initiating HAART. Eighty-five deaths were observed, and the mortality hazard ratio associated with HAART, compared with non-HAART regimens, was 0.24 after adjusting for measured confounding by severity (95% confidence interval, 0.11-0.51). CONCLUSIONS The use of HAART was highly effective in reducing mortality during the period 1996-2006 among children and adolescents infected with HIV. With improved long-term survival, continued follow-up is necessary to evaluate the effects of prolonged use of HAART on potential adverse events, immune function, growth, sexual maturation, and quality of life in this population.

Clinically relevant differences between the statins : Implications for therapeutic selection

Although the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, share a common lipid-lowering effect, there are differences within this class of drugs. The low-density lipoprotein (LDL) cholesterol-lowering efficacy, pharmacokinetic properties, drug-food interactions, and cost can vary widely, thus influencing the selection of a particular statin as a treatment option. The statins that produce the greatest percentage change in LDL cholesterol levels are atorvastatin and simvastatin. Atorvastatin and fluvastatin are least affected by alterations in renal function. Fewer pharmacokinetic drug interactions are likely to occur with pravastatin and fluvastatin, because they are not metabolized through the cytochrome P450 (3A4) system. The most cost-effective statins, based on cost per percentage change in LDL cholesterol levels, are fluvastatin, cerivastatin, and atorvastatin. Awareness of these differences may assist in the selection or substitution of an appropriate statin for a particular patient.

Risk of thromboembolism in women taking ethinylestradiol / drospirenone and other oral contraceptives.

OBJECTIVE: The oral contraceptive ethinylestradiol 0.03 mg/drospirenone 3 mg contains a progestin component that differs from other oral contraceptives. Case reports and prescription event monitoring suggested that ethinylestradiol/drospirenone might be associated with an elevated risk of thromboembolism. We sought to estimate the association between ethinylestradiol/drospirenone and risk of thromboembolism relative to the association among other oral contraceptives. METHODS: We identified ethinylestradiol/drospirenone initiators and a twofold larger group of other oral contraceptive initiators between June 2001 and June 2004 within a U.S. health insurer database. The comparison group was selected to have demographic and health care characteristics preceding oral contraceptive initiation that were similar to ethinylestradiol/drospirenone initiators. Thromboembolism during the follow-up of the cohorts was identified through claims for medical services, and only medical record–confirmed cases were included in analyses. The primary (as-matched) analysis used proportional hazards regression, whereas a secondary (as-treated) analysis accounted for changes in oral contraceptives during follow-up using Poisson regression. RESULTS: The 22,429 ethinylestradiol/drospirenone initiators and 44,858 other oral contraceptive initiators were followed for an average of 7.6 months, and there were 18 cases of thromboembolism in ethinylestradiol/drospirenone initiators and 39 in the comparators (rate ratio 0.9, 95% confidence interval 0.5–1.6). More than 9,000 women would need to be prescribed oral contraceptives to observe a difference of one case of thromboembolism. Results of the as-treated analysis were similar to those of the as-matched analysis. CONCLUSION: Ethinylestradiol/drospirenone initiators and initiators of other oral contraceptives are similarly likely to experience thromboembolism. LEVEL OF EVIDENCE: II

A cohort study of acute pancreatitis in relation to exenatide use

Aim: Reports of acute pancreatitis associated with exenatide treatment prompted this study to estimate the association between acute pancreatitis and exenatide use relative to other antihyperglycaemic drugs.

Statin use and risk of prostate cancer in the California Men's Health Study cohort.

Statins have known anticarcinogenic effects, however, evidence for long-term statin use as effective chemoprevention for prostate cancer is inconsistent. We examined the association between statin use and risk of prostate cancer among 69,047 eligible participants in the California Mens Health Study, a prospective cohort of Northern and Southern California Kaiser Permanente (KP) members, ages 45 to 69 years, initiated in 2002. Prostate cancer cases were identified by linkage to the KP California Cancer Registries. Statin exposure, estimated from automated KP outpatient pharmacy records (available since 1991 in Southern California and since 1994 in Northern California), was treated as time-varying and defined as the cumulative days dispensed of any statin from the first dispensing until a prostate cancer diagnosis, radical prostatectomy, termination of membership, or end of study (December 31, 2004). Cox proportional hazards models with age as the time scale were used to estimate rate ratios, while controlling for confounding variables. During follow-up, 888 prostate cancer cases, including 131 advanced cases, were identified. There was no association between ever statin use or <5 years use and prostate cancer. Conversely, ≥5 years use was associated with a 28% lower risk for prostate cancer compared with nonuse (adjusted rate ratio, 0.72; 95% confidence interval, 0.53-0.99). This association did not differ markedly for advanced disease. However, the association did seem to be restricted to those who regularly take nonsteroidal anti-inflammatory drugs. Our findings suggest that long-term statin use might be associated with a reduced risk of prostate cancer but perhaps only among regular nonsteroidal anti-inflammatory drug users. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2218–25)

Effectiveness of the Pentavalent Rotavirus Vaccine in Preventing Gastroenteritis in the United States

OBJECTIVE: In clinical trials, the pentavalent rotavirus vaccine (RV5) was efficacious in preventing severe rotavirus gastroenteritis (RGE) and related health care encounters. We assessed the vaccine effectiveness (VE) of RV5 among US infants during the first 2 rotavirus seasons after vaccine licensure. METHODS: Using a large, national, health insurance claim database, we monitored 2 cohorts of infants (infants who received 3 doses of RV5 and a concurrent group of infants who received 3 doses of diphtheria-tetanus-acellular pertussis vaccine but did not receive RV5) through the 2007 and 2008 rotavirus seasons (January 1 to May 31), to identify cases of RGE and all-cause acute gastroenteritis (AGE) resulting in medical care encounters. We estimated the VE in reducing hospitalizations, emergency department (ED) and physician office visits, and health care resource utilization, as measured by days and costs of hospitalizations and ED visits. RESULTS: A total of 33 140 RV5-vaccinated infants and 26 167 infants in the concurrent diphtheria-tetanus-acellular pertussis vaccine cohort were included in the analysis. The VE against RGE (hospitalization and ED) was 100% (95% confidence interval [CI]: 87%–100%), whereas the VE against AGE was 59% (95% CI: 47%–68%). In the outpatient setting, the VE against RGE and AGE was 96% (95% CI: 76%–100%) and 28% (95% CI: 22%–33%), respectively. There was a complete (100%) reduction in RGE hospitalization and ED visit days and a 100% reduction in costs. RV5 was associated with a 66% decrease in AGE-related hospitalization and ED visit days and a 74% reduction in costs. CONCLUSIONS: In this first nationwide study evaluating VE under conditions of routine use, RV5 was highly effective in preventing RGE and AGE and in reducing health care resource utilization. Further research is needed to assess VE with an incomplete rotavirus vaccination regimen.

Safety and effectiveness of dabigatran and warfarin in routine care of patients with atrial fibrillation

The RE-LY study demonstrated the safety and efficacy of dabigatran relative to warfarin for stroke prevention in non-valvular atrial fibrillation. It is important to further evaluate safety and effectiveness of drugs in routine care. This study used a sequential cohort design with propensity score matching to compare dabigatran with warfarin among patients in two commercial health insurance databases. New users of these anticoagulants were followed from initiation until discontinuation, the end of the study, or the occurrence of a study outcome (primary study outcomes were stroke and major bleeding). Proportional hazards regression was conducted separately within each data source and results were pooled. Among 19,189 matched dabigatran and warfarin initiators (mean age: 68 years, 36 % female), as-treated follow-up (average of 5 months for dabigatran, 4 months for warfarin) identified 62 and 69 strokes, respectively (pooled HR = 0.77; 95 % CI = 0.54 to 1.09), and 354 and 395 major haemorrhages, respectively (HR = 0.75; 0.65 to 0.87). No meaningful heterogeneity was identified across subgroups, but numeric trends suggest more pronounced stroke prevention by dabigatran relative to warfarin among patients age 75+ (HR = 0.57; 0.33 to 0.97) or with < 6 months of use (HR = 0.51; 0.19 to 1.42). Major bleeds were reduced more by dabigatran among patients aged < 55 (HR = 0.51; 0.30 to 0.87) and with CHADS2 < 2 (HR = 0.58; 0.44 to 0.77). In conclusion, in routine care of patients with non-valvular atrial fibrillation, dabigatran treatment resulted in improved health outcomes compared with warfarin.