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Objective To assess risks of mortality associated with use of individual antipsychotic drugs in elderly residents in nursing homes.Design Population based cohort study with linked data from Medicaid, Medicare, the Minimum Data Set, the National Death Index, and a national assessment of nursing home quality.Setting Nursing homes in the United States.Participants 75 445 new users of antipsychotic drugs (haloperidol, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone). All participants were aged ≥65, were eligible for Medicaid, and lived in a nursing home in 2001-5.Main outcome measures Cox proportional hazards models were used to compare 180 day risks of all cause and cause specific mortality by individual drug, with propensity score adjustment to control for potential confounders.Results Compared with risperidone, users of haloperidol had an increased risk of mortality (hazard ratio 2.07, 95% confidence interval 1.89 to 2.26) and users of quetiapine a decreased risk (0.81, 0.75 to 0.88). The effects were strongest shortly after the start of treatment, remained after adjustment for dose, and were seen for all causes of death examined. No clinically meaningful differences were observed for the other drugs. There was no evidence that the effect measure modification in those with dementia or behavioural disturbances. There was a dose-response relation for all drugs except quetiapine.Conclusions Though these findings cannot prove causality, and we cannot rule out the possibility of residual confounding, they provide more evidence of the risk of using these drugs in older patients, reinforcing the concept that they should not be used in the absence of clear need. The data suggest that the risk of mortality with these drugs is generally increased with higher doses and seems to be highest for haloperidol and least for quetiapine.

Objective To examine the teratogenic potential of statins.Design Cohort study.Setting United States.Participants A cohort of 886 996 completed pregnancies linked to liveborn infants of women enrolled in Medicaid from 2000 to 2007.Methods We examined the risk of major congenital malformations and organ specific malformations in offspring associated with maternal use of a statin in the first trimester. Propensity score based methods were used to control for potential confounders, including maternal demographic characteristics, obstetric and medical conditions, and use of other drugs.Results 1152 (0.13%) women used a statin during the first trimester. In unadjusted analyses, the prevalence of malformations in the offspring of these women was 6.34% compared with 3.55% in those of women who did not use a statin in the first trimester (relative risk 1.79, 95% confidence interval 1.43 to 2.23). Controlling for confounders, particularly pre-existing diabetes, accounted for this increase in risk (1.07, 0.85 to 1.37). There were also no statistically significant increases in any of the organ specific malformations assessed after accounting for confounders. Results were similar across a range of sensitivity analyses.Conclusions Our analysis did not find a significant teratogenic effect from maternal use of statins in the first trimester. However, these findings need to be replicated in other large studies, and the long term effects of in utero exposure to statins needs to be assessed, before use of statins in pregnancy can be considered safe.

Background: Although it is known that rheumatoid arthritis is associated with an increased risk of cardiovascular disease (CVD), the pattern of this risk is not clear. This study investigated the relative risk of myocardial infarction, stroke and CVD mortality in adults with rheumatoid arthritis compared with adults without rheumatoid arthritis across age groups, sex and prior CVD event status. Methods: We conducted a cohort study among all residents aged ⩾18 years residing in British Columbia between 1999 and 2003. Residents who had visited the doctor at least thrice for rheumatoid arthritis (International Classification of Disease = 714) were considered to have rheumatoid arthritis. A non-rheumatoid arthritis cohort was matched to the rheumatoid arthritis cohort by age, sex and start of follow-up. The primary composite end point was a hospital admission for myocardial infarction, stroke or CVD mortality. Results: 25 385 adults who had at least three diagnoses for rheumatoid arthritis during the study period were identified. During the 5-year study period, 375 patients with rheumatoid arthritis had a hospital admission for myocardial infarction, 363 had a hospitalisation for stroke, 437 died from cardiovascular causes and 1042 had one of these outcomes. The rate ratio for a CVD event in patients with rheumatoid arthritis was 1.6 (95% confidence interval (CI) 1.5 to 1.7), and the rate difference was 5.7 (95% CI 4.9 to 6.4) per 1000 person-years. The rate ratio decreased with age, from 3.3 in patients aged 18–39 years to 1.6 in those aged ⩾75 years. However, the rate difference was 1.2 per 1000 person-years in the youngest age group and increased to 19.7 per 1000 person-years in those aged ⩾75 years. Among patients with a prior CVD event, the rate ratios and rate differences were not increased in rheumatoid arthritis. Conclusions: This study confirms that rheumatoid arthritis is a risk factor for CVD events and shows that the rate ratio for CVD events among subjects with rheumatoid arthritis is highest in young adults and those without known prior CVD events. However, in absolute terms, the difference in event rates is highest in older adults.

Summary Bisphosphonate-related osteonecrosis of the jaw (BONJ) is an adverse effect of bisphosphonate use with a poorly described epidemiology in osteoporosis patients. We examined the literature and two new cohorts for BONJ. The literature suggests an incidence rate of 0.028 % to 4.3 %. Our cohort studies found an incidence of 0.02 % (95 % CI 0.004 %–0.11 %). Introduction We examined the epidemiology of BONJ associated with osteoporosis dosing of bisphosphonates. Methods First, we systematically searched the literature about osteoporosis BONJ. Identified studies were abstracted by two authors. Second, we attempted to estimate the relative risk of BONJ among bisphosphonate users with osteoporosis. Two different large insurance databases, one from 2005–2007 and another from 2007–2010, combined with medical record review, were searched. The older dataset did not include the International Classification of Diagnoses (ICD) diagnosis code for osteonecrosis of the jaw (ONJ; ICD 733.45). Incidence rates and relative risks were estimated using Cox regression. Results The literature review produced nine studies of varying quality. The incidence rates for BONJ among osteoporosis patients varied from 0.028 % to 4.3 %. Two prior studies estimated the relative risk of ONJ related to bisphosphonates and found odds ratios of 7.2 and 9.2. Our attempts to estimate the incidence rate of BONJ encompassed 41,957 in the dataset from 2005–2007 and 466,645 in a separate dataset from 2007–2010. From the older dataset, we found 51 potential cases of BONJ using a broad definition of possible ONJ. One case was confirmed by a dentist for a prevalence of 0.02 % (95 % CI 0.004 %–0.11 %) among bisphosphonate users. From the newer dataset, we found 13 possible cases, but none could be confirmed. Most subjects with the ONJ diagnosis code appeared to have had an osteoporosis-related fracture and not ONJ. Conclusions The literature suggests a broad range of possible values for the prevalence of BONJ; our estimate fell within the range from prior literature.

Background:Uric acid lowering therapy (UALT) is considered a chronic treatment for gout. Relatively little is known about adherence to UALT.Methods:We assessed adherence with UALT over a 1-year study period among 9823 older adults enrolled in a pharmacy benefit program. Two adherence measures were calculated, the percentage of days covered (PDC) and the time until an extended break (at least 60 days) in treatment. A PDC <80% was considered poor adherence and its predictors were examined in multivariable logistic models.Results:The mean (SD) PDC was 54% (36%) with 64% of patients considered poorly compliant over the study period. A total of 56% had experienced an extended break in UALT. Predictors of poor adherence included younger age (odds ratio (OR) 1.50, 95% CI 1.33–1.69 for ages 65–74 compared with 85 and above) and African–American race (OR 1.86, 95% CI 1.52–2.27 compared with Caucasian race). Most patients (93%) received their initial UALT prescription from a non-specialist and this also predicted poor adherence (OR 1.15, 95% CI 0.96–1.38 compared with rheumatologists or nephrologists).ConclusionAdherence with UALT is poor. While uric acid levels were not measured in this study, poor adherence with UALT is likely to reduce attainment of goal uric acid levels.

Dr. Jerry Avorn explains that there is one area of biomedicine in which the government allows — even defends — a minimal standard that would be unacceptable anywhere else in research. It is the set of evidentiary requirements maintained by the Food and Drug Administration for the approval of new drugs. The cliché “good enough for government work” implies that lower standards are acceptable for a job sponsored by a public agency. But in biomedical research, the opposite is usually true. The National Institutes of Health has always had tough standards; its newly constrained funding is leading to an even more stringent review process, so that near-perfect evaluation scores are now required to win support. Similarly stringent criteria prevail at the National Science Foundation. Yet there is one area of biomedicine in which the government allows — even defends — a minimal standard that would be unacceptable anywhere else in research. . . .

Summary Adherence and persistence with osteoporosis medications are poor. We conducted a systematic literature review of interventions to improve adherence and persistence with osteoporosis medications. Seven studies met eligibility requirements and were included in the review. Few interventions were efficacious, and no clear trends regarding successful intervention techniques were identified. However, periodic follow-up interaction between patients and health professionals appeared to be beneficial. Introduction Adherence and persistence with pharmacologic therapy for osteoporosis are suboptimal. Our goal was to examine the design and efficacy of published interventions to improve adherence and persistence. Methods We searched medical literature databases for English-language papers published between January 1990 and July 2008. We selected papers that described interventions and provided results for control and intervention subjects. We assessed the design and methods of each study, including randomization, blinding, and reporting of drop-outs. We summarized the results and calculated effect sizes for each trial. Results Seven studies met eligibility requirements and were included in the review. Five of the seven studies provided adherence data. Of those five studies, three showed a statistically significant (p ≤ 0.05) improvement in adherence by the intervention group, with effect sizes from 0.17 to 0.58. Five of the seven studies provided persistence data. Of those five, one reported statistically significant improvement in persistence by the intervention group, with an effect size of 0.36. Conclusions Few interventions were efficacious, and no clear trends regarding successful intervention techniques were identified in this small sample of studies. However, periodic follow-up interaction between patients and health professionals appeared to be beneficial.

Large health care utilization databases are frequently used in variety of settings to study the use and outcomes of therapeutics. Their size allows the study of infrequent events, their representativeness of routine clinical care makes it possible to study real-world effectiveness and utilization patterns, and their availability at relatively low cost without long delays makes them accessible to many researchers. However, concerns about database studies include data validity, lack of detailed clinical information, and a limited ability to control confounding. We consider the strengths, limitations, and appropriate applications of health care utilization databases in epidemiology and health services research, with particular reference to the study of medications. Progress has been made on many methodologic issues related to the use of health care utilization databases in recent years, but important areas persist and merit scrutiny.

With more than a decade of experience accumulated, it is clear that the FDAAA introduced important improvements in the FDA’s capacity to track medication effects and mitigate risk. But challenges persist.

Background. Systemic antifungal medications can be lifesaving but can also have important toxicities. With a number of new antifungal drugs being introduced, there is a compelling need to define the toxicities associated with existing therapies. Methods. We identified cases of hepatotoxicity among patients who underwent bone marrow transplantation and selected matched control subjects from the same population. Multivariable logistic regression modeling was used to control for patient characteristics in evaluating the relationship between hepatotoxicity and exposure to antifungal medications. Follow-up analyses were performed for patients who continued receiving antifungal medications after developing hepatotoxicity. Results. The unadjusted incidence of hepatotoxicity was 0.78 cases per 100 patient-days of exposure to amphotericin deoxycholate, 0.98 for fluconazole, and 1.50 for liposomal amphotericin B. Case-control analyses found that liposomal amphotericin B was associated with a substantial increase in the risk of hepatotoxicity in these patients (odds ratio [OR], 3.33; 95% confidence interval [CI], 1.61–6.88); a smaller increase in risk was found for fluconazole (OR, 1.99; 95% CI, 1.21–3.26). There was no statistically significant association between amphotericin B deoxycholate and the development of hepatotoxicity. Patients had greater elevations of serum transaminase values associated with exposure to larger cumulative doses of liposomal amphotericin B. In the follow-up analysis of patients who developed hepatotoxicity and who continued receiving antifungal medication, one-third of those receiving liposomal amphotericin B had marked increases in bilirubin levels, as opposed to 8% of patients treated with fluconazole. Conclusions. In these bone marrow transplant recipients, liposomal amphotericin B and fluconazole were both associated with increased risk of hepatotoxicity, independent of other treatments received or patient characteristics; the magnitude of the risk was larger for liposomal amphotericin B. Patients who develop hepatotoxicity appear to tolerate continued therapy with fluconazole, but a large fraction of those who received liposomal amphotericin B have worsening conditions with continued treatment.