Influence of baseline neurologic severity on disease progression and the associated disease-modifying effects of tafamidis in patients with transthyretin amyloid polyneuropathy.

BACKGROUND: Emerging evidence suggests that several factors can impact disease progression in transthyretin amyloid polyneuropathy (ATTR-PN). The present analysis used longitudinal data from Val30Met patients participating in the tafamidis (selective TTR stabilizer) clinical development program to evaluate the impact of baseline neurologic severity on disease progression in ATTR-PN. METHODS: A linear mixed-effects model for repeated measures (MMRM) was constructed using tafamidis and placebo data from the intent-to-treat Val30Met population of the original registration study as well as tafamidis data from the two consecutive open-label extension studies. The second extension study is ongoing, but a prospectively-planned interim analysis involving a cleaned and locked database was conducted (cut-off: December 31, 2014). Val30Met patients are presented by treatment groups as those who received tafamidis during the registration and open-label studies (T-T group), or who received placebo during the registration study and were switched to tafamidis in the open-label studies (P-T group). Neurologic functioning was assessed at baseline and subsequent visits using the Neuropathy Impairment Score-Lower Limbs (NIS-LL). The analysis focused on the disease trajectory over the first 18 months of treatment. RESULTS: The T-T (n = 64) and P-T (n = 61) cohorts were predominantly Caucasian and presented with early-stage neurologic disease (mean [standard deviation] baseline NIS-LL values were 8.4 [11.4] and 11.4 [13.5], respectively). The MMRM analysis demonstrated that baseline severity is an independent significant predictor of disease progression in addition to the treatment effect: patients with a lower baseline NIS-LL showed less progression than those with a higher baseline NIS-LL (p < 0.0001). Neurologic progression in the T-T group was less than in the P-T group across all levels of baseline NIS-LL (p = 0.0088), and the degree of separation increased over the 18-month period. Similar results were seen with the NIS-LL muscle weakness subscale. CONCLUSIONS: This analysis of patients with Val30Met ATTR-PN demonstrates that neurologic disease progression strongly depends on baseline neurologic severity and illustrates the disease-modifying effect of tafamidis relative to placebo across a range of baseline levels of neurologic severity and treatment durations. These data also underscore the benefit of early diagnosis and treatment with tafamidis in delaying disease progression in ATTR-PN. TRIAL REGISTRATION: NCT00409175 , NCT00791492 and NCT00925002 registered 08 December 2006, 14 November 2008 (retrospectively registered), and 19 June 2009, respectively.

Potential Clinical and Economic Impact of Switching Branded Medications to Generics.

Switching branded to generic medications has become a common cost-containment measure. Although this is an important objective for health care systems worldwide, the impact of this practice on patient outcomes needs to be carefully considered. We reviewed the literature summarizing the potential clinical and economic consequences of switching from branded to generic medications on patient outcomes. A literature search of peer-reviewed articles published 2003-2013 using key words of "generic switching" or "substitution" was conducted using PubMed, OvidSP, and ScienceDirect. Of 30 articles identified and reviewed, most were related to the diseases of the central nervous system, especially epilepsy. Based on our review, potential impacts of switching fell into 3 broad categories: patient attitudes and adherence, clinical and safety outcomes, and cost and resource utilization. Although in many cases generics may represent an appropriate alternative to branded products, this may not always be the case. Specifically, several studies suggested that switching may negatively impact medication adherence, whereas other studies found that generic switching was associated with poorer clinical outcomes and more adverse events. In some instances, switching accomplished cost savings but did so at increased total cost of care because of increased physician visits or hospitalizations. Although in many cases generics may represent an appropriate alternative, mandatory generic switching may lead to unintended consequences, especially in certain therapeutic areas. Although further study is warranted, based on our review, it may be medically justifiable for physicians and patients to retain the right to request the branded product in certain cases.

Patterns of cholinesterase-inhibitor use in the nursing home setting: a retrospective analysis.

OBJECTIVE: This study compared dosing and utilization patterns of the cholinesterase inhibitors (ChEIs) donepezil, rivastigmine, and galantamine in the nursing home setting. METHODS: An exploratory, retrospective analysis of prescription claims data from January 1, 2001, to March 31, 2003, was conducted using data from a nationwide network of long-term care facilities in the United States. Nursing home residents with > or =1 new prescription for donepezil, rivastigmine, or galantamine during the index period from June 1, 2001, through March 31, 2002, were identified, and those who received an index prescription for a ChEI >45 days after nursing home admission and remained in the nursing home for > or=1 year after the initiation of ChEI treatment were included in the analysis. Utilization patterns were evaluated based on prescription claims for 1 year after the initiation of therapy. The study end points were the proportions of patients discontinuing or switching ChEI therapy, the proportion reaching an effective daily dose of ChEI therapy, the mean time to effective dose, and the mean daily dosage. RESULTS: : Two thousand eight hundred seventy-three residents of 1417 nursing homes were included in this analysis, of whom 1906 (66.3%) were prescribed donepezil, 507 (17.6%) rivastigmine, and 460 (16.0%) galantamine. The proportion of residents who were prescribed an effective dose at any point during the 1-year study period was significantly greater for donepezil than for rivastigmine or galantamine (99.3%, 72.5%, and 65.1%, respectively; both, P < 0.001). The difference between rivastigmine and galantamine also was statistically significant (P < 0.014). Donepeziltreated residents had a significantly shorter mean time to effective dose than rivastigmine- and galantamine-treated residents (1.5, 76.7, and 99.9 days; P < 0.001). The mean daily dosage of donepezil was above the effective dose throughout the study period, whereas the mean daily dosage was below the effective dose for the first 3 months with rivastigmine and did not approach the effective dose for galantamine until month 12. ChEl therapy was discontinued during the study period by 43.1%, 46.2%, and 47.0% of donepezil-, rivastigmine-, and galantamine-treated residents, respectively. The corresponding proportions of residents switching therapy were 3.3%, 4.7%, and 2.0%. CONCLUSIONS: The results of this study suggest that early effective dosing occurred more often with donepezil than with rivastigmine or galantamine in these nursing home residents. Almost half of residents discontinued donepezil, rivastigmine, or galantamine, whereas rates of switching from one ChEI to another were low.

Predictors of self-neglect in community-dwelling elders.

OBJECTIVE: The study assessed the contribution of depressive symptoms and cognitive impairment to the prediction of self-neglect in elderly persons living in the community. METHOD: Data were drawn from the New Haven Established Populations for Epidemiologic Studies of the Elderly cohort, which included 2,812 community residents age 65 years and older in 1982. The principal outcome examined was the incidence of self-neglect, corroborated by the state's investigation, during 9 years of follow-up (1982-1991). RESULTS: Among the 2,161 subjects included in the analysis, 92 corroborated cases of self-neglect occurred from 1982 to 1991. The prevalence of clinically significant depressive symptoms at baseline (score > or=16 on the Center for Epidemiologic Studies Depression Scale [CES-D]) was 15.4%, and the prevalence of clinically significant cognitive impairment (four or more errors on the Pfeiffer Short Portable Mental Status Questionnaire) was 7.5%. Subjects with clinically significant depressive symptoms and/or cognitive impairment were more likely than others to experience self-neglect. Clinically significant depressive symptoms and cognitive impairment remained significant predictors of self-neglect in a multivariate model that included age, gender, race, and income. A final model for self-neglect constructed with stepwise selection of risk factors included depressive symptoms and cognitive impairment, as well as male gender, older age, income less than $5,000 per year, living alone, history of hip fracture, and history of stroke. CONCLUSIONS: Elderly individuals living in the community who experience clinically significant depressive symptoms and/or cognitive impairment may be at risk for the development of self-neglect and may become candidates for intervention.

Major depression in elderly home health care patients.

OBJECTIVE: Despite the growth of geriatric home health services, little is known about the mental health needs of geriatric patients seen in their homes. The authors report the distribution, correlates, and treatment status of DSM-IV major depression in a random sample of elderly patients receiving home health care for medical or surgical problems. METHOD: Geriatric patients newly admitted to a large, traditional visiting nurse agency were sampled on a weekly basis over a period of 2 years. The 539 patients ranged in age from 65 to 102 years; 351 (65%) were women, and 81 (15%) were nonwhite. The Structured Clinical Interview for DSM-IV Axis I Disorders was used to interview patients and informants. The authors reviewed the results of these interviews plus the patients' medical charts to generate a best-estimate DSM-IV psychiatric diagnosis. RESULTS: The patients had substantial medical burden and disability. According to DSM-IV criteria, 73 (13.5%) of the 539 patients were diagnosed with major depression. Most of these patients (N=52, 71%) were experiencing their first episode of depression, and the episode had lasted for more than 2 months in most patients (N=57, 78%). Major depression was significantly associated with medical morbidity, instrumental activities of daily living disability, reported pain, and a past history of depression but not with cognitive function or sociodemographic factors. Only 16 (22%) of the depressed patients were receiving antidepressant treatment, and none was receiving psychotherapy. Five (31%) of the 16 patients receiving antidepressants were prescribed subtherapeutic doses, and two (18%) of the 11 who were prescribed appropriate doses reported not complying with their antidepressant treatment. CONCLUSIONS: Geriatric major depression is twice as common in patients receiving home care as in those receiving primary care. Most depressions in patients receiving home care are untreated. The poor medical and functional status of these patients and the complex organizational structure of home health care pose a challenge for determining safe and effective strategies for treating depressed elderly home care patients.