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Dosis más altas de Inhibidores de Colinesterasas mejoran la "funcionalidad" del paciente con enfermedad de Alzheimer.
 

Dosis más altas de Inhibidores de Colinesterasas mejoran la "funcionalidad" del paciente con enfermedad de Alzheimer.

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Presentado en el II CURSO DE ACTUALIZACION EN ENFERMEDADES NEURODEGENERATIVAS REALIZADO

Presentado en el II CURSO DE ACTUALIZACION EN ENFERMEDADES NEURODEGENERATIVAS REALIZADO

01 de Junio 2013

Punta Sal Tumbes - Perú

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  • Los factores evaluados (características de pacientes y cuidadores) fue usado en un análisis multivariado según un modelo de regresión lineal usando “costos totales variables de los 3 meses” como variable dependiente para explicar el análisis. Debido a que los costos variables mostraron una distribución con tendencia hacia la derecha, el estimado fue también realizado con una escala logaritmica (logaritmo transformado de los costos totales variables). Este tipo de análisis fue aplicado también para subtipos de demencia. Aplicando este método notamos que el mejor modelo para explicar los costos totales de demencia incluyeron las siguientes variables: subtipo de demencia, CDR y edad del cuidador. También, el análisis multivariado mostró que estas variables no son significativas por subtipos de demencia. Solo CDR y edad del cuidador fue asociada a costos significativamente altos en pacientes con demencia de Alzheimer y pacientes con demencia vascular. En pacientes con demencia frontotemporal, sólo los cuidadores que fueron pagados fueron estadisticamente asociados con elevados costos totales variables.
  • Recientemente, se han propuesto unos nuevos criterios de investigación para la EA, que pueden resultar en un gran avance para el diagnóstico de la EA probable en cualquier estadio de la enfermedad, incluida la fase prodrómica . El principal cambio respecto a los bien establecidos criterios NINCDS-ADRDA es que la presencia de deterioro significativo de la memoria episódica, independientemente del grado de pérdida funcional, junto con la presencia de al menos un biomarcador anormal, son suficientes para el diagnóstico de EA probable. En consecuencia, esta nueva propuesta de criterios de investigación de la EA permite tanto el diagnostico etiológico como el establecimiento de un diagnóstico en la fase prodrómica de la enfermedad.
  • En los nuevos criterios diagnósticos propuestos para la EA, la fase prodrómica se define como la fase sintomática predemencia de la EA, que se caracteriza por la presencia de síntomas que no son lo suficientemente graves como para cumplir los criterios diagnósticos actuales de EA. De acuerdo con estos criterios, la EA probable se define por un criterio central, que es la alteración de la memoria episódica, junto con la presencia de un marcador biológico anormal. Los criterios complementarios requieren un cambio gradual y progresivo en la función de la memoria al inicio de la enfermedad referidos por los pacientes o los cuidadores durante un período mayor de seis meses y una evidencia objetiva de deterioro de la memoria episódica evaluado mediante test neuropsicológicos. Se ha descrito en numerosas ocasiones que la EA típica se caracteriza por un cuadro de deterioro de la memoria, a veces llamado ‘síndrome amnésico de tipo hipocampal’ [ Sarazin M, Berr C, De Rotrou J, Fabrigoule C, Pasquier F, Legrain S, et al. Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study. Neurology 2007; 69: 1859-67. ], que se caracteriza por una alteración significativa en el recuerdo libre de la información que no se beneficia de facilitaciones semánticas, además de presentar numerosas intrusiones y falsos reconocimientos . Por esta razón, se recomienda el uso de tests que proporcionen codificación específica de la información que se debe recordar mediante pistas semánticas. Además del criterio central de memoria, el paciente debe cumplir con uno de los criterios adicionales propuestos, que tienen su base en la presencia del resultado positivo de un marcador biológico de EA. Éstos son la presencia de atrofia en el lóbulo temporal medial evaluada mediante resonancia magnética (RM), concentraciones anormales de proteína tau o beta-amiloide en el líquido cefalorraquídeo (LCR), hipometabolismo temporoparietal o detección de beta-amiloide evaluado mediante tomografía por emisión de positrones (PET). La presencia de una mutación autosómica dominante en cualquiera de los genes descritos que producen una EA en un paciente sintomático implicaría el diagnóstico de EA definitiva. En resumen, los nuevos criterios diagnósticos para EA se basan en la presencia de un déficit de memoria episódica, junto con un resultado anormal en la RM, LCR, PET o la presencia de una mutación autosómica de EA. Estos criterios permiten hacer un diagnóstico específico debido a la presencia de un perfil de biomarcadores positivo, y precoz, incluso en la fase prodrómica, lo que puede ser de gran utilidad a la hora de realizar ensayos clínicos para probar nuevos fármacos modificadores del curso evolutivo de la enfermedad.
  • Los resultados mostraron que las alteraciones en la memoria episódica y la memoria semántica podían considerarse factores de riesgo para la evolución a EA. Este resultado es consistente con un estudio de cohorte anidada del grupo de Molinuevo en el que se definió la EA-Prod como un grupo de pacientes amnésicos al inicio del estudio que desarrollaron demencia típica de EA después de dos años de seguimiento. Comparando los resultados obtenidos por los dos grupos al inicio del estudio, el grupo EA-Prod obtuvo puntuaciones significativamente más bajas en memoria episódica y memoria semántica que el grupo de amnésicos estables, que no evolucionaron a EA después del período de seguimiento [ Molinuevo JL, Gómez-Anson B, Monte GC, Bosch B, Sánchez-Valle R, Rami L. Neuropsychological profile of prodromal Alzheimer’s disease (Prd-AD) and their radiological correlates. Arch Gerontol Geriatr 2010; Apr 6. Epub ahead of print ]. Además de un claro deterioro de la memoria episódica, definido en numerosos trabajos como predictor de conversión a EA [ Sarazin M, Berr C, De Rotrou J, Fabrigoule C, Pasquier F, Legrain S, et al. Amnestic syndrome of the medial temporal type identifies prodromal AD: a longitudinal study. Neurology 2007; 69: 1859-67. ] [ Tounsi H, Deweer B, Ergis AM, Van der Linden M, Pillon B, Michon A, et al. Sensitivity to semantic cuing: an index of episodic memory dysfunction in early Alzheimer disease. Alzheimer Dis Assoc Disord 1999; 13: 38-46. ], los pacientes presentaban también dificultades incipientes en la recuperación de datos semánticos, aunque con puntuaciones situadas dentro del rango de la normalidad. Obviamente, en este estudio, y de acuerdo con la definición de la EA-Prod, el resto de dominios cognitivos se encontraba dentro del rango de funcionamiento normal. Es ya una evidencia que el deterioro de la memoria episódica en fases incipientes de la EA está relacionado con la deposición de ovillos neurofibrilares en la corteza entorrinal y el hipocampo [ Braak H, Braak E. Neuropathological staging of Alzheimer related changes. Acta Neuropathol 1991; 82: 239-59 ]. Además, a medida que la enfermedad progresa, la patología se extiende hacia la región temporal inferior y lateral, lo que podría explicar la disfunción temprana de la memoria semántica que se observa en pacientes no dementes con EA-Prod. Resultados obtenidos por el grupo de Molinuevo aplicando los nuevos criterios también confirman la correlación del déficit de memoria con la pérdida de sustancia gris en las áreas descritas en esta fase predemencia de la enfermedad [Molinuevo JL, Solé-Padullés C, Fortea J, Bosch B, Lladó A, Antonell A, et al. Applying the new research diagnostic criteria: MRI findings and neuropsychological correlations of predementia AD. Eur J Neurol 2010 . Under review]. El concepto de deterioro cognitivo leve (DCL) es muy util para la practica clinica; pero en los circulos de investigacion, esta siendo abandonado y reemplazado por EA prodromica (DCL asociado a un biomarcador de EA), y recuerde que antes de EA prodromica, viene EA pre-clinica.
  • Enfermedad de Alzheimer : Este nivel diagnóstico se restringe ahora al desarreglo clínico que se inicia con la aparición de los primeros síntomas clínicos específicos de la enfermedad, e incluyen tanto las fases de pre-demencia y demencia. De tal forma, el término “Enfermedad de Alzheimer” se refiere a todo el espectro de la fase clínica de la enfermedad y no está restringido al síndrome de la demencia. El diagnóstico está ahora establecido (según el artículo de Dubois) en vivo y recae sobre una entidad dual clínico-biológica que requiere la evidencia tanto de cambios específicos en la memoria y de marcadores en vivo que la patología de Alzheimer puede incluir: niveles de β -amiloine en líquido cerebro-espinal (líquido cefaloraquídeo LCR), TAU total, y fosfo-TAU; retención de trazadores PET específicos de amiloide; atrofia del lóbulo medial-temporal; y/o hipometabolismo temporo-parietal sobre PET fluorodeoxiglocusa. El fenotipo clínico puede ser típico o atípico. Además, dos etapas diferentes todavía podrían ser útiles: una “fase prodómica” y una “fase demencia”. La EA prodómica. Este término se refiere a la fase sintomática temprana, fase de predemencia de la EA en la cual los síntomas clínicos, incluyendo la pérdida episódica de memoria del tipo hipocampal está presente, pero no es lo suficientemente severa como para afectar las actividades instrumentales de la vida diaria y no garantiza un diagnóstico de demencia; y en la cual la evidencia en vivo (por biomarcadores), bien sea niveles LCR de β -amiloine o neuroimagen, es soporte de la presencia de cambios patológicos de la EA. El término de EA prodómica podría desaparecer en el futuro si la EA es considerada al incluir tanto las etapas de predemencia y demencia. Demencia EA . Este término se refiera la fase de la Ea durante la cual los síntomas cognitivos son lo suficientemente severos como para interferir con el funcionamiento social y las actividades instrumentales de la vida diaria, un umbral que se considera para definir la demencia, en asociación con cambios de la memoria episódica y, al menos, otro dominio cognitivo. Este término todavía podría ser útil para identificar el umbral de demencia para ensayos clínicos o evaluaciones socio-económicas EA típica . Este término se refiere al fenotipo clínico más común de la EA, que es caracterizado por un temprano déficit de memoria episódico significativo y progresivo que permanece dominante en las etapas posteriores de la enfermedad, y es seguido de, o asociado con, otros alteraciones cognoscitivas (disfunción ejecutiva, lenguaje, práctica, y alteraciones en el procesamiento visual complejo). El diagnóstico es además soportado por uno de más biomarcadores en vivo. EA atípica . Este término se refiere al fenotipo clínico menos común y menos caracterizado de la EA que ocurre con la patología Alzheimer. Estos sindromes clínicos incluyen una afasia primaria progresiva no-fluida, afasia logopenica, variante frontal de EA, y posterior atrofia cortical. En la presencia de una de estas presentaciones clínicas, el diagnóstico de EA es apoyado por pruebas en vivo de amyloidosis en el cerebro (con la retención de amiloide específico) o en el LCR (con la característica de cambios de la patología del alzheimer en la B amyloid, tau, y concentraciones fosfo-tau). EA combinada. Este término se refiere al diagnóstico que de personas que cumplen con los criterios diagnósticos para EA típico y, además, presentan evidencia, bien sea a través de la evaluación clínica, neuroimagen cerebral o pruebas biológicas, de otros desórdenes comórbidos, como la enfermedad cerebrovascular o la enfermedad de cuerpos de Lewy.
  • Prevención secundaria significa detectar y tratar la enfermedad antes que los síntomas ocurran. Vale decir que prevención secundaria es sinónimo de tratamiento muy temprano, o mejor dicho evitar la declinación relacionada al amiloide en adultos mayores cognitivamente normales. Prevención primaria significa inhibir la enfermedad antes que ocurra, lo cual podría clarificar la transición del envejecimiento normal hacia EA apoyados en la epidemiología y la genética, pudiendo establecer medidas de prevención en las etapas medias de la vida. Pero, hoy día, contamos con estrategias de tratamiento sintomático, que sólo logran retrasar modestamente la evolución de los síntomas cognitivos, retrasan la aparición de síntomas conductuales y pueden preservar la funcionalidad del individuo con demencia.
  • Los objetivos son: Mantener calidad de vida. Maximizar funcionalidad. Estabilizar funcion cognitiva. Tratar sintomas psicologicos y conductuales de demencia Disminuir la carga del cuidador.
  • Table 6 shows the results of a regression analyses. The results from the full model that included all predictors, as well as results from the reduced model that included only significant predictors are presented. Patients dependent upon others to perform activities of daily living clearly had a lower QoL than independent patients . The QoL of independent patients suffering from dementia as assessed by their capacity to perform activities of daily living was 0.641 (95% confidence interval: [0.612 – 0.669]) whereas the QoL of dependent patients for the same assessment was 0.343 (95% CI: [0.251 – 0.436]). Severity of dementia and setting has no statistically significant impact on QoL. Discussion For the first time, this study provides health utilities for patients with dementia in Denmark. This study has shown that the factor that most affects the HRQoL of a patient with dementia is their dependency status as defined based by their ability to perform activities of daily living . The type of dementia doesn't seem to have a great an influence on patient's HRQoL, and severity does not appear to discriminate significantly between health utilities. However, due to missing data – particularly among patients with severe dementia – caution must be exercised when interpreting the results. In the utility results previously measured by Neumann et al. [7] using the Health Utility Index (HUI), AD patients‘ utilities decreased significantly with their severity levels. However, this could be explained by the fact that the EQ- 5D does not consider cognition as a separate attribute, unlike the HUI scales. Despite this difference, results obtained with the HUI and the EQ-5D instruments were within the same range. As the EQ-5D values were estimated based on mapped questions, it raises the possibility of quotation bias and goodness of fit. Also, both patients and caregivers answered questions. Yet, with AD – and especially when patients are severely demented – it is impossible to collect non-proxy measurements in the later stages. The same methodology was performed in previous evaluations without knowing the impact of the difference between caregivers' and patients' perceptions. A particular strength of this study was that all data have been collected in conjunction with an epidemiological study wherein patients with dementia had been examined carefully and dementia criteria were explicitly stated. Conclusion Measuring HRQoL is as important as measuring disease severity, progression, symptom response, cognition and behavioural disturbance when assessing the impact of disease and determining proper intervention in the treatment and management of dementia. However, HRQoL is difficult to assess in a disease such as dementia for which patients suffer from cognitive disabilities. Based on study results and as previously shown by Kurz et al. [3], dependency level greatly influences patients' HRQoL and, when viewed as a global measure, reflects a certain level of HRQoL. Determining dependency levels could be considered as an indirect evaluation of HRQol. Other studies with disease specific questionnaires such as QoL-AD are needed to confirm these findings.
  • Behavioural symptoms appear at all stages of AD, sometimes 2 years prior to diagnosis (Jost and Grossberg, 1996). Peak frequencies of disturbances are indicated on a time line of disease progression. Social withdrawal occurred an average of 33 months before diagnosis and was the earliest recognisable psychiatric symptom observed. Suicidal ideation, depression, paranoia, and diurnal rhythm disturbances also occurred early in the course of the disease, whereas agitation, hallucinations, and aggression were documented an average of 1–2 years after diagnosis.
  • In a US, 5-month multicentre, placebo-controlled, double-blind trial, following a~4-week placebo run-in, 978 patients with mild to moderate AD were randomly assigned to placebo treatment or galantamine escalated to final maintenance doses of 8, 16 or 24 mg/day (Tariot et al., 2000). Patients included in the trial did not have a high level of behavioural disturbances at baseline (baseline NPI scores: placebo=11; 8 mg/day=12.9; 16 mg/day= 12.4; 24 mg/day=11.9). At 5 months, both 16 and 24 mg/day groups had significantly better NPI total scores than placebo (OC and ITT analyses; p<0.05 both groups).
  • 9. INCREASED PROBABILITY OF INSTITUTIONALIZATION BY DISEASE SEVERITY Hauber and colleagues 1 used a hazard model to estimate direct cost savings attributable to delay in cognitive decline with rivastigmine treatment in the US. Disease progression was defined in terms of intervals in the MMSE scale. Clinical trial data 2,3 were then used to determine the time at which a particular patient moved into a more severe stage of the disease. Direct and indirect costs (US $) of transition from one stage of AD to another based as a function of MMSE, using a formula established by Ernst and colleagues. 4 Probability of institutionalization at each MMSE score 1 based on CERAD database 5 Cost savings due to rivastigmine = (incremental cost of transitioning from one disease severity to the next)  (additional days spent in the less severe stage) The probability of institutionalization increased with AD progression, suggesting that early intervention is the optimal management strategy with ultimate expectations for decreased overall costs. --------------------------------------------------------------------------------- Pharmacoeconomics. 2000 Apr;17(4):351-360 Comment in: Pharmacoeconomics. 2000 Dec;18(6):609-12. Potential savings in the cost of caring for Alzheimer's disease. Treatment with rivastigmine. Hauber AB, Gnanasakthy A, Snyder EH, Bala MV, Richter A, Mauskopf JA. Research Triangle Institute, Research Triangle Park, North Carolina, USA. OBJECTIVE: To estimate savings in the cost of caring for patients with Alzheimer's disease (AD) during 6 months, 1 year and 2 years of treatment with rivastigmine. An intermediate objective was to estimate the relationship between disease progression and institutionalisation. DESIGN AND SETTING: We assessed the relationship between Mini-Mental State Examination (MMSE) score and institutionalisation using a piecewise Cox proportional hazard model. To estimate cost savings from treatments lasting 6 months, 1 year and 2 years, estimates of the probability of institutionalisation were integrated with data from two 6-month phase III clinical trials of rivastigmine and a hazard model of disease progression. MAIN OUTCOME MEASURES AND RESULTS: Our data suggest that savings in the overall cost of caring for patients with mild and moderate AD can be as high as $US4839 per patient after 2 years of treatment. Furthermore, the probability of institutionalisation increases steadily as MMSE score falls. Among our study individuals, age, race, level of education and marital status were significant predictors of institutionalisation, whereas gender had little effect. CONCLUSIONS: Using rivastigmine to treat AD results in a delay in disease progression for patients who begin treatment during the mild or moderate stages of the disease. By delaying the probability that a patient will be institutionalised, the cost of caring for AD patients can be significantly reduced. Publication Types: Review; Review, Tutorial PMID: 10947490 [PubMed - indexed for MEDLINE] Clin Ther. 2000 Apr;22(4):439-451 Savings in the cost of caring for patients with Alzheimer's disease in Canada: an analysis of treatment with rivastigmine. Hauber AB, Gnanasakthy A, Mauskopf JA. Research Triangle Institute, Center for Economics Research, Research Triangle Park, North Carolina 27709-2194, USA. Hauber@RTI.org OBJECTIVE: To estimate per-patient potential cost savings using rivastigmine in the treatment of Alzheimer's disease (AD) in Canada. BACKGROUND: In recent years, new members of a class of pharmaceuticals known as cholinesterase inhibitors have been introduced for the treatment of patients with AD. Two recent studies conducted in the United Kingdom and the United States estimated potential cost savings from the new cholinesterase inhibitor rivastigmine. The present study combined the disease-progression model used in those 2 studies with Canadian costs to estimate per-patient potential savings resulting from the treatment of AD in Canada. METHODS: Efficacy data from 2 pivotal, phase III clinical trials of rivastigmine were used in a hazard model of disease progression to estimate long-term differences in cognitive functioning between patients receiving rivastigmine and patients receiving no treatment. We used the Mini-Mental State Examination (MMSE) score as our measure of disease progression. We also used Canadian costs of AD care, estimated as a function of MMSE score, to estimate cost savings experienced by treated patients compared with patients receiving no treatment. All costs and cost savings are presented in 1997 Canadian dollars. We used a societal perspective in this analysis. RESULTS: Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment. For patients with mild-to-moderate and moderate disease, this delay was estimated to be 106 and 44 days, respectively. For patients with the mild stage of AD, estimated average daily cost savings (excluding the cost of rivastigmine) ranged from Can $0.45 per patient per day at 6 months to Can $6.44 per patient per day after 2 years of treatment. For all patients, these estimated average daily cost savings ranged from a low of Can $0.71 per patient per day after 6 months of treatment to a high of Can $4.93 per patient per day after 2 years. CONCLUSION: On average, treatment with rivastigmine yields savings in the direct cost of caring for AD patients that exceed the cost of the drug after 2 years of treatment. Publication Types: Clinical Trial; Clinical Trial, Phase III PMID: 10823365 [PubMed - indexed for MEDLINE]
  • Objective: To quantify the impact of activities of daily living (ADL) scores on the risk of nursing home placement (NHP) in Alzheimer’s disease (AD) patients. Setting: Models predicting NHP for AD patients have depended on cognitive deterioration as the primary measure. However, there is increased recognition that both patient functioning and cognition are predictive of disease progression. Methods: Using the database from a prospective, randomised, double-blind trial of rivastigmine and donepezil, two treatments indicated for AD, Cox regression models were constructed to predict the risk of NHP using age, gender, ADL and MMSE (Mini-Mental State Examination) scores as independent variables. Participants: Patients aged 50–85 years, with MMSE scores of 10–20, and a diagnosis of dementia of the Alzheimer type. Results: Cox regression analyses indicated that being female, older age, lower ADL score at baseline, and deterioration in ADL all significantly increased the risk of NHP. Over 2 years, risk of NHP increased by 3% for each 1-point deterioration in ADL score independent of cognition. Conclusion: Data analyses from this long-term clinical trial established that daily functioning is an important predictor of time to NHP. Further research may be required to confirm whether this finding translates to the real world. Survival curves were constructed to illustrate the risk of NHP for an ‘average’ patient, defined as a 75 year-old woman with a mean baseline total ADL score. Using this patient, three separate trends were constructed for hypothetical ADL declines: mean study population total ADL decline, 50% of the mean study population total ADL decline, and no total ADL decline. Two years from baseline, the difference in risk of NHP between the hypothetical ADL declines highlights the impact of total ADL deterioration (19%, 15% and 12% probability of NHP after 2 years for analyses [a], [b] and [c], respectively). DISCUSSION The results indicate that the deterioration of patients’ ADL was associated with an increased risk of NHP. Greater deterioration in ADL corresponded to greater risk. Modelled data suggest that delaying the deterioration of patients’ ability to function will result in a measurable reduction in the time to NHP. Appraisal of the clinical effectiveness of AD treatments has traditionally focused on the improvement of cognitive abilities18. Until recently, most health economic studies examining the impact of AD and its treatments on healthcare financing have focused predominantly on the relationship between AD patients’ cognitive deterioration (MMSE or ADAS-cog) and the commensurate costs of AD19. Today it is widely recognised that review of the clinical and cost effectiveness of AD treatments should encompass multiple AD domains: global, cognitive, function/quality of life and behaviour/mood20,21. Yet controversially, the eligibility of patients for ChEI treatment from a cost-effectiveness perspective in the UK, as assessed by the National Institute for Health and Clinical Excellence (NICE) in 2007, was based solely on an MMSE score of 10–20. Nonetheless, the same guidance acknowledges that ChEIs may be helpful for the behavioural symptoms of AD, as well as cognition22. The role that ADL scores play in predicting the economic burden of AD is not well defined. However, our data suggest that change in ADL may be a better indicator than measures of cognition in predicting NHP and healthcare financing. The results of our analysis demonstrate that whereas both baseline ADL (daily functioning) and MMSE (cognitive) scores contributed to NHP, the impact of ADL score deterioration was the more dominant factor versus MMSE, as indicated when both variables were included in the same model. These findings are also supported by a recent meta-analysis of studies carried out in the US, which found prior NHP to be the strongest predictor of NHP (summary odds ratio [OR] = 3.47), followed by three or more ADL dependencies (OR = 3.25) and then cognitive impairment12. As the data used in this modelling analysis comprised only patients who were treated with ChEIs for up to 2 years, a considerably lower rate of NHP was evident versus nontreated historical AD populations. Using the 1989–1994 data from Medicare Alzheimer’s Disease Demonstration and Evaluation study for a cohort of 5788 dementia patients living in the community, Yaffe and colleagues estimated the NHP rate to be 22%, 40%, and 52% for 1, 2, and 3 years of follow-up , respectively23. The figures reported by Yaffe and colleagues23 reflect the pre-ChEI era, whereas the NHP rate (16.8% in 2 years) reported here is more indicative of the modern AD population, possibly reflecting the benefits of ChEIs on treatment outcomes. As a result, these data are of practical application to the health economics community interested in modelling the impact of AD progression on NHP, and its related cost implications. A decade ago, Stern and colleagues24 reported an algorithm that used gender, duration of illness, age at onset, MMSE score, and the presence or absence of extrapyramidal signs to predict NHP for AD patients, without considering the functional aspects of the disorder such as ADL. The results reported here predict that approximately 6% of AD patients showing a mean total ADL decline of 15 points will be institutionalised after 1 year of ChEI treatment, with a rate reduction to 3.7% if there is no decline in total ADL. Nursing home costs are estimated to be approximately $60,000 per year per patient in the US25, and £30,000 in the UK26. Therefore measures to prevent or delay ADL deterioration not only maintain patients’ Health-related Quality of Life (HRQoL) and delay NHP, but may also help to substantially reduce healthcare costs. Managing AD patients requires a multi-faceted approach, with a variety of interventions and the potential to reduce the burden on patients, their caregivers, and the healthcare financing systems. Previous studies have indicated that greater access to effective programmes of counselling and support for caregivers yields a measurable reduction in the rate of NHP27, and that caregiver HRQoL also has a significant impact on a patients’ time to NHP28. Hence, the symptomatic treatment of AD with ChEIs represents but one of many available options to delay NHP. The data used in these analyses were based on clinical trial results from AD patients treated with ChEIs for up to 2 years. Apart from the lower rate of NHP in the study population versus an untreated population, one must also consider the high level of scrutiny which patients in clinical trials receive. As such, outcome measures may be over- or underestimated compared to those observed in a naturalistic milieu. The lack of a placebo group in the clinical trial must also be considered. Although this could be attributed to ethical considerations, results from a placebo arm would have further enhanced the credibility of this analysis. Conclusion The accurate determination of changes in the risk of NHP is important not only for the development of more effective therapies, but also for the evaluation of the cost-effectiveness of treatment by health authorities, as NHP is the largest direct cost of care in the latter stages of AD. This analysis of data from a long-term clinical trial demonstrates that daily functioning is an important predictor of time to NHP. Although baseline ADL score influences the risk of, and time to, NHP, the decline in ADL over time was found to be a more stable predictor. This highlights the importance of maintaining patients at baseline health status; preserving or delaying the deterioration of a patient’s functioning may significantly delay NHP, not only benefiting the patient, but also reducing the considerable cost to healthcare authorities. The addition of MMSE to the regression model did not significantly change the outcome, suggesting that deterioration in ADL may provide a better predictive metric. This may have important implications for future research, clinical practice, and policy making.
  • The three measures were moderately correlated with each other ( r ranged from 0.43 between caregivers’ distress and depression to 0.58 between depression and burden) indicating related but distinct aspects of the same construct. All three burden measures were also correlated with symptoms with correlation coefficients ranging from 0.18 to 0.32 for the BPRS, 0.34–0.74 for the NPI, and 0.27– 0.45 for the Cornell Scale for Depression. Changes in symptoms and behavioral problems were significantly and positively associated with changes in caregivers’ perception of burden and in their depressive symptoms. The correlations of change in the NPI symptom scores with the change in burden measure ranged from 0.23 with the BDI to 0.43 with the burden Interview. The correlation of change in the CSDD (patient depression measure) and in the burden measure ranged from 0.18 with the BDI (caregiver depression measure) to 0.37 with the NPI caregivers’ distress scale. Change in quality of life was negatively associated with significant change in caregiver’s perceived burden because increased quality of life was associated with reduced burden. Change in the MMSE was significantly but only weakly associated with change in caregivers’ distress associated with symptoms. Variables with significant correlations with change in any of the burden measures in bivariate analyses were entered into three separate stepwise multiple regression models (although change in the NPI symptoms was not entered in the regression model with the NPI caregiver Distress Scale). Six-month changes in symptoms predicted most of the explained variance in the change in burden measures. For example, the NPI symptom score predicted changes in both caregivers’ burden and depression (partial R2 0.11– 0.19). Changes in the other two symptoms measures (BPRS and CSDD) were also significantly associated with changes in the NPI Caregivers Distress scores (partial R2 0.04 and 0.02). However, the correlation between the change in the CSDD and changes in the NPI Caregivers Distress scores was notably small. Change in patients’ quality of life and MMSE predicted small amount of variance in burden and distress albeit inconsistently. This study differed from previous studies in that it used a large dataset from a recent clinical trial to simultaneously examine both the cross-sectional and longitudinal relationship of measures of caregiver burden to multiple measures both patient and caregiver sociodemographic characteristics, clinical status, and functioning. We found consistent relationships between measures of perceived burden and depression among care givers and patients’ psychiatric and behavioral symptoms and quality of life but only limited relationships to cognitive function and activities of daily living. More importantly, this study reports significant relationships between changes in patient symptoms and behavioral problems at 6-month follow-up and changes in caregiver burden and identified patient factors that account for most of the explained variance in change in all three measures of caregiver burden. This finding is unique to this study and it highlights the importance of developing interventions that specifically target these behavioral symptoms. Our findings that more severe psychiatric and behavioral problems, along with decreased quality of life were all significantly associated with higher levels of burden, and depression among caregivers are consistent with findings of other studies29,30 and replicate earlier suggestions that burden may be related more to behavioral disturbances and social dysfunction than to cognitive deficits.20,49 Some studies have also identified the particular family relationship of the patient and the caregiver as associated with different experiences of burden of.24–26 In our sample, a spouse was also found to be associated with heightened perception of burden. Our finding that changes in behavioral problems at follow-up was associated with change in caregivers burden contributes significantly to the literature in this area and points to the potential amenability of caregiver burden to treatments that are effective in ameliorating patients’ behavioral disturbances. As informal caregivers play such a crucial role in the care of patients with AD, development of appropriate management strategies that incorporate interventions which address the specific correlates of burden deserves special attention. These strategies may be important in maintaining patients with AD in the community as long as possible. Addressing the specific factors that are associated with caregivers’ stress and psychological morbidity may have important social and humanitarian as well as economic implications. Psychiatric and behavioral symptoms occur in the majority of patients with AD over the course of the illness,50–52 with symptoms of depression among 20%– 50%; patients with AD; agitated or aggressive behaviors appearing in 70%; and delusions or hallucinations in as many as 30%–50%.53–57 In fact, depression and psychosis are included as descriptors in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for AD.45 As such, the CATIE-AD sample, while selected to have these problems, is representative of the vast majority of patients with AD. The recent publication of specific clinical outcomes in CATIE-AD58 supports earlier findings that behavioral symptoms of the kind we found to be most strongly associated with caregiver burden may be improved by pharmacotherapy with atypical or second generation antipsychotics.59–61 Our results suggest that at least for those patients who experience symptom relief with or without antipsychotic medications, such improvement may be associated with decrease in caregiver burden. Olanzapine and risperidone, in particular, were found to have beneficial effects on the NPI total score, a summary measure of psychiatric and behavioral symptoms. Because the NPI was the strongest predictor of perceived burden among caregivers and changes in the NPI total score were most strongly associated with changes in burden measure, it can be hoped the effective treatment of symptoms as measured with the NPI will also reduce caregiver burden. These results form a foundation of further analysis of data from the CATIE trial that will explore this possibility. There is also some evidence that some psychological interventions with care receivers can improve certain behavioral symptoms in dementia62 and others. However, more evidence is required in this area.63 Interventions targeting caregivers, such as enhancing caregiver support, increasing “time for self,” and providing caregivers with education and training in the management of behavioral and psychological symptoms of dementia have also been shown to be effective in decreasing burden and its impact on caregivers.64–66 Additional studies have shown that caregivers consider improvement in their relatives’ quality of life to be just as important as efforts to prolong the patient’s life when choosing treatment options and that improvement in quality of life is more important than either simply lengthening survival time or delaying a move to a nursing home.67 AD-related quality of life such as social interaction, maintaining interests, and participation in activities also emerged as a robust predictor of reduced caregiver burden in this study. However, because antipsychotic medications were not beneficial in improving patients’ overall quality of life (Sultzer et al., 2008),58 additional psychosocial interventions that aim at improving patients’ quality of life directly through increased socialization, and social interactions may prove valuable both for patients and caregivers. Several methodological limitations require comment. First, although we used a longitudinal dataset, the findings remain associational in nature. In the absence of an experimental design, we cannot conclude that more severe symptoms and behavioral disturbances increase perceived caregivers’ burden. However, the fact that both the cross-sectional and the change-and-change analyses yield the same results adds to our confidence in these findings. Alternative explanations for these associations such as reverse causality and bidirectionality cannot be ruled out because although symptom severity may increase caregiver burden and distress in the caregiver, it may also result in increased symptomatology in the patient with AD. Caregiver stress and maladaptive coping may predict behavioral problems in patients with dementia.68 The second limitation is that because some measures of patients’ symptoms were based on the caregivers’ reports, it is possible that caregivers’ ratings of the severity of these symptoms reflect, at least in part, their own emotional state. However, the use of proxy reporting is inevitable in AD research, and we tried to overcome this limitation by using multiple measures of both patients symptoms and caregivers distress. CONCLUSION Severity of psychiatric symptoms and behavioral disturbances and patients’ quality of life have stronger association with caregiver perception of burden than cognitive functioning and functional skills. Combinations of pharmacologic and behavioral and family interventions targeting these two aspects of the disorder are likely to not only alleviate patient suffering but also mediate improved caregiver well-being and may also delay nursing home placement thus reducing both direct and indirect costs of care.
  • Purpose : To summarize cognitive outcomes in the Reisberg trial Key Points : Orientation to slide: — Points on the y-axis represent mean change in SIB score from baseline while points on the x-axis represent time. — As higher scores indicate better performance than placebo on cognitive tasks, positive mean changes above baseline indicate clinical improvement . There was a significant difference on the SIB outcome measure favoring memantine treatment at end point Over the 6-month period, memantine patients decreased by 3.9 points at end point, while placebo patients decreased by 9.8 points. Therefore, memantine patients had significantly less cognitive decline on the SIB total score compared with placebo. Additional Information : The SIB evaluates cognitive performance in moderate to severe AD. It includes a 40-item scale, which measures such skills as attention, language, praxis, visuospatial ability, construction, memory, and social interaction. The test is scored from 0 (greatest impairment) to 100. SIB baseline scores were 68.33 for placebo and 65.86 for memantine. ADCS reports that for patients with untreated AD whose MMSE scores are 5-9, the average deterioration rate on the SIB is roughly 3.19 points per month; and for patients with untreated AD whose MMSE are 10-15, the rate of change is 2.08 points per month. Over the 6-month period, this resulted in a 12- to 18-point drop.
  • Similar study K Edwards poster AAGP: half the pts with sx at baseline had a 30% improvement in the NPI-NH ( Dose 1.5-6.0 bid of exelon) General improvement in behavioural sx as evidenced by 46% decrease in neuroleptic therapy
  • Figure 1A illustrates the longitudinal IADL mean±95% CI outcome for the 4 different groups based on length of time in the study. The actual mean IADL outcome in the ChEI-treated patients showed a favorable effect compared with the computed scores from the baseline-dependent (comparable initial level of function) Green equation,12 assuming that the patients in this study had remained untreated. This estimation indicated significant differences between the IADL mean scores from 6 months and onward (P<0.001). The mean PSMS outcomes for the four different groups of completers are displayed in Figure 1B. As an illustration of the mean rate of PSMS decline with 95% CI for a cohort of nontreated AD patients, the longitudinal study by Green et al12 was used. Performance on the IADL and PSMS scales was stable (no change or improvement) in 32% and 56% of the patients respectively after 1 year, 18% and 38% after 2 years and 14% and 32% after 3 years. In conclusion, this study shows that the functional ability declined during the 3-year ChEI-treatment program but was, not surprisingly, best preserved among the 3-year completers. Lower cognitive ability at baseline, older age, higher education levels, and solitary living were identified as risk factors for faster decline in ADL ability, whereas a higher mean dose of ChEI during the study was associated with slower IADL decline. Regression models for treated naturalistic patients were built and could predict the longterm IADL and PSMS outcomes with the variance explained to a large extent. Furthermore, long-term ADL studies in clinical practice are needed, as ADL ability is a key domain in AD and functional evaluations should be regarded as important as cognitive. Recommendations and general acceptance for a common ADL scale that is non gender biased in future placebo-controlled trials and clinical studies would be desirable, to facilitate comparisons between studies.
  • Purpose of the Study: To identify risk factors for early nursing home placement (NHP) in Alzheimer’s disease (AD), focusing on the impact of longitudinal change in cognition, activities of daily living (ADL), service utilization, and cholinesterase inhibitor treatment (ChEI). Design and Methods: In an open, 3-year, prospective, multicenter study in a routine clinical setting, 880 AD patients were treated with either donepezil, rivastigmine, or galantamine. At baseline and every 6 months, they were assessed with several rating scales including Mini-Mental State Examination, Instrumental Activities of Daily Living scale (IADL), and Physical Self-Maintenance scale. Moreover, the dose of ChEI, the amount of weekly assistance (home help service and adult day care), and the date of NHP were recorded. Cox regression models were constructed to predict the risk of NHP. Results: During the study, 206 patients (23%) were admitted to nursing homes. Factors that precipitated institutionalization were lower cognitive and functional abilities at baseline, faster rate of decline in IADLs, female gender, solitary living, and a lower mean dose of ChEI. The men living alone and patients with a substantial increase in adult day care also demonstrated shorter time to NHP. Implications: The rate of functional but not cognitive decline was a strong risk factor for NHP. The results could be used to identify the care recipients that might risk early NHP to ensure that these individuals receive a sufficient level of assistance. Furthermore, higher doses of ChEI might postpone institutionalization in AD. Figure 1. Kaplan–Meier graphs of the distribution of time from the start of ChEI treatment to NHP for the significant category variables gender, living status, and drug dose. Log-rank test showed differences between gender ( p = .001), solitary living (p < .001), and dose of ChEI (p < .001). Cutoff median values for ChEI dose were donepezil 6.9 mg, rivastigmine 6.0 mg, and galantamine 16.0 mg. The median time from baseline to NHP was 24 months for men versus 18 for women, and 17 months for subjects living alone versus 23.5 for those residing with a spouse or relative. The patients who received a high dose of ChEI exhibited longer median time to NHP, 23.5 months, compared with 16.5 for those who received a lower dose. DISCUSSION In this longitudinal study, we found that the rate of change in IADL decline, but not in cognitive deterioration, was an important predictor of the time to NHP, after controlling for multiple factors previously shown to be of importance. Moreover, higher doses of ChEI, regardless of the specific drug agent, might postpone institutionalization in AD. Other factors that precipitated admission to nursing homes in the multivariate Cox regression model were lower cognitive and functional abilities at baseline; female gender; solitary living; and the interaction effect, men living alone. A substantial increase in adult day care predicted shorter time to NHP as well. This study shows that a more rapid deterioration in IADL increases the risk for early NHP. One possible explanation could be that the subjects who undergo change or decline in functional health status while living at home may cause greater strains to caregivers and support services than those who remain stable over time, even with low ADL ability. Considerable changes in function can make it difficult for the caregivers and the service providers to adapt to, and offer sufficient home-based care (Wolinsky, Callahan, Fitzgerald, & Johnson, 1993). In the present study, which includes patients from routine clinical settings, the multivariate Cox regression models demonstrated that individuals with an average decline of −0.2 IADL points/month were 1.54 times more likely (hazard ratio) to be admitted to nursing homes as those with no decline. Consistent with our findings, results from a long-term clinical trial (Hatoum et al., 2009) suggested that deterioration in ADL provided a better predictive measure for NHP than deterioration in cognition. A patient with mean ADL decline participating in that trial exhibited a hazard ratio of 1.65 for NHP. Similarly, a large-scale 3-year dementia evaluation (Gaugler et al., 2003), which controlled for a considerable number of discrete variables, showed that subjects who had an increase of one or more ADL limitations were 1.48 times more likely to be institutionalized earlier. A faster decline in IADL ability leading to early NHP may also have an impact on the amount of service utilization. In the present study, a lower (0.25–3.5 hr) or higher (>7 hr) increase in home help service per week, and an increase in three or more days per week in adult day care predicted early admission. The individuals living with a spouse or other relative received a smaller increase in home help service per week than did those living alone. A low increase in home help service that preceded NHP indicated that the increased level of care was not sufficient to support the caregiver and prevent institutionalization. This is in agreement with the observations made by Gaugler et al. (2003), who described a similar relationship between community-based service and admission to nursing homes. By identifying the care recipients at risk of an inadequate level of service, and focusing on their actual needs, it might be possible to postpone NHP for these individuals. The increase in adult day care of more than 2 days/week remained a predictor of early NHP in the multivariate models in this study. Consistent with our findings, Hope, Keene, Gedling, Fairburn, and Jacoby (1998) described in a dementia study that one of the four best characteristics predicting NHP was, being away from the caregiver for more than 16 hours/week (the majority of time due to day care). When the care recipient gradually spends more time away from the home, the caregiver might become more accustomed to leaving the daily care to the social services, thus experiencing some relief in their burden, which perhaps facilitates the decision to resign care (Gaugler et al., 2003). Similarly, a previous AD study of adult day care services (McCann et al., 2005) suggested that those using more adult day care per week had an increased risk of NHP, even after adjusting for disease severity and caregiver burden. This indicates that adult day care served more as a transitional period to institutionalization than a form of respite, and thus precipitated NHP. In this longitudinal naturalistic study, we found that a higher mean dose of ChEI, regardless of the specific drug agent, might postpone institutionalization in AD. Previously, few studies have investigated the impact of pharmacological interventions such as ChEI treatment on the outcome of NHP. In a recent review of predictors of NHP by Gaugler et al. (2009), the utilization of various types of medication yielded no consistent outcome. In an early open label extension of tacrine (Knopman et al., 1996), patients who remained on the drug and received effective doses of more than 80 mg/day were less likely to have entered a nursing home than those on lower doses. No similar dose—time to NHP effect was detected in a long-term naturalistic tacrine study from our group (Wallin, Gustafson, Sjogren, Wattmo, & Minthon, 2004); however, these patients received the higher effective doses during the 5 years. In a pooled study of AD patients previously enrolled in randomized placebo-controlled trials and subsequent extensions, Geldmacher et al. (2003) proposed that the use of effective doses of donepezil (>5 mg/day) and longer term sustained donepezil use was associated with significant delays in NHP. Lopez et al. (2002, 2005) showed in a comparison between treated and untreated matched AD cohorts that ChEI use was associated with a delay in institutionalization. In summary, these results suggest the clinical importance of prescribing sufficient doses of ChEI to the individual patient. When investigating possible interaction effects between the risk factors in this study, the only significant interaction term was the association between gender and living status. The effect of these variables should therefore be interpreted together. A substantial number of previous dementia studies have separately analyzed the effects of gender and marital status but hardly any considered the interaction (Luppa et al., 2008). In our study, the risk of NHP was almost fourfold for a man living alone compared with a man living with the spouse or relative. For a woman living alone, the risk was less than double compared with a woman living with a family member. A prior study of AD patients (Heyman et al., 1997), focusing on this interaction effect, found that the median time from enrollment in that study to NHP was at least a year less among the unmarried men compared with the married men and all the women. The strengths of the 3-year SATS study are the prospective, regular, well-structured, semiannual follow-up investigations of large cohorts of ChEI-treated AD patients in routine clinical settings. This longitudinal study adds to the current knowledge, regarding NHP, measures of change in cognition, function, and service utilization. Moreover, it enables analyses of clinical characteristics before the event NHP, as well as of potential differences between the ChEI agents and doses. The scheduled 6-month visits at the memory clinic and the presence of an identified contact nurse for each individual represent security and continuity for the patients. This work procedure reduces the risk that it is mainly the patients with active informal caregivers whose clinical and functional problems are reported to the attending physician and therefore receive better management of treatment and service utilization. The SATS study design has evolved into a clinical follow-up program, within the context of offering individualized care, which is nowadays applied to all AD patients in our memory clinic. One implication of this study, which is directly applicable to clinical praxis in our clinic, was that the occupational therapists would observe and follow up, in particular, the male patients living alone. In Sweden, the amount of community-based care or admission to a nursing home is based solely on the individual’s need and is almost exclusively publicly funded (Holm, Liss, & Norheim, 1999). Decisions on the adequate level of care are made in a similar way within the social services system regardless of the care recipient’s place of residence. The family’s income or insurance coverage is rarely an issue when deciding the necessary amount of care given by the social services. Another advantage of the SATS is that only patients fulfilling the diagnostic criteria for AD are included. Prior studies regarding NHP mainly included the diagnosis of dementia in general and different diagnostic criteria were used or not reported, complicating the possibility of comparisons (Luppa et al., 2008). Different dementia diagnoses may yield different outcomes and costs. Bostrom, Jonsson, Minthon, and Londos (2007) showed, in a comparison between AD and dementia with Lewy bodies (DLB) cohorts, matched for identical cognitive severity, that the DLB patients utilized more community services and care resources than the AD patients. The limitations of this study are that other factors that may influence the time to NHP, such as concomitant somatic diseases, behavioral symptoms of dementia, and the caregivers’ situation, were not evaluated in the SATS program. The inclusion of additional candidate predictors might influence the multivariate models. Yet, our results are consistent with other studies and there are no indications that the significant predictors would be less important even if mediated by other variables. For example, past research (Fisher & Lieberman, 1999; Severson et al., 1994) showed that when caregiver factors are predictive of NHP, they interact with the severity of the disease. Moreover, half of the individuals in this study later admitted to nursing homes were living alone at baseline. The influence of caregiver factors for those subjects, therefore, may be limited. Future research should focus on how the service providers can best identify care recipients at risk of an inadequate level of service utilization. Moreover, identifying the interventions that would be most effective in helping the individuals at risk—for example, those with a faster rate of functional decline—remain at home longer. To provide a more conclusive understanding of the association between AD and resource utilization given by the social services, longitudinal analysis of the possible interactions between changes in disease severity, service utilization, and ChEI treatment are needed. In conclusion, this study shows that a faster rate of IADL decline and a lower dose of ChEI were essential predictors for early NHP. Other risk factors were lower cognitive and functional abilities at baseline, female gender, solitary living, the interaction of men living alone, and a substantial increase in the use of adult day care. These critical characteristics could be used as a tool by the clinician in the multifaceted AD investigation and treatment process, involving both medication and support to patients and caregivers. Furthermore, the use of an effective dose of ChEI is important because this appears to prolong the time to NHP in AD. Service providers might use the results to identify care recipients at considerable risk of NHP, thus ensuring that they receive a sufficient amount of home care intervention.
  •           The Neuropsychiatric Inventory Nursing Home version (NPI-NH) is the same as the standard NPI, except that two additional symptom domains are included: night-time behaviour and appetite/eating changes.           In this 24-week, placebo-controlled, US study, donepezil 10 mg/day failed to significantly improve behavioral symptoms in 208 nursing home patients with AD (Baseline NPI-NH score 21.0).           As shown on the slide, improvement from baseline NPI-NH scores was greater in placebo-treated patients compared with patients treated with donepezil for total score (-4.9 vs -2.3 points) and for 10 of the 12 individual NPI-NH items.           A secondary analysis revealed a statistically significant response in favor of donepezil for agitation/aggression.   Reference Tariot PN, Cummings JL, Katz IR, et al. A randomized, double-blind, placebo- controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. J Am Geriatr Soc. 2001;49:1590- 1599. **************************************************************************************** [ref 1] J Am Geriatr Soc 2001 Dec;49(12):1590-9 A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting. Tariot PN, Cummings JL, Katz IR, Mintzer J, Perdomo CA, Schwam EM, Whalen E. Department of Psychiatry, University of Rochester Medical Center, Monroe Community Hospital, Rochester, New York 14620, USA.
  • Purpose : To illustrate in graphic and tabular form the results of the ADCS-ADL 19 Key Points : There was a statistically significant difference in function at end point between treatment groups in favor of memantine (3.2-point decline in placebo group; 1.8-point decline in memantine group). Statistically significant differences between the memantine and placebo groups were evident from week 4 to end point. Additional Information : The ADCS-ADL 19 inventory is a comprehensive battery of ADL/instrumental ADCS questions aimed at measuring the functional ability of patients with moderate to severe AD. It includes a subset of 19 items selected across moderate to severe patients. The ADCS-ADL 19 determines a patient’s ability to perform ADL ranging from total independence to total disability. Some of the 19 items evaluated included eating, walking, toileting, bathing, grooming and dressing, attending to conversation, doing household activities, and traveling beyond home. Baseline and end point values were as follows: Placebo Memantine Baseline 36.2 35.9 End: OC 32.9 34.2 End: LOCF 32.8 33.9
  • Effectiveness SIB At study end (week 24), the LSM (SE) Δ in SIB score (ITT-LOCF) was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). Similar results were found in the OC population, with a 2.4-point LSM difference between the 2 treatment groups ( P < 0.001) ( Figure 2 and Table III). In the OC population, the LSM Δ was significantly greater with donepezil 23 mg/d at weeks 6 ( P < 0.05), 12 ( P < 0.001), 18 (P < 0.01), and 24 (P < 0.001) ( Figure 2). In both subgroups of patients concurrently taking and not taking memantine, the LSM Δ was significantly greater with donepezil 23 mg/d ( P = 0.003 and P = 0.007, respectively, vs 10 mg) ( Table III). CIBIC+ In the ITT population, mean (SD) CIBIC+ scores at week 24 (LOCF) were 4.23 (1.07) with donepezil 23 mg/d and 4.29 (1.07) with donepezil 10 mg/d; the difference was not statistically significant. In the CIBIC+ OC population analysis, global scores were 4.18 (1.11) with 23 mg/d versus 4.28 (1.09) with 10 mg/d ( P = NS). In the subgroups of patients receiving and not receiving concurrent memantine, CIBIC+ overall change scores were not statistically significantly different between treatment groups ( Table III). In this large-scale, randomized, double-blind study in patients with moderate to severe AD who were already receiving 10 mg/d of donepezil IR, statistically significant benefit on 1 of the 2 prespecified coprimary outcome measures was found with donepezil 23 mg/d compared with continued 10-mg/d treatment. Although benefit was found in cognition as measured on the SIB, no incremental benefit above that achieved with 10-mg/d treatment was found on global functioning as measured using the CIBIC+. This study assessed whether patients with moderate to severe dementia, who are presumed to have greater loss of brain cholinergic function and therefore reduced acetylcholine production, would respond to higher doses of a cholinesterase inhibitor. The data support the idea that patients with more advanced AD can still achieve therapeutic benefit. The post hoc analyses found greater treatment effect on the SIB when the less impaired patients were excluded from the analysis. Although these analyses were post hoc, they are also consistent with significant benefit of donepezil 23 mg/d on the CIBIC+ in more advanced patients. The magnitude of change on the SIB found in the more impaired patients was similar to that observed when memantine was added to a regimen of donepezil in the study by Tariot et al.5 The findings from that trial were used to support the approval of combination therapy with donepezil and memantine, which is now used in clinical practice. From the standpoint of clinical use, it is expected that a higher dose of donepezil would be tried when lower doses had already been used and either did not achieve the expected effect, or after initial treatment benefit was either clinically insufficient or appeared to wane. This study was therefore designed to compare the effects of a dose increase to 23 mg/d with those of continued treatment with 10 mg/d of donepezil. Because continued treatment in practice would likely be based on tolerability, it is of interest to examine the results in those patients who were able to complete the entire 24 weeks of study treatment. In this OC population (n = 1084), the difference between treatments on the SIB and the effect of 23 mg/d on the CIBIC+ were more robust than in the ITT population. In addition, clinicians commonly prescribe memantine for an additive benefit in patients with moderate to severe AD who are already receiving donepezil 10 mg/d. Benefits on cognition were found in this study regardless of whether patients were receiving memantine concurrently. Data from the US patient population, ~32% of the total safety population, also support the view that donepezil 23 mg/d benefited patients with more advanced AD: US patients were somewhat more impaired at baseline and were more likely to be receiving memantine than was the overall patient population. In those patients, there was a treatment difference favoring the higher dose on both coprimary measures.
  • Secondary End Points No incremental benefit of high-dose donepezil was found in ADCS-ADL or MMSE total scores in the ITT population. There was little change from baseline on the ADCS-ADL scale at study end (LSM Δ, –1.2 in both groups). The MMSE score was numerically increased compared with baseline (LSM, +0.4 and +0.2 with 23 and 10 mg/d, respectively) ( Figure 2), with no statistically significant incremental benefit with the 23-mg/d dose ( Table III). There was no significant incremental benefit with the 23-mg/d dose above that with the 10-mg/d dose on the secondary end points, ADCS-ADL and MMSE. The ADCS-ADL scale has shown good sensitivity to changes in function in response to treatment compared with placebo.33 However, there are limitations for this class of instruments,34 and some previous studies report no difference in ADCS-ADL even when the active drug showed significant cognitive advantage.35,36 In addition, the ADCS-ADL scale may not be sufficiently applicable in global studies; variability in cultural differences in activities of daily living, caregiving practices, or disease stage severity of the patient population being assessed may have limited the ability to measure change despite common training across all raters who conducted the assessments, which was aimed at harmonizing assessment methodology. In a previously published study in patients with severe AD who were receiving donepezil,8 little change occurred on the ADCS-ADL scale in the 10-mg/d treatment group over 24 weeks (–1.4 points from baseline). Similarly, patients in the current study had little change in ADCS-ADL during the study (–1.2 points in 24 weeks). That there was little change on the MMSE may be due in part to the fact that the patient population had moderate to severe AD, as the scale is known to exhibit floor effects and thus there would be little opportunity for change in patients with lower MMSE scores.37 When donepezil is titrated from 5 to 10 mg/d, there is an increase in AEs.3,38 The current study design involved increasing the dose to 23 mg/d from background treatment with 10 mg/d donepezil in patients who tolerated the latter dose. Thus, the observed pattern of AEs was expected. Overall, the TEAEs of nausea, vomiting, and diarrhea were the most common treatment-related events in the 23-mg/d group and also occurred more frequently than in the 10-mg/d group and in association with the dose escalation. Patients of lower initial weight (<55 kg) experienced more TEAEs than did those weighing more. The discontinuation rate due to TEAEs was numerically higher in the 23-mg/d group, mostly reflecting a higher rate of GI-related TEAEs. There were no dose-related increases in serious TEAEs, deaths, or TEAEs associated with institutionalization, such as agitation and falls. Because of the global nature of this trial, the ability to detect treatment differences may have been confounded by different interpretations of the assessment scales and variations in the patient population with respect to baseline disease severity or duration of prior donepezil exposure, because these varied considerably in the different regions. The trial design also did not permit an assessment of the interaction between the effects of the higher donepezil dose and concurrent use of memantine, because patients were enrolled regardless of concurrent memantine use, and at baseline, patients who were concurrently receiving memantine had more severe AD compared with those who were not. The analyses based on disease severity and region were not prespecified (post hoc). In addition, the methodology for compliance assessment, while standard, cannot be used to assess actual medication intake. Future research should further examine the suggestion that patients with more cognitive impairment are the most appropriate population for higher donepezil doses and the long-term outcome of such treatment. CONCLUSIONS In this study in patients with moderate to severe AD who were receiving a stable dose of donepezil 10 mg/d, donepezil 23 mg/d provided significantly greater cognitive benefit as measured using the SIB. Although no significantly greater effect on global functioning as measured by CIBIC+ was found with the dose increase in the overall population, findings from the post hoc analyses of the SIB suggested that more severely impaired patients may also experience a global benefit (CIBIC+) with an increase to the higher donepezil dose.
  • Tolerability TEAEs occurring in ≥2% of patients in the 23-mg/d group that were also reported at a higher frequency than in the 10-mg/d treatment group are presented in Table IV. Overall, 710 of 963 patients (73.7%) who received the 23-mg/d dose and 300 of 471 (63.7%) in the 10-mg/d group experienced ≥1 AE during the study. In both treatment groups, gastrointestinal (GI) TEAEs occurred at the highest frequency within the first month after starting study medication (23 mg/d, 21.0% of patients reporting first onset of any GI TEAE in the first month, ~3% thereafter; 10 mg/d, 5.9% and ~2% thereafter). In both treatment groups, most patients reported TEAEs that were mild or moderate in severity (23 mg/d, 297 [30.8%] mild, 332 [34.5%] moderate, and 81 [8.4%] severe; 10 mg/d, 147 [31.2%] mild, 119 [25.3%] moderate, and 34 [7.2%] severe). More patients in the 23-mg/d dose group had TEAEs that were classified by the investigators as possibly or probably related to treatment (301 [31.3%] and 173 [18.0%], respectively) compared with the 10-mg/d dose group (97 [20.6%] and 33 [7.0%]). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]). There were no notable findings or clinically meaningful differences between treatment groups in clinical laboratory assessments, vital signs, or ECGs. Although no notable changes in mean weight were observed in either treatment group, decreased weight as an AE was reported in 45 patients (4.7%) in the 23-mg/d group and 12 patients (2.5%) in the 10-mg/d group. Compared with baseline weight, 11.3% of patients in the donepezil 23-mg group had a weight decrease of ≥ 7% at any time during the study (79 [8.4%] at the end of the study) compared with 7.4% at any time in the group who received 10 mg (23 [4.9%] at the end of the study). Patients in the 23-mg/d treatment group with lower weight at baseline (<55 kg) experienced more TEAEs than did those weighing more . The discontinuation rate due to TEAEs was numerically higher in the 23-mg/d group, mostly reflecting a higher rate of GI-related TEAEs. There were no dose-related increases in serious TEAEs, deaths, or TEAEs associated with institutionalization, such as agitation and falls.
  • Los objetivos en pacientes con estadio Moderadamente severo-Severo de EA: 1. Restaurar la capacidad funcional y enlentecer la declinación. 2. Reduce severidad de los cambios conductuales. 3. Reducir y prevenir nuevos usos de neurolepticos. 4. Otorga beneficios farmacoeconómicos al: Mejorar la conducta y reducir el uso de neurolepticos. Reducción en la carga del cuidador. Reduccion en la carga de comorbilidades agudas.
  • Nursing Home AD patients 26 week open label prospective study, with 26 week open label extension N=173, MMSE range 6-15 Neuropsychiatric Inventory, Nursing Home Version (NPI-NH) 85% of patients receiving therapeutic doses at study end (6-12mg/day)
  • Primary Efficacy Assessments ADCS-IADL Scores Both treatment groups showed decline on the ADCS-IADL total score from baseline during the 48-week DB phase. This decline was less at all time points in patients randomized to receive the 13.3 mg/24 h rivastigmine patch. Significantly less decline was observed on ADCS-IADL total scores at weeks 16, 24, 32 and 48 (primary end point; p = 0.025, 0.005, <0.001 and 0.002, respectively) in patients receiving the 13.3 mg/24 h patch compared with the 9.5 mg/24 h patch (fig. 2a; table 2). ADAS-cog Scores Both treatment groups demonstrated cognitive decline from baseline at weeks 24–48 in the ITT(DB)- LOCF population. At all time points, cognitive decline was less in the 13.3 mg/24 h rivastigmine patch group compared with the 9.5 mg/24 h patch group (fig. 2b; table 2). Between-group differences did not reach significance at week 48 (p = 0.227); significant treatment differences in favour of the 13.3 mg/24 h patch were observed at week 24 (p = 0.027). Results consistent with those from the primary analyses were documented on the ADCS-IADL and ADAS-cog in the OC analysis (table 2), and several sensitivity analyses (mixed-effects repeated measures model, van Elteren test, and multiple imputations under MAR and various MNAR scenarios). In the PP-DB population (LOCF and OC analyses), significantly less decline was observed at all time points on the ADCS-IADL (weeks 8–48), and less cognitive decline was observed at all time points on the ADAS-cog, although between-group differences did not reach significance. In this study, patients with AD demonstrating functional and cognitive decline while receiving the currently approved maintenance dose of 9.5 mg/24 h rivastigmine as a patch showed additional benefit with titration to the higher-dose 13.3 mg/24 h patch. The 13.3 mg/24 h rivastigmine patch demonstrated statistically superior efficacy on functional outcomes over the 9.5 mg/24 h patch from week 16 onwards. Patients receiving the 13.3 mg/24 h patch also showed less decline at all time points on the ADAS-cog and demonstrated statistically superior efficacy over the 9.5 mg/24 h patch at week 24 of the DB phase (p = 0.027), but failed to show a significant difference at week 48 (coprimary end point). Other supportive and sensitivity analyses confirmed the results obtained in the ITT-LOCF population. The rivastigmine patch has previously been associated with reduced caregiver burden [30]. Since functional decline is an important predictor of caregiver burden [2], the superior efficacy of the 13.3 mg/24 h patch, particularly on IADLs, may translate into clinically important benefits for patients and their caregivers
  • Secondary Efficacy Assessments Time to Functional Decline Functional decline on the ADCS-IADL [ITT(DB)-OC] tended to occur later in the 13.3 mg/24 h patch group than in the 9.5 mg/24 h patch group, although the observed difference did not reach significance. Over the 48-week DB phase, the proportion of patients with functional decline was also lower in the 13.3 mg/24 h patch group (77.0%) compared with the 9.5 mg/24 h patch group (81.2%), but the difference was not statistically significant. Other Secondary Efficacy Assessments There were no significant between-group differences on the other secondary efficacy outcomes. The mean time to complete the TMT-A and TMT-B was slightly longer in the 9.5 mg/24 h patch group compared with the 13.3 mg/24 h patch group at DB baseline. Patients in the 13.3 mg/24 h patch group had numerically smaller increases in time to complete the TMT-A at DB weeks 24 and 48 compared with those in the 9.5 mg/24 h patch group. The greatest differences between groups were observed at week 24; differences in LS means (DLSM) were not significant for the ITT(DB)-LOCF (table 3) or -OC populations (data not shown). The 13.3 mg/24 h patch group had numerically larger increases in time to complete the TMT-B at weeks 24 and 48 compared with the 9.5 mg/ 24 h patch group. The greatest DLSM was observed at week 24; however, there were no significant differences between groups at any time point in the ITT(DB)-LOCF (table 3) or -OC populations (data not shown). Both treatment groups showed slight deterioration or no change from baseline at the study end point for both the NPI-10 and NPI-D scales. Between-dose treatment differences were not significantly different (table 3). There were no between-dose statistically significant differences in the time to functional decline, and performance on the TMT-A and TMT-B tests for executive function. Likewise, no significant effect of the higherdose patch was observed on the behavioural scales, the NPI-10 and NPI-D. However, numerical trends towards greater efficacy of the 13.3 mg/24 h patch were observed in all but one (TMT-B) of these secondary outcomes. Interpretation of the TMT-B test results was limited due to the fact that the majority of patients were not able to perform the test within the given time period at DB baseline and later assessments. This may contribute to the observed lack of treatment effect on the TMT-B since a maximum time of 420 s was recorded for these patients. The NPI-D provides a reliable measure of caregiver distress related to neuropsychiatric symptoms and behavioural disturbances [28]; global measures of caregiver burden and quality of life were not assessed. However, these measures may show treatment-related benefits as a result of the reduced decline in the patients’ ability to perform IADLs seen in this study.
  • Deaths, SAEs and Discontinuations There were no unexpected safety effects of treatment with either rivastigmine patch dose. The incidences of SAEs and deaths were similar between treatment groups in the DB phase (SAEs: 15.7 and 15.5%, 13.3 and 9.5 mg/24 h patch, respectively; deaths: 1.1 and 1.8%, 13.3 and 9.5 mg/24 h patch, respectively). No deaths were considered to be related to the study medication. The most frequently reported SAEs in the DB phase, by primary system organ class, were infections and infestations (4.6 vs. 4.2%, 13.3 and 9.5 mg/24 h patch, respectively) and nervous system disorders (5.0 vs. 3.9%, respectively). The incidence of AEs and SAEs leading to discontinuation in the DB phase was lower with the 13.3 mg/24 h patch than with the 9.5 mg/24 h patch (AEs leading to discontinuation: 9.6 vs. 12.7%, 13.3 and 9.5 mg/24 h patch, respectively; SAEs leading to discontinuation: 4.3 vs. 6.4%, respectively). The most common AEs leading to discontinuation were GI disorders, general disorders and administration site conditions, and psychiatric disorders. Incidence of AEs Overall, in the DB phase AEs were reported in a greater proportion of patients in the 13.3 mg/24 h patch group than the 9.5 mg/24 h patch group (table 4). The most frequently reported AEs in the DB phase, by primary system organ class, were GI disorders (29.3 vs. 19.1%, 13.3 and 9.5 mg/24 h patch, respectively), psychiatric disorders (25.4 vs. 21.6%, respectively) and nervous system disorders (21.4 vs. 18.4%, respectively). Skin and subcutaneous tissue disorders were less frequently observed with the 13.3 mg/24 h than the 9.5 mg/24 h patch (2.1 vs. 6.0%, respectively). Cholinergic GI AEs were more frequently reported with the 13.3 mg/24 h patch than with the 9.5 mg/24 h patch and were most commonly: nausea, vomiting, weight decreased, appetite decreased and upper abdominal pain (table 4). When AEs were summarized according to time during the DB phase, i.e. those with onset during weeks 1–24 and those with onset during weeks 25–48 (>24 weeks), the percentages of patients with these events decreased over time in both treatment groups, with the exception of ‘weight decreased’. The percentage of patients treated for >24 weeks who reported an AE of vomiting was comparable in the 13.3 and 9.5 mg/24 h patch groups (table 4). Application site erythema and application site pruritus were reported in comparable proportions of patients in the two treatment groups (table 4), and the percentage of patients with these events decreased over time in both treatment groups. The percentage of patients treated for >24 weeks who reported an AE of application site erythema or pruritus was lower with the 13.3 mg/24 h patch than with the 9.5 mg/24 h patch (table 4). The incidence of AEs leading to a dose adjustment or study medication interruption in the DB phase was 13.9% in the 13.3 mg/24 h patch group and 5.3% in the 9.5 mg/24 h patch group. There were no clinically relevant changes from baseline to the end of the DB phase for any vital sign parameter in either treatment group. During the DB phase, the incidence of patients experiencing newly occurring electrocardiogram abnormalities was low and was similar in the two patch groups (17.5 vs. 15.2%, 13.3 mg/24 h patch vs. 9.5 mg/24 h patch). The administration of the higher-dose (13.3 mg/24 h) rivastigmine patch had no new or unexpected concerns relating to safety and tolerability. The 13.3 mg/24 h patch was not associated with an increase in the incidence of SAEs, and despite a modest increase in reported AEs, fewer patients discontinued treatment as a result of Aes compared with those in the lower-dose (9.5 mg/24 h) patch group. An increased incidence of AEs is often associated with a dose titration step [37]. AEs in the OPTIMA study decreased over time, with a similar incidence of most AEs reported in both treatment groups in the second half of the DB phase (weeks 25–48). Throughout the course of the study, slightly more patients in the higherdose group experienced an AE of ‘weight decreased’. The potential weight loss in patients receiving the 13.3 mg/24 h patch may require clinical attention and consideration of possible counteracting interventions such as protein enriched nutritional supplements. The overall decrease in the incidence of AEs observed over time may have contributed to the high degree of persistence and low rate of discontinuations observed with both patch doses. Overall, safety data confirm the good tolerability of the rivastigmine patch. The most common AEs were cholinergic in nature and were as expected when compared with previous studies of rivastigmine treatment, including IDEAL [8]. The high-dose rivastigmine patch would enable physicians to optimize efficacy, while maintaining good tolerability, for appropriate patients. Such patients could include those who show signs of functional decline on current stable therapy, or those whom the physician perceives would gain additional benefit from up-titration, in order to achieve optimal efficacy. In all cases, the decision to up-titrate from the maintenance dose of 9.5 to the 13.3 mg/24 h patch should be based on good tolerability of the current dose and be considered after a minimum of 4 weeks of treatment at previous dose levels.
  • Riesgos para seguridad en el hogar: Accidentes domésticos, ejm, fuego de la cocina, herramientas electricas Caidas Deterioro del juicio, percepción visual, y percepción espacial incrementan significativamente el riesgo de caídas en individuos con EA y otras demencias. Las caidas son la principal causa de injuria severa y visitas a Emergencia en la poblacion adulta mayor. “ Vagabundeo” Prevalencia de “vagabundeo” en pacientes con demencia varía ampliamente en los estudios clínicos del 12% al 63% en estudios basados en comunidad. [Rowe et al. Am J Alz Dis Oth Dement. 2010;25:27-31. Klein et al. Int J Geriatr Psych. 1999;14:272-279. Calkins et al. J Alz Care & Related Dis Research. 1991; 6:25-29. Sayva et al. B J Psych. 2009; 194:212-219. Rolland et al. Alzheimer’s Dis Assoc Disord. 2007;21:31-38. Hope et al. Int J Geriatr Psychiatry. 1994;9:149-155. Ter et al. JAGS. 1988;36:1-6.] Debido a las diferentes definiciones de “vagabundeo”. Pues, suele usarse para describir multiples conductas, incluyendo marcha con ritmo, entrar ir salir de las habitaciones, pedrir reiteradamente “ir para su casa”, perderse en un paseo, o intentar salir de casa en contra de los consejos. “Vagabundeo” también puede ser definido en función de si el movimiento tiene un propósito (busqueda de algo para comer) vs un propósito no identificable (marcha con ritmo). Debido a esto, las estadisticas de “vagabundeo” son dificiles de discernir. Según la AAN, basada en una revisión sistemática de la literatura científica actual, ha encontrando que las características más útiles para identificar la los pacientes con demencia que tienen un riesgo más elevado de conducción insegura de vehículos a motor son las siguientes: 1. La escala  Clinical Demencia Rating  (CDR) de Hughes, que muestra el nivel más alto de evidencia para identificar a los conductores de riesgo. 2. La capacidad del paciente para conducir, calificada como insegura o límite mediante un cuestionario a su cuidador. 3. Que el paciente tenga un historial de choques o de multas de tráfico. 4. Que el paciente tienda espontáneamente a conducir poco, o que él mismo cuente que evita el conducir en situaciones determinadas, como poca luz, lluvia, autopistas, etcétera. 5. Una puntuación igual o inferior a 24 en el MMSE. 6. Que el paciente tenga características de personalidad agresiva o impulsiva. Por el contrario, los autores llegan a la conclusión de que para identificar a los conductores de riesgo no son últiles las siguientes características: 1. La calificación que el propio paciente se atribuya sobre su capacidad para conducir con seguridad. 2. La ausencia de autolimitaciones situacionales por parte del paciente. Por último, los autores de esta revisión indican que no existe un grado de evidencia suficiente para respaldar ni rechazar la utilidad que puedan tener para identificar a los conductores de riesgo otros tests neuropsicológicos, el grado de severidad de la demencia, ni el uso de estrategias de intervención para conductores con demencia. Referencia bibliográfica: D.J. Iverson, G.S. Gronseth, M.A. Reger, S. Classen, R.M. Dubinsky, M. Rizzo. Practice Parameter update: Evaluation and management of driving risk in dementia, Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2010;74:1316-1324

Dosis más altas de Inhibidores de Colinesterasas mejoran la "funcionalidad" del paciente con enfermedad de Alzheimer. Dosis más altas de Inhibidores de Colinesterasas mejoran la "funcionalidad" del paciente con enfermedad de Alzheimer. Presentation Transcript

  • Dosis mas altas de Inhibidores de ColinesterasasDosis mas altas de Inhibidores de Colinesterasas mejoran la «funcionalidad» del paciente conmejoran la «funcionalidad» del paciente con enfermedad de Alzheimer?enfermedad de Alzheimer? Evidencia de eficacia sobre las actividadesEvidencia de eficacia sobre las actividades de la vida diariade la vida diaria Nilton CustodioNilton Custodio II Jornada de Actualización enII Jornada de Actualización en Enfermedades NeurodegenerativasEnfermedades Neurodegenerativas Punta Sal-TumbesPunta Sal-Tumbes 01 Junio 201301 Junio 2013
  • Agenda • El costo de las demencias, asumido por las familias. • Demencia involucra, trastorno de “funcionalidad”. • EA y el impacto de la “declinación funcional”. • La “declinación funcional” con altas dosis de donepezilo. • La “declinación funcional” con altas dosis de rivastigmina.
  • Agenda • El costo de las demencias, asumido por las familias.El costo de las demencias, asumido por las familias. • Demencia involucra, trastorno de “funcionalidad”. • EA y el impacto de la “declinación funcional”. • La “declinación funcional” con altas dosis de donepezilo. • La “declinación funcional” con altas dosis de rivastigmina.
  • Estudio de costos en una cohorte retrospectiva de pacientes con demencia en Lima: Características demográficas y clínicas Característica No demencia (n=30) Demencia de Alzheimer (n=44) Demencia Fronto temporal (n=18) Demencia Vascular (n=44) n (%) n (%) Valor p n(%) Valor p n (%) Valor p Edad (años)* 67.1 (2.3) 71.9 (5.2) 0.01˂ 67.7(3.1) 1.00† 69.1(4.5) 0.30† Sexo (femenino) 19 (63.3) 29(65.9) 0.82 10(55.6) 0.59 24(54.5) 0.45 Educación (años) 10.2 (2.6) 11.9(2.9) 0.06 11.6(2.1) 0.56 12.3(2.8) 0.01˂ TE (meses)* 0 33.3(7.9) 0.01˂ 29.6(7.9) 0.01˂ 31.91(9.8) 0.01˂ CDR* 0.17 (0.3) 2.3(0.6) 0.01˂ 1.9(0.5) 0.01˂ 1.6(0.7) 0.01†˂ MMSE* 28.5 (1.2) 22.4(3.3) 0.01˂ 25.8(1.4) 0.01†˂ 20.9(2.4) 0.01†‡˂ PFAQ* 3.26 [0.73] 20.9(2.8) 0.01˂ 19.7(1.3) 0.01˂ 19.0(3.6) 0.01†˂ NPI* 4.9(2.2) 25.7(6.5) 0.01˂ 32.6(8.3) 0.01†˂ 17.9(3.8) 0.01†‡˂ BDI-II* 4.3(1.3) 16.1(4.1) 0.01˂ 21.2(3.1) 0.01†˂ 12.9(3.8) 0.01†‡˂ * Valores expresados como media (desviación estándar) †Estadísticamente diferente con demencia de Alzheimer ‡ Estadísticamente diferente con demencia Custodio N, et al. In preparationCustodio N, et al. In preparation
  • Estudio de costos en una cohorte retrospectiva de pacientes con demencia en Lima: Características del cuidador primario Característica No demencia (n=30) Demencia de Alzheimer (n=44) Demencia Fronto temporal (n=18) Demencia Vascular (n=44) n (%) n (%) Valor p n(%) Valor p n (%) Valor p Edad (años)* NA 48.7 (15.4) NA 51.2(13.7) NA 50.3(13.1) NA Sexo (femenino) NA 38(86.4) NA 17(94.4) NA 36(81.8) NA Educación (años)* NA 10.1(2.5) NA 9.6(3.1) NA 9.8(2.8) NA Relación con paciente Esposo(a)/pareja NA 9(20.3) NA 5(27.8) NA 15(34.2) NA Hijo o Hija NA 13(29.6) NA 5(27.8) NA 13(29.5) NA Hermano o hermana NA 5(11.4) NA 4(22.2) NA 2(4.6) NA Otro familiar NA 5(11.4) NA 1(5.6) NA 5(11.4) NA Cuidador pagado NA 12(27.3) NA 3(16.6) NA 9(20.4) NA Inventario Zarit* NA 28.4(9.1) NA 27.7(6.9) NA 31.3(8.9) NA * Valores expresados como media (desviación estándar) Custodio N, et al. In preparationCustodio N, et al. In preparation
  • Estudio de costos en una cohorte retrospectiva de pacientes con demencia en Lima: Fuente y consumo de recursos Ítem de consumo No demencia (n=30) Demencia de Alzheimer (n=44) Demencia Fronto temporal (n=18) Demencia Vascular (n=44) n (%) n (%) Valor p n(%) Valor p n (%) Valor p Sin cobertura Salud 9 (30.0) 8(18.2) Ref. 5(27.8) Ref. 7(15.9) Ref. «Salud Familiar» 11(36.7) 24(54.5) 0.14 9(50.0) 0.59 19(43.2) 0.20 Prestadores de Salud 10(33.3) 12(27.3) 0.64 4(22,2) 0.69 18(40.9) 0.19 Consumo de recursos Hematología + TC 30 (100.0) 11(25.0) Ref. 0 Ref. 11(25.0) Ref. Hematología + IRM 0 33(75.0) 0.01˂ 18(100.0) 0.01†˂ 33(75.0) 0.01˂ Cita Médica/trimestre* 2.0(0.0) 3.3(0.6) 0.01˂ 3.3(0.6) 0.01†˂ 3.2(0.5) 0.01˂ Hospitalización/trimestre* 1.0(0.0) 1.2(0.5) 0.22 1.2(0.5) 0.63 1.1(0.5) 0.57 Anti-demencia 0.0 35(79.5) 0.01˂ 8(44.4) 0.01†˂ 19(43.2) 0.01†˂ Psicotrópicos 0.0 29(65.9) 0.01˂ 18(100.0) 0.01†˂ 39(88.6) 0.01†˂ * Valores expresados como media (desviación estándar) †Estadísticamente diferente con demencia de Alzheimer Custodio N, et al. In preparationCustodio N, et al. In preparation
  • Estudio de costos en una cohorte retrospectiva de pacientes con demencia en Lima: Costos relacionados a salud en 3 meses Ítem de costos relacionados a salud No demencia (n=30) Demencia de Alzheimer (n=44) Demencia Fronto temporal (n=18) Demencia Vascular (n=44) p50 (min-max ) p50 (min-max) Valor p p50 (min-max) Valor p p50 (min-max) Valor p Pruebas médicas basales 372(372-372) 437(372-437) 0.01˂ 437(437-437) 0.01†˂ 437(372-437) 0.01˂ ‡ Cita médica/Trimestre 37(22-74) 56(33-148) 0.01˂ 56(33-185) 0.01˂ 56(33-111) 0.03 Hospitalización/Trimestre 0 0(0-1519) 0.01 0(0-1154) 0.02 0(0-1519) 0.04 Anti-demencia 0 437(0-846) 0.01 0(0-558) 0.01†˂ 0(0-801) 0.01˂ † Psicotrópicos 0 125(0-1138) 0.01 927(324-1647) 0.01†˂ 227(0-1423) 0.01˂ ‡ Sub-Total 393(372-409) 1167(703-3487) 0.01˂ 1544(849-3296) 0.01†˂ 908(471-3126) 0.01˂ †‡ †Estadísticamente diferente con demencia de Alzheimer ‡ Estadísticamente diferente con demencia frontotemporal Custodio N, et al. In preparationCustodio N, et al. In preparation
  • Estudio de costos en una cohorte retrospectiva de pacientes con demencia en Lima: Costos no relacionados a salud en 3 meses Ítem de costos relacionados a salud No demencia (n=30) Demencia de Alzheimer (n=44) Demencia Fronto temporal (n=18) Demencia Vascular (n=44) p50 (min-max ) p50 (min-max) Valor p p50 (min-max) Valor p p50 (min-max) Valor p Pañales/Trimestre 0(0-198) 0(0-396) 0.18 0(0-297) 0.07 0(0-396) 0.18 Cuidador/Trimestre 0 667(667-1111) 0.01˂ 676(667-1111) 0.01˂ 667(667-1111) 0.01˂ Sub-Total 0(0-198) 666(0-1508) 0.01˂ 667(0-1409) 0.03 667(0-1409) 0.01 †Estadísticamente diferente con demencia de Alzheimer ‡ Estadísticamente diferente con demencia frontotemporal Custodio N, et al. In preparationCustodio N, et al. In preparation
  • Estudio de costos en una cohorte retrospectiva de pacientes con demencia en Lima: Costos totales y variables en 3 meses Ítem de costos relacionados a salud No demencia (n=30) Demencia de Alzheimer (n=44) Demencia Fronto temporal (n=18) Demencia Vascular (n=44) p50 (min-max ) p50 (min-max) Valor p p50 (min-max) Valor p p50 (min-max) Valor p Costos relacionados a salud 393(372-409) 1167(703-3487) 0.01˂ 1544(849-3296) 0.01†˂ 908(471-3126) 0.01˂ †‡ Costos no relacionados a salud 0(0-198) 666(0-1508) 0.01˂ 667(0-1409) 0.03 667(0-1409) 0.01 Costos Totales 394 (372-607) 1878(715-4896) 0.01˂ 2252(1397-4705) 0.01˂ 1727(644-4188) 0.01˂ ‡ Costos Totales Variables 22(0-235) 1470(344-4459) 0.01˂ 1869(960-4268) 0.01†˂ 1291(207-3751) 0.01˂ ‡ †Estadísticamente diferente con demencia de Alzheimer ‡ Estadísticamente diferente con demencia frontotemporal Los costos totales variables excluyen los costos del diagnóstico. Custodio N, et al. In preparationCustodio N, et al. In preparation
  • Estudio de costos en una cohorte retrospectiva de pacientes con demencia en Lima: Factores asociados a costos variables Custodio N, et al. In preparationCustodio N, et al. In preparation Factores Todo demencia (n=106) Demencia de Alzheimer (n=44) Demencia Fronto temporal (n=18) Demencia Vascular (n=44) Coeficiente ß Valor p Coeficiente ß Valor p Coeficiente ß Valor p Coeficiente ß Valor p Pacientes Edad (años) 0.01˂ 0.57 0.01 0.47 - 0.01˂ 0.63 Sexo: Femenino -0.03 0.73 0.06 0.67 -0.23 0.20 Educación (años) - 0.01˂ 0.82 0.01 0.60 -0.05 0.14 CDR 0,38 0.01˂ -0.47 0.01˂ 0.06 0.75 0.40 0.01˂ MMSE 0.02 0.31 0.03 0.11 -0.03 0.75 -0.06 0.10 PFAQ - 0.01˂ 0.80 - 0.01˂ 0.68 -0,06 0.38 0.01 0.61 Cuidador Primario Edad (años) -0.02 0.01˂ -0.04 0.01˂ -0.02 0.02 Educación (años) 0.05 0.12 Cuidador contratado -0.17 0.27 -0,47 0.09 0.67 0.02 -0.26 0.34
  • Agenda • El costo de las demencias, asumido por las familias. • Demencia involucra, trastorno de “funcionalidad”.Demencia involucra, trastorno de “funcionalidad”. • EA y el impacto de la “declinación funcional”. • La “declinación funcional” con altas dosis de donepezilo. • La “declinación funcional” con altas dosis de rivastigmina.
  • Diagnóstico de demencia, al final de los procesos Dubois B, et al. Lancet Neurol 2007;6:734-746Dubois B, et al. Lancet Neurol 2007;6:734-746 EA DV DFT APP DcLDemencia Umbral Demencia Estadios Pre-clínicos Estadios Pre-demencia (DCL)
  • El diagnóstico definitivo de EA requiere histopatología Corteza Parietal Estríado GP/SN Tálamo Neocórtex Temporal Hipocampo Corteza Entorrinal
  • Diagnóstico Probable y Posible de EA: NINCDS-ADRDA • Compromiso de memoria: Aprendizaje o Recuerdo • Uno o más de: Afasia, Apraxia, Agnosia, Función disejecutiva (Planificación, Organización, Secuencia y Abstracción) • Deficit cognitivo de suficiente severidad para afectar el funcionamiento ocupacional o social, y éste representa un cambio desde el nivel previo. • El curso clínico es de inicio gradual y declinación progresiva. • No es debido a delirio. • No es explicado por otro problema del SNC: ECV, EP.
  • Limitaciones de los criterios del NINCDS-ADRDA • Baja exactitud (20-80%), debido a que no toman en cuenta características especificas de la enfermedad: – Ninguna especificación en el perfil de la memoria. – Ninguna referencia a marcadores biológicos. • Tarde en el curso de la enfermedad: – Sólo cuando el umbral de demencia fue alcanzado. • Dificultad para demostrar la eficacia de los tratamientos modificadores de la enfermedad.
  • Dubois B, et al. Lancet Neurol 2007;6:734-746Dubois B, et al. Lancet Neurol 2007;6:734-746 El deterioro de la memoria episódica, independiente del grado funcional en el diagnóstico de EA probable
  • Criterios propuestos en diagnóstico probable de EA Criterio clínico principal Uno o más Criterios Menores A. Desorden de memoria episódica: • Gradual y progresivo al menos 6 meses de evolución. • Demostración del déficit de evocación que no mejora con pistas. • Aislada o asociada a otros cambios cognitivos. B. Atrofia del lobulo temporal medial : IRM C. Biomarcador anormal en LCR: • Bajas concentraciones en ß–amiloide • Aumento concentraciones en Tau/fosfo-Tau B. Hipometabolismo T-P en PET.
  • Estadios Braak I-II Estadios Braak III-IV Estadios Braak V-VI DCL Amnésico Demencia de EAEA Pre-clínico EA típica tiene una presentación clínica homogénea • Compromiso precoz de Corteza entorrinal/Hipocampo (Braak, 1991). • Sindrome amnésico del LTM en EA prodrómica (Dubois, 2004; Sarazin, 2007). • Deterioro memoria episódica, seguida de memoria semántica (Molinuevo, 2010).
  • EA Pre-clínica: Existe EA sin demencia? Dubois B, et al. Lancet Neurol 2010;9:1118-1127Dubois B, et al. Lancet Neurol 2010;9:1118-1127
  • Finalmente, qué es enfermedad de Alzheimer? Marcadores biológicos Desórdenes específicos memoria DEMENCIA Asintomático Primeros síntomas Cognitivo- Conductual- Funcional 5 a 6 años> 20 años Demencia EAEA ProdrómicaEA Pre-clínica Enfermedad de Alzheimer
  • Una gran brecha entre prevención y el tratamiento sintomático en EA diagnóstico estándar Criterios de Dubois “ EA prodrómica” Criterios modificados de Dubois “EA muy precoz” Pre-sintomática = EA Pre-clínica No síntomas, Evidencia de biomarcador disregulación de amiloide Síntomas muy leves y cualquier biomarcador Alteración de memoria episódica y cualquier biomarcador Demencia Inicio depósito de “marcas” PREVENCIÓN SECUNDARIA modificado de Aisen PS, et al. Alzheimer’s Res Ther 2009;modificado de Aisen PS, et al. Alzheimer’s Res Ther 2009; 1:2. doi:10.1186/alzrt21:2. doi:10.1186/alzrt2 PREVENCIÓN PRIMARIA TRATAMIENTO SINTOMÁTICO
  • El tratamiento sintomático en demencia EA Manejo síntomas cognitivos Manejo SPCD Soporte paciente/familia IncrementoIncremento en calidad deen calidad de vida paravida para paciente ypaciente y familiafamilia FUNCIONALIDADFUNCIONALIDAD
  • En el curso de EA, se afectan inicialmente AVDs instrumentales; y luego, las básicas Galasko D, et al. Eur J Neurol. 1998;5(suppl 4):S9-S17.Galasko D, et al. Eur J Neurol. 1998;5(suppl 4):S9-S17. ActividadesdeVidaDiaria (AVDs) Pérdida Progresiva de Funcionalidad Puntaje MMSE Mantener citas Uso adecuado de teléfono Conseguir comida Viajar sin compañía Utilizar electrodomésticos Encontrar sus pertenencias Seleccionar ropas de vestir Vestirse sin asistencia Aseo personal 25 20 15 10 5 0 0 2 4 6 8 10Años Mantener actvidades de diversión Deshechar la basura Recoger servicio de mesa Caminar Comer 25% 75% Pérdida del rendimiento óptimo (independiente)
  • Evaluación clínica en pacientes con EA: RCTs Funcionalidad (ADCS-ADL) Cognición (ADAS-Cog) (SIB) Conducta (NPI) Global (CIBIC-plus) (ADCS-CGIC) ADAS-Cog Alzheimer’s Disease Assessment Scale, Cognitive subscale SIB Severe Impairment Battery CIBIC-plus Clinician Interview-Based Impression of Change with Caregiver Input ADCS-CGIC Alzheimer's Disease Co-Operative Study – Clinical Global Impression of Change ADCS-ADL Alzheimer's Disease Co-Operative Study – Activities of Daily Living NPI Neuropsychiatric Inventory
  • Evaluación de la funcionalidad en EA ADCS-ADL Lista de ítems seleccionados 1. Comer 2. Desplazamiento 3. Orinar/defecar 4. Tomar una ducha 5. Aseo personal 6. Vestirse 7. Usar un teléfono 8. Mirar TV 9. Mantener conversación 10. Recoger servicios mesa 11. Encontrar pertenencias 12. Obtener bebida fria/caliente 13. Preparar comida/merienda 14. Deshechar la basura 15. Salir sólo de la casa 16. Sale de compras 17. Acude a citas 18. Puede quedar solo 19. Temas de actualidad 20. Comenta lectura 21. Logra escribir 22. Mantiene pasatiempos 23. Usa electrodomésticos Galasko D, et al. Alzheimer´s Disease and Associated Disorders 1997;11(suppl 2):S33-S39.Galasko D, et al. Alzheimer´s Disease and Associated Disorders 1997;11(suppl 2):S33-S39.
  • Agenda • El costo de las demencias, asumido por las familias. • Demencia involucra, trastorno de “funcionalidad”. • EA y el impacto de la “declinación funcional”.EA y el impacto de la “declinación funcional”. • La “declinación funcional” con altas dosis de donepezilo. • La “declinación funcional” con altas dosis de rivastigmina.
  • La declinación funcional es el principal factor que afecta la calidad de vida relacionada a la salud Andersen CK. et al. Health and quality of life outcomes 2004;2:52–59Andersen CK. et al. Health and quality of life outcomes 2004;2:52–59
  • Indicaciones aprobadas para demencia de EA • Inhibidores de Colinesterasa (IChEs) – Tacrine – Donepezilo – Galantamina – Rivastigmina Fallas en RCTs: • Memantina – Monoterapia – Combinación con IChE EA LEVE-MODERADA
  • Indicaciones aprobadas para demencia de EA • Memantina – Monoterapia – Combinación con IChE Recientes aprobaciones en EA Severa: • IChEs – Monoterapia – Combinación con memantina • Inhibidores de Colinesterasa (IChEs) – Tacrine – Donepezilo – Galantamina – Rivastigmina Fallas en RCTs: • Memantina – Monoterapia – Combinación con IChE EA LEVE-MODERADA EA SEVERA
  • Monoterapia con IChEs en EA leve-moderada: Eficacia Cambiospromediosdesdebasal .2 .1 0 –.1 –.2 –.3 –.4 –.5 12 18 26 † * * * Semanas Placebo Rivastigmina 1- 4 mg Rivastigmina 6-12 mg Global: CIBIC-Plus2 Rivastigmina Meses –4 –2 0 –5 –3 –1 1 1 2 3 4 5 Galantamina 8 mg/d Galantamina 16 mg/d Galantamina 24 mg/d Placebo † † Funcionalidad: ADCS-ADL3 Galantamina *P<.05; † P<.01; ‡ P≤.001. CIBIC-Plus = Clinician's Interview-Based Impression of Change with caregiver input; ADCS-ADL = Alzheimer's Disease Cooperative Study – Activities of Daily Living inventory. 1. Winblad B, et al. Neurology. 2001;57:489-495.1. Winblad B, et al. Neurology. 2001;57:489-495. 2.2. Corey-Bloom J, et al. Int J Geriatr Psychopharmacol. 1998;1550:55-65Corey-Bloom J, et al. Int J Geriatr Psychopharmacol. 1998;1550:55-65 3.3. Tariot PN, et al. Neurology. 2000;54:2269-2276Tariot PN, et al. Neurology. 2000;54:2269-2276 Cognición: MMSE1 Donepezilo –2.5 –2.0 –1.5 –1.0 –0.5 0 0.5 1.0 Donepezilo Placebo Semanas 52362412 ‡ 0 LOCF ‡ * ‡
  • Los IChEs retrasan modestamente la evolución de síntomas cognitivos en EA leve-moderada Cambiospromediosen ADAS-CogdesdeelBasal Declinación en puntaje de ADAS-Cog basado en la historia natural de pacientes no tratados con EA moderada* -6 0 6 12 18 0 6 12 14 26 38 50 62 74 85 98 Mejoría Deterioro n =133 Rogers SL, et al. Neurology 1998; 50 (1):136-145Rogers SL, et al. Neurology 1998; 50 (1):136-145 * Stern RG, et al, Am J Psychiatry 1994;151:390-396* Stern RG, et al, Am J Psychiatry 1994;151:390-396
  • Frecuencia de síntomas psicológicos y conductuales en la evolución de la demencia de EA Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081Jost BC, Grossberg GT. J Am Geriatr Soc. 1996;44:1078-1081 Meses Antes/Después de Diagnóstico -40 -30 -20 -10 0 10 20 30 Frecuencia(%dePacientes) 100 80 60 40 20 0 Agitación Alteración Ritmo Diurno Irritabilidad Conducta motora aberrante Agresividad Alucinaciones Cambio Humor Socialmente Inaccesible Delusiones Sexualmente Inapropriado Acusatorio Ideación Suicida Paranoia Depresión AnsiedadAislamiento Social
  • Efectos de Galantamina, según dosis sobre la conducta en EA leve-moderada *p<0.05 vs. placebo; N=978 Tariot PN, Solomon PR, Morris JC, et al. Neurology. 2000(June 27); 54(12):2269-2276Tariot PN, Solomon PR, Morris JC, et al. Neurology. 2000(June 27); 54(12):2269-2276 CambiosenpuntajeNPI desdeelbasal Mejoría Deterioro Basal 1 2 3 4 5 -2 -1 0 1 2 3 4 5 Tiempo (Semanas) * Placebo Galantamina 8 mg/d Galantamina 16 mg/d Galantamina 24 mg/d
  • Incremento en la probabilidad de institutionalización por severidad de la enfermedad Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360Hauber AB, Gnanasakthy, Snyder EH, et al. Pharmacoeconomics. 2000(April);17(4):351-360 Probabilidadde Institucionalización 0.0 0.2 0.4 0.6 0.8 1.0 Leve (MMSE: 21-30) Moderada (MMSE: 11-20) Severa (MMSE: 0-10) Severidad de EA 0.017 0.345 0.867
  • La declinación funcional es el principal predictor del tiempo para admisión en “casa de reposo” Hatoum HT. et al. Journal of Medical Economics 2009;12:98–103Hatoum HT. et al. Journal of Medical Economics 2009;12:98–103
  • La declinación funcional y conductual incrementan la “carga de cuidador”, la cual se puede aliviar Mohamed S. et al. Am J Geriatr Psychiatry2010;18:917–927Mohamed S. et al. Am J Geriatr Psychiatry2010;18:917–927 a: p < 0.001 , b: p < 0.01 , c: p < 0.0001 a: p < 0.001 , b: p < 0.0001 , c: p < 0.01
  • Monoterapia con Memantina en EA Moderada a Severa: Eficacia Reisberg B,et al. N Engl J Med. 2003;348:1333-1341.Reisberg B,et al. N Engl J Med. 2003;348:1333-1341. Diferenciaenpuntajes -12 -10 -8 -6 -4 -2 0 2 4 12 28 Semanas Memantina Placebo 0 End Point (LOCF) P=.002 P<.001*P<.001*P=.068 Cognition: SIB 4 12 28 Semanas 0 End Point (LOCF) -7 -5 -4 -3 -2 -1 0 1 -6 Memantina Placebo P=.003 P=.02*P=.106*P=.145 ADCS-ADL19 PorcentajedePacientes Puntaje global CIBIC-Plus Mejoría Deterioro No Cambio Memantina Placebo 0 5 10 15 20 25 30 35 40 45 1 2 3 4 5 6 7 CIBIC-Plus
  • * * * ** * * * Mejoría de sintomas conductuales con Rivastigmina en EA M-S: Cambios en NPI-NH desde el basal -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0 Agitación Irritabilidad Ansiedad Conducta Motora Aberrante Apatía Depresión Delusiones Desinhibición Alucinaciones Euforia Conducta nocturna Apetito CambiospromediosenNPI-NH desdeelBasal *p<0.05 vs. baseline; **p<0.001 vs. baseline; Baseline MMSE = 9.2; OC analysis; N=98 Anand R, Kourmaras B, Hartman RD. Neurobiol Aging. 2000;21:S220Anand R, Kourmaras B, Hartman RD. Neurobiol Aging. 2000;21:S220 Mejoría Estudio a 26 semanas en “casa de reposo”
  • La declinación funcional puede ser retrasada por IChE Wattmo C. et al. Alzheimer Dis Assoc Disord 2011;25:63–72Wattmo C. et al. Alzheimer Dis Assoc Disord 2011;25:63–72
  • Mayores dosis de IChE retrasan la admisión a “casa de reposo” al retrasar la declinación funcional Wattmo C. et al. The gerontologist 2011;51:17–27Wattmo C. et al. The gerontologist 2011;51:17–27
  • Agenda • El costo de las demencias, asumido por las familias. • Demencia involucra, trastorno de “funcionalidad”. • EA y el impacto de la “declinación funcional”. • La “declinación funcional” con altas dosis de donepezilo.La “declinación funcional” con altas dosis de donepezilo. • La “declinación funcional” con altas dosis de rivastigmina.
  • Efectos de Donepezilo 10 mg sobre la conducta en pacientes en “casa de reposo” a las 24 semanas MejoríaPlacebo (N=105) Donepezil (N=103) Cambiospromediosdesdeelbasal ítemsindividualesdelNPI-NH Puntajesalasemna24 Delusiones Alucinaciones Agitación/Agresión Depresión/Disforia AnsiedadElación/Euforia Apatía/IndiferenciaDesinhibición Irritabilidad/Labilidad ConductaMotoraAberrante ConductaNocturnaApetito/Comer * Basal Deterioro -3 -2 -1 0 1 2 3 4 *p<0.05 vs. placebo, análisis secundario ITT, análisis LOCF Tariot PN, Cummings JL, Katz IR, et al. J Am Geriatr Soc. 2001;49:1590-1599Tariot PN, Cummings JL, Katz IR, et al. J Am Geriatr Soc. 2001;49:1590-1599
  • Beneficios del tratamiento regular y continuo: Retraso en el ingreso a “casa de reposo” Geldmacher DS, et al. J Am Geriatr Soc. 2003;51(5 Suppl Dementia):S289-S295.Geldmacher DS, et al. J Am Geriatr Soc. 2003;51(5 Suppl Dementia):S289-S295. Tiempo promedio para primer ingreso a “casa de reposo” Meses Exposición a dosis máximas: Donepezilo (n=310) 66.1 Exposición a dosis limitadas: Donepezilo (n=113) 44.7Exposición a dosis limitadas: Donepezilo (n=113) 44.7 21.4 Meses de retraso 0 10 20 30 40 50 60 70 El tratamiento continuo con donepezilo 10 mg puede retrasar el tiempo para el ingreso a una “casa de reposo” motivado por demencia, por aproximadamente 2 años
  • *P=.03; análisis LOCF ; n=394 Tariot P, et al. JAMA. 2004;291:317-324.Tariot P, et al. JAMA. 2004;291:317-324. ADCS-ADL19 CIBIC-Plus Cambiospromediosdesdeelbasal enPuntajedelADCS-ADL19 Deterioro n = 198 198 190 185 181 172 198 n = 197 195 182 170 163 152 197 P=.03P=.02P=.03P=.02P=.01P=.03 Mejoría -4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 Memantina Placebo PorcentajedePacientes Mejoría Deterioro Puntaje Global CIBIC-Plus Placebo + Donepezilo (n=196) Memantina+ Donepezilo (n=198) 0 5 10 15 20 25 30 35 40 45 1 2 3 4 5 6 7 No Cambio 0 4 8 12 18 24 End Point (LOCF) Semanas de tratamiento Terapia de combinación Memantina/Donepezilo 10 mg en EA Moderada-Severa: Eficacia
  • Medidas de eficacia primaria en Donepezilo 23 mg en EA Moderada-Severa Farlow MR. et al. Clin Ther 2010;32:1234–1251Farlow MR. et al. Clin Ther 2010;32:1234–1251 Cognición: SIB CIBIC-Plus
  • Farlow MR. et al. Clin Ther 2010;32:1234–1251Farlow MR. et al. Clin Ther 2010;32:1234–1251 Medidas de eficacia secundaria en Donepezilo 23 mg en EA Moderada-Severa ADCS-ADL Cognición: MMSE
  • Mediciones de seguridad en donepezilo-altas dosis Farlow MR. et al. Clin Ther 2010;32:1234–1251Farlow MR. et al. Clin Ther 2010;32:1234–1251
  • Agenda • El costo de las demencias, asumido por las familias. • Demencia involucra, trastorno de “funcionalidad”. • EA y el impacto de la “declinación funcional”. • La “declinación funcional” con altas dosis de donepezilo. • La “declinación funcional” con altas dosis de rivastigmina.La “declinación funcional” con altas dosis de rivastigmina.
  • Algunos beneficios del tratamiento de EA Moderada-Severa Conducta Funcionalidad Cognición Bienestar físico y Psico-social Reduce carga del cuidador Beneficio farmaco- económico Mejoría de conducta
  • Efectos de Rivastigmine en EA Severa sobre la conducta: Basal Edwards, et al: Clin Drug Invest 2005; 125(8) 507-515Edwards, et al: Clin Drug Invest 2005; 125(8) 507-515
  • n=43 n=36 n=62 n=55 n=36 n=72 Edwards, et al: Clin Drug Invest 2005; 125(8) 507-515Edwards, et al: Clin Drug Invest 2005; 125(8) 507-515 Efectos de Rivastigmine en EA Severa sobre la conducta: Semana 52
  • El estudio OPTIMA en la declinación funcional y cognitiva de EA leve-moderada con Rivastigmina a altas dosis
  • Cummings J. et al. Dement Geriatr Cogn Disord 2012;33:341–353Cummings J. et al. Dement Geriatr Cogn Disord 2012;33:341–353 Medidas de eficacia primaria en Rivastigmina-altas dosis: Evaluación funcional (ADCS-IADL) y cognición (ADAScog) OPTIMA (OPtimising Transdermal Exelon In Mild-to-moderate Alzheimer’s disease) Menor declinación en ADCS-IADL a las semanas 16, 24, 32 y 48 en el grupo Exelon-Patch 15 Menor declinación en ADAScog, pero significativo a la semana 24 en el grupo Exelon-Patch 15
  • Mayores dosis de rivastigmina mantienen actividades funcionales complejas de interacción social Cummings J. et al. Poster presentado en AAIC-Vancouver,Canada, July 14-19, 2012Cummings J. et al. Poster presentado en AAIC-Vancouver,Canada, July 14-19, 2012
  • Cummings J. et al. Dement Geriatr Cogn Disord 2012;33:341–353Cummings J. et al. Dement Geriatr Cogn Disord 2012;33:341–353 Medidas de eficacia secundaria en Rivastigmina-altas dosis: Funciones ejecutivas (TMT A y B) y conductual (NPI-10 y NPI-D)
  • Eventos adversos mas frecuentes con altas dosis, pero disminuyen en el tiempo, sobre todo nauseas, vómitos y eritema Cummings J. et al. Dement Geriatr Cogn Disord 2012;33:341–353Cummings J. et al. Dement Geriatr Cogn Disord 2012;33:341–353
  • No olvide, recomendaciones para familia y cuidadores • Problemas relacionados a seguridad: – Ambiente doméstico. – Conducción vehicular. – Adherencia a la medicación. – Explotación financiera. – Abuso del cuidador. • Atienda necesidades futuras: Planificación financiera, voluntades anticipadas, poderes notariales, protección legal (interdicción).