Check Up: So far, very little flu


CDC Director Gerberding Gives Green Light to G...
CDC Director Gerberding Gives Green Light to Gardasil then Goes to Work for Merck (g1a2d0049c1) (Photo credit: watchingfrogsboil)

Check Up: So far, very little flu

The U.S. Centers for Disease Control and Prevention has confirmed what you already guessed: This has been a remarkably mild flu season.
The influenza virus likes cold weather, so infections normally occur from October through March. But technically, the flu season doesn’t start until labs that test respiratory swabs from sick people find the virus in more than 10 percent of the samples.
This season, that threshold wasn’t reached until the week ended Feb. 11, making this the kindest flu spell in 29 years.
Pennsylvania, for example, had only 80 confirmed cases in all of January – barely more than one achy, feverish, nauseated citizen per county.
What’s going on?
No one really knows.
“With flu, everything is unpredictable,” said immunologist Scott Hensley, a flu expert at the Wistar Institute in Philadelphia. “I don’t think we’re out of the woods; it could just be a delayed season.”
Then again, maybe the flu has been as scarce as snow because snow has been scarce.
“Flu is more easily transmitted in colder temperatures. This has been a mild winter,” Hensley said.
Another theory is that the population has high levels of immunity to the influenza strains now circulating, which include the one that caused the 2009 “swine flu” pandemic. Because the strains have been so stable, people have had time to develop antibodies against them. Vaccination has also boosted immunity.
Although Hensley subscribes to this theory, he adds a caveat: “If that’s true . . . the virus will start mutating” to evade human defenses. “A novel strain might emerge in the next couple of months.”
While there’s no room for complacency, let us celebrate the signs, monitored by the CDC, that the flu has given the nation a respite:
One person per 100,000 has been hospitalized with the flu since October. That’s a 95 percent drop from last season’s rate of 22 people per 100,000.
Only 1 percent to 2 percent of visits to doctors since October have been for flulike illness. The usual rate is 3 percent to 8 percent.
This flu season, there have been three flu-related deaths among children, compared with 122 pediatric deaths last season – and 348 during the 2009 pandemic.
– Marie McCullough

Read more: http://www.philly.com/philly/health/20120227_Check_Up__So_far__very_little_flu.html#ixzz1neP8n4sM Watch sports videos you won’t find anywhere else

Effect of Aspirin on Vascular and Nonvascular Outcomes Meta-analysis of Randomized Controlled Trials


English: Schematic diagram of a plasma CVD (Ch...Image via WikipediaEffect of Aspirin on Vascular and Nonvascular Outcomes

Meta-analysis of Randomized Controlled Trials
Sreenivasa Rao Kondapally Seshasai, MD, MPhil; Shanelle Wijesuriya, MA, MBBChir; Rupa Sivakumaran, MA, MBBChir; Sarah Nethercott, MA, MBBChir;Sebhat Erqou, MD, PhD; Naveed Sattar, MD, PhD; Kausik K. Ray, MD 
Arch Intern Med. Published online January 9, 2012. doi:10.1001/archinternmed.2011.628
Background  The net benefit of aspirin in prevention of CVD and nonvascular events remains unclear. Our objective was to assess the impact (and safety) of aspirin on vascular and nonvascular outcomes in primary prevention.
Data Sources  MEDLINE, Cochrane Library of Clinical Trials (up to June 2011) and unpublished trial data from investigators.
Study Selection  Nine randomized placebo-controlled trials with at least 1000 participants each, reporting on cardiovascular disease (CVD), nonvascular outcomes, or death were included.
Data Extraction  Three authors abstracted data. Study-specific odds ratios (ORs) were combined using random-effects meta-analysis. Risks vs benefits were evaluated by comparing CVD risk reductions with increases in bleeding.
Results  During a mean (SD) follow-up of 6.0 (2.1) years involving over 100 000 participants, aspirin treatment reduced total CVD events by 10% (OR, 0.90; 95% CI, 0.85-0.96; number needed to treat, 120), driven primarily by reduction in nonfatal MI (OR, 0.80; 95% CI, 0.67-0.96; number needed to treat, 162). There was no significant reduction in CVD death (OR, 0.99; 95% CI, 0.85-1.15) or cancer mortality (OR, 0.93; 95% CI, 0.84-1.03), and there was increased risk of nontrivial bleeding events (OR, 1.31; 95% CI, 1.14-1.50; number needed to harm, 73). Significant heterogeneity was observed for coronary heart disease and bleeding outcomes, which could not be accounted for by major demographic or participant characteristics.
Conclusions  Despite important reductions in nonfatal MI, aspirin prophylaxis in people without prior CVD does not lead to reductions in either cardiovascular death or cancer mortality. Because the benefits are further offset by clinically important bleeding events, routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis.


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Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome.


Kaptchuk TJ, Kelley JM, Conboy LA, Davis RB, Kerr CE, Jacobson EE et alComponents of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 2008; 336: 999-1003.    TC   PDF

Introducción

Se han descritos 3 componentes en el efecto placebo: la respuesta a la observación y evaluación (efecto Hawthorne), la respuesta del paciente a la administración de un ritual terapéutico (la prescripción de un fármaco, por ejemplo) y la respuesta del paciente a la interacción-médico paciente. Sin embargo, la importancia relativa de estos 3 componentes no se ha estudiado.

Objetivo

Estudiar si el efecto placebo se puede separar experimentalmente en sus 3 componentes y éstos se pueden combinar gradualmente para producir una mejoría clínica aditiva en pacientes con síndrome del intestino irritable (SII).

Perfil del estudio

Tipo de estudio: Ensayo clínico
Área del estudio: Tratamiento
Ámbito del estudio: Comunitario

Métodos

Se invitó a participar en el estudio a los pacientes afectos de SII atendidos en un centro, que se reclutaron mediante anuncios en prensa y derivaciones de otros profesionales. Los participantes debían tener ≥18 años, cumplir los criterios diagnósticos de Roma II y tener una puntuación ≥150 en la escala de intensidad de los síntomas. Se excluyó a los pacientes con datos sospechosos de presentar otra enfermedad (pérdida de peso, presencia de sangre en las heces, etc.) y a los que habian recibido acupuntura previamente.
El estudio se dividió en dos periodos de 3 semanas. Durante el primer periodo, los participantes fueron distribuidos aleatoriamente en 3 grupos:
  1. Lista de espera. Sirvió como grupo de control de la evolución natural de la enfermedad, la regresión a la media y el efecto Hawthorne. No recibieron ningún tratamiento, pero fueron valorados a las 3 y 6 semanas.
  2. Interacción limitada. Se le ofrecía al paciente sesiones de acupuntura placebo (sham) con una interacción mínima con el médico. Éste tenía una visita inicial fría de <5 minutos y se le colocaban las agujas y se dejaba al paciente sólo en una habitación durante 20 minutos. Con posterioridad se le administraban 2 sesiones semanales de acupuntura sham durante la duración del estudio.
  3. Interacción potenciada. Además de la acupuntura se permitía una interaccion con el médico más intensa. La visita inicial era más cálida y duraba unos 45 minutos en los que se les ofrecía al paciente mucha más información y se le transmitían ánimos y expectativas positivas sobre el éxito del tratamiento.
Al final del periodo de 3 semanas los pacientes de los grupos 2 y 3 fueron distribuidos de nuevo aleatoriamente sin su conocimiento a continuar con la acupuntura sham o con acupuntura genuina, pero sin cambiar el tipo de relación con el médico que se le había asignado.
Se permitió a los pacientes que siguiesen con su medicación habitual, siempre que esta permaneciese constante antes y durante el estudio. Las valoraciones de los participantes fueron llevadas a cabo por enfermeras que desconocían a qué grupo habían sido asignados los participantes. Las variables de resultado principales fueron una escala de mejoría global de los síntomas en los últimos 7 días comparados con el inicio del estudio (de 1 [mucho peor] a 7 [mucho mejor]) y la respuesta a una pregunta al paciente sobre si en la última semana había notado una mejoría adecuada de sus síntomas. Como variables secundarias se utilizaron los resultados de las escalas de intensidad de los sintomas y de calidad de vida, que se midieron también al inicio del estudio.

Resultados

Participaron en el estudio 262 pacientes (fig. 1). La composición de los grupos fue parecida. La edad media fue de 38 años. Un 76% eran mujeres. No se encontraron diferencias entre los grupos en las puntuaciones medias de las escalas de ansiedad, depresión y calidad de vida, aunque la intensidad de los síntomas fue ligeramente inferior en el grupo de intervención limitada.
Figura 1. Flujo de los participantes.
Para todas las variables estudiadas la intervención potenciada fue superior a la limitada y ésta superior a la lista de espera (fig. 2).
Figura 2. Resultados de las diferentes intervenciones.
El tratamiento fue bien tolerado y los efectos adversos fueron los típicos de la acupuntura: dolor en el momento de la inserción de las agujas y de su retirada y enrojecimiento de la zona. A las 3 semanas no se detectaron diferencias estadísticamente significativas en la proporción de pacientes de los grupos placebo que creían que habían recibido acupuntura genuina (más del 75% en ambos grupos). En cambio, a las 6 semanas, más participantes del grupo de placebo potenciado creían haber recibido el tratamiento real (84 frente a 56%; P=0,02).

Conclusiones

Los autores concluyen que los diferentes componentes del efecto placebo se pueden aislar y combinar progresivamente para conseguir un efecto aditivo y que el componente más robusto es la relación médico-paciente.

Conflictos de interés

Algunos de los autores han recibido honorarios de laboratorios farmacéuticos y de empresas dedicadas a terapias naturales por diferentes conceptos. Financiado por varias agencias de investigación públicas.

Comentario

El efecto placebo está presente permanentemente en la relación médico-paciente y es muy utilizado por los profesionales: en varios estudios llevados a cabo en diferentes países se observó que una parte importante de los profesionales administran placebos en su práctica habitual y es probable que una parte significativa de los beneficios de los medicamentos recetados se deban a este efecto. Pese a todo, los estudios sobre el tema son escasos y poco conocidos por los médicos en ejercicio. Ello se debe en parte a los problemas éticos de estos estudios, a sus dificultades metodológicas y según algunos autores a la pérdida de prestigio que supone a la profesión médica el estudio exhaustivo de este fenómeno.
Pese a todo, se han producido avances en el tema, como por ejemplo, el hecho de que se haya demostrado que en algunas ocasiones su efecto se vea anulado por la administración de naloxona, lo que sugiere la participación de las endorfinas en el proceso, la importancia que tienen sobre la intensidad del efecto las expectativas del paciente y del médico sobre la eficacia del tratamiento, el efecto que tiene el aspecto físico y el precio del medicamento y el hecho de que cuanto más compleja sea la intervención, más probable es que sea eficaz.
En este estudio, los autores han intentado aislar qué parte del efecto placebo se debe puramente a la intervención y qué parte se debe a la interacción con el medico. Para ello eligieron una enfermedad con una elevada tasa de respuesta al placebo y una intervención (la acupuntura sham) que, al menos en el tratamiento de la dispepsia, se ha mostrado más eficaz como placebo que la utilización de un placebo farmacológico. El principal resultado del estudio es que la intervención resultó eficaz, pero lo fue mucho más la interacción con el médico durante una visita larga y cálida. Esto debería llevarnos a la reflexión sobre el modelo de atención primaria existente en nuestro país en el que la premura de las visitas puede afectar de forma importante a la eficacia de las intervenciones.

Bibliografía

  1. Forcades T, Caminal. Núria Rodríguez J, Gutiérrez T, Grupo de investigación en MCAEfecto placebo frente a efecto terapéutico en la práctica clínica y medicinas complementarias y alternativas. Aten Primaria 2007; 39: 99-102.   TC   PDF
  2. González P, de Benedetto MAC, Ramírez IEl arte de curar: el médico como placebo. Aten Primaria 2008; 40: 93-95.   TC   PDF
  3. Skrabanek P, McCormick J. Follies and fallacies in Medicine. Eastbourne: Tarragon Press. 1989.

Autor

Manuel Iglesias Rodal. Correo electrónico: mrodal@menta.net.
Claves
R Resumen    TC Texto completo    PDF Portable Document File (Adobe Reader)    RC Resumen comentado    (s) Sólo suscriptores   
AP al día [ http://www.apaldia.com ]
© MEDIGRAF 2011. 
Esta web se dirige exclusivamente a los profesionales del sector médico.
Se otorga permiso para copiar y distribuir este documento completo (http://www.apaldia.com/resumenes/resumen.php?idresumen=577), si se hace de forma literal y se mantiene esta nota.

Placebo

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Occult papillary carcinoma of the thyroid. A "normal" finding in Finland. A systematic autopsy study.


Papillary Carcinoma of the Thyroid This illust...Image via Wikipedia

Cancer. 1985 Aug 1;56(3):531-8.

Occult papillary carcinoma of the thyroid. A “normal” finding in Finland. A systematic autopsy study.

Abstract

The thyroids from 101 consecutive autopsies from Finland were subserially sectioned at 2- to 3-mm intervals. From 36 thyroids, 52 foci of occult papillary carcinoma (OPC) were found, giving a prevalence rate of 35.6%, the highest reported rate in the world. The rate was higher, although not significantly, in males (43.3%) than in females (27.1%), but it did not correlate to the age of the patients. Twenty-six glands contained one tumor focus and ten glands contained two to five tumor foci. Only a minority of the smallest tumors can be detected with the method used. The probable number of OPCs over 0.15 mm in diameter was calculated to be about 300 in this material. The tumor diameter varied from 0.15 mm to 14.0 mm, with 67% of tumors under 1.0 mm. The smallest tumors were usually circumscribed and were composed almost solely of follicles. Larger tumors had more papillary structures and were often invasive. Fibrosis and, in the largest OPCs, lymphocytic reaction were seen around the invasive islands. All tumors were positively stained for thyroglobulin and all but one of the tumors stained positively for epidermal keratin. OPC appears to arise from follicular cells of normal follicles. Apparently the great majority of the tumors remain small and circumscribed and even from those few tumors that grow larger and become invasive OPCs only a minimal proportion will ever become a clinical carcinoma. According to the study, OPC can be regarded as a normal finding which should not be treated when incidentally found. In order to avoid unnecessary operations it is suggested that incidentally found small OPCs (less than 5 mm in diameter) were called occult papillary tumor instead of carcinoma.

PMID:

 

2408737

 

[PubMed – indexed for MEDLINE]

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https://www.excellencis.org/images/site/logo_excellencis.png
14-12-2011

La enfermedad arterial periférica es una manifestación común de la aterosclerosis cuya prevalencia aumenta con la edad (12% en la población general, alcanzando el 20% en mayores de 70 años) y la presencia de factores de riesgo cardiovascular. El tabaco (más del 80% de los pacientes son o han sido fumadores) y la diabetes mellitus son los principales factores de riesgo1,2.
La mayoría de las personas con esta enfermedad se encuentran asintomáticas y su diagnóstico requiere del cálculo del índice tobillo/brazo junto con una anamnesis y exploración física completa1,3,4.
Alrededor de un tercio de los pacientes con enfermedad arterial de las extremidades inferiores presentan sintomatología5. Dentro de estos síntomas, la claudicación intermitente es el más característico, y se define como un dolor intenso y atenazante en grupos musculares de la extremidad afectada, que aparece al caminar y se alivia con el reposo6.
La enfermedad cardiovascular es la principal causa de muerte en pacientes con claudicación intermitente, por lo que el abordaje de esta patología debe centrarse no solo en mejorar la movilidad y la calidad de vida, sino también en disminuir el riesgo cardiovascular. Para ello han de llevarse a cabo varios tipos de intervenciones1-7:
– Control de los factores de riesgo cardiovascular con especial énfasis en el ejercicio físico y el abandono del tabaco.
– Tratamiento antiagregante.
– Tratamiento farmacológico para el alivio de los síntomas.
– Angioplastia o revascularización cuando la sintomatología es incapacitante a pesar del tratamiento conservador1,3,4.

Las alertas de seguridad y los cambios producidos en la disponibilidad de varios fármacos utilizados en el alivio de los síntomas de la claudicación intermitente hacen necesario actualizar la información disponible y en este aspecto se va a centrar este boletín INFAC
Te recomendamos su lectura haciendo clic aquí 
Equipo de GAPURMED y Excellencis
El boletín INFAC es parte de la Sociedad Internacional de Boletines de Medicamentos, independientes de la industria farmacéutica (ISDB)

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10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis


Halliday A, Harrison M, Hayter E, Kong X, Mansfield A, Marro J et al on behalf of the Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 2010; 376: 1074-1084.  TC PDF (s)

Introducción

Las personas con una estenosis significativa de las carótidas presentan un riesgo significativamente superior de sufrir un AVC, aunque no tengan antecedentes de síntomas neurológicos recientes. La endarterectomía de esas lesiones produce una mejoría del flujo sanguíneo pero aumenta el riesgo de AVC a corto plazo, por lo que se desconoce si el balance entre riesgos y beneficios a largo plazo es favorable.

Objetivo

Estudiar los efectos a largo plazo de la endarterectomía carotídea exitosa.

Perfil del estudio

Tipo de estudio: Ensayo clínico
Área del estudio: Tratamiento
Ámbito del estudio: Comunitario

Métodos

El estudio ACST-1 se llevó a cabo entre 1993 y 2003. Se invitó a participar a pacientes con estenosis significativa de carótida (>60%) uni- o bilateral, sin que hubiese presentado síntomas neurológicos en los últimos 6 meses, en los que tanto el médico como el paciente tuviesen dudas sobre si era mejor intervenirlo inmediatamente o demorar la intervención.
Las personas incluidas fueron distribuidas aleatoriamente a recibir una endarterectomía tan pronto como fuera posible o a demorar la intervención hasta que el paciente desarrollase síntomas neurológicos o se diese alguna otra circunstancia que indicaba claramente la intervención. Se siguió a los pacientes anualmente y en los 5 primeros controles se les practicaron eco-Doppler carotídeos. Los participantes de los dos grupos recibieron el tratamiento médico que sus médicos personales decidieron.
Las variables de resultado fueron la mortalidad y AVC perioperatorios (<30 días después de la intervención) y los AVC no perioperatorios. Los informes sobre los AVC fueron valorados por un comité que desconocía la asignación de cada uno de los pacientes y se clasificaron en función de su topografía (ipsilateral, contralateral o vértebro-basilar), su causa (hemorrágico, cardioembólico o isquémico de otro tipo) y en función del resultado a los 5 meses del AVC (mortal, invalidante o no invalidante).

Resultados

Participaron en el estudio 3.120 personas (fig. 1). No se encontraron diferencias estadísticamente significativas entre las características de los individuos de los dos grupos, aunque los autores no proporcionan datos para describirlos. El seguimiento medio fue de 9 años. No se apreciaron diferencias importantes entre los tratamientos médicos que habían recibido los participantes de los dos grupos. A los 5 años se les había practicado una endarterectomía al 92% del grupo intervención y al 24% del grupo control (en una tercera parte por haber presentado síntomas).
Figura 1. Evolución de los participantes.
Inicialmente se observó un mayor número de AVC y muertes perioperatorias en el grupo intervención, pero la tendencia se invirtió a partir del segundo año. Cuando se analizaron los AVC no perioperatorios, desde un primer momento se apreció un mayor número en los participantes asignados al grupo control que en los asignados al grupo placebo (fig. 2).
Figura 2. Evolución de las variables de resultados.
La reducción fue parecida independientemente de la gravedad del AVC y aunque fue superior para los AVC homolaterales, las diferencias entre los dos grupos fueron estadísticamente significativos para los contralaterales y los vertebrobasilares. Casi la totalidad de la reducción de la incidencia se dio en los AVC isquémicos, aunque el número de los hemorrágicos y cardioembólicos fue muy pequeño. Las diferencias fueron superiores para los menores de 75 años y perdieron la significación estadística por encima de esta edad.
Los autores informan que el número de muertes por otras causas diferentes de los AVC perioperatorios no fueron estadísticamente diferentes entre los dos grupos, pero únicamente las informan separadas en subgrupos. Si se analizan en su totalidad, se dieron 554 muertes en el grupo de intervención inmediata y 499 en el de intervención diferida.

Conclusiones

Los autores concluyen que la endarterectomía inmediata en pacientes <75 años asintomáticos con estenosis carotídea asintomática reduce el riesgo de AVC a los 10 años, pero que el balance riesgo-beneficio de los pacientes futuros dependerá de los riesgos asociados a las lesiones no intervenidas (que se pueden reducir mediante la medicación), de los riesgos de la técnica operatoria (que pueden diferir de los observados en este estudio) y de la esperanza de vida de los pacientes.

Conflictos de interés

Ninguno declarado. Financiado por becas del UK Medical Research Council, la BUPA Foundation, y la Stroke Association.

Comentario

Los AVC son una causa importante de mortalidad y de invalidez en los países desarrollados. En los últimos decenios se ha reducido de forma importante la mortalidad por esta causa, hecho que se atribuye a la mejoría de los factores de riesgo cardiovascular, como el tabaquismo y la HTA. Casi el 90% son de mecanismo isquémico. El 20% de éstos presentan lesiones ateroscleróticas en la carótida que en teoría serían accesibles a la cirugía. Sin embargo, la estenosis carotídea es sólo un factor de riesgo más. Los principales son los antecedentes previos de enfermedad cerebrovascular, la fibrilación auricular, el sexo masculino, la edad avanzada, la HTA, el tabaquismo y la estructura de la placa.
En una revisión reciente de la US Preventive Services Task Force, este grupo no recomienda el cribado sistemático de la población para detectar estenosis carotídeas asintomáticas por varios motivos. A pesar de que la ultrasonografía presenta unas buenas sensibilidad y especificidad (94 y 92% respectivamente) para detectar lesiones >60%, el hecho de que la prevalencia de la enfermedad sea baja (1% de los mayores de 65 años) hace que los falsos positivos sean numerosos, por lo que se necesita llevar a cabo una prueba de confirmación diagnóstica. La más habitual (angiografía) conlleva un riesgo de un 1% de sufrir un AVC. Si se opta por una prueba no invasiva como el TAC o la RMN, algunos pacientes con menor grado de estenosis pueden verse expuestos a los riesgos de la endarterectomía.
En cuanto a la eficacia de la endarterectomía, los autores de la revisión alertan sobre que los resultados de los trabajos publicados (entre otros un informe previo de éste) son poco generalizables, dado que se han llevado a cabo en pacientes de muy alto riesgo cardiovascular y por cirujanos muy seleccionados, con tasas de complicaciones peroperatorias <3%, que no se dan en muchas áreas geográficas.
Finalmente, hay que remarcar que los autores han desplazado al material complementario de la publicación principal un resultado relevante como son las muertes totales en los dos grupos, en la que se detecta un exceso de un 10% de la mortalidad total sobre la que no aplican ninguna prueba de significación estadística. Por lo tanto, parece que las pruebas disponibles son insuficientes para recomendar la endarterectomía en los pacientes con estenosis carotídea asintomática y, de hecho, persiste el debate sobre su idoneidad. Es posible que la situación cambie a medida que mejoren técnicas alternativas a la endarterectomía como la angioiplastia con stent , pero que hasta la fecha no han mejorado los resultados de aquélla.

Bibliografía

  1. Wolff T, Guirguis-Blake J, Miller T, Gillespie M, Harris R. Screening for Carotid Artery Stenosis: An Update of the Evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2007; 147: 860-870.  TC PDF
  2. Roffi M. Is there a role for revascularisation in asymptomatic carotid stenosis? Yes. BMJ 2010; 341: c4898   TC PDF
  3. Spence JD. Is there a role for revascularisation in asymptomatic carotid stenosis? No. BMJ 2010; 341: c4900   TC PDF
  4. MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004; 363: 1491-1502.  TC (s)PDF (s)

Autor

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

Estimating treatment effects for individual patients based on the results of randomised clinical trials


BMJ 2011; 343:d5888 doi: 10.1136/bmj.d5888 (Published 3 October 2011)

Cite this as: BMJ 2011; 343:d5888

  • Research

Estimating treatment effects for individual patients based on the results of randomised clinical trials

Free via Creative Commons: OPEN ACCESS

  1. Johannes A N Dorresteijn, epidemiologist and medical doctor1,
  2. Frank L J Visseren, professor of vascular medicine, epidemiologist, and internist1
  3. Paul M Ridker, Eugene Braunwald professor of medicine, epidemiologist, and cardiologist2
  4. Annemarie M J Wassink, internist and postdoctoral researcher1
  5. Nina P Paynter, assistant professor of epidemiology2
  6. Ewout W Steyerberg, professor of medical decision making, and methodologist3
  7. Yolanda van der Graaf, professor of epidemiology and imaging4
  8. Nancy R Cook, associate professor of biostatistics and epidemiology2
Author Affiliations

  1. 1Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, Netherlands


  2. 2Division of Preventive Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA


  3. 3Department of Public Health, Erasmus Medical Center, Rotterdam, Netherlands


  4. 4Julius Center for Health Sciences and Primary Care, Utrecht, Netherlands

  1. Correspondence to: F L J Visseren F.L.J.Visseren@umcutrecht.nl
  • Accepted 12 August 2011

Abstract

Objectives To predict treatment effects for individual patients based on data from randomised trials, taking rosuvastatin treatment in the primary prevention of cardiovascular disease as an example, and to evaluate the net benefit of making treatment decisions for individual patients based on a predicted absolute treatment effect.
Setting As an example, data were used from the Justification for the Use of Statins in Prevention (JUPITER) trial, a randomised controlled trial evaluating the effect of rosuvastatin 20 mg daily versus placebo on the occurrence of cardiovascular events (myocardial infarction, stroke, arterial revascularisation, admission to hospital for unstable angina, or death from cardiovascular causes).
Population 17 802 healthy men and women who had low density lipoprotein cholesterol levels of less than 3.4 mmol/L and high sensitivity C reactive protein levels of 2.0 mg/L or more.
Methods Data from the Justification for the Use of Statins in Prevention trial were used to predict rosuvastatin treatment effect for individual patients based on existing risk scores (Framingham and Reynolds) and on a newly developed prediction model. We compared the net benefit of prediction based rosuvastatin treatment (selective treatment of patients whose predicted treatment effect exceeds a decision threshold) with the net benefit of treating either everyone or no one.
Results The median predicted 10 year absolute risk reduction for cardiovascular events was 4.4% (interquartile range 2.6-7.0%) based on the Framingham risk score, 4.2% (2.5-7.1%) based on the Reynolds score, and 3.9% (2.5-6.1%) based on the newly developed model (optimal fit model). Prediction based treatment was associated with more net benefit than treating everyone or no one, provided that the decision threshold was between 2% and 7%, and thus that the number willing to treat (NWT) to prevent one cardiovascular event over 10 years was between 15 and 50.
Conclusions Data from randomised trials can be used to predict treatment effect in terms of absolute risk reduction for individual patients, based on a newly developed model or, if available, existing risk scores. The value of such prediction of treatment effect for medical decision making is conditional on the NWT to prevent one outcome event.
Trial registration number Clinicaltrials.gov NCT00239681.

Critical Moments — Doctors and Patients


Lenore M. Buckley, M.D., M.P.H.
N Engl J Med 2011; 365:1270-1271October 6, 2011

I lost myself in the very properties of [my patients‘] minds, for the moment at least, I actually became them . . . so that when I detached myself from them at the end of intense concentration over an illness that was affecting them, it was as though I was awakening from sleep. For the moment I myself did not exist, nothing of myself affected me. As a consequence, I came back to myself as if from any other sleep, rested.

William Carlos Williams, M.D.

A pale, thin, anxious 9-year-old boy sits in front of me. As I start to talk to him, I realize that he is in pain, stoic, and not very verbal. I glance down and notice a markedly swollen ankle. He has been losing weight and uncomfortable for months, his anxious parents report. The pain seems to come and go, but now it’s so severe that he has trouble getting off the bus.
I gently probe for more information. “Have you had diarrhea?” I ask the boy. Yes, he nods. His mother looks startled; he has obviously never mentioned it to her. “Any blood in the diarrhea?” He nods again, and now we’re both startled. The boy looks even more anxious, and I’m aware of his parents’ escalating panic. It’s then that I realize that this is one of those critical moments. I’ll confess that most of the time, I’m not the slow, thoughtful, organized, wise physician with an endless fund of knowledge that I always imagined I’d become. More often, I’m the harried, absent-minded doctor who rushes into the room an hour late and tries to organize her thoughts in front of you as you remind her who you are and why you’re there. But at moments like this, I become completely focused. William Carlos Williams, the poet and primary care physician, eloquently described these moments and the intensity of the relationship between doctors and patients as they embark on the treatment of a serious illness.
Such moments occur at most a few times a month, usually when I least expect them. I walk into an exam room prepared to hear about a straightforward problem or to see a child with pain “everywhere” who’s struggling with the social challenges of middle school, and then, as I listen, I realize that the person in front of me is seriously ill. Sometimes the patient or the parents already know; sometimes they have no idea. The dawning of this realization is followed by a call to full attention. In the next hour and over the next few months, what I do (or don’t do) will change the life of this child and family; what I say and how I say it will be critical, providing the information, reassurance, and hope to keep everyone moving forward.
With this boy, Sam, my questions and exam follow the usual order, and then it’s time to talk. I remind myself of my responsibilities — education, treatment, support, advocacy. I look into Sam’s eyes and try to describe, in language he can understand, general concepts that will give him a sense of what’s happening in his body. This basic explanation is usually adequate for the parents as well, who are often in a state of shock; we’ll have more time to talk later.
I explain it to Sam first, respecting the fact that it’s his body and he is able to understand — and needs to know — what’s happening. It’s an important step in showing him respect and giving him back some control. We’re beginning a relationship, and obtaining his trust will be key to getting his cooperation. I want him to know that I see who he is, care about what he thinks, and will be his ally.
As I talk, I envision myself building a protective wall around him and his parents to hold back the wave of fear, vulnerability, and loss of control that is rushing in as they realize something serious has occurred. I look into his eyes and explain with confidence and reassurance that things will get better. I offer hope: “We know what this is, and together we will get you better.” We are now a team, and he’s the most important team member. We discuss the possible diagnoses, treatment, the need for a GI referral, and how to reach me over the next few days.
As I leave the room, I feel like I’m rising to the surface of the water after a deep dive. I have been in another world, where outside sounds are muffled and time slows. Now I reemerge in the noisy, fast-paced world of outpatient medicine. I’m an hour behind schedule, and the nurses — and my next patient — are understandably annoyed. A long day awaits. But somehow the rest of the day is easier. The world comes into better focus. I have been reminded of why I’m here and how lucky I am to be doing what I do.
In the afternoon, I pass the pediatric gastroenterologist, who reassures me he will see Sam quickly, and within a week he’s diagnosed with Crohn’s disease and starts treatment.
I see Sam regularly over the next few months. I smile when I go into the room, look at him first as I say hello, and ask how things are going. I’ve learned to warn my patients about the ups and downs of glucocorticoid treatment: first, there’s relief when the medicine finally controls the symptoms, then there’s discouragement about side effects and changes in appearance and mood, followed by the struggle to discontinue them as the other medications begin to work. It’s an emotional roller coaster, and it’s my job to prepare them.
Sam has followed this path. There’s the visit at 4 weeks when the diarrhea has stopped and the joints are not painful. He is still quiet but looks relieved. When he returns at 8 weeks, he is markedly cushingoid, embarrassed, and dejected — it’s not easy to have a pumpkin face with acne in elementary school. Again, I sit next to him and look directly into his eyes. Sometimes this is not so easy with teens and preteens, who tend to stare down at the floor. In an attempt at humor, I bend down and turn my head up so I can see his face. “It will be better,” I reassure him. “A few more weeks.” He smiles. I walk him through the treatment plan again. I explain what’s happening to his body and go over the timelines.
By the 12th week, he is still cushingoid but surprisingly chatty and looks straight into my eyes as he reports what’s happened since the last visit. He seems to understand now that I am here to see and talk to him, and he is proud of his role in managing the illness. He looks more hopeful. The prednisone dose has been reduced, and he knows the tapering schedule well enough to correct his father, who is momentarily confused about the gastroenterologist’s treatment plan. He sees the light at the end of the tunnel.
Sam and his parents are at the beginning of a long journey. This illness will influence who Sam will become — affecting his self-image, relationships, and aspirations. His parents face one of life’s most difficult challenges. The course of their lives and their relationship shifted, almost imperceptibly, at that first visit. How their story will play out is still unclear to me, although I’ve seen hundreds of other versions of it over the years.
This time, I’ve been lucky enough to be there from that critical moment at the beginning, to be a part of the story’s evolution and, I hope, acceptable resolution. All physicians experience these moments. They shape our lives, inform our values, and educate and prepare us for the next patient who needs our help. The expectation of these moments and the satisfaction they bring keep us moving forward through difficult times. The challenge is to continue to notice them — to remember the personal impact of the diagnoses we make and our ability and obligation to soften the blows, to build that protective wall.
The name of the patient has been changed to protect his privacy.
Disclosure forms provided by the author are available with the full text of this article at NEJM.org.

SOURCE INFORMATION

From Virginia Commonwealth University School of Medicine, Richmond.

Vacunación antigripal en el otoño boreal


Juan Gérvas, claro como siempre, repitiendo lo inútil de esta vacuna. No ahora, sino desde siempre. Veamos cuando hagan una que sirva, y dure toda la vida, y no sólo un año. Seguramente nuestro desarrollo tecnológico lo puede hacer, pero no seria negocio. 

RESUMEN:
La vacuna antigripal es inútil. Lo ha revisado la Cochrane Library, concluyendo sin dudas sobre su falta de eficacia. No obstante se presiona a la población y a los profesionales sanitarios para conseguir una vacunación masiva. Tal propuesta falta a la ciencia y a la ética.

Algunos hechos:1. Se difunden porcentajes de efectividad que convierten de facto a la vacuna antigripal en un milagro.


Hablan de que la vacuna disminuye el 88% las bajas del personal sanitario por gripe, pero la mayor parte de los casos de “gripe clínica” no son casos de “gripe”. Los médicos centinelas, especialmente entrenados para el diagnóstico de gripe, aciertan entre el 15 y el 25% de los casos.
Es decir, en torno al 80% de los casos de “gripe clínica” son causados por virus no gripales (y el 20% por el virus gripal, obviamente).
Si la efectividad de la vacuna fuera del 100% sólo se evitaría el 20% de las ausencias (la “gripes clinicas” causadas por virus de la gripe).
En los porcentajes que se difunden ¿hay un milagro, un error o un negocio? Para responder, eche un ojo a los patrocinadores de los eventos, conferencias y textos sobre la vacuna contra la gripe.
Hablan de la disminución a la mitad de la mortalidad entre los vacunados. Es decir, disminuye la mortalidad el 50%. Parece que la mitad de los pacientes de riesgo no se morirán sin son vacunados. Pero las muertes por gripe son en total en España, unas 1.500 al año (o menos, ver texto adjunto), por lo que si la vacuna tuviera el 100% de efectividad no se morirían 750 personas al año, en toda España. En realidad, la efectividad de la vacuna es de menos del 5% (ver texto adjunto), de forma que como mucho se podrían evitar 75 muertes (1,5 por millón de españoles), al coste de complicaciones graves tipo Gillain Barré y de vacunar a millones de personas.
De nuevo, eche un ojo a los patrocinadores de textos como “Manual de supervivencia del periodista para un invierno sin gripe”, y a los patrocinadores del Grupo Estudio de la Gripe y a sus conferencias, ruedas de prensa y demás. Uno no sabe si venden milagros, difunden errores o hacen negocio.
2. Tergiversan los resultados sobre efectividad de la vacuna antigripal

Se ha demostrado que los estudios sobre efectividad de la vacuna antigripal tergiversan el resumen de la publicación científica, de forma que sea favorable, en contra de los resultados incluídos en el propio artículo.
Es decir, el resumen es casi siempre favorable, por más que los datos no lo sean tanto (o nada).
Muchos médicos sólo leen el resumen, lo que lleva a una impresión favorable sobre la efectividad de la vacuna antigripal.
Increíble pero cierto:
Jefferson T, DiPietrantong C, Debalini MG, Rivetti A, Dimicheli
V. Relation of study quality, concordance, take home
message, funding and impact in studies or influenza vaccines:
systematic review. BMJ. 2009;338:b354 doi: 10.1136/
bmjb354.
Estos hechos, y más, en el comentario sobre diez artículos acerca de la falta de efectividad de la vacuna antigripal:
http://www.equipocesca.org/uso-apropiado-de-recursos/las-vacunas-contra-el-virus-de-la-gripe/
http://www.equipocesca.org/uso-apropiado-de-recursos/las-vacunas-contra-el-virus-de-la-gripe-respuesta-a-carta-al-director/
3. Sabíamos que la vacuna estacional 2009-2010 carecía de efectividad, pero se puso dicha vacuna en septiembre de 2009 a millones de españoles, a sabiendas de su inutilidad
Fuimos varios los que advertimos sobre el daño que se iba a producir al poner la vacuna estacional de septiembre de 2009, cuando se sabía que era inútil ante la pandemia de gripe A. Lo habían demostrado los australianos:
Kelly H, Grant K. Interim analysis of pandemic influenza (H1N1) 2009 in
Australia: surveillance trends, age of infection and effectiveness of seasonal
vaccination. Euro Surveill. 2009;14:pii=19288. Available at: http://www.
eurosurveillance.org/ViewArticle.aspx?ArticleId=19288.
No obstante, se vacunó a la población española, atemorizada ante la pandemia de gripe A, con la vacuna estacional de 2009, a sabiendas de que era inútil, como habíamos difundido varios:
http://vicentebaos.blogspot.com/2009/09/hay-que-vacunar-de-la-gripe-estacional.html
Gripe A, paciencia y tranquilidad. Gérvas, J. [Notas clínicas]. Agosto 2009. [Última actualización 13/09/2009]
Millones de españoles vacunados innecesariamente a sabiendas. Como siempre, pero en esa ocasión, más sangrante, por el pánico creado con la pandemia de gripe A.
4. Insisten e insisten en vacunas sin efectividad y con ello desacreditan todas las vacunas
Hay vacunas y vacunas. Algunas han sido y son clave en salud pública, como la de la viruela, la del sarampión, la de la rabia o la del tétanos. Otras sobran, o deberían restringirse a grupos muy específicos. Otras son claramente inútiles:
http://www.equipocesca.org/uso-apropiado-de-recursos/vacunas-uso-y-abuso/
Los abusos de los que anuncian milagros, difunden errores y hacen negocio están desacreditando a todas las vacunas.
En concreto sobre la vacuna antigripal no hay ensayos clínicos a largo plazo, por lo que seguiremos un año y otro sin poder decidir sobre efectividad:
http://www.equipocesca.org/wp-content/uploads/2010/05/gripe-a-mayo-2010-incoherencias-falta-transparencia.pdf
En 2011 el colmo es emplear el mismo contenido de 2010, lo que demuestra su escasa inmunidad:
http://www.equipocesca.org/uso-apropiado-de-recursos/vacuna-contra-la-gripe-2011-2012-una-vacuna-terminator-mas-razones-para-el-no-razonable-de-profesionales-y-pacientes-flu-vaccine-2011-2012-a-terminator-vaccine-more-reason-to-say-a-reasonabl/
Sobre los que promueven vacunas sin efectividad pesa una gran responsabilidad.
5. Como se esperaba, falta de efectividad ante la gripe H1N1 (gripe A, de 2009) de la vacuna estacional 2008-2009 que contenía antígenos contra el virus H1N1 de la gripe
La vacuna estacional de la gripe 2008-2009 tenía antígenos contra el virus H1N1, y por ello se podía esperar algún efecto ante la pandemia de gripe A, de 2009.
Pero eso era sólo posible si la vacuna antigripal tuviese efectividad.
Los estudios confirman su falta de efecto.
La vacuna antigripal estacional 2008-2009 careció de efectividad contra la pandemia de gripe A, pese a contar con antígenos contra el virus H1N1.
Demostrado con datos españoles, en una revista española, y publicados en inglés (va adjunto):
Larrauri A et al. Influenza pandemic (H1N1) 2009 activity during summer 2009. Effectiveness of the 2008-2009 trivalent vaccine againts pandemic influenza in Spain. Gac Sanit. 2011;25:23-8.
En Madrid (España), a 8 de octubre de 2011. Escrito por Juan Gérvas jgervasc@meditex.es SE PUEDE DIFUNDIR, SIEMPRE QUE SEA EL TEXTO ÍNTEGRO.

Juan Gérvas

www.equipocesca.org

I just want permission to be ill’: towards a sociology of medically unexplained symptoms


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Soc Sci Med. 2006 Mar;62(5):1167-78. Epub 2005 Aug 30.

I just want permission to be ill’: towards a sociology of medically unexplained symptoms.

Source

University of York, York, UK. sjn2@york.ac.uk

Abstract

A significant proportion of symptoms are medically unexplained. People experience illness but no pathological basis for the symptoms can be discerned by the medical profession. Living without a clinical diagnosis or medical explanation has consequences for such patients. This paper reports on a small qualitative interview-based study of 18 neurology outpatients in England who live with such medically unexplained symptoms (MUS). The findings broadly concur with those identified in the related literatures on medically unexplained syndromes and unexplained pain: the difficulties of living with uncertainty; dealing with legitimacy; and a resistance to psychological explanations of their suffering. From a thematic analysis of the interview data we identify and elaborate on three related issues, which we refer to as: ‘morality’; ‘chaos’; and ‘ambivalence’. Although this article presents empirical data its aim is primarily conceptual; it integrates the findings of the empirical analysis with the existing literature in order to try to make some sociological sense of the emergent themes by drawing on sociological and cultural analyses of risk and the body. We draw on Bauman‘s concept of ambivalence to suggest that the very processes associated with more precise ‘problem solving’ and ‘classification’ do, in fact, generate even more uncertainty and anxiety. On the one hand, we seek closure and certainty and yet this leaves no means of living with uncertainty. Indeed, society does not readily grant permission to be ill in the absence of disease. We conclude by suggesting that an appreciation of the experience of such embodied doubt articulated by people who live with MUS may have a more general applicability to the analysis of social life under conditions of late modernity.

PMID:

 

16135395

 

[PubMed – indexed for MEDLINE]

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SIAP 2011: Cancer de mama


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Osteoporosis: Las guías de la discordia


Las guías de la discordia
Maria Valerio. El Mundo (España) 12/11/2010
http://tinyurl.com/Mac-guia-osteo




Un documento de consenso avalado por el Ministerio de Sanidad y Consumo y la Generalitat de Cataluña sobre el tratamiento de la osteoporosis ha desatado la polémica en la Red. Algunos de los autores que aparecen como revisores del texto han mostrado su descontento con la versión final y muchos especialistas critican el ‘abuso’ de los fármacos que promueve.


El doctor Rafael Bravo, especialista en Atención Primaria, fue el primero en soltar la liebre desde su blog al criticar la “dudosa calidad científica” de la llamada Guía de Práctica Clínica sobre Osteoporosis y Prevención de Fracturas por Fragilidad .


A su juicio, el manual apuesta por tratar preventivamente a mujeres postmenopáusicas, sin factores de riesgo, con el objetivo de prevenir supuestamente la aparición de fracturas y empleando unos fármacos (como los bifosfonatos o el raloxifeno) no exentos de riesgo. “Erróneamente se iguala menopausia, osteoporosis y tratamiento farmacológico”, explica este experto a ELMUNDO.es.
La osteoporosis es una pérdida de la densidad ósea relacionada con la caída de estrógenos que sufren las mujeres en la menopausia. Como recogen los Institutos Nacionales de Salud de EEUU, el tratamiento está reservado para los casos ya diagnosticados (por medio de un estudio que mide la densidad del hueso) o bien para mujeres con osteopenia (una fase previa a la osteoporosis en la que los huesos están debilitados), pero que ya han sufrido una fractura.


Descontento
Bastó una entrada en su blog, para que algunos de los especialistas que presuntamente habían revisado el documento de ‘consenso’ manifestaran su sorpresa y su disconformidad con la versión final. Es el caso de Cecilia Calvo, del servicio balear de salud y miembro de la Sociedad Española de Farmacia Hospitalaria. “En mayo de 2009 enviamos los comentarios a un primer borrador del texto y desde entonces no hemos vuelto a saber nada más”, se queja. “Hasta que hemos visto nuestro nombre en la publicación final, sin tener en cuenta nuestras consideraciones”.
Oriol Solá-Morales, director de Evaluación de la Agència d’Informació, Avaluació i Qualitat en Salut (AIAQS) de Cataluña, el organismo encargado de elaborar la guía a petición del Ministerio, tiene su propia versión de los hechos. “Sabíamos que la osteoporosis es un terreno pantanoso y todo este ruido transmite la idea de que hacía falta una guía; aunque seguramente ésta sea mejorable”, admite.
A su juicio, toda esta polémica enfrenta a las dos “posturas” que existen en torno a la osteoporosis “sobre si el tratamiento previene o no las facturas”.
De los 15 revisores a quienes se les envió el texto, un 25% de ellos lo devolvió con “cambios mayores” lo que provocó que se incluyeran algunas modificaciones en la versión definitiva que se ha publicado, “pero no es posible incorporar todas las sugerencias porque si no tendríamos que iniciar otra vez el proceso de validación de la evidencia”.
Solá-Morales también despeja cualquier duda sobre el papel que haya podido tener la industria farmacéutica en su elaboración: “No conoció el documento hasta que éste se publicó”. La agencia ha emitido una nota en la que confirma que 22 de los 25 revisores han aceptado finalmente constar en la versión final de la guía.
Cecilia Calvo recuerda que los fármacos para prevenir las fracturas son más útiles en las mujeres de mayor riesgo, “aunque la guía es muy laxa en este sentido y menciona cualquier medicamento que haya demostrado cualquier cosa, sin tener en cuenta el balance riesgo-beneficios y sin analizar el impacto económico que puede tener su uso en el sistema nacional de salud”. A su juicio, con esta guía, el ministerio avala la medicalización de la menopausia, “creando la sensación de que todo el mundo tiene que tratarse”.


La entrada de Rafa en su blog: http://tinyurl.com/Mac-guia-rafa
la Guía sobre Osteoporosis: http://tinyurl.com/Mac-guiabestias






Martin Cañás
Fundación Femeba
Grupo Argentino Para el Uso Racional del Medicamento (GAPURMED)
La Plata (Argentina)

Designing a Smarter Patient


[medical]Edel Rodriguez

When given clearer information, patients weigh risks and benefits differently from their doctors.

“I’m comfortable with that,” or “No, it wouldn’t be comfortable for me.”
That’s what our patients often tell us when faced with a choice about taking a medication or undergoing a procedure. And the discussion usually stops there.
But what makes someone comfortable or uncomfortable with one treatment or another, or with no treatment at all? Where do these views come from? And how can patients make better decisions?
For answers, we spent four years interviewing scores of patients of different ages. We found that a host of powerful and often hidden influences, inside and outside the patient’s mind, can sway thinking and distort judgment. We also discovered that, by unmasking those influences, it is possible for patients to gain greater confidence and control over their medical decisions.
Consider the case of Susan Powell (not her real name), a nurse’s assistant now in her 50s. She had been healthy all her life, but when she turned 45, she decided to see a primary-care doctor. Susan ate healthy foods and was physically active, but she was a bit overweight, and her blood tests showed that she had high cholesterol. Her doctor prescribed a statin drug and asked her to come back in a month.


Statins are among the most commonly prescribed medications in the world. In the U.S. alone, more than 25 million people take the drugs to lower their cholesterol, which is a key factor leading to heart attack and stroke.
Soon after seeing her doctor, Susan spoke with an acquaintance at church who had developed muscle pain after starting to take a statin. Susan also thought of her father, who had high cholesterol and never took any medication for it. “People take too many pills,” he often told his children. He lived a long, full and active life.
Susan decided not to take the statin.
Many people decline treatment because they know someone who suffered from side effects or someone who lived well into old age without treatment. Stories deeply affect all of us, and they can make real the risks and benefits that might otherwise seem abstract—but they can also distort our vision by making the rare appear routine.
Statistics can help to put lessons drawn from stories into a larger context, letting us make a more considered choice than we possibly could by using narratives alone.
At Susan’s follow-up appointment a month later, her doctor told her that “by taking a statin pill, you’ll reduce your risk of a heart attack over the next 10 years by as much as 30%.” The risk of side effects, she continued, was very small, and the benefits far outweighed the risk. Susan promised to give it serious thought.
She continued to search for information, reading everything she could about cholesterol. What caught her eye was a government-sponsored link to a “10-Year Heart Attack Risk Calculator.”
She entered her age, total cholesterol number of 240, and “good” cholesterol (HDL) of 37. She was not a smoker, her blood pressure was fine, and she was on no medications. The result: “Risk Score: 1%: Means 1 of 100 people with this level of risk will have a heart attack in the next 10 years.”
This means that 99 of 100 people like me won’t have a heart attack in the next 10 years, Susan told herself. She started to feel much better. She had found a key number in health literacy: her risk for disease without treatment.
Without treatment, Susan’s risk for a heart attack was 1 in 100. If 1 in 100 women has a heart attack, that means 2 in 200 do, or 3 in 300. The statin treatment reduces risk by 30%, or about one-third.
Let’s apply that benefit to a group of 300 women like Susan, where three would have a heart attack without taking statins. If we treat them all, we would prevent one heart attack—because we protect one-third of those three. The other two women would still have a heart attack despite taking the medicine. The remaining 297 would not have had a heart attack even without the medication, so they wouldn’t benefit from taking it.
This statistic comes as a surprise to many people. When you hear that a statin lowers Susan’s risk by 30%, it sounds as if she is at a 100% risk of suffering a heart attack if she doesn’t take the medication.
Another component of health literacy is understanding the risks of a therapy. Statins cause muscle pain in 1% to 10% of people who take them. However, if we “flip” the frame, the number without any side effects is 90 to 99 out of 100, a much more reassuring statistic.
Advertisements for drugs may include statistics, but fundamentally these ads are designed to communicate a compelling tale. Over the weeks that followed her appointment with her physician, Susan paid particular attention to ads for statins. Once she started looking for them, they seemed to be everywhere.
In 2007, a team of researchers from the UCLA Medical Center and other medical centers studied prescription drug ads broadcast on national networks. They found that the average American TV viewer sees over 1,000 prescription drug ads in the space of a year. That’s 16 hours all told—much more time than the average person spends with his or her primary-care physician.
The study concluded that the large majority of TV ads fail to fulfill an educational purpose. But they clearly work, at least from the point of view of sales: Every $1,000 spent on advertising translated into 24 new prescriptions, according to an analysis by the House Energy and Commerce Committee.

Another illuminating study, conducted by researchers at the Dartmouth Institute for Health Policy and Clinical Practice, examined the impact of printed drug ads on patient preferences. One group was given actual ads. A second group received the same ads, except that the brief summary at the end of the text was replaced by a “drug-facts box.” The box presented information in a clear, accessible fashion, similar to the way we recalculated the benefits and risks of a statin for Susan.
The results of the Dartmouth research are impressive. Nearly two-thirds of the group that saw the original ads overestimated the benefits of the treatment. They believed it was 10 times more effective than it actually was. But nearly three-quarters of the participants who saw the information in the drug-facts box correctly assessed the actual benefits of the treatment.
Even more striking was another finding. When people were given readily understandable information about the statin’s actual benefit in preventing future heart disease, nearly twice as many said they wouldn’t take the drug in light of its side effects. When given clearer information, the patients weighed the risks and benefits differently from their doctors and were less likely to take the medication.
Susan Powell’s decision was not simple. More than five years later, her doctor continues to encourage her to take the drug, and she continues to say no—but now, at least, she can more fully explain why.

—Dr. Groopman and Dr. Hartzband are on the faculty of Harvard Medical School and the staff of Beth Israel Deaconess Medical Center, both in Boston. This essay is adapted from their new book, “Your Medical Mind: How To Decide What Is Right for You.

Breast Cancer Screening


By Graham McMahon

The latest article in our Clinical Practice series reviews current recommendations for breast-cancer screening and thesupporting evidence, including the controversy regarding mammographic screening of women in their 40s.
Worldwide, breast cancer is now the most common cancer diagnosed in women and is the leading cause of deaths from cancer among women, with approximately 1.3 million new cases and 458,000 deaths reported in 2008.OK

Clinical Pearls

 How have the screening recommendations from the U.S. Preventive Services Task Force (USPSTF) changed in recent years?
In contrast to its 2002 guidelines, the more recent recommendations of the USPSTF, published in November 2009, support a reduction in the use of screening mammography. The two most controversial changes were the reclassification of screening for women between the ages of 40 and 49 years from a B recommendation (based on moderately strong evidence) to a C recommendation (“the decision . . . should be an individual one and take into account patient context, including the patient’s values regarding specific benefits and harms”), and the recommendation that the frequency of screening be reduced from every 1 to 2 years to every 2 years.
 What is the consensus recommendation regarding mammographic screening for women between the ages of 50 and 69?
Screening mammography for women 50 to 69 years of age is universally recommended. All but one of the trials that included women in their 60s showed a significant reduction in mortality in the screened group, although this was not true for the subgroup of women in their 50s. Still, a meta-analysis revealed significant reductions in the number of deaths in both these age groups — 14% for women in their 50s and 32% for those in their 60s.

Morning Report Questions

Q: For a 42-year-old woman with no risk factors, what are the benefits and risks of screening mammography?
A: Her chance of having invasive breast cancer over the next 8 years is about 1 in 80, and her chance of dying from it is about 1 in 400. Biennial mammographic screening will detect two out of three cancers in women her age and will reduce her risk of death from breast cancer by 15%. However, there is about a 40% chance that she will be called back for further imaging tests and a 3% chance that she will undergo biopsy, with a benign finding.
Q: What are the benefits of digital mammography?
A: The contrast between breast tumors and surrounding normal parenchyma is greater with digital mammography than with film mammography, particularly when the breast tissue is dense. In one study in which almost 50,000 asymptomatic women 40 years of age or older underwent both digital and film mammography, the two techniques were equivalent overall in sensitivity (70% and 66%, respectively) and specificity (92% for both). However, in women under the age of 50 years, digital mammography was significantly more sensitive than film (78% vs. 51%).
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Who defends lilly and novonordisk diabetes meds


Source: Pharmalot

conflictsofinterest212The scene at the European Association for the Study of Diabetes being held in Lisbon this week has included a heated debate over the extent to which a particular type of diabetes medicine called GLP-1 therapies can increase the risk of pancreatic and thyroid cancer. These include Byetta, which is sold by Eli Lilly and its partner, Amylin Pharmaceuticals, and Victoza, which is marketed by Novo Nordisk.
The issue has actually been percolating for more than a year (read here), although a review published two months ago in Gastroenterology that reviewed the FDA database of side effects showed patients taking Byetta had a much larger chance of developing pancreatitis, which can increase the risk of tumors (read the abstract). The drugmakers maintain their meds are safe.
And so there was a debate among researchers in attendance, including Peter Butler of the University of California at Los Angeles, who was one of the authors of the Gasterenterology study. One of his opponents was Michael Nauck, head of the Diabeteszentrum Bad Lauterberg in Germany, who told Bloomberg News that “the bulk of findings tends to speak against such an association. There is no general agreement.”
In fact, he believes the FDA database not only fails to establish a link to thyroid and pancreatic cancer, but may instead show the drugs could protect against other forms of cancer, such as prostate tumors. “Looking at same database and using very, very similar methods, I find evidence that some forms of cancer are reduced.”
Similarly, Matteo Monami, a physician at the University of Florence and Carreggi Teaching Hospital in Italy, told Bloomberg that the Gasteroenterology study is “erroneous analysis” and its results “are really not reliable at all.” He presented a study showing no increase in cancer or pancreatitis for so-called dipeptidyl peptidase-4 inhibitors such as Januvia.
However, what was not made clear is that both Nauck and Monami have ties to the drugmakers that sell the GLP-1 treatments. For instance, Nauck has worked as a consultant to both Lilly and Novo Nordisk, and also received clinical research grants from both drugmakers (look here). And Monami has received speaking fees from Lilly (see this).
Of course, it does not automatically follow that one or both researchers is biased due to their relationships with either drugmaker. Just the same, such ties would have been helpful to know, given that they were rather outspoken in defending the medications at an important meeting where the scientific community gathers to absorb and ponder research that is used to influence medical practice.

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A cure for the disease of hate


BMJImage via Wikipedia

BMJ 2011; 343:d5715 doi: 10.1136/bmj.d5715 (Published 14 September 2011)

Cite this as: BMJ 2011; 343:d5715
  • Views & Reviews
  • Review of the Week

A cure for the disease of hate

  1. Iain McClure, consultant child and adolescent psychiatrist, Royal Hospital for Sick Children, Edinburgh
  1. imcclure@nhs.net
A Gazan doctor working in Israel describes his life and extraordinary tragedy, with a determination that good must come from bad. Iain McClure recommends his book to all doctors
On 16 January 2009 three Palestinian sisters were killed when an Israeli tank fired two shells into their bedroom. They were the daughters of Dr Izzeldin Abuelaish, a Palestinian gynaecologist, who, uniquely for a Gazan doctor, held a consultant post in an Israeli hospital. Abuelaish’s book, I Shall Not Hate, is an account of his life up to this momentous event and movingly explains his remarkable reaction. In essence, Abuelaish, who likens hate to disease and communication to cure, has drawn on his medical experience to seek a new approach to the resolution of apparently insoluble conflict.
For the three weeks prior to January 2009 the Israeli Defense Forces had been pursuing an incursion into the Gaza Strip to eradicate Quassam rocket attacks into Israel. The Israeli government had prevented Israeli or foreign journalists broadcasting from within Gaza during the operation. However, Abuelaish, a well known public figure in Gaza, had …

Enfermedad Celiaca en niños y adolescentes


Wheat is the third most produced cereal cropImage via Wikipedia

Autores: Polanco Allué I1

1Servicio de Gastroenterología y Nutrición. Hospital Infantil Universitario La Paz. Madrid (España).

Correspondencia: Isabel Polanco Allué. Correo electrónico: ipolanco.hulp@salud.madrid.org
Fecha de recepción: 26/08/2011   Fecha de aceptación: 27/08/2011   Fecha de publicación: 07/09/2011   

La enfermedad celíaca (EC) es un proceso autoinmune y multisistémico que ocurre en individuos genéticamente predispuestos y consiste en una intolerancia permanente a las proteínas del gluten del trigo (gliadina), del centeno (secalina), de la cebada (hordeína) y del triticale (híbrido de trigo y centeno). Estudios recientes sugieren que la avena en estado puro (no contaminada por harina de trigo) no parece influir en la patogénesis de la enfermedad. La causa de la EC es multifactorial y a su desarrollo contribuyen factores genéticos (HLA DQ2 y DQ8), ambientales (gluten) e inmunológicos.
El contacto de la mucosa intestinal con el gluten conduce a la aparición de un daño en la mucosa cuyo espectro oscila desde casos en los que únicamente se aprecia un aumento de la población de linfocitos intraepiteliales (enteritis linfocítica) hasta formas avanzadas de atrofia vellositaria1-3. Cualquiera de las formas histológicas de la enfermedad, incluso las más leves, pueden cursar con diversos estados carenciales, incluyendo anemia, osteopenia u osteoporosis y un amplio abanico de síntomas digestivos y extradigestivos4. Todas estas manifestaciones, así como las alteraciones serológicas e histológicas, desaparecen al retirar el gluten de la dieta y reaparecen al introducirlo de nuevo en la alimentación. El único tratamiento eficaz de la enfermedad celíaca es una dieta estricta sin gluten de modo indefinido.
La EC afecta tanto a niños como a adultos y la relación mujer/varón es de 2:1. Está presente tanto en Europa y los países poblados por personas de ascendencia europea, como en Oriente Medio, Asia, Sudamérica y Norte de África. Puede llegar a afectar hasta al 1% de la población en países occidentales y hasta al 5% de la población nativa del África subsahariana5. Sin embargo, se considera que la epidemiología de la EC tiene las características de un iceberg, ya que esta prevalencia puede ser mucho mayor, debido a que un porcentaje importante de casos permanece sin detectar6. Hoy día se considera que las formas silentes son más frecuentes que las sintomáticas, constituyendo su diagnóstico un reto para el sistema sanitario.
La historia clínica y el examen físico constituyen la piedra angular para orientar el diagnóstico en el ámbito de la Atención Primaria7,8 y deben sustentarse en el conocimiento de los distintos patrones de presentación de la enfermedad, incluyendo las formas atípicas, paucisintomáticas o monosintomáticas, sin duda las más frecuentes en la actualidad (tabla 1). La pertenencia a grupos de riesgo (tabla 2), ya sea por presentar alguna enfermedad que se pueda asociar con la enfermedad celíaca, o bien por que el paciente tenga familiares afectados, también debe de alertar al pediatra y médico de Atención Primaria.
Tabla1. Síntomas, signos y alteraciones analíticas que obligan a considerar el diagnóstico de enfermedad celíaca. Mostrar/ocultar
Tabla 2. Grupos de riesgo. Mostrar/ocultar
Los marcadores séricos son de gran utilidad como indicadores de EC, siempre que su interpretación sea correcta (edad, ingesta de gluten, tratamiento con fármacos inmunosupresores, etc.). Ayudan a seleccionar a los individuos con mayor probabilidad de presentarla, siendo particularmente útiles en aquellos sin síntomas gastrointestinales, en pacientes con enfermedades asociadas a la EC y para su búsqueda en familiares de primer grado de enfermos diagnosticados9-11. Debe considerarse, no obstante, que la negatividad de estos marcadores no excluye definitivamente el diagnóstico, siendo necesario en ocasiones recurrir a pruebas más complejas (estudio genético) cuando la sospecha diagnóstica es elevada12.
Los anticuerpos antitransglutaminasa tisular humana de clase IgA (AAtTG) se han mostrado como los marcadores más útiles, baratos y rentables en el cribado de la enfermedad, debiendo solicitarse sistemáticamente, junto con los niveles plasmáticos de IgA sérica total, ante la sospecha clínica de EC. No es excepcional encontrar un déficit de IgA en la población de celíacos, lo que podría condicionar un falso negativo en la determinación de anticuerpos. En tal situación, pueden analizarse los AAtTG de clase IgG y, solo en caso negativo, validar definitivamente la serología como negativa.
Recientemente se ha publicado un interesante estudio realizado en 5000 escolares italianos, comunicando que la EC se podría detectar mediante una determinación de anticuerpos antitransglutaminasa tisular de clase IgA en saliva13. Aunque se trata de una prueba simple e inocua de cribado (que podría permitir un diagnóstico precoz de la enfermedad con las ventajas indudables que conllevaría su aplicación), se necesitan más estudios que confirmen la sensibilidad y especificidad de los anticuerpos salivales14. En todo caso, tienen igualmente la limitación de no ser detectables en pacientes con déficit aislado de IgA.
Los anticuerpos antigliadina (AGA) fueron los primeros en utilizarse. Se emplean preferentemente los de clase IgA y su eficacia para el cribado de EC es mayor en niños que en adultos. Son sensibles, pero muy poco específicos, por lo que en el momento actual no está indicado su uso en el cribado de EC. Más interés podría tener la determinación de anticuerpos para péptido de gliadina deamidado (DGP), aunque su especificidad no es superior a los AAtTG ni a los anticuerpos antiendomisio (EMA)15.
También se utiliza la detección de EMA de clase IgA. Su sensibilidad y su especificidad son variables según la edad. Tienen el inconveniente de la laboriosidad de su determinación y que su interpretación es subjetiva. Sin embargo, niveles superiores a diez veces el valor límite de la normalidad pueden considerarse altamente específicos de EC incluso cuando los AAtTG son negativos (Symposium Gastroenterology: New Diagnostic criteria for Coeliac disease. The ESPGHAN Working Group for CD diagnosis. 43rd Annual meeting of ESPGHAN, 9-12 june 2010, Istambul) .
En la práctica, el resultado de la serología determina la conducta a seguir, debiéndose considerar las siguientes situaciones9-11:
  • La sensibilidad de la serología es muy elevada (próxima al 100%), especialmente en personas con lesiones histológicas avanzadas (atrofia vellositaria). Por lo tanto, y únicamente en casos muy concretos y en atención especializada, ante la presencia de síntomas muy sugestivos con serología francamente positiva ( AAtTG = niveles superiores a 100 UA, diez veces el valor límite de la normalidad, verificados por EMA) y susceptibilidad genética demostrada (individuos HLA DQ2 o DQ8 positivos) se podría retirar el gluten de la dieta sin necesidad de realizar una biopsia intestinal. Las respuestas clínica y serológica favorables permitirían confirmar definitivamente el diagnóstico (Symposium Gastroenterology: New Diagnostic criteria for Coeliac disease. The ESPGHAN Working Group for CD diagnosis. 43rd Annual Meeting of ESPGHAN, 9-12 june 2010, Istanbul).
  • En el resto de los casos, es decir, siempre que existan dudas diagnósticas en cualquier sentido, la biopsia intestinal (realizada en medio especializado) sigue constituyendo el criterio diagnóstico definitivo. En caso de alteraciones morfológicas compatibles, se procederá a retirar el gluten de la dieta.
  • Recientes evidencias sugieren que la serología negativa no permite excluir con seguridad el padecimiento de la enfermedad. Ello resulta particularmente cierto en pacientes con lesiones histológicas poco avanzadas (Marsh 1 y 2). Por otro lado, el hecho de presentar alteraciones morfológicas poco relevantes (enteritis linfocítica, sin atrofia vellositaria) no excluye que el paciente presente síntomas y signos de enfermedad clínicamente evidentes (astenia, flatulencia, anemia, osteopenia, etc.). Por este motivo, ante la presencia de síntomas sospechosos con serología negativa, especialmente en grupos de riesgo, debe considerarse la posibilidad de derivar el caso para proseguir su evaluación en un medio especializado.
  • Los estudios genéticos (HLA-DQ2/DQ8) son útiles en el manejo de la enfermedad celíaca12, dado que casi la totalidad de los pacientes celíacos son HLA-DQ2 o DQ8 positivos. El 90% de los pacientes con EC son HLA-DQ2 positivos, mientras que solo lo expresan un 20-30% de los individuos de la población general. El resto de pacientes celíacos poseen variantes alélicas que codifican HLA-DQ8 sin HLA-DQ2 (6% del total) o un solo alelo del HLA-DQ2. Por tanto, la ausencia de HLA-DQ2 y HLA-DQ8 hace que el diagnóstico de EC sea muy poco probable. El estudio genético tiene, por tanto, un alto valor predictivo negativo, permitiendo excluir la EC con un 99% de certeza.
Aunque la necesidad de practicarla en todos los casos está en revisión15,16, la prueba de oro para establecer el diagnóstico definitivo consiste en la práctica de una biopsia del duodeno proximal o del yeyuno (procedimiento más habitual en niños). Siempre debe llevarse a cabo antes de proceder a la retirada del gluten de la dieta (es necesario disponer de un estudio de coagulación previo, ya que algunos pacientes pueden tener un déficit de protrombina secundario a la malabsorción de vitamina K).
Dado que las lesiones histológicas pueden ser parcheadas, se aconseja la toma de, al menos, cuatro muestras para el análisis histológico2. El resultado del estudio anatomopatológico permite confirmar la existencia de lesiones compatibles y establecer el estadío de la lesión (clasificación de Marsh17). El espectro de lesiones histológicas que presentan estos pacientes es amplio y oscila desde formas de enteritis linfocíticas, donde únicamente se encuentra un incremento de la población de linfocitos intraepiteliales (> 25%, Marsh 1), hasta formas de atrofia grave de la mucosa (Marsh 3). Es importante disponer de inmunotinciones, para llevar a cabo el contaje de linfocitos intraepiteliales, cuando las tinciones con hematoxilina-eosina no son concluyentes. Solo de este modo pueden diagnosticarse con razonable seguridad las formas de enteritis linfocítica (> 25 linfocitos/100 células epiteliales).
Cualquiera de las formas histológicas mencionadas es compatible con la enfermedad, pero ninguna de ellas es específica. De ahí la importancia del estudio serológico y del estudio genético (en caso de serología negativa y alta sospecha clínica), para reforzar el diagnóstico y la necesidad de verificar la mejoría clínica tras la supresión de gluten de la dieta. En cuanto a la prueba de provocación con gluten, únicamente se realizará cuando existan dudas sobre la certeza del diagnóstico.
En la clasificación de Marsh17 de las lesiones del intestino delgado (figura 1), los criterios anatomopatológicos son los siguientes: Marsh 0 (mucosa preinfiltrativa); Marsh 1 (incremento en el número de linfocitos intraepiteliales); Marsh 2 (hiperplasia de criptas); Marsh 3 (atrofia vellositaria parcial 3a, subtotal 3b, total 3c); Marsh 4 (hipoplasia).
Figura 1. Clasificación de Marsh de las lesiones del intestino delgado. Mostrar/ocultar
La diversidad y diferente sensibilidad y especificidad de los métodos diagnósticos utilizados en el diagnóstico de la EC hacen que, actualmente, estén en una revisión global, buscando especialmente nuevas estrategias diagnósticas no invasivas.
El único tratamiento eficaz de la enfermedad celíaca es una dieta estricta sin gluten durante toda la vida18,19. Con ello se consigue la mejoría de los síntomas aproximadamente a partir de las dos semanas, la normalización serológica entre los 6 y los 12 meses y la recuperación de las vellosidades intestinales en torno a los dos años de iniciado el tratamiento.
En los últimos años se están investigando otras posibles estrategias de utilidad terapéutica, distintas a la dieta sin gluten20. Sin embargo, antes de su aplicación clínica deberán demostrar su eficacia y seguridad respecto a la dieta sin gluten.
Es preciso realizar un seguimiento clínico de los pacientes con objeto de vigilar la evolución de los síntomas, controlar el crecimiento en los niños y vigilar el cumplimiento de la dieta. La determinación de AAtTG es de utilidad para el control del seguimiento correcto de la dieta, cuando la serología ha sido positiva. En aquellos pacientes que continúan con síntomas o presentan recidivas a pesar del régimen sin gluten, es obligado llevar a cabo una búsqueda intencionada de fuentes ocultas de gluten en la dieta o de transgresiones mínimas. Ambas situaciones explican la mayoría de los casos que persisten sintomáticos o mantienen títulos elevados de marcadores séricos.

Cómo citar este artículo

Polanco Allué I. Estado actual del diagnóstico de la enfermedad celíaca en el niño y adolescente. Evid Pediatr. 2011;7:52.

Bibliografía

  1. Green PHR, Cellier C. Celiac Disease. N Eng J Med. 2007;357:1731-3a.
  2. Polanco I y Grupo de Trabajo sobre “Diagnóstico precoz de la enfermedad celíaca”. Diagnóstico precoz de la enfermedad celíaca. Madrid: Ministerio de Sanidad y Consumo. 2008.
  3. Polanco I, Ribes C. Enfermedad celíaca. En: SEGHNP-AEP (ed.). Protocolos diagnóstico-terapéuticos de gastroenterología, hepatología y nutrición pediátrica. Madrid: Ergon; 2010. p. 37-46.
  4. Polanco I, Mearin ML. Enfermedad celíaca. En: Argüelles F, García Novo MD, Pavón Belinchón P, Román Riechmann E, Silva García G, Sojo Aguirre A (eds.). Tratado de gastroenterología, hepatología y nutrición pediátrica aplicada de la SEGHNP. Madrid: Ergon; 2011. p. 284-91.
  5. Lohi S, Mustalahti K, Kaukinen K, Laurila K, Collin P, Rissanen H et al. Increasing prevalence of coeliac disease over time. Aliment Pharmacol Ther. 2007;26:1217-25.
  6. West J, Logan RFA, Hill PG, Lloyd A, Lewis S, Hubbard R et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut. 2003;52:960-5.
  7. Polanco I, Roldán B, Arranz M. Documento técnico protocolo de prevención secundaria de la enfermedad celíaca. Madrid: Dirección General Salud Pública y Alimentación; 2006.
  8. Catassi C, Kryszak D, Louis-Jacques O, Duerksen DR, Hill I, Crowe SE et al. Detection of Celiac Disease in Primary Care: A Multicenter Case-Finding Study in North America. Am J Gastroenterol. 2007;102:1454-60.
  9. Rostom A, Murray JA, Kagnoff MF. American Gastroenterological Association (AGA) Institute technical review on the diagnosis and management of celiac disease.Gastroenterology. 2006;131:1981-2002.
  10. Rostom A, Dube C, Cranney A, Saloojee N, Sy R, Garritty C et al. The diagnostic accuracy of serologic tests for celiac disease: a systematic review. Gastroenterology. 2005;128(4 Suppl 1):S38-46.
  11. Polanco I, Román E. Marcadores serológicos en la Enfermedad Celíaca. An Pediatr Contin. 2006;4:176-9.
  12. Wolters VM, Wijmenga C. Genetic background of celiac disease and its clinical implications. Am J Gastroenterol. 2008;103:190-5.
  13. Bonamico M, Nenna R, Montuori M, Luparia RP, Turchetti A, Mennini M et al. First salivary screening of celiac disease by detection of ant-transglutaminase autoantobody radioimmunoassay in 5000 Italian primary schoolchildren. J Pediat Gastroenterol Nutr. 2011;52:17-20.
  14. Cuestas Montañés E, Ortega Páez E. La enfermedad celíaca se podría detectar con una determinación de anticuerpos antitransglutaminasa en la saliva. Evid Pediatr. 2011;7:56.
  15. Lindfors K, Koskinen O, Kaukinen K. An update on the diagnostics of celiac disease. Int Rev Immunol. 2011;30:185-96.
  16. Guideline for the Diagnosis and Treatment of Celiac Disease in Children: Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediat Gastroenterology Nutr. 2005;40:1-19.
  17. Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology. 1992;102:330-54.
  18. Case S. The gluten-free diet: How to provide effective education and resources. Gastroenterology. 2005;128:S128-34.
  19. Libro Blanco de la Enfermedad Celíaca. Isabel Polanco (Dirección y Coordinación). Ed: ICM. Consejería de Sanidad de la Comunidad de Madrid. 2008.
  20. Polanco I, Arranz E. Nuevos avances en el tratamiento de la Enfermedad Celíaca. An Pediatr Contin. 2006;4:46-9.

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Medicamentos: cura o dependencia de por vida ?


Nothing new here, but can you imagine a flu vaccine for the whole life ? Is it possibley is not good for bussines. Can you imagine an Health Pandemia ? Oh my god, no more patients in my visit ? Why to pay for disease, and not for health ? Another world is possible, we need another world, right now. 
Fuente: eltiempo.com
 Prefieren centrar el negocio en medicamentos que sea necesario tomar durante “toda la vida”, dijo Steitz, quien opina que “muchas de las grandes farmacéuticas han cerrado sus investigaciones sobre antibióticos porque estos curan a la gente.
 Investigador del Instituto Médico Howard Hughes de la Universidad estadounidense de Yale, Steitz asiste en Madrid al Congreso Internacional de Cristalografía (estudio de la estructura ordenada de los átomos en los cristales de la naturaleza). En el caso de la tuberculosis, Steitz ha averiguado el funcionamiento que debería seguir un nuevo antibiótico para combatir cepas resistentes a la enfermedad que surgen sobre todo en el sur de África.
El científico comentó en una rueda de prensa que el desarrollo de este medicamento precisa una gran inversión económica y la colaboración de una farmacéutica para avanzar en la investigación. “Nos resulta muy difícil encontrar una farmacéutica que quiera trabajar con nosotros, porque para estas empresas vender antibióticos en países como Sudáfrica no genera apenas dinero y prefieren invertir en medicamentos para toda la vida”.
Por el momento, según Steitz, estos nuevos antibióticos son “sólo un sueño, una esperanza, hasta que alguien esté dispuesto a financiar el trabajo”. Steitz y los españoles Enrique Gutiérrez-Puebla y Martín M. Ripoll, del Consejo Superior de Investigaciones Científicas (CSIC), hicieron hoy un llamamiento a los países para que inviertan más en ciencia. Los científicos creen que la resistencia de las bacterias a los antibióticos hará necesario continuar investigando “indefinidamente”

Azithromycin for Prevention of COPD Exacerbations


Azithromycin for Prevention of COPD Exacerbations

Summer’s coming to a close and the patient sitting in your office is worried.  A bad cough and wheeze sent him to the hospital for three days last winter, and he feels like he’s never quite gotten back to normal. He stopped smoking a few years ago, and uses the long-acting bronchodilators and inhaled corticosteroids you prescribed. But he still worries about another COPD exacerbation; it seems like each time he gets sick, it’s more difficult to recover.  Is there anything else he can do to make it less likely he’ll get sick again this year?
The answer, according to a study published in this week’s NEJM, is yes. Azithromycin taken daily for a year decreased the frequency of COPD exacerbations and improved quality of life in a cohort with COPD, reports Richard Albert and colleagues.
Why azithromycin? The macrolide antibiotic has anti-inflammatory and immune-modulatory benefits (which is why it is given to patients with cystic fibrosis and bronchiectasis) on top of its antibiotic action. However, studies have been split on the question of whether long-term antibiotics benefit patients with COPD.
Enter the current study, which enrolled 1,142 patients with COPD from 12 academic centers across the United States.  To be eligible for the study, all patients either used continuous supplemental oxygen or had suffered a COPD exacerbation in the past year that required systemic steroids, a visit to the ED or hospitalization. Approximately 80 percent were receiving inhaled corticosteroids and/or long-acting bronchodilators. (Patients with prolonged QTc or hearing loss were excluded from the study – as these are known to be adverse effects associated with azithromycin).
Participants were randomly assigned to take either azithromycin at a 250 mg daily dose or a placebo pill for a year. Those with daily azithromycin stayed exacerbation-free for a significantly longer time: 266 days prior to first exacerbation versus 174 days for those with placebo. There was no statistically significant difference in mortality.  
The daily antibiotic also helped patients’ quality of life, as measured by a commonly used survey which asks about symptoms, activity level and overall comfort. However, taking an antibiotic daily does not come without risk.
The biggest concern, of course, is increasing microbial resistance.  To investigate this question, each patient had nasopharyngeal swabs taken at study visits. More patients in the azithromycin group became colonized with bacteria that were resistant to macrolide antibiotics, but this finding didn’t have any clear clinical significance. It remains unknown what this resistance pattern could mean for patients’ families or community.
Hearing loss was also a potential issue. More patients taking azithromycin than placebo experienced a decrement in their hearing over the year.
In an accompanying editorial, Nikolaos M. Siafakis, a pulmonologist who is the president of the European Respiratory Society, balanced these risks and benefits, and wrote that the study data come out in favor of azithromycin: “The findings of Albert and co-workers…in my opinion turns the balance towards the benefits of azithromycin treatment. However, if azithromycin is going to be used in patients known to be frequent COPD exacerbators, then the local antibiotic resistance patterns should be closely monitored…On balance however the long term use of azithromycin to prevent AECOPD seems to be a risk in accord with the classical advice of Hippocrates – do good – no harm.”
Question:  Would you put the patient in question on long-term azithromycin based on this study?   

Ante la incorporación de la vacuna HPV como obligatoria en Argentina


Juan GérvasImage via Wikipedia

Ante la incorporación de la vacuna HPV como obligatoria en Argentina
Gérvas J. La incierta prevención del cáncer de cuello de útero con la vacuna contra el virus del papiloma humano. Rev Port Clín Geral. 2007;23: 547-55
Gérvas, J. Prevention of cervical cancer by the HPV vaccine is not definitive. Rev. Port Clin Geral. 2007; 23: 547-55.
Juan Gérvas
jgervasc@meditex.es
Médico de Canencia de la Sierra, Garganta de los Montes y El Cuadrón (Madrid) España
Equipo CESCA, Madrid, España
Abstract with Eleven Questions & Answers into Spanish and English.
English translation by Juan Gérvas (“nogracias” Spain, http://www.nogracias.eu) and Joana Ramos, (www.healthyskepticism.og )
Resumen
En 2007 se ha comercializado de la vacuna contra el virus del papiloma humano, con la que se propone vacunar a niñas de 11 y 12 años para la prevención primaria del cáncer de cuello de útero, dada la fuerte asociación entre el cáncer y algunos tipos oncogénicos del virus. La vacuna ha sido rápidamente incluida en los calendarios vacunales de la mayoría de los países desarrollados. En este texto se revisa el fundamento científico de dicha decisión. Son puntos clave: la ausencia de cambios en la epidemiología de la infección, la estabilidad o disminución del la incidencia y mortalidad del cáncer de cuello de útero, la falta de correlación entre respuesta inmunitaria serológica y la inmunidad natural, el impacto de la vacuna en la ecología del virus, las evaluaciones coste-efectividad que dependen de la duración desconocida de la inmunización, la dependencia excesiva de la investigación financiada por la industria farmacéutica, y la necesidad de mantener la citología de cribado. Se precisaría más tiempo e información antes de introducir la vacunación en el calendario vacunal.
Palabras clave: Vacunas, Virus del papiloma humano, Evaluación.
Abstract
Sales of the vaccine against human papilloma virus began in 2007, promoted for administration in girls 11 -12 years old, as preventative measure against cervical cancer, due to the strong link between this cancer with the presence of certain oncogenic strains of the papilloma virus. The vaccine was quickly included in the official immunization programs in many developed countries. In this paper I review the scientific basis for that decision. Critical questions for review are: the absence of changes in the epidemiology of the infection; stability or reduction in the incidence and mortality from cervical cancer; lack of correlation between levels of serologic immune response and natural immunity; the effect of the vaccine on virus ecology; evaluation of the cost-effectiveness of immunization in the face of lack of definitive information about the length of its effectiveness; pharmaceutical industry sponsorship of most of the HPV vaccine research; and the need to maintain screening with Papanicolau exams. More time and information are needed before including this vaccine in the official immunization program.
Key words: Vaccines, Human papilloma virus, Evaluation.
Once preguntas básicas (sin respuesta concluyente)
Eleven basic questions (with no definitive answer)
Con un ímpetu frenético, sin parangón en el campo vacunal, la vacuna contra el virus del papiloma humano se ha incluido en los calendarios vacunales de casi todos los países europeos, Alemania, Austria, Bélgica, Dinamarca, España, Grecia, Holanda, Italia, Luxemburgo, Reino Unido, Suecia y Suiza (1) y en otros desarrollados como Australia, Canadá y EEUU.
With a speed never before seen in the field of immunization, the HPV vacccine has been added to the vaccination schedules of almost all the European countries, including Germany, Austria, Belgium, Denmark, Spain, Greece, the Netherlands, Italy, Luxemburg, the UK, and Switzerland (1) and in other developed nations like Australia, Canada, and the USA.
¿Indica la unanimidad lógica y certeza científica? No. La prevención es campo aparte, como se deduce de otros casos; por ejemplo, respecto al cribado de la displasia del desarrollo de caderas en el recién nacido (2-4).
Does this mean that there is complete agreement and solid scientific basis for this action? No.
The field of preventive medicine is a whole different matter as we can learn from other cases; for example, with respect to screening of newborns for hip displasia (2-4).
En el caso de la vacuna contra el virus del papiloma humano existen dudas razonables acerca de la racionalidad de la decisión de su inclusión en el calendario vacunal. Al menos hay once preguntas básicas sin respuesta concluyente, que hacen dudar de la oportunidad de la aprobación del nuevo calendario:
Reasonable doubts exist about the rationale for the decision to include the HPV vaccine in the immunization schedules. At the very least, there are eleven basic unresolved questions, which raise doubts about the appropriateness of its inclusion in the new [vaccination] schedule.
¿Hay cambios recientes en lo que respecta a la infección por virus del papiloma humano? No. De hecho, desconocemos su historia natural. Es la enfermedad de transmisión sexual más frecuente y la más benigna (el 90% de las infecciones curan espontáneamente) (5). Seguimos sin saber porqué algunas infecciones son persistentes y cancerígenas (al cabo de 20-30 años provocan cáncer de cuello de útero).
Have there been any recent changes in our understanding of the papilloma virus infection? No.
In fact we do not know its natural history. It is the most common sexually transmitted disease, but most cases are benign (90% clear spontaneously) (5). We still don’t know why some infections become chronic and cause cancer (it takes about 20-30 years for [the infection] to transform into cervical cancer).
2. ¿Hay cambios en los países desarrollados de la epidemiología del cáncer de cuello de útero que lo justifiquen? Por ejemplo, en España la incidencia se mantiene estable y baja, así como la mortalidad (respectivamente, de 7,11 y de 2,4 casos por 100.000 mujeres y año) (6). En EEUU disminuye, y cada año hay unos 11.100 nuevos casos y unas 3.700 muertes por cáncer de cuello de útero (5).
Are there known changes in the epidemiology of cervical cancer in developed countries that would justify vacciantion? No.
In most developed countries mortality is stable or decreasing.
No. In Spain, for example, the incidence has remained stable to low, as has the monthly rate (some 7. 11 cases and 2.4 deaths yearly per 100,000 women, respectively) (6). In the USA, there has been a decrease, and there are about 11,100 new cases and about 3700 deaths from cervical cancer annually (5).
3. ¿La inmunidad natural, ¿conlleva la presencia de anticuerpos en sangre? No. La cifra de anticuerpos en sangre es muy baja o inexistente (en la mitad de los casos) en las mujeres inmunes naturalmente. La infección no conlleva viremia (la replicación vírica se produce en la superficie epitelial, muy lejos de la células presentadoras de antígeno y de los macrófagos) (7). Desconocemos en detalle la respuesta inmunológica normal, pero es muy efectiva. Además, no se ve afectada por la re-exposición debida a la actividad sexual continuada.
Is natural immunity correlated with levels of antibodies in the blood? No.
In most cases, the quantity of blood antibodies is very low to nonexistent (in half of all cases) among women with natural immunity. Infection does not correlate with viremia (viral replication occurs on the epithelial surface, very far from the antigen-presenting cells and from the macrophages) (7). Viral replication is a cellular phenomenon. We do not understand very well the normal immune response, but it is very effective. Furthermore, it does not seem to be affected by re-exposure resulting from ongoing sexual activity.
4. La vacuna, y re-vacuna, provoca la presencia en sangre de anticuerpos, en dosis de hasta veinte veces las máximas normales, pero ¿existe relación demostrada entre el nivel de anticuerpos y la eficacia de la vacuna? No. No hay correlación inmunológica demostrada. Ignoramos el mecanismo de acción de la vacuna. Se supone que los anticuerpos en sangre ayudan a eliminar los virus en la superficie epitelial, pero no sabemos cómo (5, 8). La inmunidad natural es celular, no serológica.
Vaccination, and re-vaccination, boost the presence of antibodies in the blood, up to twenty times the normal maximum counts, but is there any relationship shown between the antibody levels and the effectiveness of the vaccine? No.
There is no immunological correlation shown at all. The vaccine’s mode of action is unknown. It is theorized that antibodies in blood might help in getting rid of the infection, but we don’t know how (5,8). Natural immunity is cellular, not serological.
5. Si la vacuna elimina los virus, puede tener un doble efecto beneficioso y perjudicial? Por ejemplo, la vacuna disminuye las infecciones persistentes y las lesiones pre-malignas causadas por los virus contra los que se vacuna (beneficioso). Pero si eliminase otros virus del papiloma humano no sabríamos cómo valorarlo. Por ejemplo, la co-infección con los tipos 6 y 11 (bajo riesgo oncológico) disminuye naturalmente la posibilidad de ser infectado por el tipo 16 (alto riesgo oncológico) (9). En general se acepta que la vacuna evita la presencia o actividad de los virus contra los que vacuna. Por ello cambia la “ecología” del cuello uterino y alrededores, y hay datos (10) que sugieren un efecto de “nicho vacío”, que permite la proliferación de otros virus de alto riesgo oncológico, o la transformación de los de bajo riesgo.
If the vaccine eliminates the viruses, is it possible that it might have two effects, both beneficial and harmful? Yes.
For example, the vaccine might reduce chronic infections and pre-malignant lesions caused by the viruses which the vaccine acts against (helpful). But if this eliminated other human papilloma viruses, we wouldn’t know how to assess such a change. For example, co-infection with types 6 and 11 (low cancer risk) naturally decreases the probability of infection by type 16 (high cancer risk) (9). It is generally accepted that the vaccination blocks the appearance or activation of the viruses that it targets. Because of these changes occur in the “ecology” of the uterine cervix and surrounding areas, and there are data (10) to support the existence of an “empty niche” effect, that permits the proliferation of other high cancer risk viruses, or that permits the transformation of low-risk viruses into high-risk ones.
6. ¿Se ha demostrado su efectividad? No; no se tienen datos sobre su resultado en la práctica clínica diaria, ni siquiera ensayos clínicos con resultados en salud en las niñas en que se propone la vacunación. Se tienen datos de eficacia de casi el 100% (resultados de ensayos clínicos para los que cumplen todas las condiciones ideales, muy diferentes de la clínica diaria), para lesiones asociadas a los virus contra los que se vacuna, en mujeres de 16 a 26 años, generalmente blancas, sanas, de países desarrollados y educadas (10-14). Cuando se tiene en cuenta “la intención de tratar” (se incluyen todos los pacientes participantes en los ensayos, aunque no hayan cumplido las condiciones ideales) la eficacia baja al 50% (10-14), y si se incluyen las lesiones no asociadas a los virus contra los que se vacuna, la eficacia baja hasta el 17% (11).
Has the vaccine been shown to be effective? No.
There are no clinical data about its effectiveness, nor have there been clinical trials showing health outcomes for girls in the age group being targeted for vaccination. There is data showing almost 100% effectiveness (results from clinical trials conducted under the most ideal conditions, quite different from real-life clinical practice) for lesions associated with the viruses that the vaccine targets, in women ages 16 to 26, who were mostly white, healthy, well educated and living in developed countries (10-14). When “intention to treat” is taken into account (if all patients who participated in the trials are included, even if not meeting ideal inclusion criteria), the vaccine’s effectiveness decreases to 50% (10-14). And if all those patients whose cervical lesions are not associated with the viruses targeted by the vaccine are included then the rate of effectiveness of the vaccine falls to 17% (11).
7. ¿Se sabe cuánto dura la inmunidad? No, no se sabe. Lo máximo demostrado son cinco años. Si la inmunidad decae, se podría precisar de una re-vacunación cada cierto tiempo. Además del gasto y complicaciones que ello implica, no sabemos si al ceder la inmunidad artificial se debilitaría la inmunidad natural y habría infecciones oncogénicas más graves y agresivas (algo parecido sucede con la vacunación contra la varicela) (7,12).
Do we know how long immunity [from the vaccine] will last? No.
So far, it has been shown to work for five years. If immunity would decrease, then re-vaccination would be necessary after a certain length of time. Besides the expense and logistical complications this would entail, we do not know if inducing artificial immunity would inhibit natural immunity, resulting in serious and more aggressive oncogenic infections. (something similar to what has happened with small pox vaccination) (7,12).
8. ¿Se ha determinado el coste-efectividad de la vacuna? Sí. Pero se asumen condiciones no demostradas. Especialmente respecto a la efectividad y respecto a la duración de la vacuna. De hecho, en condiciones muy probables, si la inmunidad provocada por la vacuna dura menos de treinta años, y si la efectividad es del 70%, en Canadá, el coste-efectividad es nulo. Es decir, habría que vacunar a infinitas niñas para evitar un caso de cáncer de cuello de útero (15).
Has the vaccine’s cost-effectivenes been determined? Yes.
But some unproven assumptions have been made about its effectiveness and duration of immunity it offers. In fact, under ordinary conditions, if the period of immunity from the vaccine lasts less than 30 years, and if its rate of effectiveness is 70%, in the case of Canada, then it is not cost-effective at all. In other words, it would be necessary to vaccinate all girls in order to prevent one case of cervical cancer (15).
9. ¿Sirve en mujeres que ya han iniciado la actividad sexual? No. Las mujeres se contagian al comienzo de la actividad sexual. La eficacia (ensayos clínicos, condiciones ideales) es muy baja en mujeres que ya han iniciado la actividad sexual, de alrededor del 17% (10,16). Es una vacuna profiláctica (que evita el contagio), no terapéutica (que elimine el virus de las células epiteliales) (5, 10).
Is the vaccine effective for women who are already sexually active? No.
Women get the infection when they become sexually active. Clinical trials done under ideal conditions show that the vaccine has very low efficacy in sexually active women, about 17% (10,16). The vaccine is prophylactic (blocks transmission), not therapeutic (which would eliminate virus in the epithelial cells) (5, 10).
10. ¿Hay ensayos clínicos y estudios independientes, no financiados o promovidos por la industria farmacéutica? No, o son irrelevantes. El grueso de la investigación sobre la vacuna contra el virus del papiloma humano ha dependido, depende y dependerá de la industria que fabrica dichas vacunas (10). Se ignora porqué los gobiernos de los países desarrollados han renunciado a tener un papel activo en el conjunto de la salud sexual, y se reservan sólo el papel pasivo de “pagador” de la vacuna.
Are there clinical trials and independent research that have not been financed or sponsored by the pharmaceutical industry? No, or if so, they are irrelevant.
The bulk of the research on the HPV vaccine has been, is, and will continue to be dependent on the manufacturers of the vaccine. It is unclear why the governments of wealthy countries have declined to take an active role in this area of sexual health services, and instead have assumed merely a passive role as “payor” for the vaccine (10).
11. ¿Se precisa mantener el programa actual de detección precoz del cáncer de cuello de útero? Sí. Los actuales programas de cribaje con la citología (Papanicolau) tienen graves problemas de cobertura y fundamento científico, pero la vacuna no los evita, pues combate sólo dos de los quince virus oncogénicos. No sabemos en qué forma se modificará la sensibilidad y especificidad del cribaje (5,7).
Is it still necessary to continue the current early dectection programs for cervical cancer? Yes.
Current screening programs to detect cervical cancer by cytology (Pap smears) have serious problems in terms of patient access as well as scientific basis, the vaccine doesn’t replace them, as the vaccine only acts against 2 of the 15 oncogenic viruses. We do not know how the specificity and sensibility of screening tests should be modified (5,7).
Bibliografía
Bibliography
Vacuna.org. Calendario de vacunación. Europa. http://www.vacunas.org/index.php?option=com_content&task=view&id=2472&Itemid=336. Consultado el 13 de octubre de 2007.
Gervas J, Pérez Fernández M, González de Dios J. Problemas prácticos y éticos de la prevención secundaria. A propósito de dos ejemplos en pediatría. Rev Esp Salud Pública. 2007;81:345-52.
Starfield B, Hyde J, Gérvas J, Heath I. The concept of prevention: a good idea gone astray? J Epidemiol Community Health. 2008 [in press].
Gérvas J, Starfield B, Heath I. Caution in clinical prevention. Lancet. 2008 [in press].
Markowitz LE, Dunne EF, Saraiya M, Lawson HW, Chessm H, Unger E for the ACIP. Quatrivalent human papilloma virus vaccine. MMWR. 2007;56(RR02): 1-24.
Galceran J, Marcos R, Izquierdo A, Borrás J. Carcinoma invasor y lesiones premalignas del cuello uterino en los registros poblacionales: utilidad y limitaciones. En: Sanjosé S, García A (coordinadoras). Madrid: Sociedad Española de Epidemiología (4ª Monografía); 2006. p. 15-29.
Navarro JA, Bernal PJ, Pérez JJ. Interrogantes en la introducción de la vacuna frente al virus del papiloma humano en los calendarios sistemáticos. Med Clín (Barc). 2007;129:55-60.
EMEA. EPARS for authorised medicinal products. Gardasil. http://www.emea.europa.eu/humandocs/Humans/EPAR/gardasil/gardasil.htm. Consultado el 13 de octubre de 2007.
Hughes JP, Garnett GP, Koutsky L. The theoretical population-level impact of a prophylactic human papilloma virus vaccine. Epidemiol. 2002;13: 361-9.
Sawaya GF, Smith K. HPV vaccination. More answers, more questions. N Engl J Med. 2007;356:1991-3.
Kahn JA, Burk RD. Papillomavirus vaccines in perspective. Lancet. 2007;369:2135-7.
Lippman A, Melnychuk R, Shimmin C, Boscope M. Human papillovirus, vaccines and women’s health: questions and cautions. CMAJ. 2007;177:484-7.
Joura EA, Leodoter S, Hernández-Ávila M, Wheeler CM, Pérez G, Loutsky LA et al. Efficacy or quadrivalent prophylactic human papillomavirus (types 6, 11,16, and 18) L1 virus-like-particle vaccine against high-grade vulvar, and vaginal lesions: a combined analysis of three randomised clinical trials. Lancet. 2007;369:1693-702.
Rambout L, Hopkins L, Hutton B, Fergusson D. Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials. CMAJ. 2007;177:469-79.
Brisson M, Velde N, Wals P, Boily MC. Estimating the number needed to vaccinate to prevent diseases and death related to human papillomavirus infection. CMAJ. 2007;175:464-8.
Future II Study Group. Quatrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007:356:1915-27.
Fuente: Gervas, J. (2008, June 8). June08. Retrieved Sep. 21, 2008, from http://www.healthyskepticism.org/news/2008/June08.htm.

Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial


Age-standardised disability-adjusted life year...                          Image via WikipediaGriffin SJ, Borch-Johnsen K, Davies MJ, et al. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trialLancet. 2011 Jun 24. (Original) PMID: 21705063


BACKGROUND: Intensive treatment of multiple cardiovascular risk factors can halve mortality among people with established type 2 diabetes. We investigated the effect of early multifactorial treatment after diagnosis by screening.
METHODS: In a pragmatic, cluster-randomised, parallel-group trial done in Denmark, the Netherlands, and the UK, 343 general practices were randomly assigned screening of registered patients aged 40-69 years without known diabetes followed by routine care of diabetes or screening followed by intensive treatment of multiple risk factors. The primary endpoint was first cardiovascular event, including cardiovascular mortality and morbidity, revascularisation, and non-traumatic amputation within 5 years. Patients and staff assessing outcomes were unaware of the practice`s study group assignment. Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00237549.
FINDINGS: Primary endpoint data were available for 3055 (99.9%) of 3057 screen-detected patients. The mean age was 60.3 (SD 6.9) years and the mean duration of follow-up was 5.3 (SD 1.6) years. Improvements in cardiovascular risk factors (HbA(1c) and cholesterol concentrations and blood pressure) were slightly but significantly better in the intensive treatment group. The incidence of first cardiovascular event was 7.2% (13.5 per 1000 person-years) in the intensive treatment group and 8.5% (15.9 per 1000 person-years) in the routine care group (hazard ratio 0.83, 95% CI 0.65-1.05), and of all-cause mortality 6.2% (11.6 per 1000 person-years) and 6.7% (12.5 per 1000 person-years; 0.91, 0.69-1.21), respectively.
INTERPRETATION: An intervention to promote early intensive management of patients with type 2 diabetes was associated with a small, non-significant reduction in the incidence of cardiovascular events and death.
FUNDING: National Health Service Denmark, Danish Council for Strategic Research, Danish Research Foundation for General Practice, Danish Centre for Evaluation and Health Technology Assessment, Danish National Board of Health, Danish Medical Research Council, Aarhus University Research Foundation, Wellcome Trust, UK Medical Research Council, UK NIHR Health Technology Assessment Programme, UK National Health Service R&D, UK National Institute for Health Research, Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, Novo Nordisk, Astra, Pfizer, GlaxoSmithKline, Servier, HemoCue, Merck.

Putting research into primary care practice


BMJ 2011; 343:d3922 doi: 10.1136/bmj.d3922 (Published 5 July 2011)

Cite this as: BMJ 2011; 343:d3922

  • Editorial

Putting research into primary care practice

  1. Frede Olesen, professor
1Research Unit for General Practice, Department of Public Health, Aarhus University, Bartholins Allé 2, DK-8000 Aarhus C, Denmark
  1. fo@alm.au.dk
The European initiative is a good start, but excludes too many patients and crucial aspects of primary care
The European Medical Research Council and European Science Foundation recently published a strategic report in its series of “Current Forward Looks” entitled Implementation of Medical Research in Clinical Practice. 1 The collaboration has previously published two strategic reports on the ways forward for basic biological research and for investigator driven clinical trials. 1 By suggesting a strategy on the use of research in practice, it now intends to close the loop. The strategy holds much potential for improving the quality of clinical practice and clinically oriented health services research.
The report has three main strengths: firstly, it takes strategy and policy to the level of specific recommendations for improving the quality of clinical research; secondly, it presents a strong case for the implementation of good research; and, thirdly, it gives special attention to the particular problems encountered in general practice.
The report proposes that the quality of clinical research could be improved by closer national and European coordination of independent funding of larger projects, …

Comparison of the once-daily levofloxacin-containing triple therapy with the twice-daily standard triple therapy for first-line Helicobacter pylori eradication: a prospective randomised study


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Chen LW, Chien RN, Chang JJ, et al. Comparison of the once-daily levofloxacin-containing triple therapy with the twice-daily standard triple therapy for first-line Helicobacter pylori eradication: a prospective randomised study. Int J Clin Pract. 2010 Oct;64(11):1530-4. doi: 10.1111/j.1742-1241.2010.02482.x. (Original) PMID: 20846200

Structure of Helicobacter pylori without annot...BACKGROUND/AIMS: Simple compound of Helicobacter pylori eradication therapy may improve drug compliance of patients. The aims of this study were to compare the efficacy and tolerability of a simple combination containing levofloxacin 7-day once-daily with standard twice-daily triple therapy.
PATIENTS AND METHODS: This was a prospective, randomised, open-label trial. A total of 189 consecutive patients diagnosed with peptic ulcer and H. pylori infection were enrolled. Patients were randomly divided into two groups: LEC group–levofloxacin 500 mg, esomeprazole 40 mg and clarithromycin 500 mg once daily for 7 days; AEC group–amoxicillin 1 g, esomeprazole 40 mg and clarithromycin 500 mg twice daily for 7 days.
RESULTS: There were 90 patients in the LEC group and 99 patients in the AEC group. By intention-to-treat and per-protocol analysis, the H. pylori eradication rate was 78.9% [71/90; 95% confidence interval (CI), 70.3-87.5%] and 83.5% (71/85; 95% CI, 75.5-91.6%) respectively, in the LEC group; and 74.8% (74/99; 95% CI, 66.0-83.5%) and 86.0% (74/86; 95% CI, 78.6-93.5%) respectively, in the AEC group. The incidence and tolerability of side effects were similar between these two groups.
CONCLUSION: The efficacy and tolerability of once-daily levofloxacin-containing triple therapy are equal to those of the standard twice-daily triple therapy in this study. However, none of the treatment regimens evaluated achieved enough eradication efficacies to be considered as a recommendable first-line treatment

Antitrypanosomal Therapy for Chronic Chagas’ Disease


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Antitrypanosomal Therapy for Chronic Chagas’ Disease

Caryn Bern, M.D., M.P.H.
Article

References
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the author’s clinical recommendations.
A 42-year-old woman presents to her physician with a letter stating that after she made a recent blood donation, a serologic test of her donated blood was positive for Chagas’ disease. The patient was born in El Salvador and moved to the United States when she was 18 years of age. Her three children are 8, 13, and 16 years of age. Her medical history is remarkable only for a cholecystectomy 2 years earlier; she reports no cardiac or gastrointestinal symptoms. Her physical examination is unremarkable. Electrocardiography (ECG) shows sinus rhythm at a rate of 72 beats per minute and a complete right bundle-branch block. An echocardiogram shows mild left ventricular segmental wall-motion abnormalities, but a normal ejection fraction and left ventricular diameter. The patient is referred to an infectious-disease consultant, who recommends antitrypanosomal therapy.

THE CLINICAL PROBLEM

Chagas’ disease is caused by the protozoan parasite Trypanosoma cruzi.1 An estimated 8 million to 10 million people are infected with this parasite, primarily in the Americas.1-3 An estimated 300,000 infected persons live in the United States, most of whom are immigrants from areas of Latin America where the infection is endemic.4 Enzootic T. cruzi transmission has been reported across the southern half of the United States, but locally acquired cases in humans are rare.
Clinical Chagas’ disease is classified into acute and chronic phases. During the acute phase of infection, most patients have mild, self-limited symptoms such as fever that do not come to medical attention. If inoculation of the parasite occurred through the conjunctiva, the patient may present with nonpainful unilateral edema of the upper and lower eyelids that lasts for several weeks; this is known as Romaña’s sign. Severe acute infection with myocarditis, meningoencephalitis, or both is life-threatening; the acute-phase case fatality rate is estimated to be 0.25 to 0.50%.1
The acute phase lasts 4 to 8 weeks. The infection then enters the chronic phase, and without successful treatment, it is lifelong. Persons with chronic T. cruzi infection, but without signs or symptoms of Chagas’ disease, are considered to have the “indeterminate” form of infection. An estimated 20 to 30% of people who initially have the indeterminate form have progression to clinically evident cardiac disease, gastrointestinal disease, or both over a period of years to decades.1
The earliest cardiac manifestations are usually conduction-system abnormalities and segmental left ventricular wall-motion abnormalities.1,5, Later manifestations include high-degree heart block, sustained and nonsustained ventricular tachycardia, sinus-node dysfunction leading to severe bradycardia, apical aneurysm (usually in the left ventricle), embolic phenomena due to thrombus formation in the dilated left ventricle or aneurysm, and progressive dilated cardiomyopathy with congestive heart failure. 5 These abnormalities are associated with palpitations, syncope, and a high risk of sudden death.6,7
Gastrointestinal Chagas’ disease usually affects the esophagus, colon, or both.8,9 Advanced disease results in megaesophagus, megacolon, or both. Gastrointestinal involvement is much less common than Chagas’ heart disease. This clinical form is seen predominantly in patients who are infected in the countries of the Southern Cone (Argentina, Bolivia, Chile, Paraguay, Uruguay, and parts of Brazil) and is rare in northern South America, Central America, and Mexico.8

PATHOPHYSIOLOGY AND EFFECT OF THERAPY

T. cruzi is carried in the gut of hematophagous triatomine bugs. Transmission most often occurs when the feces of an infected bug are inoculated through a bite wound or through intact mucous membranes (Figure 1FIGURE 1The Life Cycle ofTrypanosoma cruzi.). Thus, the great majority of cases of Chagas’ disease occur in the zones of distribution of these vectors.
T. cruzi can also be transmitted through transfusion, through organ or tissue transplantation, and congenitally.1 Because of the risk of transmission through transfusion, most blood banks in the United States screen donated units of blood; however, such screening is voluntary and is not required by the Food and Drug Administration (FDA).
The incubation period after exposure to vectorborne T. cruzi is 1 to 2 weeks.1The acute phase of infection is characterized by active parasite replication and microscopically detectable parasitemia (Figure 2FIGURE 2Phases and Forms ofTrypanosoma cruziInfection.). After 4 to 8 weeks in the acute phase, replication is controlled by the host immune response, and parasitemia decreases to levels that are undetectable by means of microscopy. However, intracellular T. cruzi amastigotes remain in infected tissues, especially in cardiac and skeletal muscle.
Chagas’ cardiomyopathy is characterized by a chronic inflammatory process causing damage to the myocardium of all four chambers of the heart as well as the conduction system.10 The pathogenesis may involve several mechanisms, including immunologically mediated tissue damage, cardiac autonomic dysfunction, and coronary microvascular disease.10 In the past, it was hypothesized that the chronic cardiomyopathy was solely attributable to cross-reacting autoantibodies to cardiac tissue and that the presence of the parasite was unnecessary for pathogenesis.11 This belief led to skepticism about the usefulness of antiparasitic treatment in chronic T. cruzi infection, which persisted until the late 1990s.12 More recently, a consensus has emerged that parasite persistence is essential to the development and progression of Chagas’ cardiomyopathy.13-15 Experimental data from animal models also provide support for the hypothesis that elimination of the parasite reduces the risk of progression of cardiac disease.16 In contrast, gastrointestinal manifestations are thought to result from damage to intramural neurons that occurs primarily during the acute phase of the disease and is unmasked by neural attrition later in life.8,9
The only currently available drugs with proven efficacy against T. cruzi are nifurtimox and benznidazole,1,17-19,– which were developed empirically in the late 1960s and early 1970s, respectively.20 Benznidazole, a nitroimidazole derivative, is thought to act through covalent binding of nitroreduction intermediates to parasite molecules. 18,21 Nifurtimox, a nitrofuran compound, acts through production of reduced oxygen metabolites (e.g., superoxide and hydrogen peroxide), for which the parasites have lower detoxification capacity, as compared with vertebrate cells.12,19,22

CLINICAL EVIDENCE

In acute T. cruzi infection, treatment with either benznidazole or nifurtimox reduces the severity of symptoms and shortens the clinical course and duration of detectable parasitemia.1,23,24Parasitologic cure is reported in 60 to 85% of patients treated in the acute phase.1,17,23,24
Clinical trial data for the treatment of chronic T. cruzi infection are sparse. Uncertainty remains regarding the degree of efficacy because of the lack of a reliable test of cure.17,25-27 The diagnosis of chronic infection relies on serologic methods to detect IgG antibodies to T. cruzi. No single assay has sufficient sensitivity and specificity to be relied on alone; two tests based on different antigens, techniques (e.g., enzyme-linked immunosorbent assay [ELISA], immunofluorescence antibody assay, and immunoblot assay), or both are used in parallel to increase the accuracy of the diagnosis.28 Patients with discordant results from two serologic assays require further testing. In a small proportion of cases, the infection status remains difficult to resolve even after a third test because there is no accepted reference assay for the detection of chronic T. cruzi infection.27 Most clinical trials have therefore required that participants have positive results on three separate serologic tests at baseline.29,30
Early trials of nifurtimox for chronic infection used a technique called “xenodiagnosis,” in which laboratory-reared triatomine vectors were allowed to feed either directly on the patient’s arm or leg or indirectly on blood from the patient, kept for 30 to 60 days, and examined for T. cruzi in the contents of the gut.31 However, only 30 to 60% of untreated patients with chronic T. cruzi infection have positive results of xenodiagnosis.32,33 Similar considerations affect the use of polymerase-chain-reaction (PCR) assays for the assessment of treatment response. Because the circulating parasite load is low in the chronic phase, PCR sensitivity in untreated patients is not high and varies depending on the gene target, methods, and population tested.34-36
These test limitations likewise have implications for assessing the outcome of therapy. The results of conventional serologic assays remain positive for years or even decades after successful treatment; the length of time for serologic assays to become negative is reported to be proportionate to the duration of the infection.37 Since they lack sensitivity for detecting chronic infection, xenodiagnosis and PCR are not reliable indicators of cure if the results are negative after treatment.
In the 1990s, two double-blind, randomized, placebo-controlled trials evaluated the efficacy of a 60-day course of benznidazole treatment in children with chronic T. cruzi infection.29,33 Each trial used a different, nonconventional serologic assay to document the response. In one of these trials, which enrolled 130 children, 58% of those who received benznidazole, as compared with 5% of those who received placebo, had seroconversion to negative titers with the nonconventional assay at 3 years.29In the second trial, which involved 106 children, negative seroconversion rates at 48 months with another nonconventional assay were 62% with benznidazole as compared with 0% with placebo, whereas rates of positive xenodiagnosis were 4.7% and 51.2%, respectively.33
Another small, randomized, placebo-controlled clinical trial compared the efficacy of 30 days of treatment with either nifurtimox or benznidazole with placebo in 77 adults with chronic T. cruziinfection.38 At the end of the 12-month follow-up period, all patients continued to have positive results on conventional serologic assays, but patients who had received benznidazole and nifurtimox were significantly less likely to have a positive xenodiagnosis than the placebo group (1.8% and 9.6%, respectively, vs. 34.3%).38
More recently, a nonrandomized, nonblinded cohort study compared 283 adults who received benznidazole with 283 untreated patients over a median follow-up period of 9.8 years.30 The analysis showed a significant decrease in the proportion of patients with progression of cardiomyopathy (4.2% of treated patients vs. 14.1% of untreated patients; adjusted hazard ratio, 0.24; P=0.002) and a trend toward decreased mortality (1.1% vs. 4.2%; adjusted hazard ratio, 0.2; P=0.09) in treated as compared with untreated patients.30 Conversion to negative serologic results occurred in 14.7% of treated and 5.7% of untreated patients (adjusted hazard ratio, 0.55; P<0.001); however, the median time to negative seroconversion was 11.7 years. Progression of cardiac disease was more frequent among patients with persistently positive results on serologic testing than among those with negative seroconversion (10.7% vs. 2.4%; adjusted hazard ratio, 4.88; P=0.009).
The Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT; ClinicalTrials.gov number, NCT00123916), a large, multicenter, double-blind, randomized, placebo-controlled trial of benznidazole for patients with mild-to-moderate Chagas’ cardiomyopathy, is under way.25,39

CLINICAL USE

Before therapy for presumed Chagas’ disease is initiated, it is necessary to confirm the diagnosis with the use of appropriate testing. As noted above, the diagnosis of chronic infection requires two separate serologic tests; if the results are discordant, further testing should be performed. Options for T. cruzi serologic testing in the United States are relatively limited; several ELISA kits based on parasite lysate or recombinant antigens have been cleared by the FDA for diagnostic application. The Centers for Disease Control and Prevention (CDC) offers consultation to health care providers concerning diagnostic testing for Chagas’ disease and acts as a reference laboratory for serologic testing and PCR assays to detect Chagas’ disease; contact information is provided below.
On the basis of the pediatric trials reviewed above, antitrypanosomal drug treatment in children with chronic T. cruzi infection was accepted as the standard of care throughout Latin America by the late 1990s, followed in recent years by a growing movement to offer treatment to older patients.3,15,28,30,39 Most experts now believe that the majority of patients up to 50 years of age who have chronic T. cruzi infection, including those without symptoms and those with early manifestations of cardiomyopathy, should be offered antitrypanosomal treatment.1,3,15 Because treatment is expected to reduce the probability of congenital transmission, stronger consideration may be warranted for women of reproductive age. 40
In patients older than 50 years of age, treatment decisions should take into account the current lack of certainty about the benefit of such treatment, the need for a prolonged course, and the frequent side effects. 1,3 Patients with advanced Chagas’ cardiomyopathy, especially those with poorly compensated congestive heart failure, are not considered to be candidates for antitrypanosomal treatment. Such treatment would not be expected to reverse the cardiac structural abnormalities, and the drugs are likely to be poorly tolerated.1,3,39
There is no evidence that antitrypanosomal treatment affects the progression of gastrointestinal Chagas’ disease.1,3 In patients with such disease, treatment decisions should be based on the potential to decrease the progression of heart disease. In patients with megaesophagus, absorption may be impaired, and treatment should be delayed until after corrective surgery has been performed.
Neither benznidazole nor nifurtimox is approved by the FDA, but both can be obtained free of charge from the CDC and used under investigational protocols. Consultations and requests for drugs should be addressed to the Parasitic Diseases Public Inquiries Line (            770-488-7775 begin_of_the_skype_highlighting            770-488-7775      end_of_the_skype_highlighting      ; www.cdc.gov/parasites/chagas), the CDC Drug Service (            404-639-3670 begin_of_the_skype_highlighting            404-639-3670      end_of_the_skype_highlighting      ) or, in emergencies after business hours, on weekends, and on federal holidays, to the CDC Emergency Operations Center (            770-488-7100 begin_of_the_skype_highlighting            770-488-7100      end_of_the_skype_highlighting      ). Questions about access to drugs outside the United States can be addressed to the World Health Organization (www.who.int/neglected_diseases/diseases/chagas/en/index.html).
Because benznidazole is usually better tolerated, this drug is viewed by most experts as the first-line treatment.1,3 Nevertheless, some patients tolerate nifurtimox better than benznidazole. Both agents are administered orally on an outpatient basis. Both drugs are contraindicated in pregnant women and in patients with severe renal or hepatic dysfunction. Alcohol use should be avoided during treatment with either agent, since it has been suggested that a disulfiram-like effect may occur, although the data are limited.19,22
The treatment regimen for benznidazole in adults consists of 5 to 7.5 mg per kilogram of body weight per day, administered orally in two divided doses for 60 days. In children younger than 12 years of age, the recommended dose is higher (10 mg per kilogram per day).41 A complete blood count and levels of hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen should be obtained before the start of treatment, and the complete blood count should be repeated every 2 to 3 weeks during treatment. Patients should be monitored weekly for dermatologic side effects (described below), beginning 9 to 10 days after the initiation of treatment.
The treatment regimen for nifurtimox in adults is 8 to 10 mg per kilogram per day, administered orally in three or four divided doses for 90 days. In children 11 to 16 years of age, the recommended dose is 12.5 to 15 mg per kilogram per day, and in children 10 years of age or younger, the recommended dose is 15 to 20 mg per kilogram per day.41 Laboratory testing (a complete blood count and levels of hepatic enzymes, bilirubin, serum creatinine, and blood urea nitrogen) should be carried out before the start of treatment, 4 to 6 weeks into the course of treatment, and at the end of treatment. Patients should be weighed and monitored for symptoms and signs of peripheral neuropathy (described below) every 2 weeks, especially during the second and third months of treatment.

ADVERSE EFFECTS

Both benznidazole and nifurtimox have frequent side effects, especially in adults38,42-45 (Table 1TABLE 1Frequency of Adverse Effects Associated with Benznidazole and Nifurtimox in Adults.). Benznidazole causes dermatitis and photosensitization in one third to one half of patients.30,38,44,45 Mild rashes may respond to antihistamines, and moderate dermatitis can be managed with topical or low-dose oral glucocorticoids.46 Severe or exfoliative dermatitis or dermatitis associated with fever and lymphadenopathy should prompt immediate discontinuation of treatment. Benznidazole can also cause peripheral neuropathy (in up to 30% of patients), which is also an indication for discontinuation of treatment. The neuropathy is nearly always reversible, but it may take months to resolve. Bone marrow suppression is a rare side effect (in <1% of patients) that should prompt immediate discontinuation. In the two placebo-controlled trials of benznidazole in children, adverse effects were less frequent than in adults (12% of the children had rash and <5% had gastrointestinal symptoms in one study; <10% had moderate reversible side effects in the other).29,33
Nifurtimox causes gastrointestinal side effects in 50 to 75% of patients.31,38,43 These side effects include anorexia leading to weight loss, nausea, vomiting, and abdominal discomfort. Patients’ weight should be monitored at regular intervals. Neurologic toxicity is common (occurring in up to 50% of patients), including irritability, insomnia, disorientation, mood changes, paresthesias, and, less often, tremors. Peripheral neuropathy is a rare, dose-dependent side effect that may appear late in the course of drug treatment and should prompt discontinuation. The condition is reversible, but complete resolution may require months.

AREAS OF UNCERTAINTY

The assessment of drug efficacy has been hampered by the lack of a sensitive, timely test of cure, the slowly progressive natural history of the disease, and the inability to predict which patients will have cardiomyopathy and which patients will remain asymptomatic. The trend toward offering treatment to adults with long-standing T. cruzi infection rests largely on the observation that treated patients are less likely than untreated patients to have progression of cardiomyopathy.1,3,30 Current data are insufficient to determine whether this effect is due to parasitologic cure or a reduced parasite burden.15
Physicians are often reluctant to treat patients with chronic T. cruzi infection because of both the frequency of side effects with the drugs that are currently available and the inability to confirm cure conclusively.43,47 New drugs with better safety profiles and proven efficacy would alter the risk–benefit balance considerably and lead to wider treatment. Data from in vitro studies and studies in animals suggest that several triazoles that inhibit ergosterol synthesis, including posaconazole and ravuconazole, have curative activity against T. cruzi.47,48 In a single case report, a patient with chronic T. cruzi infection and prior failure of benznidazole treatment had a good response to posaconazole according to PCR monitoring.49 A phase II trial of posaconazole (Clinical Trial for the Treatment of Chronic Chagas Disease with Posaconazole and Benznidazole; NCT01162967) is under way. Additional trials of the ravuconazole prodrug E1224 are planned.50

GUIDELINES

Consensus documents from the World Health Organization, the United States, and Brazil3,28,51strongly recommend antitrypanosomal treatment for acute, congenital, and reactivated T. cruziinfection, and for children (up to 12 or up to 18 years of age, depending on the publication) with chronic infection. Recommendations for adults with long-standing infection carry a lower evidence grade and strength because of the lack of data from randomized clinical trials; nevertheless, most recommendations published since 2000 include provisions to offer treatment for this group of patients.3,28,51,52

RECOMMENDATIONS

For the patient described in the clinical vignette, the diagnosis of Chagas’ disease should be confirmed on the basis of positive results of at least two serologic tests. She should receive counseling, including the advice not to donate blood in the future. Assuming that the diagnosis is established, antitrypanosomal treatment should be offered, accompanied by a careful discussion of uncertainty regarding benefits and potential side effects. The patient has characteristic ECG signs of early Chagas’ cardiomyopathy, indicating a higher risk of subsequent progression as compared with the risk among infected patients with normal ECG findings.30,53 Our best current understanding suggests that treatment will decrease the risk of further progression.25,30 Treatment may also decrease the risk of congenital transmission in subsequent pregnancies. The patient’s children should undergo serologic testing for congenital Chagas’ disease. Regular cardiologic follow-up should be scheduled to monitor the patient for disease progression and to optimize her cardiac care.
    The findings and conclusions in this article are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention.
    Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
    No potential conflict of interest relevant to this article was reported.
    I thank Susan Montgomery for helpful comments.

    SOURCE INFORMATION

    From the Division of Parasitic Diseases and Malaria, Center for Global Health, Centers for Disease Control and Prevention, Atlanta.
    Address reprint requests to Dr. Bern at the Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, 1600 Clifton Rd., Atlanta, GA 30333, or at .

    Lactobacillus GG in the Prevention of Nosocomial Gastrointestinal and Respiratory Tract Infections


    Schematic diagram of the respiratory tract ant...Image via Wikipedia

    1. PEDIATRICS Vol. 125 No. 5 May 1, 2010 
      pp. e1171 -e1177 
      (doi: 10.1542/peds.2009-2568)
    1. » AbstractFree

    1. Iva Hojsak, MDa
    2. Slaven Abdović, MDa
    3. Hania Szajewska, MDb,
    4. Milan Milošević, MDc
    5. Željko Krznarić, MD, PhDd
    6. Sanja Kolaček, MD, PhDa
    +Author Affiliations

    1. aReferral Center for Pediatric Gastroenterology and Nutrition, Children’s Hospital Zagreb, Klaićeva 16, Zagreb, Croatia;

    2. b2nd Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland;

    3. cDepartment for Environmental and Occupational Health, “Andrija Štampar” School of Public Health, Rockefellerova 4, Zagreb, Croatia; and

    4. dDivision of Gastroenterology and Hepatology, University Hospital Center Zagreb, Kispaticeva 12, Zagreb, Croatia

    ABSTRACT

    OBJECTIVE: The incidence of nosocomial infections, predominantly gastrointestinal and respiratory, in children in developed countries is high, ranging from 5% to 44%. There is no effective strategy for preventing these infections. The objective of our study was to investigate the role ofLactobacillusGG (LGG) in preventing nosocomial gastrointestinal and respiratory tract infections at a pediatric hospital.
    METHODS: We conducted a randomized, double-blind, placebo-controlled trial of 742 hospitalized children. They were randomly allocated to receive for their hospitalization LGG at a dose of 109 colony-forming units in 100 mL of a fermented milk product (LGG group, n = 376) or placebo that was the same postpasteurized fermented milk product without LGG (placebo group, n = 366).
    RESULTS: In the LGG group, compared with the placebo group, we found a significantly reduced risk for gastrointestinal infections (relative risk [RR]: 0.40 [95% confidence interval (CI): 0.25–0.70]; number needed to treat: 15 [95% CI: 9–34)], respiratory tract infections (RR: 0.38 [95% CI: 0.18–0.85]; number needed to treat: 30 [95% CI: 16–159]), vomiting episodes (RR: 0.5 [95% CI: 0.3–0.9]), diarrheal episodes (RR: 0.24 [95% CI: 0.10–0.50]), episodes of gastrointestinal infections that lasted >2 days (RR: 0.40 [95% CI: 0.25–0.70]), and episodes of respiratory tract infections that lasted >3 days (RR: 0.4 [95% CI: 0.2–0.9]). Groups did not differ in hospitalization duration (P = .1).
    CONCLUSIONS: LGG administration can be recommended as a valid measure for decreasing the risk for nosocomial gastrointestinal and respiratory tract infections in pediatric facilities.

    New drugs for prostate cancer


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    A group of new drugs is promising to prolong the lives and relieve the symptoms of men with advanced prostate cancer, but could also add billions of dollars to the nation’s medical bills.
    Bone-scan images before and after treatment with Cabozantinib. The dark spots are where cancer had spread to bones.
    Multimedia
    Jenny Mass
    Mark Moldanado, a retired postal worker in Omaha, said that Jevtana had helped keep his cancer in check.
    In the last 15 months, three new drugs that extended the lives of prostate cancer patients in clinical trials have been approved by the Food and Drug Administration and several other promising medicines are in clinical trials. Before last year, only one drug had been shown to improve survival — docetaxel, which was approved in 2004.
    “What a great time it is in prostate cancer,” Dr. Daniel J. George of the Duke Cancer Institute proclaimed earlier this month at the annual meeting of the American Society of Clinical Oncology.
    And it’s a great time for the drug makers, with several drugs competing to fill a niche for longer-term survival. Analysts estimate that some of the new drugs, particularly Dendreon’s Provenge and Johnson & Johnson’s Zytiga, could reach annual sales of $1 billion or even much more.
    The recently approved drugs and most of those in development are for cases in which the disease has spread beyond the prostate gland and is no longer held in check by hormone therapy.
    Men with that late-stage cancer had a median survival of about a year and a half using docetaxel. The new drugs each added two to five months to median survival when tested in clinical trials. Doctors say that men taking more than one of the drugs in succession would be expected to live more than two years.
    But the price of these drugs has already stirred concerns about the costs of care among patients, providers and insurers. For example, Provenge costs $93,000 for a course of treatment, while Zytiga costs about $5,000 a month. Another of the new drugs, Sanofi’s Jevtana, costs about $8,000 every three weeks.
    With other pricey drugs on the way, said Joel Sendek, an analyst at Lazard, “We could be talking easily $500,000 per patient or more over the course of therapy, which I don’t think the system can afford, especially since 80 percent of the patients are on Medicare.”
    Medicare has already fired what some analysts interpret as a warning shot over prices, conducting a yearlong inquiry into whether to pay for Provenge. In its final decision, due Thursday, Medicare is expected to pay for the drug when used according to the label.
    Medicare officials denied that price was the reason for the review. But some patient advocates and politicians portrayed the review as a step toward rationing.
    Private insurers are also paying only if drugs are used according to the label, according to doctors and patient advocates.
    “The reality is, there’s pushback,” said Dr. Oliver Sartor of Tulane University.
    Still, for now, one company’s price is prompting the next one to follow suit.
    “The pricing environment is encouraging and getting better for us,” Andrew Kay, the chief executive of Algeta, told securities analysts earlier this month, after announcing that his company’s experimental drug had extended median survival nearly three months in a clinical trial.
    Mr. Kay said he had initially thought that his company, which is based in Norway, would charge about $25,000 for a typical course of treatment with the drug, Alpharadin. But with the rival drug Jevtana costing about $50,000, Algeta and its partner, Bayer, are considering a higher price.
    About 218,000 men in the United States get prostate cancer each year and about 32,000 die, according to the American Cancer Society.
    In many cases, the cancer is caught before it has spread beyond the prostate gland and can be cured with surgery or radiation therapy.
    If the cancer has spread, men usually are given drugs, particularly Abbott Laboratories’ Lupron, that suppress the body’s production of the hormone testosterone, which can fueltumor growth.
    The new drugs, for now at least, are for use when this hormone-deprivation therapy has stopped working.
    “This is a small subset of people with prostate cancer,” said Dr. Charles Myers, a prostate cancer specialist in private practice in Charlottesville, Va., who is a survivor of the disease himself. However, he noted, “It’s the group of people who are dying.”
    Provenge was approved in April 2010 for patients whose cancer was late-stage but not yet causing many symptoms.
    Once symptoms, mainly bone pain, have appeared, men are likely to receive docetaxel, a generic drug also sold by Sanofi as Taxotere .
    Two other new drugs are approved for use only after docetaxel has been tried. One, Sanofi’s Jevtana, is a chemotherapy drug in the same class as docetaxel; it was approved in June 2010. The other is Johnson & Johnson’s Zytiga, approved this April.
    Many patients and doctors are most enthusiastic about Zytiga and Provenge because they are alternatives to chemotherapy, which many men want to avoid because of side effects. Provenge works by training the body’s immune system to fight the tumor.
    Zytiga is a new form of hormone therapy. While Lupron mainly blocks production of testosterone by the testes, there is still some hormone produced by the adrenal gland or even by the tumor itself. Zytiga, by inhibiting an enzyme called CYP17, clamps down on testosterone production.
    Doctors and patients say the new drugs can offer some men a decent quality of life, although they are not free of side effects. For instance, Zytiga, also known as abiraterone, can cause hypertension and liver damage and must be taken with the steroid prednisone.
    Many men are likely to try several of the drugs. Mark Maldonado, a retired postal worker in Omaha, said that Jevtana had helped keep his cancer in check without debilitating side effects. But knowing that the drug would eventually stop working, he and his doctor “talked about abiraterone being the next step in our progress through the drugs.”
    More competition is coming. Takeda Pharmaceutical and Medivation, a San Francisco company, are separately developing other drugs that block testosterone’s production or its effects.
    Some of the most exciting advances, doctors say, are in the area of fighting the spread of prostate cancer to the bone. Such bone metastases are very common in men with advanced prostate cancer and account for most of the death and disability from the disease.
    Cabozantinib, an experimental drug being developed by Exelixis, seems to be able to virtually eradicate bone metastases in some patients, at least as measured by bone scans, something no other drug has done.
    Amgen won F.D.A. approval in November for Xgeva, a drug that reduces the risk of fractures and other problems caused by cancer in the bones. The drug can also delay the spread of cancer to the bones, according to the results of a more recent trial.
    Dr. Christopher J. Logothetis, of the M. D. Anderson Cancer Center, predicted further progress.
    “It’s beyond the individual drugs,” he said. “One sees a manual now on how to go forward.”

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    Statins, Diabetes, and Attacking a Meta-Analysis


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    Source: Evidence Based Medicine

    I’m a little late reading the June 19th 2010 Lancet, but was intrigued to find letters in response to the meta-analysis by Sattar et al. looking at whether statin therapy increases the risk of diabetes.

    I had previously written about this well-performed meta-analysis, and also written about some unfair ways that people use to try to attack randomized trials, and these letters provide an interesting (at least to me) intersection between these posts.
    Letters in academic scientific journals are sociologically revealing. There’s typically a polite veneer on even the most vicious attacks. Letters written to European medical journals have a somewhat different feel from those to American medical journals, and letters to the Lancet often seem to have a sneering tone that would be unusual to find in the NEJM or JAMA.
    One letter about the meta-analysis objects that the results cease to be statistically significant when diabetes diagnosed only by physician report are excluded, and secondly that the results involved a post-hoc analysis of the data, with the warning that we might fall victim to the logical fallacy, “Post hoc ergo propter hoc“.
    Are these fair objections?
    Diagnosing diabetes by physician report rather than blood glucose measurement is likely to lead to misclassification: some patients will be classified as having diabetes who don’t, and some who have diabetes will be missed. In an RCT, though, misclassification like this will almost certainly be random as well, leading to random misclassification bias. Bias of this sort is toward the null hypothesis (no difference between the groups), as you can convince yourself of if you imagine that the classification is perfectly random such that there is no relation between the classification and diabetes. Under such perfect misclassification, the two groups would have equal numbers of patients classified as having diabetes and there would be no difference between treatment and control. In a meta-analysis that found higher rates of diabetes in patients receiving statins, misclassification bias can be expected to have somewhat reduced the true effect, not to have created an effect out of thin air.
    The second objection might be called the “post-hoc-ergo-propter-hoc-fallacy fallacy”. The actual fallacy is, of course, a way of saying that just because B follows A, you should not conclude that A caused B. This question of causality is central to epidemiologic research and one of the primary reasons for performing randomized trials, which have particular strengths when arguing for causality. The fallacy has nothing to do with performing post hoc analyses of trials. (To be fair, it’s possible the letter writer understood this and was being humorous when writing of this fallacy.) The main problem with a post hoc analysis of a randomized trial is that it often involves multiple comparisons/data dredging, where statistical blips are likely to confuse the issue of what is a true effect. As discussed in my earlier post, a prime issue preceding this meta-analysis was whether JUPITER had found just such a random blip or detected a real problem. The meta-analysis’ reason for being performed was primarily to answer this question, and in such a setting there is nothing at all concerning about going back to previously conducted RCTs and performing post hoc analyses looking for diabetes effects. No data dredging was involved, and the analysis should not be looked at askance simply for being post hoc. Revealingly, the meta-analysis found an increased risk of diabetes even when data from JUPITER were excluded.
    A second letter complained that the analysis would have been better had it been carried out using hazard ratios rather than odds ratios. While this would likely be true, such an analysis was not possible given the information available to the authors, and it is hard to imagine why an OR analysis would have shown statins to be causing diabetes if it were not true. The same letter also re-raised the possibility that statins appeared to be causing people to have more diabetes by keeping them alive longer to develop diabetes. However, the authors had already addressed this in their meta-analysis and reiterated in their response to the letters that differences in survival were much too small to produce such an effect.
    A third letter mis-states the definition of a type I error on its way to arguing that the meta-analysis should have used 99% confidence intervals (p-value cutoff of 0.01) for some reason that was not made terribly clear, but seemed related to concerns that a very large meta-analysis would be more likely to detect a spurious result. It is true that given the enormous N in the analysis, it was possible to find a statistically significant difference in diabetes rates that is likely of little clinical significance, but this has nothing to do with the truth or falsehood of the result itself. The letter also argues that the result is biologically implausible, though it does not seem implausible that a medication could increase diabetes rates during the time of a randomized trial, if only by raising blood sugars in patients near the margin between insulin resistance and diabetes.
    A fourth letter suggests that the “diabetes” found in the study might be different in terms of patient-important outcomes than the clinical condition we think of as diabetes. That is, statins might be raising blood sugars in a way that is harmless. While this is possible, it’s interesting that when a drug class raises blood sugar people are willing to argue it might be harmless, but when a drug class lowers  blood sugar there’s a tendency (at least for the manufacturer) to argue that blood sugar control is an excellent surrogate for clinical outcomes. The author of the letter suggests an analysis that might have been done to sort out this issue, which the authors of the meta-analysis correctly point out would not have answered the question.
    There were a few other replies to the article, which I have not detailed. Overall, though, this is a fairly typical picture of what happens when someone publishes a trial that conflicts with conventional beliefs, such as “statins are good”. This occurs even when the conflict is quite minor — the meta-analysis merely shows a small increase in diabetes that would be heavily outweighed by cardiovascular benefit in anyone who would be appropriately treated with a statin.
    There is no guarantee that the meta-analysis by Sattar et al. is correct about statins and diabetes, but none of the letters published by Lancet raise a sensible reason to think that the post-analysis state of knowledge should change: it is now far more likely than not that statins cause a small increase in diabetes risk. Our response to a meta-analysis like this should be to congratulate the authors on a job well done, while recognizing the possibilities for errors and chance to disrupt the conclusions. It should not be to search high and low for far-fetched flaws that would allow us to discard the inconvenient likelihood that a new statin side-effect has been detected.

    El cribado del cancer de prostata no se asocia a una disminucion de la mortalidad


    Age-standardised death rates from Prostate can...                              Image via WikipediaConcato J, Wells CK, Horwitz RI, Penson D, Fincke G, Berlowitz DR, et al. The Effectiveness of Screening for Prostate Cancer: A Nested Case-Control Study. Arch Intern Med 2006; 166: 38-43. R TC (s) PDF (s)

    Introducción

    Diferentes grupos de trabajo han hecho distintas recomendaciones sobre el cribado del cáncer de próstata. A pesar de que el cribado con PSA se ha mostrado eficaz para detectar tumores de próstata asintomáticos, no se ha demostrado claramente que esta detección redunde en una reducción de la mortalidad.

    Objetivo

    Estudiar si el cribado del cáncer de próstata mediante determinación del PSA con o sin tacto rectal mejora la supervivencia.

    Perfil del estudio

    Tipo de estudio: Estudio de casos y controles
    Área del estudio: Prevención
    Ámbito del estudio: Comunitario
    Métodos
    La población de estudio estuvo formada por los pacientes varones >50 años que se visitaron entre 1989 y 1990 en cualquiera de los 10 centros del departamento de Veterans Affairs del estado de Nueva Inglaterra y que no tenían un diagnóstico de cáncer antes de 1991. Se incluyeron como casos los pacientes a los que se les diagnosticó un cáncer de próstata entre esa fecha y 1995 y que murieron antes de 2000. Para cada uno de los casos se seleccionó un control entre los pacientes que estaban vivos en la fecha de la muerte del caso hubiese sido o no diagnosticado de cáncer de próstata en ese momento ajustado por fecha de nacimiento y centro en el que se había visitado.
    Un investigador que desconocía la asignación del paciente a los grupos revisaba las historias clínicas para saber si se le había hecho cribado del cáncer de próstata mediante una determinación del o tacto rectal desde 1991 hasta la fecha del diagnóstico del cáncer de próstata del caso.
    La variable principal de resultado fue la muerte por cualquier causa. Como variables secundarias se utilizaron la muerte por cáncer de próstata y el cáncer de próstata progresivo.

    Resultados

    La figura 1 muestra el flujo de los participantes en el estudio. La edad media fue de 72 años. Entre los casos se detectó un exceso de pacientes de raza negra (10,0% frente a 4,2%; P<0,001)>

    Se había llevado a cabo un cribado previo en el 14% de los casos y en el 13% de los controles. No se apreciaron diferencias estadísticamente significativas ni en la mortalidad total, ni en la mortalidad específica por cáncer de próstata ni en los análisis por subgrupos de los pacientes por edad ni en los pacientes con hipertrofia benigna de próstata (tabla 1).

    OR (IC95%) P
    Mortalidad total 1,08 (0,71 a 1,64) 0,72
    Muerte por cáncer de próstata 1,13 (0,63 a 2,08) 0,68

    Conclusiones

    Los autores concluyen que los resultados de este estudio no sugieren que el cribado mediante PSA ni mediante tacto rectal reduzcan la mortalidad total ni por cáncer de próstata.

    Conflictos de interés

    Ninguno declarado. Financiado por una beca del Department of Veterans Affairs.

    Comentario

    El cribado del cáncer de próstata sigue siendo objeto de polémica. A pesar de que el PSA se ha mostrado eficaz para detectarlo, siguen existiendo dudas importantes sobre si este adelanto diagnóstico aporta más beneficios que riesgos. Desde que se ha extendido el cribado mediante PSA (sin que se haya llegado a la universalización del mismo), la probabilidad de que a un adulto se le diagnostique un cáncer de próstata casi se ha doblado. Por otro lado, la cirugía de próstata se acompaña de un elevado riesgo de disfunciones sexuales y de incontinencia. Valdría la pena pagar este precio si los beneficios en términos de mejoría del pronóstico estuviesen claros, pero los resultados de este trabajo arrojan más dudas sobre el tema.
    En ausencia de datos inequívocos sobre la eficacia de una técnica de cribado provinientes de estudios de intervención, los estudios de casos y controles se han mostrado útiles para esclarecer la eficacia de algunas técnicas (como en el caso del Papanicolaou). Los autores de este trabajo han elegido como variable de respuesta principal la mortalidad total que parece una variable importante, que evita algunos de los sesgos inherentes a los estudios de prevención (sesgo del adelanto diagnóstico) y permite salvar el problema del posible error en la causa de muerte en el certificado de defunción. Un estudio de casos y controles publicado recientemente y que utilizaba como variable principal la presencia de metástasis por cáncer de próstata sí que encontró una asociación entre el cribado y un menor riesgo.
    En 2009 está prevista la publicación de dos estudios de intervención, uno americano y otro europeo, que es probable que despejen las dudas actuales sobre la conveniencia de llevar a cabo o no el cribado.

    Bibliografía

    1. Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Engl J Med 2003; 349: 366-381. TC (s) PDF (s)
    2. Barry MJ. The PSA Conundrum. Arch Intern Med 2006; 166: 7-8. TC (s) PDF (s)

    Autor

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

    Does this child have a urinary tract infection?


    Bacteriuria and pyuria demonstrated at urinary...                                  Image via Wikipedia

    JAMA. 2007 Dec 26;298(24):2895-904.

    Abstract  

    CONTEXT:

    Urinary tract infection (UTI) is a frequently occurring pediatric illness that, if left untreated, can lead to permanent renal injury. Accordingly, accurate diagnosis of UTI is important.

    OBJECTIVE:

    To review the diagnostic accuracy of symptoms and signs for the diagnosis of UTI in infants and children.

    DATA SOURCES:

    A search of MEDLINE and EMBASE databases was conducted for articles published between 1966 and October 2007, as well as a manual review of bibliographies of all articles meeting inclusion criteria, 1 previously published systematic review, 3 clinical skills textbooks, and 2 experts in the field, yielding 6988 potentially relevant articles.

    STUDY SELECTION:

    Studies were included if they contained data on signs or symptoms of UTI in children through age 18 years. Of 337 articles examined, 12 met all inclusion criteria.

    DATA EXTRACTION:

    Two evaluators independently reviewed, rated, and abstracted data from each article.

    DATA SYNTHESIS:

    In infants with fever, history of a previous UTI (likelihood ratio [LR] range, 2.3-2.9), temperature higher than 40 degrees C (LR range, 3.2-3.3), and suprapubic tenderness (LR, 4.4; 95% confidence interval [CI], 1.6-12.4) were the findings most useful for identifying those with a UTI. Among male infants, lack of circumcision increased the likelihood of a UTI (summary LR, 2.8; 95% CI, 1.9-4.3); and the presence of circumcision was the only finding with an LR of less than 0.5 (summary LR, 0.33; 95% CI, 0.18-0.63). Combinations of findings were more useful than individual findings in identifying infants with a UTI (for temperature >39 degrees C for >48 hours without another potential source for fever on examination, the LR for all findings present was 4.0; 95% CI, 1.2-13.0; and for temperature <39 degrees C with another source for fever, the LR was 0.37; 95% CI, 0.16-0.85). In verbal children, abdominal pain (LR, 6.3; 95% CI, 2.5-16.0), back pain (LR, 3.6; 95% CI, 2.1-6.1), dysuria, frequency, or both (LR range, 2.2-2.8), and new-onset urinary incontinence (LR, 4.6; 95% CI, 2.8-7.6) increased the likelihood of a UTI.

    CONCLUSIONS:

    Although individual signs and symptoms were helpful in the diagnosis of a UTI, they were not sufficiently accurate to definitively diagnose UTIs. Combination of findings can identify infants with a low likelihood of a UTI.

    PMID:

     

    18159059

     

    [PubMed – indexed for MEDLINE] 

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    ¿Hay que perseguir cifras más bajas de PA en los pacientes con enfermedad renal crónica?


    Structures of the kidney: 1.Renal pyramid 2.In...Image via Wikipedia

    ¿Hay que perseguir cifras más bajas de PA en los pacientes con enfermedad renal crónica?

    Upadhyay A, Earley A, Haynes SM, Uhlig K. Systematic Review: Blood Pressure Target in Chronic Kidney Disease and Proteinuria as an Effect Modifier. Ann Intern Med 2011; 154: 541-548.  R   TC   PDF

    Introducción

    Las guías de práctica clínica recomiendan que en los pacientes con enfermedad renal crónica (ERC) las cifras objetivo de PA sean inferiores a las de los otros hipertensos, siendo de 130/80 o menos. Sin embargo, existen pocos estudios que hayan intentado comprobar los beneficios de esta estrategia terapéutica.

    Objetivo

    Comparar en pacientes con ERC los efectos del tratamiento con un objetivo de cifras de PA más bajas comparadas con otras más altas, prestando especial atención a la proteinuria como posible modificadora del efecto.

    Perfil del estudio

    Tipo de estudio: Metaanálisis
    Área del estudio: Tratamiento
    Ámbito del estudio: Comunitario

    Métodos

    Se llevó a cabo una búsqueda en MEDLINE y en el Cochrane Central Register of Controlled Trials para localizar los ensayos clínicos aleatorios publicados entre 2001 y 2010 que comparaban diferentes cifras meta de PA en pacientes con ERC (filtrado glomerular [FG]  <60, albuminuria  >30 mg/día, razón albúmina creatinina urinarias >0,03 o proteinuria >300 mg/día) que no precisaban diálisis y que analizaban al menos alguno de los siguientes resultados: muerte, insuficiencia renal, eventos cardiovasculares, cambio de categoría en la función renal, tasa de cambio en el FG y el número de agentes antihipertensivos necesarios para alcanzar la cifra objetivo.  Se exluyeron los estudios con <50 pacientes y <1 año de seguimiento. También se analizaron como efectos adversos la tasa de abandonos y de reducción de dosis por este motivo y los síntomas relacionados con la hipotensión arterial.

    Resultados

    Se localizaron 3 estudios que cumplían los criterios de inclusión (fig. 1) con un total de 2.272 participantes. Los estudios eran:

    • MDRD. Tenía un diseño factorial 2×2, en el que se comparaban cifras de PA objetivo más bajas frente a las usuales y dos tipos de dieta. Incluyó pacientes con un FG ≤55 mL/min. Se dividió en dos subestudios (A: FG 25-55 mL/min y B: 13-24 mL/min). Se excluyó a los pacientes con diabetes que requerían insulina. Se permitió la utilización de todos los grupos de antihipertensivos, pero se promocionaba el empleo de IECA como fármacos de primera elección y a los calcioantagonistas como los de segunda elección. Media de seguimiento 2,2 años. Se publicó un estudio de seguimiento postintervención a los 7 años.
    • AASK. Se llevó a cabo en pacientes de raza negra con nefrosclerosis hipertensiva. También se excluyó a los diabéticos. Tenía un diseño 3×2 de forma que se comparaba la utilización como fármacos de primera elección los IECA, betabloqueantes y calcioantagonistas. Mediana de seguimiento 3,8 años. Se publicó un estudio de seguimiento postintervención a los 8,8-12,2 años.
    • REIN-2. Se llevó a cabo en pacientes con proteinuria >1.000 mg/d durante ≥3 meses con algunas restricciones adicionales. Se excluyó a los pacientes con diabetes mellitus tipo 1. Todos los pacientes se trataron con ramipril 5 mg/d y los asignados al grupo de PA objetivo inferior recibieron además felodipino. Se permitió la utilización adicional de otros antihipertensivos si era necesario. Mediana de seguimiento 1,6 años.
    Figura 1. Proceso de selección de los estudios.

    La calidad de los estudios se calificó como buena en la fase de intervención, pero débil en la fase postintervención. En la fase de intervención no se detectaron diferencias estadísticamente significativas entre los dos grupos para ninguna de las variables analizadas (tabla 1). Únicamente  se alcanzó la significación estadística para la reducción del desarrollo de insuficiencia renal en la fase de seguimiento postintervención en el estudio MDRD (tabla 2).

    Tabla 1. Principales resultados (IC95%) de los estudios en la fase de intervención.
    MDRD AASK REIN-2
    Reducción al 50% del FG,
    insuf. renal o muerte
    Reducción de riesgo (ReR)
    2% (–22 a 21%)
    Insuf. renal o muerte Estudio A: sin datos
    Estudio B: Razón de riesgo (RR)
    0,85 (0,60 a 1,22)
    ReR 12% (–13 a 32%)
    Reducción al 50% del FG o insuf. renal ReR –2% (–22 a 21%)
    Insuf. renal Hazard ratio (HR)
    0,76 (0,52 a 1,10)
    ReR 6% (–29 a 31%) 23% frente a 20%;
    P=0,99
    Mortalidad (%) 2 frente a 1%.
    Sin datos de significación est.
    2 frente a 2%.
    Sin datos de significación est.
    2 frente a 1%.
    Sin datos de significación est.
    Mortalidad cardiovascular Hazard ratio (HR)
    0,98 (0,48 a 2,01)
    1% frente a 1%;
    Sin datos de significación est.
    Eventos cardiovasculares RR 1,03 (0,59 a 1,79) 2% frente a 3%.
    Sin datos de significación est.
    Tasa de disminución del FG (mL/min) Estudio A: 1,6 (–0,8 a 3,9)
    Estudio B: 0,5 (–0,4 a 1,4)
    0,26 (–0,21 a 0,64) 0,22 frente a 0,24; P=0,62
    Tabla 2. Principales resultados (IC95%) de los estudios en la fase postintervención.
    MDRD AASK
    Reducción al 50% del FG,
    insuf. renal o muerte
    HR 0,91 (0,77 a 1,08)
    Insuf. renal o muerte HR 0,77 (0,65 a 0,91) HR 0,85 (0,71 a 1,02)
    Reducción al 50% del FG o insuf. renal HR 0,95 (0,78 a 1,15)
    Insuf. renal HR 0,68 (0,57 a 0,82)
    Mortalidad (%) 10 frente a 6%.
    Sin datos de significación est.

    Los puntos de corte para el análisis de subgrupos en relación con la proteinuria difirieron entre los estudios incluidos. Se llevaron a cabo 11 comparaciones en función de subgrupos de proteinuria, de las cuales 7 mostraron resultados positivos. En concreto, los pacientes con cifras objetivo de PA más bajas resultaron beneficiados en los subgrupos con proteinuria más elevada en los estudios MDRD y AASK.
    La media del número total de fármacos empleados por paciente fue entre 0,3 y 0,6 superior en los grupos con cifras objetivo de PA más bajas. Los efectos adversos fueron superiores en los grupos de intervención intensiva respecto a los de intervención estándar.

    Conclusiones

    Los autores concluyen que los resultados sobre los beneficios de la reducción hasta cifras más bajas de la PA en pacientes con ERC no son concluyentes y que es posible que sí que resulte positiva en pacientes con proteinuria, pero que es necesario llevar a cabo más estudios que lo prueben de forma fehaciente.

    Conflictos de interés

    Estudio financiado por Kidney Disease: Improving Global Outcomes (KDIGO), una fundación financiada por numerosos laboratorios farmacéuticos.

    Comentario

    Las guías de práctica clínica más prestigiosas recomiendan que en los pacientes con ERC se intenten alcanzar cifras de PA más bajas que en el resto de la población. La cifra más utilizada es la de 130/80, pero algunas recomiendan cifras aún menores. Estas recomendaciones se basan en metaanálisis de los datos de estudios de intervención que no tenían como objetivo comparar diferentes objetivos de reducción de la PA, sino que únicamente encontraron una correlación entre las cifras inferiores de PA y una menor progresión de la enfermedad renal.
    En este trabajo se revisan los resultados de los estudios diseñados específicamente con esta finalidad. A pesar de que no se dispone de un metaanálisis conjunto de los resultados de los mismos, en ninguno de ellos se encontró ninguna relación estadísticamente significativa entre plantearse un objetivo inferior de cifras de PA y una menor incidencia de enfermedades cardiovasculares ni de progresión de la enfermedad renal.
    Únicamente en uno de ellos se apreció una reducción de la incidencia de insuficiencia renal en los pacientes asignados al grupo de intervención intensiva una vez había finalizado la intervención y en la fase de seguimiento posterior, que presentaba una menor fortaleza metodológica. También se encontró una relación entre la intervención intensiva y una mejor evolución en los pacientes con proteinuria, pero se trata de un análisis secundario de los datos que sería necesario confirmar con estudios específicamente diseñados con este fin.

    Bibliografía

    1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,et al and the National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure. JAMA 2003; 289: 2560-2571.  R   TC (s)   PDF (s)
    2. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. Management of Arterial Hypertension of the European Society of Hypertension. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and .. J Hypertens 2007; 25: 1105-1187.   TC (s)
    3. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, et al. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Ann Intern Med 2003; 139: 244-252.  R   TC   PDF

    Autor

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

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