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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Impact of facilitating physician access to relevant medical literature on outcomes of hospitalised internal medicine patients: a randomised controlled trial


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  • Methods
  • Qualitative research                                  

Impact of facilitating physician access to relevant medical literature on outcomes of hospitalised internal medicine patients: a randomised controlled trial

Editor's Choice

  1. Ariel Izcovich1
  2. Carlos Gonzalez Malla1
  3. Martín Miguel Diaz1
  4. Matías Manzotti1,
  5. Hugo Norberto Catalano1
+Author Affiliations

  1. 1Medical Clinical Service, Internal Medicine Department, School of Medicine, Hospital Alemán de Buenos Aires, Buenos Aires, Argentina
  1. Correspondence toAriel Izcovich Pueyrredon 1640, Zip code C1118AAT, Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina; hambp2008@gmail.com
  • Accepted 5 July 2011

Abstract

Introduction There is limited high-quality evidence regarding the usefulness of bibliographic assistance in improving clinically important outcomes in hospitalised patients. This study was designed to evaluate the impact of providing attending physicians with bibliographic information to assist them in answering medical questions that arise during daily clinical practice.
Methods All patients admitted to the Internal Medicine ward of Hospital Aleman in Buenos Aires between March and August 2010 were randomly assigned to one of two groups: intervention or control. Throughout this period, the medical questions that arose during morning rounds were identified. Bibliographic research was conducted to answer only those questions that emerged during the discussion of patients assigned to the intervention group. The compiled information was sent via e-mail to all members of the medical team.
Results 809 patients were included in the study, 407 were randomly assigned to a search-supported group and 402 to a control group. There was no significant difference in death or transfer to an intensive care unit (ICU) (RR 1.09 (95% CI 0.7 to 1.6)), rehospitalisation (RR 1.0 (95% CI 0.7 to 1.3)) or length of hospitalisation (6.5 vs 6.0 days, p=0.25). The subgroup of search-supported physicians’ patients (n=31), whose attending physicians received hand-delivered information, had a significantly lower risk of death or transfer to an ICU compared with the control group (0% vs 13.7%, p=0.03).
Conclusions The impact of bibliographic assistance on clinically important outcomes could not be proven by this study. However, results suggest that some interventions, such as delivering information by hand, might be beneficial in a subgroup of inpatients.

Introduction

Searching for information in books or consulting a specialist has been the most traditional way to answer questions that arise during patient care.1 The ability to search for information, along with its increasing accessibility, allows physicians who have the skills to perform critical appraisal to answer questions based on high-quality evidence. Therefore, it is extremely important to use search resources and an ability to perform critical appraisal, as tools to provide the best evidence-based patient care.
In a systematic review by Dawes and Sampson,2 different reasons are mentioned as to why most physicians do not use bibliographic searching to answer daily questions. Some of these reasons are limited time to perform the research, lack of training in critical appraisal of the information found and low expectations for finding a relevant and direct answer to questions (ie, useful for patient’s care, unbiased and easily accessible).3
Bibliographic assistance could be a useful tool for answering medical questions that arise during patient care, not only for its academic importance, but also for improving patient-important outcomes.
There is limited high-quality evidence regarding the impact of bibliographic assistance on clinically important outcomes for hospitalised patients. The vast majority of the evidence comes from uncontrolled studies that have a high risk of biased results.4
We conducted a randomised study to determine the proportion of admitted patients who generate questions for attending physicians, to compare the outcome of these patients with those who do not generate questions and to evaluate the usefulness (in terms of important patient outcomes) of facilitating information access for physicians who work with admitted patients on internal medicine services.

Context

In 2009, intending to increase the utilisation of EBM resources in daily medical practice, a specialist in internal medicine and trained and skilled in evidence-based medicine was hired in the general internal medicine unit of the Hospital Aleman de Buenos Aires. His work, starting in 2009, consisted of identifying and answering medical questions that arose mainly during daily morning reports. A review of this process found that 80% of the questions identified could be successfully answered, 60% of them based on high-quality evidence. Most of the identified questions were about treatment and prognosis and could be classified as haematology, oncology, infectious diseases or cardiopulmonary questions.5
A survey answered by resident and staff physicians working on the internal medicine ward showed that 72% of the publications delivered were useful information and 42% motivated changes in medical practice for at least one of the participating physicians.6

Methods

From March 2010 through August 2010, all patients admitted to the general internal medicine ward of the Hospital Aleman de Buenos Aires were randomly assigned to an intervention (search-supported) group or a control group in a 1:1 ratio by flipping a coin at the time of admission.
Morning report is held daily on the General Internal Medicine Service. It is attended by resident physicians, staff physicians and heads of wards, and new admissions and other inpatients are discussed.
During the course of this study, a physician who is a specialist in internal medicine and who was trained and skilled in evidence-based medicine and whose work is funded by the Internal Medicine Service identified the medical questions that arose during morning reports. Such questions were either explicitly formulated by staff or resident physicians or inferred by the physician responsible for collecting them. Questions were collected using the PICOT structure (Population/Problem, Intervention, Comparison, Outcome, Type of design that would answer the question)7 in order to gather key words for the literature search. In some cases, the questions were answered immediately by someone who was present in the session, frequently, using electronic resources such as UpToDate. Those questions were excluded from this study.
The same physician who collected the questions also searched the literature for evidence. He answered only those questions obtained from the discussions of the inpatients that were assigned to the intervention (search-supported) arm and not those obtained from inpatients assigned to the control arm. The literature search was carried out once the morning report was over and it was considered finished 12 h after it started. The sources used in this search were Cochrane Library, PubMed and Lilacs.
The literature found was sent by e-mail to the whole medical team, including those physicians directly responsible for the care of the patient who had prompted the question. Emails were sent daily, from Monday to Thursday, and they included a brief summary of the literature found to address each of the questions answered that day, a critical appraisal of the papers based on the User’s Guides8 and the papers themselves attached in PDF format. In some cases, the literature was printed out and delivered by hand, directly to the professionals involved. The following criteria were used to choose to deliver information by hand: (1) one of the physicians directly involved in the care of the patient who prompted the question requested the information in hardcopy or (2) the physician who searched for the information considered that the literature could alter the diagnostic and therapeutic strategy for the patient who prompted the question. Follow-up of the patients included in the study was done, prospectively, from 1 March 2010 to 15 August 2010 through spreadsheets that were prepared everyday by the resident physicians working on the Service.
The process of medical question identification and answering described for the intervention arm is the usual practice on the internal medicine service of the Hospital Aleman de Buenos Aires since 2009. This job is carried out since then, by the same physician who did it during the study.
The outcomes considered were a composite of in-hospital death or transfer to an intensive care unit (ICU), death, transfer to an ICU, length in days of hospital stay and rehospitalisation during the course of the study.
The primary analyses compared the randomised groups (patients assigned to the intervention arm versus patients assigned to the control arm) and the non-randomised groups (patients who prompted questions versus patients who did not prompt questions).
We also planned a priori subgroup analyses among patients who prompted at least one question, particularly regarding patients whose attending physicians received information delivered by hand.
Normally distributed numerical variables were compared by Student’s t tests and dichotomous variables were assessed using RR and absolute risks, by χ2 tests with continuity corrections or Fisher’s exact test, as applicable. Tests of significance were two-tailed, and a p value of less than 0.05 or 95% CI excluding 1 were considered significant. All the calculations were performed using STATA v11.0 software. A post hoc power analysis with α error value of 0.05 and a two-tailed test for each outcome was performed using G*power 3 software (http://www.psycho.uni-duesseldorf.de/abteilungen/aap/gpower3/). The power of the study for each of the evaluated outcomes was length of stay 16%, death or ICU 5%, and rehospitalisation 5%.

Findings

A total of 809 patients were included in the study, 407 were randomised to the search-supported arm and 402 were randomised to the control arm (figure 1).
Figure 1

View larger version:

Figure 1

Group assignment and questions identified/answered
The average age of the patients included in the study was 66 years (95% CI 65 to 67 years old). Baseline characteristics were similar in both arms (table 1).
View this table:

Table 1

Baseline characteristics
Of all the patients included in the study, 151 (19%, 95% CI 15% to 21%) prompted at least one question: 78 (19%, 95% CI 15% to 23%) randomised to the search-supported arm and 73 (18%, 95% CI 14% to 21%) randomised to the control arm. Most of the questions identified were about treatment or prognosis (table 1). The average number of questions per patient was 1.2. The total number of collected questions was 188.
The questions about 77 of the 78 patients who were randomised to the search-supported arm were satisfactorily answered. For 31 of these patients, the information was delivered by hand to their attending physicians (see figure 1).
The combined outcome of death or transfer to an ICU occurred for 76 patients (9.3%, 95% CI 7.3% to 11.4%). The number of readmissions during the course of the study was 135 (16.6%, 95% CI 14.1% to 19.2%). The average length of stay for the study population was 6.3 days (95% CI 5.8 to 6.7 days).
The patients who generated questions had an increase in the risk of being transferred to an ICU (RR 2.0, 95% CI 1.1 to 3.9) and had significantly longer hospital stays, compared with those who did not (7.7 vs 6.0 days, p=0.004). The risk of death (RR 1.5, 95% CI 0.9 to 2.5) and rehospitalisation (RR 1.03, 95% CI 0.7 to 1.5) were not different between those who did and did not generate questions.
The comparisons between search-supported and control groups were not statistically significant (table 2).
View this table:

Table 2

Primary/subgroup analysis
Among patients who prompted questions, the subgroup of patients (31 patients) whose questions were answered and whose attending physicians received hand-delivered information had a significantly lower risk of death or transfer to an ICU compared with the control group (0 vs 10 deaths or transfers, 0% vs 13.7%, p=0.03). There were no significant differences between these groups in ICU transfer (0 vs 8 (11%), p=0.1), death (0 vs 2 (2.7%), p=1.0) rehospitalisation (5 vs 14 rehospitalisations, 16.1% vs 19.1%, RR 0.8, 95% CI 0.3 to 2.1, p=0.7) and days of hospitalisation (5.5 vs 6.8, p=0.3).

Discussion

To our knowledge, this is the first randomised study that attempts to measure the impact of bibliographic assistance by physicians on clinically important outcomes for admitted patients.
Many questions arise for physicians during patient care. Ely et al9 identified 1101 questions that emerged during patient visits over a period of 732 h in the primary care ambulatory setting, which averages approximately three questions every 2 h. Sackett and Straus10 identified 98 questions generated during the care of 166 hospitalised patients in a period of 30 days.
In this study, we found that one in five patients generated at least one clinical question. Those questions were identified during case discussion and not during patient visits. This could have led to a difference in the number and complexity of questions compared with the previously mentioned studies. It is important to note that numerous questions were dismissed because they were resolved immediately using resources like UpToDate. This could be the explanation for the difference between the number of questions reported herein and by Sackett and Straus.10
In this study, we found that patients who generated questions had a twofold increase in the risk of being transferred to an ICU and had a significantly longer hospital stay compared with those who did not. We have not been able to find similar studies; therefore we could not compare our results with other experiences. Although it was not explored in the present study, one explanation for the increase in the risk of being transferred to an ICU and the longer hospital stay of those patients who generated questions could be that these patients had more complex pathologies than those who did not generate questions.
A systematic review by Weightman and Williamson4 that included 28 studies and evaluated the impact of bibliographic assistance on different outcomes found that most of the studies evaluated changes in physicians’ decisions (surrogate outcomes) and only six studies reported outcomes that could have been considered as clinically relevant. All of these studies had observational designs.
Two randomised controlled trials11 12 evaluated the usefulness of bibliographic assistance on changing physicians’ attitudes towards searching for information and their satisfaction but did not measure important patient outcomes. Banks et al13 in a case-control study evaluated the impact of facilitating information access for physicians who cared for hospitalised patients on the length of hospital stay. We intended to measure important patient outcomes using a randomised design attempting to reduce the risk of bias.
The primary analysis results did not show benefits of the intervention on the outcomes evaluated. This could be explained, as shown by the post hoc power analysis, by the limited number of patients enrolled. It is now clear that the type of intervention we evaluated and its impact on those outcomes would require a larger sample in order to prove its benefits.
The published results that are found in the literature regarding the impact of bibliographic assistance on medical practice are heterogeneous.4 Some studies have demonstrated benefits on important patient outcomes like the one performed by Banks et al,13 which suggest that facilitating information access for physicians who take care of hospitalised patients could result in a shorter length of hospital stay.
In a review performed by Bryant and Gray,14 they state that there is not only a limited amount of literature on this subject, but that it is also based on trials with small sample sizes and with high heterogeneity in quality, data analysis, way of reporting results and design. This makes it difficult to apply the results to daily practice.
Hence, considering the low methodological quality of the studies and the inconsistency of their results, we can conclude that the quality of the existing evidence regarding the impact of bibliographic assistance on important patient outcomes is poor. In this context, this study attempts to bring light to the existing evidence with a design that reduces the risk of biased results. Nevertheless, there are some weaknesses of our study that could make the interpretation of its results difficult. First, it has limited statistical power to prove the intervention benefits or to believe that this was a negative study. Second, we did not measure whether the information provided to the attending physicians was actually used in patient care. These data could have been useful for understanding why the two groups did not differ in outcomes. Finally, only questions that arose during morning reports from Mondays through Thursdays were answered. This delay in the identification and answer of questions that might have arisen from Fridays to Sundays could have negatively affected the impact of the intervention.
In the primary analysis, our results did not reach statistical significance. However, we found that bibliographic assistance might have an impact on the subgroup of patients whose attending physicians received hand-delivered information. This intervention seemed to decrease the rate of transfer to ICUs and in-hospital mortality. According to the criteria proposed by Sun et al,15 it is unlikely that the differences found in the subgroup of patients whose physicians received hand-delivered information are due to a real effect of the intervention, since the variable was measured after the allocation of the randomisation, and the number of events in one group was 0, making it difficult to appropriately estimate the effect. We believe that the differences observed in this subgroup probably stem from differences in prognosis and not from the effects of the intervention. Nevertheless, we consider that the hypothesis of the existence of a subgroup of patients, who could particularly benefit from some type of bibliographic assistance, should be considered when designing future studies.

Conclusion

Admitted patients frequently raise questions that require the assignment of specific resources to be answered. Those patients who generate questions seem to have a higher risk of being transferred to an ICU and a longer hospital stay. The usefulness of the bibliographic assistance to change patient important outcomes could not be demonstrated in this study. The results suggest the existence of a subgroup of patients who might benefit from interventions such as delivering information by hand. This hypothesis could be tested in future studies.

Acknowledgments

We appreciate Melissa Kucharczyk’s contribution to the translation of this article into English.

Footnotes

  • Competing interests None.

References

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La vacuna antineumocócica obtuvo un beneficio clínico marginal para disminuir la incidencia de episodios de otitis media aguda en niños menores de 12 años


incipiente Otitis media acuta - HyperämieImage via Wikipedia

La vacuna antineumocócica obtuvo un beneficio clínico marginal para disminuir la incidencia de episodios de otitis media aguda en niños menores de 12 años
Disponible en formato pdf
Estudio
Straetemans M, Sanders EAM, Veenhoven RH, Schilder AGM, Damoiseaux RAMJ, Zielhuis GA. Review of randomized controlled trials on pneumococcocal vaccination for prevention of otitis media. Pediatr Infect Dis J 2003; 22: 515-524
Diseño:
Revisión sistemática-Metaaanálisis.
Objetivo
Determinar si las vacunas antineumocócicas son eficaces para disminuir la incidencia de otitis media aguda (OMA) en niños menores de 12 años.
Fuentes de datos
Base de Datos Cochrane de Ensayos Clínicos (número tres, septiembre de 2002), Registro de Ensayos Clínicos del Grupo Cochrane de Infecciones Respiratorias Agudas (hasta septiembre de 2002) y Medline (hasta agosto de 2002); se contactó con la industria farmacéutica (MSD, Wyeth-Lederle) en busca de estudios no publicados; se revisaron las referencias bibliográficas de los trabajos recuperados para identificar nuevos estudios.
Selección de los estudios
Criterios de selección: 1) ensayos clínicos aleatorios; 2) el grupo de intervención recibió vacuna antineumocócica-polisacárida (VAP) 7-14 valente o conjugada (VAC) 7-9 valente-; 3) variable de respuesta: incidencia de episodios de OMA durante un periodo de seguimiento no inferior a 6 meses post-vacunación. La variable de respuesta se midió mediante la Densidad de Incidencia (DI).
Valoración de la calidad metodológica. se efectuó mediante la escala de Jadad que otorga una puntuación de 0 a 5 a cada estudio. Cinco autores valoraron cada ECA de forma independiente, resolviéndose las discrepancias mediante consenso.
Extracción de los datos
Realizada por dos autores diferentes, resolviéndose las discrepancias por consenso.
Resultados principales
Se estudió la presencia-ausencia de heterogeneidad, efectuándose el análisis estadístico final mediante un modelo de efectos fijos.
La búsqueda bibliográfica identificó 11 ECA que cumplían los criterios de selección. Ocho estaban realizados con VAP y tres con VAC. Ocho de los once ECA presentaban una puntuación igual o superior a 3 en la escala de Jadad. Todos los ECA realizados con VAC tenían una puntuación igual o superior a 3.
Resultados de la VAP: efecto de la edad.
Magnitud del efecto global para los 11 estudios no fue significativo: DI: 0,9; Intervalo de Confianza del 95% (IC 95%): 0,8 a 1. Ausencia de efecto.
Magnitud del efecto en niños menores de dos años: DI: 0,93; IC 95%: 0,83 a 1,05. Ausencia de efecto.
Magnitud del efecto en niños mayores de dos años: DI: 0,78; IC 95%: 0,63 a 0,97. Beneficio clínico moderado.
Resultados de la VAP: efecto de la presencia de antecedentes previos de OMA.
Magnitud del efecto global para todos los niños sin antecedentes de OMA: DI: 0,92; IC 95%: 0,85 a 0,99.
Magnitud del efecto en niños menores de dos años: DI: 0,94; IC 95%: 0,87 a 1,02. Ausencia de efecto.
Magnitud del efecto en niños mayores de dos años: DI: 0,81; IC 95%: 0,68 a 0,98. Beneficio clínico moderado.
Magnitud del efecto global para todos los niños con antecedentes de OMA: DI: 0,81; IC 95%: 0,72 a 0,91.
Magnitud del efecto en niños menores de dos años: DI: 0,85; IC 95%: 0,74 a 0,98. Beneficio clínico moderado.
Magnitud del efecto en niños mayores de dos años: DI: 0,74; IC 95%: 0,62 a 0.90. Beneficio clínico moderado.
Resultados de la VAC: 
De los tres ECA realizados con esta vacuna sólo pudieron combinarse dos para obtener los resultados finales ya que uno de ellos no ofreció datos concretos sobre la duración del periodo de seguimiento.
Magnitud del efecto global: DI: 0,92; IC 95%: 0,85 a 0,99. Beneficio clínico moderado.
Eficacia para disminuir la incidencia de OMA en niños con OMA recurrente: en cada uno de los estudios individuales, los resultados fueron similares: en uno la reducción fue de un 9% (IC 95%: 4% a 14%) y en otro de un 9% (IC 95%: 2% a 27%).
Efecto preventivo contra serotipos vacunales:
VAP: DI: 0,91; IC 95%: 0,64 a 1,33. Ausencia de efecto.
VAC: DI: 0,43; IC 95%: 0,34 a 0,54. Beneficio clínico. En este grupo, la DI de OMA producida por serotipos no incluidos en la vacuna se incrementó: DI: 1,32; IC 95%: 1,01 a 1,72.
Conclusión de los autores
El beneficio clínico de una vacunación sistemática con vacuna antineumocócica es escaso. Basándose en el estado actual de conocimientos, no puede recomendarse en la actualidad una vacunación sistemática cuyo objetivo sea prevenir esta enfermedad.
Conflicto de intereses
No consta.
Comentario crítico
Se trata de una interesante revisión sistemática que compila todos los estudios relevantes realizados hasta la fecha. La información derivada de esta revisión es importante para el médico de atención primaria ya que le proporciona una idea precisa de la efectividad real de esta vacuna.
El estudio presenta algunas limitaciones, reconocidas por los propios autores, derivadas de las diferencias en la definición de OMA inter-estudios. Mediante la técnica de funnel plot se detectó además la presencia de un posible sesgo de publicación que sugería la exclusión de algunos ECA de pequeño tamaño. Sin embargo, la magnitud del sesgo era pequeña y además afectaba exclusivamente al grupo de las vacunas polisacáridas (de escaso-nulo interés para el pediatra de atención primaria). El sentido del sesgo, además, era hacia una sobreestimación de la eficacia e este tipo de vacunas en la revisión por lo que puede que su efectividad real aún sea inferior.
Al pediatra le interesan fundamentalmente los resultados correspondientes a la VAC. El beneficio clínico que se obtiene de la administración sistemática de dicha vacuna es marginal: el IC 95% roza el valor 1 (0,99). Sí es cierto que las VAC consiguen disminuir la incidencia de nuevos episodios de OMA por serotipos incluidos en la vacuna, pero sin embargo se ha constatado que la incidencia de OMA por otros serotipos no incluidos en la misma se ha incrementado. Se desconoce la virulencia de estos nuevos serotipos causantes de OMA. Por tanto, a la luz de los conocimientos actuales, la OMA no debería utilizarse como “pretexto” para la planificación de campañas de vacunación sistemática. Éstas, si se llevan a cabo, deben estar basadas en la prevención de enfermedade sistémicas graves producidas por los serotipos incluidos en la VAC1.
Autor
José Cristóbal Buñuel Álvarez. Pediatra. ABS Girona- 4 (Institut Català de la Salut)
Bibliografía
  1. McIntosh EDG, Booy R. Invasive pneumococcal disease in England and Wales: what is the true burden and
    what is the potential for prevention using 7 valent pneumococcal conjugate vaccine?
    Arch Dis Child. 2002;86:403-6Artículo en formato pdf.

Statins, Diabetes, and Attacking a Meta-Analysis


P-values from Fisher's meta analysis applied t...Image via Wikipedia

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.