A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial)

Clive Ballard^1*, Marisa Margallo Lana², Megan Theodoulou³, Simon Douglas⁴, Rupert McShane⁵, Robin Jacoby³, Katja Kossakowski¹, Ly-Mee Yu⁶, Edmund Juszczak⁶, on behalf of the Investigators DART AD

1 Wolfson Centre for Age-Related Diseases, King’s College London, London, United Kingdom, 2 Northgate Hospital, Morpeth, Northumberland, United Kingdom, 3 Department of Psychiatry, University of Oxford, The Warneford Hospital, Oxford, United Kingdom, 4 Department of Psychiatry, Newcastle University, Newcastle upon Tyne, United Kingdom, 5 Oxfordshire and Buckinghamshire Mental Health NHS Trust and University of Oxford, Department of Psychiatry, Fulbrook Centre, Oxford, United Kingdom, 6 Centre for Statistics in Medicine, University of Oxford, Oxford, United Kingdom

Background

There have been increasing concerns regarding the safety and efficacy of neuroleptics in people with dementia, but there are very few long-term trials to inform clinical practice. The aim of this study was to determine the impact of long-term treatment with neuroleptic agents upon global cognitive decline and neuropsychiatric symptoms in patients with Alzheimer disease.

Methods and Findings

Design: Randomised, blinded, placebo-controlled parallel two-group treatment discontinuation trial.

Setting: Oxfordshire, Newcastle and Gateshead, London and Edinburgh, United Kingdom.

Participants: Patients currently prescribed the neuroleptics thioridazine, chlorpromazine, haloperidol trifluoperazine or risperidone for behavioural or psychiatric disturbance in dementia for at least 3 mo.

Interventions: Continue neuroleptic treatment for 12 mo or switch to an identical placebo.

Outcome measures: Primary outcome was total Severe Impairment Battery (SIB) score. Neuropsychiatric symptoms were evaluated with the Neuropsychiatric Inventory (NPI).

Results: 165 patients were randomised (83 to continue treatment and 82 to placebo, i.e., discontinue treatment), of whom 128 (78%) commenced treatment (64 continue/64 placebo). Of those, 26 were lost to follow-up (13 per arm), resulting in 51 patients per arm analysed for the primary outcome. There was no significant difference between the continue treatment and placebo groups in the estimated mean change in SIB scores between baseline and 6 mo; estimated mean difference in deterioration (favouring placebo) −0.4 (95% confidence interval [CI] −6.4 to 5.5), adjusted for baseline value (p = 0.9). For neuropsychiatric symptoms, there was no significant difference between the continue treatment and placebo groups (n = 56 and 53, respectively) in the estimated mean change in NPI scores between baseline and 6 mo; estimated mean difference in deterioration (favouring continue treatment) −2.4 (95% CI −8.2 to 3.5), adjusted for baseline value (p = 0.4). Both results became more pronounced at 12 mo. There was some evidence to suggest that those patients with initial NPI ≥ 15 benefited on neuropsychiatric symptoms from continuing treatment.

Conclusions

For most patients with AD, withdrawal of neuroleptics had no overall detrimental effect on functional and cognitive status. Neuroleptics may have some value in the maintenance treatment of more severe neuropsychiatric symptoms, but this benefit must be weighed against the side effects of therapy.

Trial registration: Cochrane Central Registry of Controlled Trials/National Research Register (#ISRCTN33368770).

Funding: The DART-AD project was made possible by a grant from The Alzheimer’s Research Trust, Cambridge, UK (http://www.alzheimers-research.org.uk) to Profs Ballard and Jacoby and to RM. The peer review process undertaken by the funder did result in some modifications to the study design. The funder has no other role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: CB has received honoraria from Novartis, Pfizer, Shire, Lundbeck, Myriad, Janssen, Astra Zeneca, and Servier pharmaceutical companies and research grants from Novartis, Lundbeck, Astra-Zeneca, and Janssen pharmaceuticals. The remaining authors have declared that they have no competing interests.

Academic Editor: Carol Brayne, University of Cambridge, United Kingdom

Citation: Ballard C, Lana MM, Theodoulou M, Douglas S, McShane R, et al. (2008) A Randomised, Blinded, Placebo-Controlled Trial in Dementia Patients Continuing or Stopping Neuroleptics (The DART-AD Trial) . PLoS Med 5(4): e76 doi:10.1371/journal.pmed.0050076

Received: May 31, 2007; Accepted: February 15, 2008; Published: April 1, 2008

Copyright: © 2008 Ballard et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abbreviations: AD, Alzheimer disease; ANCOVA, analysis of covariance; BADLS, Bristol Activities of Daily Living Scale; CGIC, Clinician’s Global Impression of Change; CI, confidence interval; DMC, data-monitoring committee; EPS, extrapyramidal signs and symptoms; FAS, Verbal Fluency Task; FAST, Functional Assessment Staging; IQR, interquartile range; NPI, Neuropsychiatric Inventory; SD, standard deviation; SIB, Severe Impairment Battery; (S)MMSE, (Standardised) Mini Mental State Examination; STALD, Sheffield Test for Acquired Language Disorders; UPDRS, Unified Parkinson’s Disease Rating Scale

* To whom correspondence should be addressed. E-mail: clive.ballard@kcl.ac.uk

Editors’ Summary

Background

The number of people with dementia (currently 25 million worldwide) is expected to increase by 5 million each year. The risk of dementia, including Alzheimer disease, increases sharply with age: Alzheimer’s Disease International estimates that 1.4% of people 65–69 have dementia, whereas almost a full quarter of those over the age of 85 years are affected. Almost all older dementia patients will experience, along with the cognitive and functional decline typical of the illness, some neuropsychiatric symptoms. These symptoms can include agitation, aggression, and psychosis, and are often devastating for the older patient and his or her family and caregiver. Managing these symptoms is often a prime concern for health-care providers and families. Neuroleptics (sometimes called antipsychotics) are the class of drugs often used to manage or control neuropsychiatric problems, but there have been questions about their safety and appropriateness. Safety concerns involve risk of stroke, parkinsonism, sedation, edema, and chest infections but also include a worsening of cognitive decline with prolonged use of neuroleptics.

Why Was the Study Done?

Previous studies on the effectiveness and safety of neuroleptics in older people have been short term. Ballard and colleagues wanted to study over a longer period of time the impact of neuroleptic drugs on elderly patients with dementia. Specifically, they wanted to know if being on a neuroleptic was associated with more cognitive decline than coming off the drug. They also wanted to investigate whether discontinuing the drug exacerbated any neuropsychiatric symptoms, Parkinson disease-like symptoms, or other functional, language, and cognition difficulties frequently associated with dementia.

What Did the Researchers Do and Find?

The researchers recruited older patients with Alzheimer disease from across England who had been on neuroleptics for at least three months. They randomised patients to one of two groups: the first group continued taking the same neuroleptic at the same dosage level while the second group was switched to an identical-looking placebo. The researchers assessed the patients’ cognitive status and neuropsychiatric symptoms upon their entry into the study. Six and 12 months later the researchers assessed any cognitive decline and the level of neuropsychiatric and other problems that patients were experiencing.

At both 6 and 12 months, the researchers found that there were no differences between the two groups (continued treatment and placebo) in terms of cognitive decline. The placebo group may have had less cognitive decline, but this was not statistically significant. They also found no overall differences between the two groups in the change in the number of neuropsychiatric symptoms over these time periods. Patients with severe neuropsychiatric problems at the outset of the trial did better on continued neuroleptic therapy, but this advantage was not statistically significant. There was a significant decline on the verbal fluency language tests among the patients who continued on their neuroleptic.

What Do these Findings Mean?

The researchers report perhaps the first trial of this duration on continued versus withdrawn neuroleptic treatment among older dementia patients. The findings do not indicate any benefit of continuing neuroleptic therapies in older patients on either cognitive or neuropsychiatric outcomes. The researchers conclude that neuroleptics, with their known safety issues, should not be used as first-line treatment to manage problems such as agitation or aggression. For older dementia patients whose neuropsychiatric symptoms are not remedied by nonpharmaceutical treatments, the researchers advise caution. More studies are urgently needed to find better solutions to help older patients with dementia who have agitation, aggression, and psychosis.

Additional Information

Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050076.

• Alzheimer’s Disease International is an umbrella organisation of organisations worldwide
• The Alzheimer’s Research Trust in the UK is a charity funding research to cure or prevent dementias
• The US National Institutes of Aging has information on Alzheimer Disease in English and Spanish
• Two governmental regulatory agencies—the Medicines and Healthcare Products Regulatory Agency in the UK and the Food and Drug Administration in the US—offer information about antipsychotics in people with dementia

Articulo completo en PLoS

Influencia de las migraciones en Reino Unido sobre conducta materna

Influence of moving to the UK on maternal health behaviours: prospective cohort study

Summer Sherburne Hawkins, research fellow, Kate Lamb, MSc student, Tim J Cole, professor, Catherine Law, professor, the Millennium Cohort Study Child Health Group

¹ Centre for Paediatric Epidemiology and Biostatistics, UCL Institute of Child Health, London WC1N 1EH

Correspondence to: S S Hawkins s.hawkins@ich.ucl.ac.uk<!–
var u = “s.hawkins”, d = “ich.ucl.ac.uk”; document.getElementById(“em0″).innerHTML = ‘<a href=”mailto:’ + u + ‘@’ + d + ‘”>’ + u + ‘@’ + d + ‘<\/a>’//–>

Abstract

Abstract
Introduction
Methods
Results
Discussion
References

Objective To compare health behaviours during pregnancy (smoking and alcohol consumption) and after birth (initiation and duration of breast feeding) between British/Irish white mothers and mothers from ethnic minority groups; and, in mothers from ethnic minority groups, to examine whether indicators of acculturation (generational status, language spoken at home, length of residency in the United Kingdom) were associated with these health behaviours.

Design Prospective nationally representative cohort study.

Setting England.

Participants 6478 British/Irish white mothers and 2110 mothers from ethnic minority groups.

Main outcome measures Any smoking during pregnancy; any alcohol consumption during pregnancy; initiation of breast feeding; breast feeding for at least four months.

Results Compared with British/Irish white mothers, mothers from ethnic minority groups were less likely to smoke (15% v 37%) or consume alcohol (14% v 37%) during pregnancy but more likely to initiate breast feeding (86% v 69%) and breast feed for at least four months (40% v 27%). Among mothers from ethnic minority groups, first and second generation mothers were more likely to smoke during pregnancy (odds ratio 3.85, 95% confidence interval 2.50 to 5.93, and 4.70, 2.49 to 8.90, respectively), less likely to initiate breast feeding (0.92, 0.88 to 0.97, and 0.86, 0.75 to 0.99), and less likely to breast feed for at least four months (0.72, 0.62 to 0.83, and 0.52, 0.30 to 0.89) than immigrants, after adjustment for sociodemographic characteristics. There were no consistent differences in alcohol consumption. Among immigrants, for every additional five years spent in the UK the likelihood of mothers smoking during pregnancy increased by 31% (4% to 66%) and they were 5% (0% to 10%) less likely to breast feed for at least four months.

Conclusions After immigration, maternal health behaviours worsen with length of residency in the UK. Health professionals should not underestimate women’s likelihood of engaging in risky health behaviours because of their ethnicity.

Introduction

Abstract
Introduction
Methods
Results
Discussion
References

The adverse effects of smoking^{1 2} and alcohol consumption³ during pregnancy and the beneficial effects of breast feeding⁴ on maternal and child health are well known. Many women from resource-rich countries, however, do not adhere to recommendations,^{1 5 6 7 8 9 10} including those to reduce smoking^{11 12} and stop drinking¹³ during pregnancy and breast feed exclusively for six months.¹⁴ Research from the United States has shown that maternal health behaviours vary by country of birth and length of residency, two indicators of acculturation.^{15 16 17 18 19 20 21 22 23 24} Acculturation is the adoption of health behaviours from the new dominant culture and loss of health behaviours from the original culture.^{25 26} In the US, acculturation has been associated with an increase in smoking^{15 16 17 18} and alcohol consumption^{15 16 17} during pregnancy as well as a reduction in initiation^{19 20 21 22 23 24} and duration^{19 23 24} of breast feeding.

Over the past 50 years immigration into the United Kingdom has increased, primarily from South Asia, the Caribbean, Europe, and Africa.²⁷ In 2001-2, 7.6% of the population was from an ethnic minority group, an increase of 44% over the previous decade.²⁸ Women from ethnic minority groups are less likely to smoke or consume alcohol than the general population in England²⁹ and more likely to initiate and continue breast feeding than white mothers.⁷

We compared health behaviours during pregnancy (smoking and alcohol consumption) and after birth (initiation and duration of breast feeding) between British/Irish white mothers and mothers from ethnic minority groups in a nationally representative, contemporary cohort of mothers in England. We also examined how indicators of acculturation (measured by generational status, language spoken at home, length of residency in the UK) were associated with these health behaviours.

Methods

Abstract
Introduction
Methods
Results
Discussion
References

Participants
The millennium cohort study is a prospective study of children born in the UK in the new century. We used a stratified clustered sampling framework to over-represent children from ethnic minority groups and disadvantaged areas. In England, electoral wards (as established in 1998) were categorised as “ethnic” (based on the 1991 census, if at least 30% of residents were from an ethnic minority group) and the remainder as “disadvantaged” (the upper quarter of the child poverty index) or “advantaged” (all remaining wards). In Wales, Scotland, and Northern Ireland there was no “ethnic” stratum.³⁰ Families were invited to participate if they were eligible for child benefit and resident in the UK when their child was aged 9 months. The original cohort comprised 18 819 children (18 553 families) born between September 2000 and January 2002 (72% response).³⁰ About 80% (14 630) participated in the second contact, in September 2003 to January 2005, when the children were aged 3 years.³¹ At both contacts, information was collected through interviews of main respondents in the home. Translators were available.³²

We focused on families in England because numbers were insufficient to analyse by ethnic group in Wales, Scotland, or Northern Ireland. Among the 11 695 mothers with singleton children at the first contact, 79% (9184) participated in the second. Families from “ethnic” and “disadvantaged” electoral wards were less likely to participate in the second contact,³¹ but non-response weights are available and were used to allow for differential attrition. Data were accessed through the UK Data Archive, University of Essex.

Among the 9184 mothers with singleton children in England at both contacts, we included 8588 in the analyses. We excluded families if information was missing on the main respondent’s ethnicity (46), the main respondent was not female (139) or a natural mother (53), there were two cohort children from the same family (8), or the main respondent had missing information on her generational status (370), language spoken at home (0), length of residency in the UK (193), initiation of breast feeding (15), duration of breast feeding (15), smoking during pregnancy (41), or alcohol consumption during pregnancy (16). Some families satisfied more than one exclusion criterion.

At the first contact, mothers reported their own ethnicity (out of 16 possible choices), which was classified according to guidelines from the Office for National Statistics.³³ White women were categorised as either from any UK country or the Republic of Ireland (referred to as “British/Irish”) or from any other country (referred to as “other white”).⁵ To increase sample size we collapsed ethnic groups into British/Irish white, Pakistani or Bangladeshi, black (black African, black Caribbean, other black), Indian, other white (such as white European, North American), other (such as Sri Lankan, Arab), or mixed.

Sociodemographic characteristics were based on maternal self report at the first contact. Maternal socioeconomic circumstances were categorised according to the National Statistics socioeconomic classification,³⁴ maternal education was defined as the highest academic qualification attained, and single motherhood status was defined as being a single mother when the child was aged 9 months. Mothers also reported whether the cohort child was their first live birth (parity), and their age at the birth of the cohort child. We included family income at the first contact; if it was missing we substituted values from the second contact (483).

Outcome measures
Smoking and alcohol consumption during pregnancy—At the first contact, mothers were asked about their smoking and drinking habits during pregnancy. Mothers reported their smoking habits before pregnancy and were asked whether they changed during pregnancy. Mothers were classified as having smoked if they reported smoking any number of cigarettes during pregnancy. Mothers also reported how often they drank alcoholduring pregnancy, ranging from never to every day. Mothers were classified as having consumed alcohol if they reported consuming any amount of alcohol during pregnancy. At the time when the mothers were pregnant, government recommendations were that pregnant women should drink no more than one or two units of alcohol once or twice a week and avoid intoxication.³⁵

Initiation and duration of breast feeding—At the first contact, mothers were asked about their infant feeding practices. Initiation of breast feeding was defined as the baby having received any breast milk. Duration was categorised as being either fully or partially breast fed for at least four calendar months (17.4 weeks) or less than four months.⁵ At the time of the cohort births, the World Health Organization recommended that babies were breast fed for at least four months.³⁶

Indicators of acculturation
Generational status—At the second contact, main respondents reported whether they, their mother, and their father were born in the UK or Republic of Ireland and, if not, their country of birth. Mothers were classified as immigrants (neither they nor either parent were born in the UK or Republic of Ireland), first generation (they were born in the UK or Republic of Ireland, but at least one parent was born outside the UK or Republic of Ireland), or second generation (both they and their parents were born in the UK or Republic of Ireland).

Language spoken at home—At the first contact, main respondents reported whether the language usually spoken at home was English, English and another language, or another language only.

Length of residency in the UK—At the second contact, main respondents who were not born in the UK or Republic of Ireland were asked the year when they arrived in the UK. This was subtracted from the year of the interview at the first contact to give the length of residency.

Statistical analyses
All analyses were conducted with STATA statistical software, version 9.2 SE (Stata Corporation, TX), with survey commands to account for the clustered sampling framework and obtain robust standard errors. We derived weighted percentages and conducted analyses using survey and non-response weights to allow for the clustered sampling and attrition between contacts. Proportions were compared with Pearson’s ² tests with the Rao and Scott second order correction.³⁷ We included British/Irish white mothers to provide baseline characteristics of the majority ethnic group in England. Health behaviours during pregnancy (smoking and alcohol consumption) and after birth (initiation and duration of breast feeding) were compared by maternal ethnic group.

Relacion entre IMC y cancer

Relación entre el IMC y el riesgo de cáncer

Renehan AW, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 336: 569-578.  R TC (s) PDF (s)

Introducción

En numerosos estudios, el exceso de peso se ha relacionado con un incremento del riesgo de desarrollar determinados tumores. Sin embargo, la diversidad de localizaciones, tipos de estudios y medidas de resultado utilizadas dificultan la comparación de los datos.

Objetivo

Rervisar la relación entre el IMC y la fuerza de la asociación con determinados tumores e investigar las diferencias respecto al sexo y distintos grupos étnicos.

Perfil del estudio

Tipo de estudio: Metaanálisis

Área del estudio: Causa

Ámbito del estudio: Comunitario

Métodos

Se llevó a cabo una búsqueda en Medline, Embase, las listas de referencias de los trabajos localizados y otras fuentes bibliográficas relevantes para localizar los estudios de cohortes (y los de casos y controles anidados dentro de éstos), publicados en cualquier idioma, en los que se investigaba la relación entre el IMC y la incidencia de 20 tipos diferentes de tumores en 15 localizaciones diferentes (colorrectal, gastroesofágico, hepatobiliar, leucemia, pulmonar, melanoma, mieloma, linfoma no hodgkiniano, leucemia, pancreático, renal, tiroideo, prostático, mamario, endometrial y ovárico.

Los criterios de inclusión fueron que se midiese el IMC al inicio del estudio, se registrase la incidencia de nuevos tumores en el seguimiento, que proporcionasen medidas de estimación del riesgo para al menos 3 categorías de IMC. Se excluyeron las publicaciones que no eran informes completos, los que sólo proporcionaban datos de mortalidad (en vez de incidencia) y los estudios sobre lesiones preneoplásicas. En función de su origen étnico, se clasificaron a los participantes como norteamericanos (>80% blancos), europeos-australianos, afroamericanos, asiáticos y multiétnicos.

Resultados

Cumplieron los criterios de inclusión 141 artículos que aportaron datos de 76 estudios con 221 conjuntos de datos que supusieron más de 133 millones de personas-año de observación y 282.173 casos incidentes de cáncer. Más de la mitad de los trabajos y los de mayor tamaño se habían publicado a partir de 2004.

Los IMC elevados se asociaron a un mayor riesgo de presentar cáncer en numerosas localizaciones en ambos sexos (adenocarcinoma de esófago, tiroides, colon, riñón, mieloma y leucemia), así como en algunos tumores propios de la mujer (endometrio y mama en la postmenopausia). En cambio, el exceso de peso se asoció a un menor riesgo de cáncer de pulmón y de carcinoma escamoso de esófago. En estos casos, es posible que esta asociación se deba en gran parte al efecto de confusión del tabaco, que se asocia a un menor peso y a un mayor riesgo de estos tipos de tumores.

Tabla 1. Riesgo relativo para diferentes tipos de tumores por cada 5 kg/m² de IMC.

	Varones	Mujeres
Adenocarcinoma de esófago	1,52 (1,33 a 1,74)	1,51 (1,31 a 1,74)
Tiroides	1,33 (1,04 a 1,70)	1,14 (1,06 a 1,23)
Colon	1,24 (1,20 a 1,28)	1,09 (1,05 a 1,13)
Renal	1,24 (1,15 a 1,34)	1,34 (1,25 a 1,43)
Hígado	1,24 (0,95 a 1,62)	1,07 (0,55 a 2,08)
Melanoma	1,17 (1,05 a 1,30)	0,96 (0,92 a 1,01)
Mieloma	1,11 (1,05 a 1,18)	1,11 (1,07 a 1,15)
Recto	1,09 (1,06 a 1,12)	1,02 (1,00 a 1,05)
Vesícula	1,09 (0,99 a 1,21)	1,59 (1,02 a 2,47)
Leucemia	1,08 (1,02 a 1,14)	1,17 (1,04 a 1,32)
Páncreas	1,07 (0,93 a 1,23)	1,12 (1,02 a 1,22)
Linfoma no hodgkiniano	1,06 (1,03 a 1,09)	1,07 (1,00 a 1,14)
Próstata	1,03 (1,00 a 1,07)	-
Gástrico	0,97 (0,88 a 1,06)	1,04 (0,90 a 1,20)
Pulmón	0,76 (0,70 a 0,83)	0,80 (0,66 a 0,97)
Escamoso de esófago	0,71 (0,60 a 0,85)	0,57 (0,47 a 0,69)
Endometrio	-	1,59 (1,50 a 1,68)
Mama (postmenopausia)	-	1,12 (1,08 a 1,16)
Ovario	-	1,03 (0,99 a 1,08)
Mama (premenopausia)	-	0,92 (0,88 a 0,97)

En los análisis de subgrupos, las asociaciones ente el IMC y el riesgo de cáncer fueron más fuertes para los varones que para las mujeres para el cáncer colorrectal y a la inversa para el cáncer renal. La mayor parte de las asociaciones fueron pareceidas para las diferentes áreas geográficas, pero para el cáncer de mama en la premenopausia se encontró una relación directa con el IMC para los estudios llevados a cabo en países asiáticos e inversa para el resto de las regiones geográficas. En los países asiáticos la relación entre el IMC y el cáncer de mama en la postmenopausia también fue mas fuerte que en las otras regiones.

Conclusiones

Los autores concluyen que el IMC elevado se asocia a un mayor riesgo de sufrir determinados tumores y que esta asociación puede variar entre los dos sexos y para personas de diferentes orígenes étnicos.

Conflictos de interés

Uno de los autores ha recibido honorarios de varios laboratorios farmacéuticos. Financiado parcialmente por una beca de la British Medical Association.

Comentario

En este estudio se confirma el hallazgo de estudios previos de que la presencia de obesidad se asocia a un mayor riesgo de desarrollar determinado tipo de tumores. El hecho de que para el mismo sólo se hayan utilizado los datos de estudios prospectivos limita la posibilidad de determinados sesgos como el del recuerdo selectivo. Por otro lado, el que sólo se hayan utilizado datos de incidencia permite limitar el efecto de otros factores como el peor pronóstico que presentan los obesos para determinados tipos de tumores, que pueden afectar a los estudios que se llevan a cabo con datos de mortalidad.

Una limitación de este estudio es que el análisis estadístico da como resultado un incremento de riesgo por cada unidad de IMC, pero es posible que el incremento de riesgo no sea lineal, puesto que en algunos estudios previos el exceso de riesgo de tumores se concentró en los pacientes con obesidades mórbidas. Por otro lado, tampoco permite analizar si, como en el caso de las enfermedades cardiovasculares, determinados tipos de obesidad, como la abdominal, se asocian a un mayor riesgo.

El hecho de que se dé esta asociación estadística no prueba por sí solo que esta relación sea causal. Irían a favor de una relación de este tipo la especificidad del efecto y el hecho de que en los estudios de intervención sobre la obesidad se detectase en las personas asignadas al grupo intervención una reducción de la incidencia de tumores malignos. Sin embargo, los estudios publicados de este tipo suelen tener unos efectos modestos y acostumbran a tener unos seguimientos no demasiado largos. No obstante, en un ensayo clínico llevado a cabo en pacientes con obesidad mórbida tratados mediante cirugía bariátrica en los pacientes asignados al grupo intervención la mortalidad fue inferior que en los asignados al grupo control y entre las enfermedades que presentaron una reducción importante de la mortalidad (próxima a la mitad) se encontraban los tumores.

Bibliografía

1. Hu FB, Stampfer MJ, Manson JE, Grodstein F, Colditz GA, Speizer FE, Willett WC. Trends in the incidence of coronary heart disease and changes in diet and lifestyle in women. N Engl J Med 2000; 343: 530-537.  R TC PDF

Autor

Manuel Iglesias Rodal. Correo electrónico: mrodal@menta.net.

Ezetimebe e hipercolesterolemia familiar

Eficacia de la ezetimiba sobre la evolución de la aterosclerosis en pacientes con hipercolesterolemia familiar

Kastelein JJP, Akdim F, Stroes ESG, Zwinderman AH, Bots ML, Stalenhoef AFH et al for the ENHANCE Investigators. Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia. N Engl J Med 2008; 358: 1431-1443.  R TC PDF

Introducción

La ezetimiba es un fármaco que aumenta la reducción de colesterol producida por las estatinas. Sin embargo, hasta ahora no se dispone de estudios que hayan demostrado su eficacia en la prevención de las enfermedades cardiovasculares.

Objetivo

Estudiar si la administración de 10 mg de ezetimiba añadidos a 80 mg de simvastatina reduce la progresión de la aterosclerosis en pacientes con hipercolesterolemia familiar.

Perfil del estudio

Tipo de estudio: Ensayo clínico

Área del estudio: Tratamiento

Ámbito del estudio: Hospital

Métodos

El estudio ENHANCE se llevó a cabo en 18 consultas de Norteamérica, Europa y Sudáfrica. Se invitó a participar a pacientes de ambos sexos de 30-75 años que habían sido diagnosticados de hipercolesterolemia familiar y que tenían niveles de LDL >210 mg/dL sin tratamiento. Se excluyó a los pacientes que presentaban lesiones oclusivas de la carótida de grado elevado, los que habían sido sometidos a endarterectomía o un stent carotídeo, los que tenían antecedentes de insuficiencia cardíaca con clases de la NYHA III o IV, arritmias, angina de pecho o eventos cardiovasculares recientes.

El estudio se dividió en 3 fases:

1. Fase de cribado.
2. Fase de lavado en el que se retiró toda la medicación hipocolesterolemiante y se administró un placebo a simple ciego durante 6 semanas.
3. Fase doble ciego de 24 meses en la que los pacientes fueron distribuidos aleatoriamente a recibir:
   • Simvastatina 80 mg/d + ezetimiba 10 mg/d.
   • Simvastatina 80 mg/d + placebo.

Se visitó a los participantes cada 3 meses y se les practicó un Doppler carotídeo y femoral cada 6 meses. La variable de resultado principal fue el cambio en el grosor de la íntima-media carotídea respecto a la basal. Como variables secundarias se utilizaron el porcentaje de pacientes que presentaron regresión de las lesiones, el porcentaje de pacientes que desarrollaron nuevas placas ateroscleróticas, el cambio detectado en el máximo grosor de la íntima media de las arterias femorales y carotídeas. También se analizó el efecto del tratamiento sobre los valores lipídicos.

Se llevó a cabo un análisis por intención de tratar.

Resultados

Participaron en el estudio 720 pacientes (fig. 1). Las características de los participantes de los dos grupos fueron similares. La edad media fue de 46 años, el 51% eran varones, el IMC medio fue de 27 y el 80% de los mismos habían recibido estatinas con anterioridad.

Figura 1. Flujo de los participantes.

El tratamiento con ezetimiba produjo una reducción del colesterol adicional del 16,5% (fig. 2) y también produjo reducciones significativas del colesterol total, los triglicéridos y la proteína C reactiva y una elevación significativa del colesterol HDL.

Figura 2. Efecto del tratamiento sobre el perfil lipídico.

En cambio, no se detectaron cambios estadísticamente significativos en el grosor de la íntima-media carotídea (fig. 3).

Figura 3. Efecto del tratamiento sobre el grosor íntima-media carotídeo.

Tampoco se detectaron diferencias estadísticamente significativas en ninguna de las variables secundarias analizadas (tabla 1).

Tabla 1. Variables secundarias analizadas.

		Simvastatina + Placebo	Simvastatina + Ezetimiba	P
Regresión de la íntima-media carotidea	% pacientes	44,4	45,3	0,92
Placas nuevas	% pacientes	1,8	4,7	0,20
Incremento en el máximo grosor íntima-media	mm	0,0103	0,0175	0,27
Efectos adversos	% pacientes	29,5	34,2	0.18
Interrupción del tratamiento	% pacientes	9,4	8,1	0,56
Eventos cardiovasculares	n	7	10

Conclusiones

Los autores concluyen que, en los pacientes con hipercolesterolemia familiar, el tratamiento combinado con ezetimiba y simvastatina no fue mas eficaz que la simvastatina sola para mejorar la evolución del grosor íntima-media carotídeo a pesar de mejorar de forma importante el perfil lipídico.

Conflictos de interés

Varios de los autores ha recibido honorarios de varios laboratorios farmacéuticos. Apoyado por Merck y Shering Plough.

Comentario

Durante los últimos años, muchos grupos de expertos han sugerido la idea de que en el tema del colesterol LDL, “menos es mejor”, es decir que existe una relación lineal entre los niveles de colesterol LDL y el riesgo de cardiopatía isquémica. Este paradigma se basaba en los resultados de diferentes estudios llevados a cabo con estatinas, no exentos de algunos problemas metodológicos, en los que se demostraba que dosis crecientes de éstas para conseguir objetivos de LDL cada vez más bajos se asociaban a un menor número de eventos cardiovasculares.

La ezetimiba es un fármaco que inhibe la absorción intestinal del colesterol, con lo que, asociado a estatinas se consigue una reducción adicional del 12-14% de los niveles de colesterol LDL. Por este motivo, se había recomendado su utilización en pacientes de alto riesgo en los que la monoterapia no hubiese bastado para conseguir los objetivos de colesterol LDL deseados. Sin embargo, hasta el momento no se ha demostrado la eficacia de la ezetimiba en la prevención de las complicaciones de la aterosclerosis.

En este estudio la adición de este fármaco a dosis elevadas de simvastatina en pacientes con hipercolesterolemia familiar no mejoró la evolución del grosor de la íntima-media carotídea. A pesar de que son posibles varias interpretaciones de los resultados, el hecho de que en una población de alto riesgo como son los pacientes con hipercolesterolemia familiar el tratamiento no sea capaz de mejorar los resultados de una variable de resultado intermedia no apoyan la utilización de este fármaco mientras no se disponga de pruebas más contundentes de su eficacia.

Bibliografía

1. Brown BG, Taylor AJ. Does ENHANCE Diminish Confidence in Lowering LDL or in Ezetimibe?. N Engl J Med 2008; 358: 1504-1507.   TC PDF
2. Drazen JM, Jarcho JA, Morrissey S, Curfman GD. Cholesterol Lowering and Ezetimibe. N Engl J Med 2008; 358: 1507-1508.   TC PDF
3. McKenney J, Ballantyne CM, Feldman TA, Brady WE, Shah A, Davies MJ et al. LDL-C Goal Attainment With Ezetimibe Plus Simvastatin Coadministration vs Atorvastatin or Simvastatin Monotherapy in Patients at High Risk of CHD. Disponible en: Medscape (http://www.medscape.com). Consultado por última vez el 14-04-2008   TC

Autor

Manuel Iglesias Rodal. Correo electrónico: mrodal@menta.net.