Intervenciones para reducir el daño por el consumo continuo de tabaco
Resumen
Antecedentes
Aunque el abandono del hábito de fumar actualmente es la única forma garantizada de reducir el daño causado por el consumo de tabaco, un enfoque secundario razonable de control del consumo de tabaco puede ser tratar de reducir el daño del consumo continuo de tabaco entre los fumadores incapaces o renuentes a abandonar el hábito. Los enfoques posibles para reducir la exposición a las toxinas del tabaco incluyen la reducción de la cantidad de tabaco consumido, y el uso de productos menos tóxicos, como productos farmacéuticos, nicotina y productos de tabaco de exposición potencialmente reducida (PREP, por sus siglas en inglés), como una alternativa a los cigarrillos.
Objetivos
Para evaluar los efectos de las intervenciones dirigidas a reducir el daño a la salud del consumo continuo de tabaco, se consideraron las siguientes preguntas específicas: ¿Las intervenciones concebidas para reducir el daño tienen un efecto sobre el estado de salud a largo plazo?; ¿Dan lugar a una reducción del número de cigarrillos consumidos?; ¿Tienen un efecto sobre la abstinencia del tabaco?; ¿Tienen un efecto sobre los marcadores biológicos de la exposición al tabaco?; ¿Y tienen un efecto sobre los marcadores biológicos del daño causado por el tabaco?
Métodos de búsqueda
Se realizaron búsquedas en el Registro de Ensayos del Grupo Cochrane de Adicción al Tabaco (CRS) el 21 de octubre de 2015 mediante el uso de texto libre y de los términos MeSH para la reducción del daño, la reducción del hábito de fumar y la reducción de los cigarrillos consumidos.
Criterios de selección
Ensayos controlados aleatorios o cuasialeatorios de las intervenciones para reducir la cantidad de tabaco consumido, o para reducir el daño causado por el hábito de fumar por medios diferentes del abandono del hábito. Se incluyen estudios realizados en fumadores sin deseo inmediato de dejar completamente el consumo de tabaco. Los resultados primarios fueron el cambio en el consumo de cigarrillos, el abandono del hábito de fumar y cualquier marcador del daño o el beneficio en la salud, medido al menos a los seis meses desde el comienzo de la intervención.
Obtención y análisis de los datos
Se evaluó la elegibilidad de los estudios para su inclusión utilizando los métodos Cochrane estándar. Se agruparon los ensayos con intervenciones y resultados similares (reducción > 50% en los cigarrillos por día [CPD] y la abstinencia del tabaco a largo plazo), mediante los modelos de efectos fijos. Cuando no fue posible metanalizar los datos, los resultados se resumieron de forma narrativa.
Resultados principales
Veinticuatro ensayos evaluaron las intervenciones para ayudar a los que fuman a reducir la cantidad consumida o a reemplazar los cigarrillos regulares con PREP, en comparación con placebo, una intervención breve, o una intervención de comparación. Ninguno de estos ensayos analizó directamente si las estrategias de reducción del daño redujeron los daños a la salud causados por el tabaco. La mayoría de los ensayos (14/24) estudiaron el tratamiento de reemplazo de nicotina (TRN) como una intervención para ayudar en la reducción. En un análisis agrupado de ocho ensayos, el TRN aumentó significativamente la probabilidad de reducir los CPD en al menos un 50% para los pacientes que utilizaron chicle de nicotina o inhalador o una opción del producto en comparación con placebo (cociente de riesgos [CR] 1,75; intervalo de confianza [IC] del 95%: 1,44 a 2,13; 3081 participantes). Cuando se compararon los cambios promedio desde el inicio para diferentes medidas, el monóxido de carbono (CO) y la cotinina en general mostraron reducciones más pequeñas que los CPD. La administración de TRN versus placebo también aumentó significativamente la probabilidad de dejar de fumar en último término (CR 1,87; IC del 95%: 1,43 a 2,44;8 ensayos, 3081 participantes; calidad de la evidencia: baja). Dos ensayos que compararon TRN y apoyo conductual con el asesoramiento breve encontraron un efecto significativo sobre la reducción pero no un efecto significativo sobre el abandono del hábito. Se encontró un ensayo que investigó cada una de las siguientes ayudas de intervención para la reducción del daño: bupropión, vareniclina, cigarrillos electrónicos, snus, más otro de los parches de nicotina para facilitar la abstinencia temporal. Por lo tanto, las pruebas para los cinco tipos de intervención fueron imprecisas, y no está claro si estas ayudas aumentan la probabilidad de reducción del hábito de fumar o el abandono. Dos ensayos que investigaron dos tipos diferentes de asesoramiento conductual e instrucciones sobre la reducción de los CPD también aportaron pruebas imprecisas. Por lo tanto, la base de pruebas para esta comparación es insuficiente para apoyar el uso de este tipo de asesoramiento conductual para reducir el hábito de fumar. Cuatro estudios de los PREP (cigarrillos con niveles reducidos de alquitrán, carbono y nicotina y en un caso proporcionado mediante un sistema de consumo de cigarrillos que se calienta electrónicamente) revelaron alguna reducción de la exposición a algunas sustancias tóxicas, aunque no está claro si la misma alteraría el riesgo de daño de manera significativa. Los estudios incluidos en general se consideraron en riesgo bajo o incierto de sesgo; sin embargo, hubo algunas calificaciones de alto riesgo, debido a una falta de cegamiento y a la posibilidad de sesgo de detección. Mediante el sistema GRADE, la calidad general de las pruebas para los resultados del abandono del hábito se consideró “baja” o “muy baja”, debido a la imprecisión y a la imposibilidad para generalizar las pruebas. Una calificación "baja" significa que es probable que la realización de más investigaciones tenga una marcada repercusión sobre la confianza en la estimación del efecto y pueda cambiarla. Una calificación "muy baja" significa que hay muy poca certeza acerca de la estimación del efecto.
Conclusiones de los autores
Los pacientes que no desean abandonar el hábito pueden ser ayudados a reducir el número de cigarrillos que fuman y a dejar de fumar a largo plazo, mediante el TRN, a pesar de las intenciones originales de no hacerlo. Sin embargo, las pruebas que contribuyeron al resultado del abandono del hábito para el TRN se calificaron como de calidad “baja” mediante el estándar de GRADE. Hay una falta de pruebas para apoyar el uso de otras ayudas a la reducción del daño para disminuir el daño causado por el consumo continuo de tabaco. Lo anterior podría deberse simplemente a la falta de estudios de alta calidad (la confianza en los resultados del abandono del hábito para estas ayudas se considera “baja” o “muy baja” debido a la imprecisión según el estándar de GRADE), lo cual significa que es posible que se haya omitido un efecto valioso, o a la falta de efecto sobre las tasas de reducción o de abandono. Por lo tanto, es importante que se realicen más ECA de alta calidad, y que los mismos también midan los efectos sobre la salud a largo plazo de los tratamientos.
Resumen en términos sencillos
¿Los fumadores pueden recibir ayuda para reducir el daño causado por el consumo de cigarrillos al fumar menos cigarrillos o al usar diferentes productos de tabaco?
Antecedentes
Lo mejor para reducir los daños causados por el tabaco es dejar el hábito, aunque algunas personas pueden no desear hacerlo o pueden sentir que no pueden dejar de fumar completamente. La reducción del número de cigarrillos consumidos diariamente o el uso de diferentes productos de tabaco, como mascar tabaco o los cigarrillos de bajo contenido de alquitrán, pueden reducir algo del daño causado por el hábito de fumar. También puede ayudar a los pacientes a dejar de fumar completamente a largo plazo. Por otro lado, la reducción del hábito de fumar o el uso de otros productos de tabaco pueden no mejorar la salud y podría reducir la motivación de las personas para dejar de fumar completamente. Es importante que se examinen las pruebas para determinar si estos enfoques podrían ayudar a los fumadores que no quieren o no pueden dejar el hábito a reducir el daño causado por el hábito de fumar. El interés estuvo principalmente en si estos enfoques mejoraron la salud de los fumadores, aunque también se consideró la reducción del hábito de fumar y las tasas de abandono del hábito.
Características de los estudios
Se encontraron 20 ensayos controlados aleatorios que evaluaron formas de ayudar a los pacientes a reducir el número de cigarrillos consumidos. Algunos de los mismos sólo aconsejaban a los fumadores fumar menos, aunque la mayoría también les proporcionó un producto para ayudarlos a reducir el hábito: tratamiento de reemplazo de nicotina (TRN), vareniclina, bupropión, cigarrillos electrónicos (e‐cigs) o snus (una forma de tabaco oral sin humo). También se encontraron cuatro ensayos controlados aleatorios que estudiaron los efectos del uso de cigarrillos diseñados para reducir el daño causado por el tabaco: cigarrillos con niveles reducidos de alquitrán, de carbono o de nicotina. La mayoría de los estudios utilizó el TRN para ayudar a los pacientes a reducir el hábito de fumar. Todos los estudios incluyeron a personas que no estaban planeando dejar de fumar a corto plazo. La investigación está actualizada hasta octubre 2015.
Resultados clave
Ocho estudios (con 3081 fumadores) encontraron que la administración de TRN duplicó aproximadamente la probabilidad de reducir a la mitad el número de cigarrillos consumidos cada día, en comparación con la administración de un placebo. La administración de TRN de esta manera también casi duplicó la probabilidad de dejar el hábito completamente. Cada uno de cuatro ensayos evaluó bupropión, vareniclina, e‐cigs y snus para ayudar a reducir los daños causados por el tabaco y no hubo pruebas de que alguno de estos tratamientos ayudara a los fumadores a reducir el número de cigarrillos que estaban fumando por día. Lo anterior puede deberse a que todavía no ha habido suficiente investigación sobre estos métodos. Sólo uno de los ensayos que evaluaron los cigarrillos diseñados para reducir el riesgo midió el efecto sobre el número de personas que dejaron de fumar. Halló que los pacientes no tenían una mayor probabilidad de dejar de fumar cuando usaban cigarrillos con niveles reducidos de nicotina que si fumaban sus cigarrillos habituales. No se encontró ningún ensayo que informara los efectos sobre la salud a largo plazo de los tratamientos, por lo cual aún no se conoce qué beneficio se obtiene sobre la salud al reducir el número de cigarrillos consumidos cada día o al fumar cigarrillos diseñados para ser menos nocivos.
Calidad de la evidencia
La industria tabacalera financió tres de los estudios incluidos de los cigarrillos diseñados para reducir el riesgo. Ninguno de los estudios consideró si había habido un cambio a largo plazo en la salud de los usuarios. La calidad de las pruebas sobre cuántas personas dejaron de fumar se calificó como “baja” o “muy baja”, en general debido a que los hallazgos se basan en un número pequeño de estudios. Se necesitan más estudios para investigar los métodos de reducción del daño causado por el consumo continuo de tabaco. Los mismos deben medir la salud de los usuarios durante un período prolongado.
Conclusiones de los autores
Summary of findings
| Interventions to reduce the harms caused by continued smoking | ||||||
| Patient or population: Smokers who cannot or do not want to quit smoking | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with control | Risk with harm reduction aid | |||||
| Long‐term change in health status | We found no studies that reported this primary outcome | Not applicable | (0 RCTs) | Not applicable | ||
| Cessation: NRT vs placebo | Study population | RR 1.87 | 3081 | ⊕⊕⊝⊝ | ||
| 5 per 100 | 10 per 100 | |||||
| Cessation: Bupropion vs. placebo | Study population | RR 1.27 | 594 | ⊕⊕⊝⊝ | ||
| 5 per 100 | 7 per 100 | |||||
| Cessation: Varenicline vs placebo | Study population | RR 1.95 | 218 | ⊕⊕⊝⊝ | ||
| 7 per 100 | 14 per 100 | |||||
| Cessation: Ecigs vs placebo | Study population | RR 2.75 | 300 | ⊕⊕⊝⊝ | ||
| 4 per 100 | 11 per 100 | |||||
| Cessation: Snus vs placebo | Study population | RR 3.06 | 319 | ⊕⊕⊝⊝ | ||
| 2 per 100 | 6 per 100 | |||||
| Cessation: Low‐nicotine cigarettes vs regular cigarettes | Study population | RR 1.38 | 135 | ⊕⊝⊝⊝ | ||
| 2 per 100 | 3 per 100 | |||||
| Cessation: Behavioural reduction advice vs health mailings | Study population | RR 1.49 | 320 | ⊕⊝⊝⊝ | ||
| 4 per 100 | 7 per 100 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded two levels due to imprecision. Small number of events (< 300), and wide confidence intervals. | ||||||
Antecedentes
Descripción de la afección
La morbilidad y mortalidad asociadas al tabaquismo están bien establecidas. Las personas que dejan de fumar pueden reducir el riesgo de contraer enfermedades relacionadas con el tabaquismo (Anthonisen 2005; Doll 2004), por lo tanto, la estrategia primaria para reducir el daño debido al tabaco debe ser la promoción del abandono del hábito. Sin embargo, a pesar del hecho de que la mayoría de los pacientes que fuman desean dejar el hábito, la prevalencia del tabaquismo está descendiendo muy lentamente, incluso en los países en los que las políticas de control del consumo de tabaco están bien desarrolladas, y en algunos casos la prevalencia todavía está subiendo (Bilano 2015). En 2005 el Framework Convention on Tobacco Control de la Organización Mundial de la Salud (OMS) formalizó un compromiso global para reducir el consumo de tabaco en todo el mundo y hacer que el control del consumo de tabaco sea una prioridad de salud global (WHO 2003). En 2014; basado en este Framework, los Estados Miembros de la OMS acordaron la meta de una reducción relativa del 30% del consumo de tabaco a nivel mundial para 2025 (WHO 2013). Sin embargo, basado en la disminución real en la prevalencia del tabaquismo, las predicciones de las tendencias hacia 2025 indican que sólo un 25% de los países de todo el mundo probablemente experimenten esta disminución en los hombres fumadores, y sólo un 52% quizás experimente esta disminución en las mujeres fumadoras desde 2010 a 2025. Lo anterior significa que menos de la mitad de los países a nivel global probablemente alcanzará las metas de la OMS, y este tema no está limitado sólo a los países de ingresos bajos y medios (Bilano 2015). Aunque es importante continuar motivando y ayudando a los pacientes a dejar el hábito, por lo tanto puede ser razonable buscar maneras de reducir el daño causado por el consumo continuo de tabaco para los pacientes que no están preparados o no pueden dejar el hábito, como una estrategia secundaria para mejorar la salud global.
Descripción de la intervención
Hay enfoques múltiples que pueden tener potencial para la reducción del daño en los pacientes que no quieren abandonar el consumo de tabaco o de nicotina completamente. Shiffman 2002 ha proporcionado un catálogo de los mismos con una estructura conceptual de sus características. Cubren muchos mecanismos y efectos intermedios con distintas intenciones. También difieren en la facilidad probable del cambio de comportamiento necesario para adoptarlos y el atractivo relacionado con los fumadores, y el riesgo esperado en la población. Shiffman 2002 categoriza la reducción del daño del tabaco en los siguientes cuatro enfoques:
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Métodos para establecer y adherirse a la abstinencia del tabaco, como se reconoce más arriba;
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El uso de productos del tabaco de una manera o en una forma que es menos perjudicial que los productos tradicionales;
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El uso de productos farmacéuticos para reducir el consumo de tabaco o el daño causado; y
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Los cambios en los comportamientos que reducirán el daño.
Las categorías dos a cuatro son el tema de esta revisión.
Los productos que se clasifican dentro de la segunda categoría se denominan productos de exposición potencialmente reducida (PREP), que son:
"(a) productos de tabaco modificado que contienen niveles reducidos de una o más toxinas (p.ej. cigarrillos con nitrosaminas específicas del tabaco reducidas mediante procesos de nueva curación, el agregado de catalizadores para reducir los carcinógenos de hidrocarburo aromáticos policíclicos producidos por el humo, el uso de plantas genéticamente modificadas para reducir la nicotina o las nitrosaminas, o el uso de filtros para reducir selectivamente las sustancias tóxicas), (b) dispositivos similares a los cigarrillos, como los que calientan tabaco en lugar quemarlo, y (c) los productos orales no combustibles, como los snus" (Hatsukami 2005a).
Se ha calculado que algunos productos de tabaco orales sin humo son aproximadamente un 90% menos perjudiciales que fumar cigarrillos (Levy 2004). La investigación sobre los productos de tabaco alternativos en gran parte se ha realizado dentro de la industria tabacalera y en general ha intentado modificar las características de los productos existentes que contienen tabaco, o diseñar nuevos tipos de productos comerciales de tabaco, para lograr que el consumo de tabaco sea menos peligroso. Se necesitan ensayos muy amplios, realizados de forma independiente y a largo plazo para evaluar de forma completa sus efectos (Murrelle 2010).
El uso de productos farmacéuticos para reducir el daño podría, por ejemplo, referirse al uso de cualquiera de las farmacoterapias existentes ya disponibles para ayudar a los pacientes a dejar de fumar, como el tratamiento de reemplazo de nicotina (TRN), vareniclina o bupropión, para reducir el consumo de tabaco. Existen variaciones en cuanto a si el TRN está autorizado para el uso como una ayuda para la reducción en todos los países; por ejemplo, la Food and Drug Administration (FDA) de los EE.UU. no ha aprobado la administración del TRN para los fumadores que desean reducir la cantidad que fuman y que no desean dejar de fumar. Sin embargo, la Medicines and Healthcare Regulatory Authority (MHRA) del Reino Unido lo ha autorizado para esta finalidad. Finalmente, los "cambios en los comportamientos que reducirán el daño" aplican a las intervenciones para el cambio de comportamiento como la reducción del número de cigarrillos consumidos por día (CPD), conocido como “tabaquismo controlado”, que podrían llevarse a cabo junto con el uso de otras ayudas, como PREP o productos farmacéuticos.
De qué manera podría funcionar la intervención
Existen dos vías principales mediante las cuales se esperaría que funcionen los enfoques de reducción del daño mencionados: 1) mediante la promoción del abandono del hábito de fumar posterior, como un subproducto de la reducción del daño (en lugar de al alentar la abandono del hábito específicamente); y 2) mediante la reducción de los efectos sobre la salud del hábito de fumar sin abandono del hábito completa. Hay pruebas de que la reducción del hábito de fumar promovida potencialmente por la mayoría de los enfoques de reducción del daño se asocia con un aumento del abandono del hábito posterior. Una revisión sistemática cualitativa (Hughes 2006) de 19 estudios observacionales y ensayos controlados aleatorios (ECA) no mostró ninguna indicación de que la reducción de los CPD tuviese un impacto negativo sobre el abandono del hábito futura; en realidad, 16 de los 19 estudios encontraron que la reducción estaba asociada con tasas eventuales de abandono más altas. Esta asociación puede deberse a que la reducción aumenta la autoeficacia, interrumpe el condicionamiento farmacológico o reduce la dependencia, o ambos. Sin embargo, también hay pruebas de que los intentos de reducción del hábito de fumar pueden ser debilitados por otros ajustes inconscientes al comportamiento del hábito de fumar, por ejemplo tomar bocanadas más largas y más profundas del cigarrillo para mantener los niveles anteriores de nicotina (Scherer 1999). El uso de una fuente alternativa de nicotina de daño reducido (como TRN, snus, cigarrillos electrónicos [e‐cigs]) para apoyar la reducción conductual podría ayudar a compensar lo anterior, mediante la reducción del síndrome de abstinencia nicotínica y el deseo posterior. En Suecia el uso de snus como un sustituto del cigarrillo ha sido acreditado para una reducción del hábito de fumar entre los hombres, que se asocia con tasas de mortalidad relacionadas con el tabaco más bajas en Suecia que en otros países europeos (Ramstrom 2014). Hay pruebas contradictorias sobre los efectos de la reducción del hábito de fumar en las enfermedades y los marcadores de salud. Por ejemplo, una revisión sistemática informa que el estudio incluido más amplio encontró una reducción del riesgo de cáncer de pulmón en los fumadores que redujeron el consumo en comparación con los que mantuvieron el comportamiento del hábito de fumar (Pisinger 2007); sin embargo, un estudio posterior no encontró pruebas de una reducción del riesgo (Hart 2013). Hay algunas pruebas de que la reducción del hábito de fumar puede reducir los marcadores biológicos relacionados con el riesgo de cáncer o la exposición a carcinógenos, o ambos; sin embargo, no está claro si lo anterior reduce la incidencia del cáncer (Pisinger 2007).
Por qué es importante realizar esta revisión
La mayoría de las pruebas que investigan la conexión entre la reducción del hábito de fumar y la salud actualmente provienen de estudios de observación epidemiológicos y existen cuestiones relacionadas con los mismos. En primer lugar, debido a que el hábito de fumar se mide en general en dos puntos temporales y si el posterior demuestra una tasa inferior que la inicial, se supone que la reducción del hábito de fumar se ha mantenido en todo el período de seguimiento, que puede no ser el caso. En segundo lugar, muchos de los estudios no han usado los marcadores biológicos para validar el consumo de tabaco, lo que podría significar que el tabaco compensatorio (como las bocanadas más profundas) no es representado. Finalmente, muchos de estos estudios no han incluido a personas que usaron productos alternativos de nicotina para compensar el consumo de tabaco, lo cual puede repercutir en el éxito de la reducción, y por lo tanto en los cambios asociados en los riesgos para la salud (Begh 2015). La naturaleza de los ECA significa que todos estos factores pueden controlarse más eficazmente (aunque este no siempre es el caso), y cuando esto se ha realizado es posible tener más seguridad en cuanto a que los resultados que indican asociaciones entre la reducción y la salud son causales. Al examinar estos estudios, es posible efectuar una contribución valiosa a la bibliografía y al debate sobre los enfoques de reducción del daño.
Sin embargo, el uso de estrategias de reducción del daño con relación al hábito de fumar es un tema polémico, con opiniones divididas. Hay inquietudes en cuanto a que al alentar a los pacientes a reducir el hábito de fumar se puede debilitar su motivación para dejar de fumar a largo plazo, y que este hecho puede promover que la industria tabacalera comercialice productos de “riesgo reducido” y realice investigación sesgada sobre su efectividad (Hatsukami 2004). La disponibilidad de los productos de tabaco aparentemente menos nocivos incluso podría llevar a los que nunca fumaron a fumar, o a los exfumadores a una recaída, con la creencia de que los riesgos son aceptables. Estas son las preguntas que no pueden ser respondidas con ECA solamente, y están fuera del alcance de esta revisión; por lo tanto, los resultados de esta revisión deben considerarse junto con la investigación que examina cualquier posible impacto negativo de promover la reducción del daño.
A pesar del debate en curso con respecto a la promoción de la reducción del daño del consumo de tabaco, en 2013 el National Institute for Health and Care Excellence (NICE) del Reino Unido publicó la primera versión de las guías sobre cómo ofrecer enfoques de reducción del daño a los fumadores renuentes o incapaces de dejar el hábito en un paso, que pueden querer usar un sustituto del hábito de fumar más seguro a largo plazo, o sólo podrían estar preparados para reducir la cantidad que fuman (NICE 2013). Por lo tanto, esta guía recomienda algunas intervenciones no tradicionales en que el objetivo máximo aún es dejar el hábito (reducir el consumo de tabaco hasta dejarlo), pero también recomienda la reducción conductual del hábito de fumar con o sin la administración de TRN y la abstinencia temporal con o sin TRN para los fumadores que necesitan dejar de fumar durante un período establecido, p.ej. durante las horas de trabajo, un vuelo de trayecto prolongado o una estancia hospitalaria. Las guías destacan que los beneficios en la salud de la reducción del hábito de fumar, las tasas de recaída y la progresión hasta dejar de fumar entre los pacientes que han optado por reducir la cantidad que fuman todavía son poco claros, y que por lo tanto aún se necesitan mejores pruebas para apoyar e informar el enfoque de reducción del daño. Además, los productos nuevos, como los e‐cigs, que tienen el potencial de usarse en una capacidad de reducción del daño también han comenzado a estar disponibles desde la última actualización de esta revisión. Se necesitan pruebas para informar si estas intervenciones para la reducción del daño podrían ser útiles para la reducción del daño relacionado con el tabaco en los fumadores que no pueden, o no desean, dejar el hábito.
Objetivos
Evaluar los efectos de las intervenciones concebidas para reducir el daño sobre la salud del consumo continuo de tabaco. Se consideraron las siguientes cuestiones específicas:
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¿Las intervenciones concebidas para reducir el daño tienen un efecto sobre el estado de salud a largo plazo?
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¿Las intervenciones concebidas para reducir el daño producen una reducción del número de cigarrillos fumados?
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¿Las intervenciones concebidas para reducir el daño tienen un efecto sobre la abstinencia del tabaco?
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¿Las intervenciones concebidas para reducir el daño tienen un efecto sobre los biomarcadores de la exposición al tabaco?
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¿Las intervenciones concebidas para reducir el daño tienen un efecto sobre los biomarcadores de daño provocado por el tabaco?
Métodos
Criterios de inclusión de estudios para esta revisión
Tipos de estudios
Ensayos controlados con asignación aleatoria o cuasialeatoria.
Tipos de participantes
Pacientes que fuman tabaco, pero que no tienen ninguna intención inmediata de dejar completamente el consumo de tabaco. Se incluyeron ensayos que no evaluaron la motivación si el objetivo era reducir el consumo de cigarrillos, pero no dejar completamente el hábito.
Tipos de intervenciones
Las intervenciones para reducir la cantidad consumida, o para reducir el daño causado por el hábito de fumar por medios diferentes del abandono del hábito, incluido el cambio a un producto de exposición potencialmente reducida (PREP), o mediante otros cambios en las características del cigarrillo. Se excluyeron las intervenciones en las que la reducción del número de cigarrillos consumidos durante un período corto, o el cambio en el tipo de cigarrillo consumido (p.ej. desvanecimiento de nicotina), estaba concebido como un precursor del abandono del hábito completa.
Los estudios se consideraron aptos para la inclusión cuando comparaban estas intervenciones con cualquier “control estándar”, como asesoramiento breve, ningún tratamiento o placebo, o comparaban un tipo de intervención de reducción del daño con otro.
Tipos de medida de resultado
Resultados primarios
El resultado primario preferido fue el cambio a largo plazo en el estado de salud, aunque se esperaba que el mismo tuviera poca probabilidad de ser evaluado en los ensayos aleatorios. No se conoce el indicador aproximado más apropiado para demostrar una reducción en la ingesta de toxinas con el consumo de tabaco, suficiente para dar lugar a un beneficio de salud a largo plazo clínicamente útil (Hatsukami 2005a). Por lo tanto, se ha considerado y extraído cualquier intento realizado para medir un marcador de salud.
A falta de mejores indicadores de salud, también se ha evaluado tanto el cambio en la tasa de tabaquismo desde el inicio como el abandono del hábito de fumar como resultados primarios. Para los resultados de la reducción del hábito de fumar, se prefirieron las tasas prolongadas o continuas a las tasas de la prevalencia puntual. Cuando los estudios no incorporaron a los participantes abstinentes en las tasas de reducción, este procedimiento se realizó para los metanálisis, debido a que los participantes que han dejado de fumar por definición se han reducido a cero. Como no había expectativas de que los participantes dejaran al comienzo de la intervención, se han favorecido las medidas de abstinencia basadas en el comportamiento hacia el final del período de seguimiento (es decir, tasas de prevalencia puntual) sobre las tasas de abstinencia continuas o sostenidas (Hughes 2003). Se prefirieron las tasas bioquímicamente validadas a las tasas informadas por los participantes tanto para los resultados de la reducción como del abandono del hábito. Para reunir los requisitos para la inclusión, un estudio debía informar sobre al menos uno de estos resultados al menos seis meses después del inicio.
Resultados secundarios
Se extrajo información sobre cualquier indicador bioquímico de la cantidad de consumo de tabaco, y sobre los eventos adversos cuando la intervención estudiada incluía la administración de un sustituto farmacéutico, basado en nicotina o tabaco para el hábito de fumar.
Métodos de búsqueda para la identificación de los estudios
We searched the Cochrane Tobacco Addiction Group Trials Register (CRS), which includes controlled trials and other evaluations of interventions to change tobacco use behaviour, derived from systematic searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO. At the time of search (21st October 2015) the Register included the results of searches of CENTRAL (Issue 10, 2015); MEDLINE (via OVID) to update 20151012; Embase (via OVID) to week 201541; PsycINFO (via OVID) to update 20151005.
The MeSH terms 'Harm reduction' and 'Risk reduction behavior' were only introduced in 2003, so free‐text searches were the main method for identifying earlier relevant trials. Original terms used were 'harm reduction', 'smoking reduction' 'reduce* smoking', 'tobacco harm', 'cigarette consumption near (reduction or reduce*)', 'controlled smoking'. Risk Assessment [MeSH], Harm reduction [MeSH], Risk reduction behavior [MeSH]. The most up‐to‐date, full search strategy for identifying studies for this review update in the CRS is shown in Appendix 1.
We also searched the reference lists of studies found in the literature search and the metaRegister of controlled trials database (www.isrctn.com/page/mrct) to October 2015.
Obtención y análisis de los datos
Selección de los estudios
Two authors (from AF, JHB, NLH, RB for this update; TL & previous author LS for previous versions) independently screened papers identified by the search strategy for possible relevance in two stages (titles and abstracts, and full‐text). Both authors discussed any differences between them, and where necessary had recourse to a third author.
Extracción y manejo de los datos
Two authors (from AF, JHB, NLH, RB for this update; TL & previous author LS for previous versions) independently extracted data from full‐text papers deemed eligible for inclusion. We checked for agreement, and discussed and resolved any differences within the author team.
We collected the following information for each trial:
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Country and setting of intervention
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Method of participant recruitment and main inclusion criteria in relation to motivation to change tobacco use
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Other participant characteristics, including age, sex, previous smoking habit, quit attempt history
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Description of intervention and control conditions
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Outcomes assessed, including all measures of tobacco use reduction and quitting, and all measures of exposure to tobacco and measures of potential harm
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The definition of 'harm reduction', and quitting
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Adverse events (where the intervention included the use of a pharmaceutical, nicotine‐ or tobacco‐based substitute for tobacco smoking)
One author then entered the data into Review Manager 5 software for analysis, and another checked them.
Evaluación del riesgo de sesgo de los estudios incluidos
Two authors (from AF, JHB, NLH, RB for this update; TL & previous author LS for previous versions) independently assessed the risk of bias for each included study, following the approach recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We used domain‐based evaluation to address the following areas: random sequence generation; allocation concealment; blinding (of participants, providers and assessors); and incomplete outcome data. We assigned a grade (low, high, or unclear) for risk of bias for each domain, resolving disagreements by discussion with a third author where necessary.
Medidas del efecto del tratamiento
For outcomes measured using continuous variables, for example carbon monoxide (CO) levels, the preferred outcome was the difference between the average change from baseline in the intervention and control groups.
For dichotomous outcomes, we summarized results of each study as a risk ratio (RR), with a 95% confidence interval (CI).
Manejo de los datos faltantes
We assessed the potential for bias due to loss to follow‐up. Where outcomes for individuals were missing, we planned to include them and assume that they had not stopped smoking or had not changed their behaviour in a favourable direction. This conservative approach is standard for the Cochrane Tobacco Addiction Group. We planned to note any exceptions to this, and to consider the sensitivity of results to different assumptions about missing data.
Evaluación de la heterogeneidad
We assessed whether trials used comparable interventions and measured similar outcomes, to guide our decision whether to pool data. Where we did decide to pool data we assessed statistical heterogeneity using the I2 statistic (Higgins 2003). We would deem a value greater than 50% as evidence of substantial heterogeneity.
Evaluación de los sesgos de notificación
We intended to assess reporting bias using funnel plots; however, this is only a robust approach where 10 or more RCTs contribute to an outcome. There are currently too few studies to support this approach.
Síntesis de los datos
We planned to pool data for meta‐analysis where appropriate, i.e. where we did not detect substantial clinical and methodological heterogeneity. For example, we did not intend to pool harm reduction interventions using different classes of pharmacotherapy (such as NRT, bupropion, varenicline). Where data was pooled the decision whether to use random or fixed‐effect models was partly informed by the statistical heterogeneity detected, with an I2 of 50% or over classed as substantial. Ultimately, we pooled studies using a Mantel‐Haenszel fixed‐effect model. We considered pooling behavioural interventions if they were of comparable intensity in terms of the presence or absence of face‐to‐face contact, and the number of contacts.
Análisis de subgrupos e investigación de la heterogeneidad
In the event of heterogeneity, we considered subgroup analyses based on the intervention type (in both the experimental and control groups) and the characteristics of participants.
Análisis de sensibilidad
We considered assessment of the sensitivity of meta‐analysis results to the exclusion of studies that we rated as being at high risk of bias.
'Summary of findings' table
Our aim was to create a 'Summary of findings' table for the primary outcome of long‐term change in health status. However, there were no studies which reported this outcome. As the only other outcome measured that we know to have a positive impact on health is complete abstinence, we created a table to summarize the smoking abstinence outcomes for the primary comparisons of each intervention. Following standard Cochrane methodology, we used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of the body of evidence for each outcome, and to draw conclusions about the quality of evidence within the text of the review.
Results
Description of studies
Results of the search
Full details of search results are not available for the previous versions of this review; however, the search we carried out for this update identified 659 non‐duplicate records. We assessed the titles and abstracts of all of these studies and acquired the full text of 60 (representing 48 studies) to conduct a further eligibility assessment. We found nine studies to be eligible after this stage, of which three were ongoing (Caponetto 2014; NCT02124187; Taskila 2012; see Characteristics of ongoing studies table for more details). We therefore performed full data extraction on six completed studies, and have added them to the review for this update (Benowitz 2012; Caponnetto 2013; Chan 2011; Hughes 2011; Joksić 2011; Nackaerts 2009), giving a total of 24 included studies.
Included studies
We include 24 studies, which aimed to test interventions to reduce the harm caused by continued tobacco smoking. Across studies, this involved behaviour change to reduce tobacco consumption or to replace traditional tobacco use with alternative products of (potentially) lower risk, or both. Studies typically recruited between 100 and 200 participants in each intervention or control group. The smallest had 93 participants in total (Riley 2002).
Participants
The methods of recruitment were varied. Most studies relied on advertising to attract community volunteers. One study proactively recruited participants by telephoning households and identifying people who smoked (Carpenter 2004). One study used multiple approaches, including direct mail to households (Etter 2004). One small study (Hanson 2008) was in adolescents in particular, and another specifically recruited electively hospitalized patients from a variety of wards in academic hospitals (Nackaerts 2009).Most studies excluded people currently interested in quitting smoking, but the assessments and cut‐off points used to establish eligibility varied. Participants generally had to lack current interest in quitting, but some studies (e.g. Batra 2005; Bolliger 2000; Haustein 2003; Joseph 2008) also required past failure in a serious quit attempt. This criterion was intended to exclude people likely to quit easily without assistance. Exceptions were Kralikova 2009, where participants were recruited on the basis that they did not have to be motivated to quit (cessation was recommended but not mandatory), and Joksić 2011, where participants did have to be motivated to quit smoking but the intervention was smokeless tobacco and therefore participants were not willing to quit tobacco completely. However, despite using criteria to exclude people willing to attempt immediate quitting in the main, the long‐term motivation to stop smoking often appeared high. For example, Wennike 2003 reported participants as having an average motivation to quit of 6.6 on a visual analogue scale of 0 to 10. Little information was available on the participants in two of the studies (Australia NNCG‐017; Nackaerts 2009). Participants in the studies of PREPs (excluding smokeless tobacco) were volunteers who were paid for participation in research studies (Benowitz 2012; Mendes 2008; Roethig 2008; Sarkar 2008). In most studies participants had a baseline average smoking rate of between 20 and 30 CPD; however, participants had a baseline rate of 12 CPD in Hanson 2008, 19 CPD in Hughes 2011, and 18 CPD in Sarkar 2008.
Interventions and controls
Nicotine replacement therapy
Fourteen included trials provided or offered nicotine replacement therapy (NRT). They took place in the USA (Carpenter 2003; Carpenter 2004; Hanson 2008; Joseph 2008; Rennard 2006); Australia (Australia NNCG‐017); Germany and/or Switzerland (Batra 2005; Bolliger 2000; Etter 2004; Haustein 2003); the Czech Republic (Kralikova 2009); Denmark (Wennike 2003); Belgium (Nackaerts 2009); and China (Chan 2011).
Nine of these trials provided behavioural support to encourage smoking reduction, and randomized participants to NRT or placebo (Australia NNCG‐017; Batra 2005; Bolliger 2000; Etter 2004; Hanson 2008; Haustein 2003; Kralikova 2009; Rennard 2006; Wennike 2003), including one (Etter 2004) which also had a control group receiving only minimal behavioural support. Etter 2004 and Kralikova 2009 offered participants a choice of products, and in one of these participants could use a combination of types (Etter 2004). Bolliger 2000 and Rennard 2006 used an inhaler alone; Australia NNCG‐017 and Wennike 2003 provided 2 mg or 4 mg gum, depending on baseline dependence, while Batra 2005 and Haustein 2003 used 4 mg gum only. Haustein 2003 involved additional stratification to arms, supporting reduction for a maximum of either four weeks or six months (resulting in a 2x2 study design). In the short‐term reduction arms participants were asked at baseline to quit at week four, while in the long‐term arm participants were asked simply to reduce as much as possible over six months. At the end of the six months, participants were advised that it was preferable to quit altogether; however, this was not the original goal and a specific cessation intervention was not offered. For the purposes of this review we are solely interested in the two long‐term reduction arms (comparing nicotine gum to placebo gum). Hanson 2008 was borderline for inclusion, and so not included in meta‐analyses. This was because after a short period of reduction (four weeks) participants were offered a cessation intervention where they set a quit date and were provided with NRT. There were two intervention arms: one used nicotine gum and the other used nicotine patch; however, these were only provided in the second phase of the study, if participants decided to set a quit day after the period of reduction.
One study (Nackaerts 2009) investigated the use of nicotine patches versus placebo patches as a substitute for smoking, to induce "temporary abstinence", during hospitalization.
A further two studies (Chan 2011; Joseph 2008) provided repeated counselling and encouragement to use NRT, compared to a control group that received only brief advice on the importance of quitting. Chan 2011 further split their counselling + NRT group, so that one group also received add‐on counselling to encourage adherence to the NRT. However, for the purposes of our analysis we combined the two counselling + NRT groups and compared them to the brief‐advice control. Joseph 2008 provided participants with nicotine gum, or, if this did not suppress withdrawal, with nicotine patch.
Two other NRT studies did not have a placebo control and were borderline for inclusion. As a result we have not included them in our meta‐analyses. In Carpenter 2003 participants were recruited on the basis that they were not interested in quitting immediately, but that they were interested in quitting within the next six months. This was a pilot study, assessing whether assistance with cutting down increased the impact of subsequent brief advice to quit completely. Intervention participants were given a choice of NRT products and a target of reducing their daily cigarette consumption by at least 50% in four weeks, after which they were advised to quit, and given self‐help materials to do so if desired. The control group received brief advice to quit at the initial visit, and those who set a quit date were offered NRT but no further support. In Carpenter 2004 the initial intervention focused on reduction, but participants were advised to quit and those that set a quit date were provided with additional support (i.e. a cessation intervention). Carpenter 2004 had three arms: a no‐intervention control, motivational interviewing intended to increase interest in quitting, and advice to reduce with an offer of NRT. Both intervention arms included eligibility for free NRT if a quit date was set. Both Carpenter 2003 and Carpenter 2004 provided participants with a choice of NRT products (gum, patch or inhaler; and gum or patch respectively).
Across all NRT studies, the maximum length of time NRT could be used to aid reduction ranged from nine months (Haustein 2003) to 18 months (Bolliger 2000). In Nackaerts 2009 the nicotine patch was used as a complete substitute for smoking rather than whilst reducing. Participants were provided with patches until they were discharged from hospital, for a maximum of seven days.
Bupropion
One USA study (Hatsukami 2004a) offered bupropion or placebo for 26 weeks to people attempting to reduce their smoking, with a target of 50% reduction in cigarettes smoked a day. Final follow‐up was six months after the end of treatment. Participants who indicated a willingness to quit at any time remained on assigned treatment but enrolled in a seven‐week cessation programme with weekly counselling visits followed by 19 weeks of follow‐up.
Varenicline
Hughes 2011, carried out in the USA, randomized participants to either varenicline or placebo for two to eight weeks. Participants were also provided with four counselling sessions (baseline, two weeks, four weeks and eight weeks) on methods that could be used to reduce the amount of cigarettes smoked. The aim of the study was to see whether varenicline would induce quit attempts in smokers who were not currently planning to quit. Final follow‐up was six months after baseline.
Electronic cigarettes
Another single study (Caponnetto 2013) encouraged participants who did not intend to quit to reduce their cigarette‐smoking using electronic cigarettes (ecigs). There were three arms, all of which were instructed to use an ecig ab libitum; the difference between the three study arms was the nicotine content of the ecig nicotine cartridges provided (7.2 mg; 5.4 mg; 0 mg). Participants received 12 weeks‐worth of cartridges. The identical appearance of the ecigs and cartridges was intended to blind participants and investigators to their treatment allocation. The study took place in Italy, at the Universita di Catania, and had a follow‐up of one year.
Snus
Joksić 2011, which took place in Serbia, used the smokeless tobacco product, snus, to encourage participants to reduce their smoking. Although participants were told that their ultimate goal should be to quit, the aim in the first 24 weeks was solely cigarette reduction. We included this study despite the goal to quit cigarettes, as it instructed participants to switch to snus, and therefore not to quit tobacco completely. Participants were told to use a sachet of snus every time they felt the urge to smoke. The control group received placebo sachets of smokeless tobacco, which were almost identical to the snus product in appearance, feel, pH and taste, but contained no nicotine or tobacco. Study follow‐up took place up to two years post‐baseline. Joksić 2011 was sponsored by Swedish Match.
Other PREPs (excluding smokeless tobacco)
There were also four studies comparing PREPs (excluding smokeless tobacco) to conventional cigarette use (Benowitz 2012; Mendes 2008; Roethig 2008; Sarkar 2008). For the purposes of this review we present studies of smokeless tobacco separately from these other PREPs, which were all products mimicking cigarette smoking whilst potentially reducing the intake of harmful components. Three of the PREP studies were funded by a tobacco company (Mendes 2008; Roethig 2008; Sarkar 2008), and the fourth was funded by the National Cancer Institute and National Institute on Drug Abuse, National Institutes of Health, but a tobacco company provided the research cigarettes (Benowitz 2012). All four studies investigated products designed to reduce the risks of smoking in different ways. Mendes 2008 evaluated light and ultra‐light tar cigarettes compared to continued use of conventional cigarettes; Sarkar 2008 investigated carbon‐filtered cigarettes; Benowitz 2012 investigated reduced‐nicotine content cigarettes, and Roethig 2008 evaluated an electrically‐heated cigarette smoking system (EHCSS), a device used to smoke regular cigarettes, rather than an ecig. These studies had six‐ to 12‐month follow‐up, including regular research clinic visits for collection of samples for biochemical assessment of levels of markers of exposure and risk.
Behavioural interventions
Two studies investigated behavioural interventions to change smoking behaviour without the use of pharmaceutical aids, nicotine or tobacco substitutes for cigarettes. Riley 2002, involving community volunteers only interested in reduction, compared two guided methods to reduce the number of cigarettes smoked. One intervention used computerized scheduled smoking to achieve a gradual reduction to 50% of baseline in two weeks. The comparison condition provided a treatment guide instructing in gradual reduction by selectively eliminating cigarettes. Glasgow 2009 provided an intervention for members of a Health Maintenance Organization who were due to have outpatient surgery or a diagnostic procedure via telephone. The individualized counselling consisted of participants being advised to gradually reduce their cigarette smoking by 50% or more, with cessation encouraged following reduction. This intervention was compared to usual care in the form of usual care plus generic health mailings.
Outcomes
The main outcomes in most of the included studies were reduction or cessation, and these all had follow‐up of at least six months. However, three of the studies investigating PREPs measured neither reduction nor cessation, and instead used biochemical assessments to measure potential markers of health risk. The smoking reduction and cessation outcomes used in this review were all assessed at least one month after the end of the treatment period, as well as being at least six months after the start of the intervention. The most consistently used reduction outcome was a reduction in self‐reported cigarettes a day of more than 50% from baseline. Most studies used sustained reduction at multiple follow‐ups, validated by any level of reduction in baseline CO. Other reduction measures reported in some studies were average reduction in CPD, and average reduction in CO levels, cotinine levels and thiocyanate levels. These reductions could be expressed as absolute or percentage reductions, and were typically calculated using available data without imputing values for dropouts, and included people who were no longer smoking at assessment.
In those studies that did investigate health outcomes, analyses of changes in biomarker levels amongst reducers did not always distinguish between treatment groups. In addition, the wide variation in the markers used and the ways these were assessed meant that we could not attempt meta‐analysis for these outcomes.
Ongoing studies
During the 2016 update we also identified three studies deemed to be ongoing (Caponetto 2014; NCT02124187; Taskila 2012), where results are not currently available. These may be eligible for inclusion in a subsequent update. Caponetto 2014 is another ecig study which recruited people with schizophrenia with no intention of quitting. It has three trial arms: 1) high‐nicotine ecig (24 mg); 2) ecig with no nicotine; and 3) nicotine‐free inhalator. NCT02124187 is a very similar ecig study with the same investigator, recruiting participants with major depressive disorder, with the same study arms. Both of these studies began in 2014 and have a planned 52‐week follow‐up. Taskila 2012 is a completed but currently unpublished study assessing the effectiveness of pharmacist‐delivered behavioural reduction programmes. Planned length of follow‐up was six months. For further detail see Characteristics of ongoing studies.
Excluded studies
We found a variety of other studies which were potentially relevant but did not meet our inclusion criteria because they recruited participants that wanted to quit as a short‐term aim, or the aim of the study was to quit smoking rather than to simply to reduce smoking or harm. Another common reason for exclusion was that the long‐term change in smoking behaviour and associated change in biomarkers of harm were not a target of the study. Many of these were very short‐term within‐subject cross‐over studies of smokers switching to PREPs developed by the tobacco industry. Another short‐term excluded study used payment for reduced levels of carbon monoxide to encourage smoking reduction (Lamb 2005). One study estimated the amount of compensatory smoking in people switching to lower‐tar cigarette brands (Frost 1995). For more detail on excluded studies and the reasons for exclusion, see Excluded studies.
Risk of bias in included studies
See Characteristics of included studies and Figure 1.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
We judged 15 of the included studies to be at unclear risk of bias for random sequence generation. This was simply because the studies stated that they were randomized but then did not specify how the randomization sequence was generated, making it impossible to judge whether or not this was done adequately. We judged all other studies to be at low risk of bias for sequence generation, as they reported being randomized with a robust method of sequence generation (Bolliger 2000; Caponnetto 2013; Chan 2011; Etter 2004; Glasgow 2009; Hatsukami 2004a; Haustein 2003; Joksić 2011; Joseph 2008).
When assessing allocation concealment, we rated most trials at unclear risk, due to a lack of reporting, i.e. 18 studies did not specify how participant allocation to study groups was concealed prior to and during randomization. However, we judged the remaining seven studies to be at low risk, as treatment was either organized and/or distributed by an independent pharmacist or researcher with no further involvement in the study (Bolliger 2000; Caponnetto 2013; Hughes 2011; Joksić 2011), or allocations were concealed up to treatment delivery in opaque sealed envelopes (Chan 2011; Haustein 2003; Joksić 2011).
Blinding
In seven cases we deemed blinding to be insufficient and rated the studies at high risk (Benowitz 2012; Carpenter 2004; Joseph 2008; Mendes 2008; Riley 2002; Roethig 2008; Sarkar 2008). Carpenter 2004 tested a behavioural intervention, which would be impossible to blind. Potential bias would have been minimized if the study arms had received the same level of support and if outcomes were biochemically verified, but this was not the case. In the other studies rated as high risk, group allocation was not blinded and the products provided across groups differed in nature so that there was a risk of performance bias. For example, in Joseph 2008 there were differences between the arms in the counselling provided, and in whether NRT was supplied. In nine cases we judged blinding to be at an unclear risk of bias (Australia NNCG‐017; Batra 2005; Caponnetto 2013; Hanson 2008; Hatsukami 2004a; Kralikova 2009; Nackaerts 2009; Rennard 2006; Wennike 2003). This was because the study was described as "blinded", "double‐blinded", or used a placebo, but with no details given as to who was blinded or how this was achieved, or both.
Incomplete outcome data
Loss to follow‐up was high in some trials. Although this is also a problem in cessation trials where participants wish to quit, study reports indicate that it was a larger problem in this population of smokers who were not as motivated to change their smoking behaviour. We rated three studies (Benowitz 2012; Mendes 2008; Sarkar 2008) at high risk of bias for this domain, as there was a substantial difference in dropout rates between study groups.
Outcomes derived from continuous variables (mainly markers of health outcomes) were generally reported for continuing participants only. If dropouts are less likely to have changed their behaviour, these outcomes will overestimate the change in the trial population. In using a dichotomous outcome for reduction in cigarettes and calculating rates on an intention‐to‐treat basis, we, like the trialists, made the assumption that dropouts had not reduced by more than 50%. This will underestimate the change in the population if our assumption is incorrect. It does not remove the potential to introduce bias if the true change in behaviour amongst dropouts is confounded by treatment group. The trials of PREPs had particularly high losses to follow‐up, which was higher in groups using the unfamiliar products.
Other potential sources of bias
Studies typically reported sustained reduction measured by a self‐reported cigarette consumption of less than 50% of baseline, validated by reduced levels of CO at follow‐up visits. However, Hanson 2008, Hughes 2011 and Nackaerts 2009 did not report full information on smoking reduction in the long term. Hanson 2008 did not report reduction or cessation rates to the full length of follow‐up (six months), or split by arm. Hughes 2011 covered self‐reported smoking reduction at two‐month follow‐up and then CO‐validated abstinence at six months, and Nackaerts 2009 gave self‐reported abstinence at six months. Etter 2004, a study in the NRT group, did not report sustained abstinence at the longest (two‐year) follow‐up, and did not use biochemical validation because there was no personal contact with participants. Since these factors could overestimate the true reduction we tested the sensitivity of the relevant meta‐analysis to exclusion of this trial.
Three of the included studies remain unpublished; two were presented at conferences (Haustein 2003; Nackaerts 2009) and one was identified from internal reports provided by Pfizer (Australia NNCG‐017).
Effects of interventions
Type of intervention
Nicotine replacement therapy
Smoking reduction outcomes
We pooled eight trials of nicotine replacement therapy (NRT) versus placebo in adults. Overall there was a statistically significant effect of NRT on the likelihood of reducing cigarette use by 50% or more from baseline (risk ratio (RR) 1.75, 95% confidence interval (CI) 1.44 to 2.13; 3081 participants; Analysis 1.1; Figure 2). There was moderate heterogeneity (I2 = 45%). Two studies, Etter 2004; Kralikova 2009, contributed most weight to the analysis. Etter 2004 used self‐reported reduction and many more participants claimed to have reduced than in other studies, although the relative effect of treatment was smaller. We used data from the two‐year follow‐up in the analyses but also tested the sensitivity to the use of five‐year follow‐up data. Kralikova 2009 was not typical because participants appear to have been more motivated to quit than to reduce, and many did so. We conducted a sensitivity analysis to assess the impact of excluding these two studies. Since they showed relatively less effect on reduction, the effect was to increase the point estimate whilst widening the confidence intervals and reducing heterogeneity. However, the effect was still statistically significant (RR 2.77, 95% CI 1.88 to 4.08, I² = 9%; 2233 participants). Etter 2004 also had a non‐placebo control group, not included in the analyses above. Including this group in the control condition would have increased the effect. Using the five‐year data for this study did not substantially alter the result.
Forest plot of comparison: 1 Nicotine replacement therapy to assist smoking reduction versus placebo, outcome: 1.1 Reduction in cigarettes/day of > 50% of baseline or cessation.
We performed a subgroup analysis to see whether the effect differed according to the type of NRT being used (i.e. a choice of NRT, nicotine gum, or nicotine inhaler; Figure 2), and found that NRT resulted in significantly more reducers than placebo in all cases. However, there is evidence of between‐group differences (P = 0.009) with nicotine gum (RR 2.50, 95% CI 1.57 to 4.00, I2 = 34%; 1404 participants; Analysis 1.1.2) and nicotine inhaler (RR 3.39, 95% CI 1.70 to 6.77, I2 = 0%; 829 participants; Analysis 1.1.3), resulting in more reducers than choice of NRT (RR 1.40, 95% CI 1.11 to 1.75, I2 = 0%; 848 participants; Analysis 1.1.3) relative to placebo.
Joseph 2008 and Chan 2011 differed from the other studies in combining NRT and counselling versus a brief advice control, so we pooled these trials separately (RR 1.75, 95% CI 1.26 to 2.43, I2 = 32%; 1306 participants; Analysis 2.1). Again, there was a statistically significant effect on reduction; however, Chan 2011 was a larger study and therefore contributed much of the weight. Joseph 2008 as a single study found a small non‐significant effect.
Cessation outcomes
Pooling the eight NRT‐versus‐placebo trials in adults, we found a statistically significant effect of NRT in increasing quit rates by the end of follow‐up (RR 1.87, 95% CI 1.43 to 2.44; 3081 participants; Analysis 1.2) with moderate heterogeneity (I2 = 30%). We again produced a subgroup analysis to assess any effect of the type of NRT used. No significant differences emerged between subgroups. For all three subgroups NRT resulted in statistically significantly higher pooled quit rates than placebo (Analysis 1.2.2; Figure 3).
Forest plot of comparison: 1 Nicotine replacement therapy to assist smoking reduction versus placebo, outcome: 1.2 Cessation at long‐term follow‐up (subgroups by type of NRT).
Pooling the two studies which compared NRT with behavioural support to brief advice found no statistically significant effect (RR 1.49, 95% CI 0.89 to 2.50, I2 = 27%; 1306 participants; Analysis 2.2), with neither study individually finding a significant effect on quit rates (Chan 2011; Joseph 2008).
Nackaerts 2009 was the only study in the review which investigated the use of NRT (specifically nicotine patches) to aid temporary abstinence. This study only reports abstinence at long‐term (six‐month) follow‐up and found almost identical quit rates in the patch (44/150; 29%) and placebo (41/146; 28%) groups.
In two studies the control groups did not get a placebo and there was the option of a cessation intervention at the end of the short‐term reduction intervention (as previously discussed, these studies were borderline included and therefore not pooled in meta‐analyses). In the first (Carpenter 2003), cessation rates were non‐significantly different (5/32 versus 3/35, RR 1.82, 95% CI 0.47 to 7.02) and non‐quitters reduced their CPD compared to controls. In the second (Carpenter 2004), reduction and quit rates were significantly higher in the NRT and behavioural support group than in the no‐treatment control, but advice to reduce before quitting had similar effects on reduction and cessation to the motivational interviewing intervention designed to increase interest in quitting. We did not pool one small pilot study amongst adolescents (Hanson 2008), which also gave the option of a cessation intervention after a four‐week reduction intervention. Furthermore, cessation was not reported by group and a reduction of more than 50% was not reported at six‐month+ follow‐up. There was no evidence of any treatment effects, and although average CPD was smaller in all three conditions at six months, average CO and cotinine levels were non‐significantly higher than at baseline.
Adverse events (AEs)
Nine of the fourteen NRT studies compared one arm receiving NRT to another arm receiving placebo or no NRT, and reported on adverse events (Batra 2005; Bolliger 2000; Carpenter 2004; Etter 2004; Haustein 2003; Joseph 2008; Kralikova 2009; Rennard 2006; Wennike 2003). The reporting across studies was generally sparse and varied. There was some evidence of a small elevation in non‐serious adverse events in the study arms receiving active treatment; for example, Haustein 2003 found that nausea and vomiting were more common in the active (59/193) than in the placebo group (17/192); Kralikova 2009 found that 82 adverse events occurred in the active arm versus 26 in the placebo arm (N = 209 and 105 respectively); and Batra 2005 reported 506 AEs in the active group and 370 in the control group (N = 184 and 180 respectively). However, this is also true for NRT used for cessation (Stead 2012), and there were no reports of any serious adverse events that might have been attributed to NRT use alongside continued smoking in any of the studies reporting safety outcomes.
Other markers of cigarette consumption
We summarize reported changes in CPD, CO, thiocyanate and cotinine, expressed as percentage or absolute differences from baseline values, for the studies for which data were available in Analysis 1.3 (NRT versus placebo) and Analysis 2.3 (NRT + counselling versus brief advice). Studies typically showed reductions from baseline in both treatment and control groups, but this was usually based on continuing participants only. Differences between groups where reported were not always statistically significant. Because of the multiple differences in the ways in which changes were calculated and reported, we did not attempt any formal meta‐analysis.
People who reduce their cigarette consumption may inadvertently compensate for the reduction in nicotine by smoking the remaining cigarettes more 'efficiently' and therefore do not reduce their intake of toxins as much as might be suggested from CPD. Using NRT to assist reduction may help avoid this compensation, so that toxin levels are reduced more for a similar level of CPD reduction. We found relatively little data about either compensation generally amongst reducers, or differential levels of compensation for NRT and placebo users. Bolliger 2000 reported that at 24 months sustained reducers had an average CPD of 25% of baseline, whilst CO and cotinine levels were only about 50% of baseline. The same study presented data on cigarette and CO reduction in the subgroup of intervention and placebo participants who were still using inhalers daily at various points during the treatment phase. After 18 months, the 22 active inhaler‐users had an average reduction in CPD of 64% of baseline with a range of 0% to 100%. CO levels were only reduced by an average of 29% of baseline. Changes in CO levels ranged from a decrease of 92% to an increase of 222%. The eight placebo‐users had a significantly smaller (P = 0.02) percentage reduction in CPD than the active inhaler‐users (reduced to 33% of baseline, range 20% to 100%) and a non‐significantly smaller percentage reduction in CO (reduced to 82% of baseline, range 50% to 177%). Batra 2005 reported the proportion of participants with a sustained reduction in CO levels of over 20% from baseline at 13‐month follow‐up. The proportions achieving this (13.6% active versus 5.6% placebo) were higher in both conditions than the proportion reporting sustained reduction greater than 50% in CPD, suggesting that all the reducers had achieved at least a 20% reduction in CO.
Health markers
Six studies (Batra 2005; Bolliger 2000; Haustein 2003; Joseph 2008; Kralikova 2009; Rennard 2006) assessed some biomarkers of disease risk, and we report these narratively in Analysis 1.4. Changes from baseline were assessed in those with available data and typically showed improvements over time but not between groups. Bolliger 2000 and Haustein 2003 assessed differences between those participants who successfully reduced and those who did not, rather than between randomized groups. Again, there were not consistent between‐group differences. One study (Rennard 2006) found no differences across treatment groups in any markers of cardiovascular risk, but also reported changes in cardiovascular risk factors from baseline to four‐month follow‐up in individuals who had reduced by more than 50%, including quitters. Results were not reported by treatment group, and we cannot separate the benefit of quitting from that of reducing; there was a significant increase in high‐density lipoprotein (HDL) cholesterol. It was not possible to meta‐analyse any of the reported data due to variations in the markers measured, the ways these were measured and the comparison groups used.
Bupropion
Hatsukami 2004a, the single study testing bupropion, did not detect a long‐term effect on reduction or cessation. Participants who became willing to make a quit attempt entered a cessation programme. When using all randomized participants as the denominator, long‐term cessation rates were not statistically significantly different between the bupropion and placebo groups (RR 1.27, 95% CI 0.67 to 2.40; 594 participants; Analysis 4.1.1), although those in the bupropion group made their quit attempts sooner and had better short‐term quit rates. Smoking reduction in participants who never attempted to quit, as defined by a reduction in urinary cotinine of more than 50%, was greater during the treatment phase but did not differ significantly at 12‐month follow‐up (RR 1.01, 95% CI 0.62 to 1.67; 594 participants; Analysis 4.1.2). Reduction in cotinine more than 50%: 2% (3/153) bupropion versus 5% (8/174) placebo, not statistically significant (P = 0.17) excludes participants who entered the cessation arm of the study. The between‐group difference in cotinine measured continuously was also non‐significant at 12‐month follow‐up (Analysis 4.2).
Health markers were not assessed in this study.
Eight participants in the bupropion group and three in the placebo group reported adverse events that met study criteria for serious events. One of these was thought to be related to the bupropion treatment.
Varenicline
Hughes 2011 assessed point prevalence CO‐verified quit rates at six‐month follow‐up, and found that 14% of the varenicline group and 7% of the placebo group were abstinent; however, this difference was not statistically significant (RR 1.95, 95% CI 0.86 to 4.40; 218 participants; Analysis 5.1). Smoking reduction was only reported at two‐month follow‐up, with statistically significant differences in self‐reported CPD and exhaled CO.
Health markers were not assessed at all in this study.
There was no significant difference in adverse events between groups, with 12% of the active group and 10% of the placebo group stopping their medication due to an AE.
Electronic cigarettes
Caponnetto 2013 was the only completed study investigating ecigs as a harm reduction aid at the time of the searches. The study compared nicotine and non‐nicotine ecigs, and found that there was a reduction in the number of regular cigarettes smoked, but without statistically significant between‐group differences. The RR for more than a 50% reduction at one‐year follow‐up was 1.28 (95% CI 0.76 to 2.17; 300 participants; Analysis 6.1.1), and for abstinence 2.75 (95% CI 0.97 to 7.76; 300 participants; Analysis 6.1.2); both were statistically non‐significantly in favour of ecigs with nicotine cartridges. The CPD reduction finding was mirrored by non‐significant between‐group differences in CO at 12‐month follow‐up (Analysis 6.2).
Caponnetto 2013 also assessed whether weight, resting heart rate, systolic blood pressure (SBP) or diastolic blood pressure (DBP) changed over time or between groups. There were no significant differences for any of these outcomes (Analysis 6.3). The frequency of adverse events was reported to be comparable across groups at each of the three assessment time points during the study (baseline, week 12, week 52). All symptoms were significantly reduced between baseline and week 52 in all groups (P < 0.001). In particular, the rates of shortness of breath were reduced from 20% to 4% two weeks into the study. No serious adverse events were reported during the study.
Snus
The one study (Joksić 2011) that investigated replacing cigarette smoking with another form of tobacco (smokeless, snus) found that there was not a significant difference in the number who achieved more than a 50% cigarette reduction (RR 0.94, 95% CI 0.81 to 1.11; 319 participants; Analysis 7.1.1) and complete abstinence (RR 3.06, 95% CI 0.84 to 11.08; 319 participants; Analysis 7.1.2) between the active and placebo groups at six months. However, statistically significantly more participants in the snus group achieved more than a 75% reduction at six‐month follow‐up (15/158, 9.5% in the snus group and 4/161, 2.5% in the placebo group; P = 0.01). It should be noted that the last of these analyses was the result of an exploratory, post hoc investigation. Although this study went on to 48‐month follow‐up, we only use the data up to 24 months here, as after this point anyone who had not reduced by more than 50% or quit was excluded. When we assessed markers of consumption (CPD, CO and cotinine) as continuous measures, there were no significant between‐group differences at 48 weeks; however, in both groups CPD and cotinine reduced by approximately a third, and CO reduced by around half (Analysis 7.2).
A number of health markers were measured; however, in no case did we find any differences over time or between groups (Analysis 7.3). Only two adverse events were reported in the snus arm of the study, and neither was judged to be associated with the use of snus.
Other PREPs (excluding smokeless tobacco)
We summarize the main findings of these four studies narratively. All reported data on multiple biomarkers at multiple follow‐up points (Analysis 8.1). Difficulties in interpreting the results include the large variation between participants, and the loss to follow‐up of participants who did not maintain use of the test products. Some measures showed marked changes from baseline to the end of follow‐up; for example, CPD typically increased in both experimental and control groups. Switching from full‐strength (F) to low‐ (L) or very low‐tar (UL) cigarettes (Mendes 2008) led to significantly lower average nicotine levels in the UL than in the F groups. CPD increased in all groups, possibly because cigarettes were provided free in a residential clinic. Carboxyhaemaglobin (COHb) levels were similar between the F and UL groups, but higher in the L groups. Overall, although some exposures were reduced in the heavy smokers who switched to lower‐tar alternatives, the absolute differences were not large, even when statistically significant. Use of carbon‐filtered low‐ and medium‐tar cigarettes led to reduced levels of gas phase biomarkers, but had no impact on particulate phase biomarkers (Sarkar 2008). Using an electrically‐heated cigarette smoking system (EHCSS) reduced exposure to tobacco smoke constituents, especially carboxyhaemoglobin. Nicotine levels were reduced, which, combined with the higher dropout in the EHCSS group, suggests that the device may not have been very acceptable to smokers (Roethig 2008). In this study markers or cardiovascular risk factors including white blood cell counts and levels of HDL and LDL did show significant change in favourable directions compared to conventional cigarette use. Benowitz 2012 conducted bi‐weekly clinics in a community clinic setting, a slightly different context to the aforementioned studies. This may account for the fact that cigarette consumption stayed relatively stable in both study conditions (reduced nicotine content‐cigarettes versus usual cigarettes). Markers of consumption, such as CO, and cardiovascular biomarkers also stayed approximately the same in both groups. However, markers of nicotine consumption decreased in the group receiving reduced nicotine content‐cigarettes. It would seem that, although nicotine consumption was successfully reduced in the experimental group, this did not result in participants compensating for this by smoking more cigarettes and thereby increasing their CO consumption.
None of the four studies of PREPs reported reduction as a binary outcome (with a 50% cut‐off), and only Benowitz 2012 assessed and reported smoking cessation. Only very small numbers quit (2/80 in the experimental, reduced nicotine cigarettes group, and 1/55 in the control, regular cigarettes group), resulting in a statistically non‐significant effect, with very wide confidence intervals (RR 1.38, 95% CI 0.13 to 14.79; 135 participants; Analysis 8.2).
A summary of measures of health markers across studies of PREPS can be found in Analysis 8.3.
Behavioural interventions
In a study comparing computerized scheduled reduction to reduction by selective elimination of cigarettes (Riley 2002), both groups achieved statistically significant reductions in cigarettes from baseline, but there was no difference between the groups (RR 0.99, 95% CI 0.42 to 2.34; 93 participants; Analysis 9.1.1). There were also reductions in CO which did not differ between groups (Analysis 9.2). Point prevalence quit rates were higher at 12‐month follow‐up than at the end of treatment in both groups, suggesting no deterrent effect on quitting. At 12 months quit rates were statistically non‐significantly higher in the computer scheduled group than the selective reduction group (RR 1.86, 95% CI 0.47 to 7.32; 93 participants; Analysis 9.1.2).
An intervention of repeated telephone counselling and mailings was not shown to assist reduction after 12 months relative to a control of health mailings in Glasgow 2009. No indicators of reduction were significantly higher in the intervention than in the control group at 12 months (25% vs 18.6% for 50% or more CPD reduction, 11% versus 7% for abstinence). The proportions reducing CO by more than 50% were also similar across groups at 12 months (14.0% versus 14.1%). When we looked at the overall continuous rates of CPD and CO reduction, both groups had reduced their cigarette consumption (by approximately a quarter of their baseline rate) and CO levels (by approximately a sixth of their baseline rate) on average (Analysis 10.2).
Discusión
Resumen de los resultados principales
Los estudios incluidos en esta revisión evalúan formas para ayudar a los pacientes que fuman a reducir potencialmente el daño causado por el hábito de fumar, ya sea al reducir el número de cigarrillos que fuman (con la ayuda de métodos conductuales para promover el cambio, o mediante productos farmacéuticos, nicotina o productos de tabaco de riesgo reducido como sustitutos parciales, o ambos), o al sustituir plenamente los productos con tabaco regular con opciones de “riesgo‐reducido”.
Los estudios incluidos evaluaron una gama amplia de enfoques en forma de intervenciones para la reducción del daño: tratamiento de reemplazo de nicotina (TRN); bupropión; vareniclina; e‐cigarrillos (e‐cigs); snus; otros productos de tabaco de exposición potencialmente reducida (PREP); asesoramiento conductual sobre la reducción; y un programa computadorizado de reducción del hábito de fumar. Las oportunidades para realizar metanálisis fueron limitadas, aunque hay pruebas de que el TRN tiene un efecto sobre la reducción exitosa del hábito de fumar (reducción del 50%+ de los cigarrillos por día [CPD]) y las tasas de abandono. No hay pruebas suficientes para sugerir si otras intervenciones para la reducción del daño son efectivas para reducir el daño causado por el tabaco. Los ensayos incluidos indican que los pacientes que reciben TRN para reducir el hábito de fumar tienen mayor probabilidad de poder reducir el consumo de cigarrillos que los pacientes que intentan reducirlo con placebo. Todos los ensayos incluyeron un período de seguimiento cuando el TRN ya no se administró, y un ensayo tuvo un seguimiento de 20 meses después del final de la administración del TRN. No hubo pruebas de que el uso de TRN, con el objetivo de ayudar en la reducción, desviara a los pacientes de intentar dejar el hábito, debido a que las tasas de abandono del hábito también fueron mayores en los grupos que recibieron TRN. Mientras las pruebas aportadas por el ensayo apoyan el concepto del uso del TRN para reducir la cantidad de tabaco consumido, y muestran un efecto significativo y un tamaño del efecto clínicamente importante en muchos tratamientos, el beneficio absoluto de este uso del TRN parece ser pequeño. El TRN aumentó el número de participantes con reducciones sostenidas a largo plazo, pero frente a una reducción muy escasa en el grupo control. El tratamiento habitualmente aumentó la proporción de los reductores exitosos de 1 ‐ 3% a 6 ‐ 9%, y no está claro el beneficio en la salud incluso para estas personas.
Algunos de los estudios incluidos permitieron una comparación entre el cambio en los CPD y los cambios en otra medida de exposición al humo del tabaco. Los datos sobre los marcadores del consumo se informaron habitualmente de diferentes formas entre los estudios, lo cual dificulta la producción de cálculos agrupados de los cambios a través de los estudios. Sin embargo, estos estudios confirman que el grado en que los participantes redujeron el consumo de CPD fue habitualmente mayor que la reducción observada en el porcentaje de otras medidas de la exposición al humo del tabaco, como el monóxido de carbono (CO) y la cotinina (Batra 2005; Joksić 2011 Rennard 2006; Wennike 2003; Glasgow 2009). Otra revisión ha estimado que la reducción del nivel de CO es habitualmente alrededor de un tercio menor que la reducción de los CPD (Hughes 2005). Sin embargo, debe observarse que como la lectura del CO inicial en un no fumador habitualmente no es cero, no necesariamente debe esperarse que las reducciones en el porcentaje de CO y CPD se correlacionen directamente entre sí, incluso en ausencia del tabaquismo compensatorio.
Tal como se predijo, los estudios proporcionaron muy poca información sobre los cambios en la salud o los marcadores de la misma. Cuando se informó sobre este hecho, en general no se hicieron comparaciones entre los grupos. Cuando se realizaron, pareció no haber pruebas de beneficios consistentes como resultado de cualquiera de las intervenciones en cuanto a la salud y los marcadores de la salud. El informe sobre los efectos adversos fue limitado, aunque los estudios que informaron sobre los mismos no encontraron nada que ya no se hubiese detectado al utilizar los fármacos evaluados para su indicación más tradicional del abandono del hábito. Lo anterior indica que no hay ningún riesgo adicional de la administración de TRN, bupropión, e‐cigs o vareniclina para la reducción del daño.
Compleción y aplicabilidad general de las pruebas
El área de la reducción del daño ha progresado desde que se publicó la última actualización de esta revisión en 2007 (parcialmente demostrado por la guía NICE sobre la reducción del daño publicada entretanto (NICE 2013). Como resultado, hay un rango mayor de intervenciones centradas en la reducción del daño del tabaco (p.ej. e‐cigs). Estos datos se tuvieron en cuenta y se ampliaron los términos de búsqueda de esta actualización, dando lugar a una búsqueda menos sensible y permitiendo expandir el alcance para obtener estudios relevantes. Como resultado existe seguridad en cuanto a que se han representado los cambios en el área de investigación y se ha encontrado bibliografía disponible relevante. Como se esperaba, se identificaron estudios que evaluaban intervenciones nuevas para esta revisión (p.ej. vareniclina, snus, e‐cigs); sin embargo, en la mayoría de los casos sólo se encontró un estudio para cada intervención, lo cual limita el poder necesario para detectar un efecto, y en consecuencia la solidez de las conclusiones que se pueden extraer, debido a la imprecisión. Por lo tanto, el TRN sigue siendo la única intervención para la cual hubo estudios múltiples y para la que se podrían producir metanálisis. La falta de investigación sobre los enfoques alternativos podría representar la ausencia de efectos observados en la reducción del hábito de fumar y el aumento de las tasas de abstinencia. Los cálculos del efecto con sus intervalos de confianza del 95% correspondientes para las intervenciones de reducción del daño diferentes del TRN se superponen con los de los metanálisis de los estudios del TRN, por lo que es posible que todos los fármacos funcionen de igual manera para apoyar la reducción, aunque la investigación adicional de alta calidad necesitaría evaluar esta presuposición.
El resultado primario que se deseaba estudiar en esta revisión era la salud a largo plazo, y fue imposible hacerlo. Lo anterior habría proporcionado una idea más clara de cualquier beneficio de la reducción del daño para las personas que no logran el abandono del hábito. Algunos estudios midieron los marcadores biológicos del riesgo para la salud, aunque los mismos se midieron habitualmente al momento del seguimiento a corto plazo, de forma inconsistente entre los estudios, y sólo en los participantes que no habían abandonado antes el estudio. En muchos casos las comparaciones se realizaron sólo entre los que habían cambiado con éxito el comportamiento versus los que no, en lugar de a través de los grupos asignados al azar, lo cual hace imposible evaluar los efectos de la intervención en comparación con la condición de control. Sin embargo, el abandono del hábito da lugar a beneficios apreciables en la salud (Anthonisen 2005; Doll 2004), por lo tanto, el anterior todavía era un resultado valioso para evaluar.
Calidad de la evidencia
Para varios dominios del “riesgo de sesgo” entre los estudios, el riesgo de sesgo se consideró incierto, debido a una falta de informe. Por ejemplo, varios ensayos (en particular los del TRN versus placebo) se describieron como "cegados", pero sin detalles completos de cómo se realizó este procedimiento, es decir en quién se realizó el cegamiento y cómo se realizó. En estos casos el sesgo probablemente no es un problema, aunque no es posible tener seguridad. Algunos estudios proporcionaron diferentes ayudas para la reducción del daño o administraron ayudas de forma diferente a través de los grupos de estudio, lo que imposibilitó el cegamiento en los estudios; todos los estudios se consideraron en riesgo alto de sesgo de realización. Otra inquietud importante para la investigación en el área de la reducción del daño es que puede motivar a los que tienen participación en la industria tabacalera a fabricar y evaluar alternativas con “daño‐reducido” al tabaco, para proporcionar una opción al abandono del hábito completa. Todos los estudios que analizaron PREP (incluidos los snus) en esta revisión estuvieron de alguna manera vinculados a la industria tabacalera: Joksić 2011; Mendes 2008; Roethig 2008 y Sarkar 2008 fueron patrocinados por la industria tabacalera. Benowitz 2012 no, pero los cigarrillos de la prueba fueron provistos directamente por la industria tabacalera.
Se planificó evaluar la calidad de las pruebas que contribuyeron con los resultados del estado de salud a largo plazo mediante el enfoque GRADE (GRADE 2012). Sin embargo fue imposible debido a que ningún estudio informó este resultado. Debido a que el abandono del hábito es el único resultado que se sabe que puede usarse como una medida exacta de la reducción del daño, se ha usado el enfoque GRADE para evaluar la calidad de las pruebas que contribuyen a la comparación principal para cada ayuda a la reducción del daño (Tabla 1 de resumen de los hallazgos). En la mayoría de los casos las pruebas se calificaron como de calidad “baja”, y en algunos casos (cigarrillos con bajo nivel de nicotina versus cigarrillos regulares; asesoramiento conductual sobre la reducción versus correos sobre la salud) “muy baja”. A través de todos los resultados lo anterior se debió a la imprecisión, es decir un número pequeño de estudios, lo cual dio lugar a un número pequeño de eventos y a intervalos de confianza amplios alrededor del tamaño del efecto. En el caso del resultado del abandono del hábito con cigarrillos con bajo nivel de nicotina versus cigarrillos regulares lo anterior también se debió al hecho de que los tratamientos del estudio no fueron cegados, lo cual resultó en la posibilidad de sesgo de detección, y en que hubo tasas diferenciales de abandonos de los participantes entre los grupos de estudio. En el caso del resultado del abandono del hábito con asesoramiento conductual sobre la reducción versus correos sobre la salud también se disminuyó la calidad de las pruebas debido a la imposibilidad para generalizar las pruebas. El único estudio que investigaba esta comparación se realizó en una población muy específica (personas en espera de una intervención quirúrgica), por lo tanto los resultados pueden no ser aplicables a la población en general.
Acuerdos y desacuerdos con otros estudios o revisiones
La bibliografía que investiga los posibles beneficios en la salud de las intervenciones dirigidas a reducir el comportamiento del hábito de fumar es muy conflictiva y no fue posible establecer ninguna conclusión clara (Begh 2015; Hughes 2006; Tverdal 2006), lo cual da lugar a que no se conozca el beneficio general sobre la salud pública. Lamentablemente, los datos sobre los marcadores biológicos de la salud examinados aquí no resuelven estos problemas. Este hecho en gran parte se debe al diseño y al informe de los estudios, que podrían mejorarse en la investigación futura.
Una revisión anterior del uso de PREP específicamente para reducir el daño concluyó que "no hay pruebas para sugerir que hay una reducción suficiente de la exposición a la toxina del tabaco con alguno de los PREP existentes para esperar una reducción significativa en el riesgo de enfermedades, ni se conoce el grado de la reducción de la exposición a la toxina que es necesario para dar lugar a una reducción de la enfermedad" (UMN TTURC 2005). Debe destacarse que algunos participantes que utilizaron algunos tipos de PREP tuvieron niveles más altos de CO de los que presentaban cuando fumaban normalmente (por ejemplo, Fagerström 2000; Fagerström 2002b; Rennard 2002; Strasser 2007). Este hecho puede deberse a que los fumadores sobrestiman el “riesgo reducido” de los PREP y lo compensan fumando más conscientemente, o a que los fumadores que usan PREP están en abstinencia del componente del PREP que se ha reducido y están aumentando el consumo de cigarrillos para compensarlo.
Además de los beneficios directos en la salud que podrían lograrse al reducir el hábito de fumar y los componentes perjudiciales de los cigarrillos, las intervenciones para la reducción del daño podrían mejorar la salud pública al dar lugar en último término a mayores tasas de abandono del hábito a largo plazo. Las pruebas limitadas significan que lo anterior actualmente es difícil de evaluar a través de las intervenciones para la reducción de daño; sin embargo, el grupo combinado de estudios que comparan el TRN con placebo en adultos proporciona apoyo a esta hipótesis. Lo anterior puede ocurrir debido a que la reducción del hábito de fumar actúa como un mediador del efecto de las intervenciones para la reducción del daño sobre el abandono del hábito. La revisión también halló que los estudios que comparaban el TRN con placebo demostraron una asociación positiva entre la reducción exitosa y la intervención. Las revisiones de Hughes 2006 y Asfar 2011 que también investigaron la asociación entre la reducción y el abandono del hábito, han encontrado que las dos están vinculados positivamente. Sin embargo, en Asfar 2011 (que, como en esta revisión, sólo consideró los estudios de fumadores renuentes o incapaces de dejar el hábito) este fue sólo el caso cuando las intervenciones incluían farmacoterapia para ayudar en la reducción; las pruebas fueron no concluyentes para las intervenciones que ofrecían sólo apoyo conductual.
Se ha encontrado que el TRN, el bupropión, la vareniclina y las intervenciones conductuales de "reducir‐hasta‐dejar" son intervenciones efectivas para el abandono del hábito en los fumadores que desean dejar el hábito (Cahill 2016; Hughes 2014; Lindson‐Hawley 2012; Stead 2012). Las pruebas sobre los e‐cigs como una ayuda para el abandono del hábito son dispersas, aunque los dos ensayos controlados aleatorios incluidos en la revisión Cochrane sobre el tema indican que también tienen un efecto favorable sobre el abandono del hábito (Hartmann‐Boyce 2016).
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Forest plot of comparison: 1 Nicotine replacement therapy to assist smoking reduction versus placebo, outcome: 1.1 Reduction in cigarettes/day of > 50% of baseline or cessation.
Forest plot of comparison: 1 Nicotine replacement therapy to assist smoking reduction versus placebo, outcome: 1.2 Cessation at long‐term follow‐up (subgroups by type of NRT).
Comparison 1 Nicotine replacement therapy to assist smoking reduction versus placebo, Outcome 1 Reduction in cigarettes/day of > 50% of baseline or cessation.
Comparison 1 Nicotine replacement therapy to assist smoking reduction versus placebo, Outcome 2 Cessation at long‐term follow‐up (subgroups by type of NRT).
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Australia NNCG‐017 | Not reported | Not reported | At 12m reductions from baseline of > 50% as verified by reduction in CO Nicotine gum group 3/218 (1.4%); placebo group 2/218 (0.9%) (NS) | ‐ |
| Batra 2005 | At 13m % reductions from baseline for attenders including quitters: (n, mean, SD) | As for CPD/CO based on attenders with data, including quitters | At 13m % reductions from baseline for attenders including quitters: (n, mean, SD) CO active 55, 43.1% (39.3%); placebo 39, 27.1% (40.5%) Sustained CO reduction > 20% at 13m; active 13.6%, placebo 5.6% | ‐ |
| Bolliger 2000 | As % of baseline value reported for participants still using inhalers every day at 18m: (n, mean, SD) Intervention 22, 36.2% (29.6%); placebo 8, 67.2% (27.8%) (P = 0.02) Among successful reducers (n = 25; 19 intervention, 6 control), mean (SD) CPD at 24m: 5.0 (6.4), entire placebo group 18.2 (11.2) | Among successful reducers (n = 25; 19 intervention, 6 control), mean (SD) cotinine (ng/ml) at 24m: 139 (167), entire placebo group 325 (163) (P < 0.05) | As % of baseline value reported for participants still using inhalers every day at 18m: (n, mean, SD) Intervention 22, 71.0% (58.8%); placebo 8, 81.7% (41.1%) (NS) Among successful reducers (n = 25; 19 intervention, 6 control), mean (SD) CO (ppm) at 24m: successful reducers 10.0 (8.5), entire placebo group 20.6 (11.2) | ‐ |
| Etter 2004 | After 26m the mean absolute reduction (ITT) in CPD was 9.8 for nicotine, 7.7 for placebo & control. Median reduction 7.5 vs 5.0. | Not reported | Not reported | ‐ |
| Hanson 2008 | Mean CPD at baseline; end of treatment; 3m; 6m: Nicotine patch: 11.1; 5.0; 6.1; 8.9 Nicotine gum: 12.7; 6.0; 7.6; 9.3 Placebo: 11.6; 5.4; 4.6; 7.8 Reduction in all groups from baseline (P < 0.0001) but difference between groups not statistically significant | Mean cotinine (ng/ml) at baseline; end of treatment; 3m; 6m: Nicotine patch: 3476; 3464; 3264; 4660 Nicotine gum: 3759; 3946; 2718; 4346 Placebo: 3072; 2505; 2734; 3949 Difference between groups not statistically significant | Mean CO (ppm) at baseline; end of treatment; 3m; 6m: Nicotine patch: 7.1; 5.2; 7.6; 8.7 Nicotine gum: 6.9; 6.7; 7.9; 9.1 Placebo: 5.7; 5.1; 5.4; 6.0 Significant interaction between treatment group and follow‐up visit reported, with higher CO in nicotine gum than nicotine patch group in third week of follow‐up (P = 0.05). | Mean total NNAL (pmol/mg) at baseline; end of treatment: Nicotine patch: 0.66; 0.65 Nicotine gum: 0.79; 0.87 Placebo: 0.54; 0.76 Difference between groups not statistically significant |
| Haustein 2003 | CPD not reported as a continuous variable | Between‐study group differences are not supplied. Comparisons were made between reducers (50%+ CPD) and non‐reducers (< 50% CPD), and reducers had a significantly greater reduction in plasma cotinine and plasma thiocyanate between baseline and 12m follow‐up reducers and non‐reducers experienced a significant reduction in plasma cotinine, whereas only reducers experienced a significant reduction in plasma thiocyanate) | Between‐study group differences are not supplied. Measures of CO reduction generally matched levels of CPD reduction i.e. those participants who reduced CPD by 50% ‐ 74% reduced their CO by a mean of 51%, those who reduced CPD by 25% ‐ 49% reduced their CO by a mean of 32.6% and those who reduced CPD by 0% ‐ 24% reduced their CO by a mean of 25.4% | ‐ |
| Kralikova 2009 | Not reported | Significant reduction in plasma cotinine in abstainers at 4m and 12m, and in reducers at 4m (mean at 12m: abstainers 40ng/mL, reducers 216, failures 271) | Significant reduction in CO in abstainers and reducers at 4m and 12m, and in failures at 12m, with larger reduction from baseline in abstainers and reducers (mean at 12m: abstainers 2.7 ppm, reducers 11.7, failures 17.2) | ‐ |
| Rennard 2006 | Amongst successful reducers at 4m (reduction in daily smoking of at least 50% from baseline) the reduction in average CPD was 74% in both active (mean dropped from 29.1 to 7.6) and placebo (31.9 to 8.1) groups. In all participants, reduction in average CPD at 24m was 14.6% in active group and 12.2% in placebo group | Reduction from baseline in cotinine and thiocyanate in both active and placebo groups. Levels fell by more in ≥ 50% reducers at 4 months than in non‐reducers | Amongst sustained reducers at 15m, reducers of 50% to < 75% reduced their average CO by 8.3 ppm. Reducers of > 75% (incl quitters) reduced average CO by 25.2 ppm | No differences across treatment groups in any markers. Exploratory analyses of successful reducers at 4m showed significant change from baseline in HDL but no other markers |
| Wennike 2003 | At 24m based on remaining participants no differences between active and placebo. CPD 54% vs 61% of baseline (P = 0.2). At 4m effect size was similar (56% vs 67%) and statistically significant (P = 0.03) | At 24m based on remaining participants no differences between active and placebo. | At 24m based on remaining participants no differences between active and placebo. CO 63% vs 76% of baseline (P = 0.1). At 4m effect size was similar (71% vs 84%) and statistically significant (P = 0.01) | ‐ |
Comparison 1 Nicotine replacement therapy to assist smoking reduction versus placebo, Outcome 3 Other outcomes ‐ consumption markers.
| Study | Lipoproteins | Haematological markers | Pulmonary function | Quality of life | Other health markers |
| Batra 2005 | Not reported | No statistically significant change in any cardiovascular risk markers (WBC, fibrinogen, CRP) between baseline and month 12 in the 20 successful sustained reducers/abstainers | Not reported | Not reported | Not reported |
| Bolliger 2000 | Comparison between 25 (19 active, 6 placebo) sustained reducers and 285 non‐reducers at 24m. Both groups had statistically significant reduction from baseline in total cholesterol/HDL ratio and LDL and increase from baseline in HDL. Placebo group also had statistically significant reduction in total cholesterol. Difference between groups statistically significant only for total cholesterol/HDL ratio, with greater reduction in reducers | Comparison between 25 (19 active, 6 placebo) sustained reducers and 285 non‐reducers at 24m. Both groups had statistically significant reduction from baseline in haemoglobin and haematocrit. Placebo group also had statistically significant increase in fibrinogen and WBC. Difference between groups statistically significant only for haemoglobin, with greater reduction in reducers | Comparison between 25 (19 active, 6 placebo) sustained reducers and 285 non‐reducers at 24m. Both groups had statistically significant reduction from baseline in FEV1 but not FVC. Difference between groups statistically significant only for FEV1, with greater reduction in reducers | Comparison between 25 (19 active, 6 placebo) sustained reducers and 285 non‐reducers at 24m. Both groups had statistically significant increase from baseline in general health, physical functioning and emotional well‐being. Placebo group additionally had statistically significant increase in energy. Difference between groups statistically significant only for general health, with greater increase in reducers | Comparison between 25 (19 active, 6 placebo) sustained reducers and 285 non‐reducers at 24m. Both groups had statistically significant reduction from baseline for SBP but not pulse rate or DBP. Weight increased in female reducers and in both sexes in placebo group. Difference between groups statistically significant only for pulse rate (greater reduction in reducers) and female weight (greater increase in reducers) |
| Etter 2004 | Not reported | Not reported | Not reported | Not reported | Average weight gain across all 3 groups over 60m was 2.4 kg (no significant difference between groups). Greater weight gain for successful quitters than for smokers was observed for men (mean 6 kg vs 2.2 kg) but not for women (mean 2.8 kg vs 2.1 kg) |
| Haustein 2003 | In those participants who successfully reduced their smoking by 50% or more there was a 0.75% increase in HDL(‐0.41 mg/dL change, N = 23), a 6.3% decrease in LDL (‐8.30 mg/dL change, N = 22), a 4.2% decrease in cholesterol and a 28.2% increases in triglycerides between baseline and 12m follow‐up. For the cholesterol and triglyceride measures a comparison was also made between reducers and non‐reducers and there was no between‐group significant differences in the changes found between baseline and 12m follow‐up | In those participants who successfully reduced their smoking by 50% or more there was a 10.3% decrease in WBC (‐0.85 109/L change, N = 24), a 10.4% decrease in fibrinogen (‐35.1 mg/dL change, N = 24) and 42.6% decrease in CRP (‐0.26 mg/dL change, N = 24) between baseline and 12m follow‐up. There was a 4.1% reduction in RBC, a 1.9% reduction in platelets, and a 4.5% decrease in haemoglobin. On these measures a comparison was made between reducers and non‐reducers and there was no between‐group significant differences in the changes found between baseline and 12m follow‐up | Not reported | In those participants who had reduced their smoking by 50%+ at 12m significant improvements were observed in 10 of 14 QOL items on a rating scale (anxiety, cognitive function, emotional well‐being, energy, general health, pain, physical functioning, self control, social interaction, worry) | After 12m the mean SBP, DBP and pulse rate were unchanged in both reducers and non‐reducers compared to baseline. At 1 year the 24 successful reducers (50%+) had gained a mean of 3.49 kg compared to a mean weight gain of 1.14 kg in the non‐reducers (P = 0.019) |
| Kralikova 2009 | Not reported | No significant changes in WBC amongst reducers | Not reported | Not reported | Not reported |
| Rennard 2006 | Reducers at 4m had a statistically significant increase from baseline in HDL (mean change 2.11 mg/dl, P = 0.003) and decrease in WBC (‐0.34 × 109/l, P = 0.03). No significant change in LDL (‐5.76 mg/dl, P = 0.23) | Reducers at 4m had a statistically significant decrease from baseline in CRP (mean change ‐0.09 mg/dl, P = 0.04) and no significant change in fibrinogen (‐18.6 mg/dl, P = 0.15) | Not reported | Greatest improvements in cough, phlegm, shortness of breath, and senses of smell and taste were observed in those who reduced consumption by ≥ 50% from baseline. These participants also reported significantly greater improvements in self‐control (P < 0.001), with no difference in other quality of life outcomes | Average weight gain among 20 participants who had quit smoking at 15m was 5.0 kg (P < 0.001 compared to those who did not quit, for whom there was no significant weight change) |
Comparison 1 Nicotine replacement therapy to assist smoking reduction versus placebo, Outcome 4 Other outcomes ‐ health markers.
Comparison 2 NRT combined with counselling to assist smoking reduction versus brief cessation advice, Outcome 1 Reduction in cigarettes/day of > 50% of baseline or cessation.
Comparison 2 NRT combined with counselling to assist smoking reduction versus brief cessation advice, Outcome 2 Cessation at long‐term follow‐up.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Chan 2011 | Among non‐quitters, CPD at 6m was significantly lower in the combined intervention group (mean (SD) 9.5 (8.4)) than in the control group (13.1 (9.3)) (P < 0.001) | Urinary cotinine only reported as a validation measure for self‐reported quitters | Difference in CO at 6m not statistically significant (mean (SD) 7.6 (9.3) in combined intervention group, 5.2 (10.7) in control group, P = 0.30) | ‐ |
| Joseph 2008 | Reductions in CPD similar in both groups; decreasing from ˜27 CPD at baseline to ˜18 CPD at 18m, but with considerable variation between individuals | Urinary cotinine: no significant difference between groups in reduction from baseline | CO (ppm) reduction in both groups (Smoking reduction group mean 24 (baseline) to 16 (18m); Usual care group mean 25 (baseline) to 18 (18m)), no significant difference (P = 0.155) | Change from baseline in nicotine, total NNAL and 1‐OHP was similar in both treatment groups |
Comparison 2 NRT combined with counselling to assist smoking reduction versus brief cessation advice, Outcome 3 Other outcomes ‐ consumption markers.
| Study | Lipoproteins | Haematological markers | Pulmonary function | Quality of life | Other health markers |
| Joseph 2008 | Not reported | Markers of inflammation and oxidation including WBC count, hs‐CRP and F2‐isoprostanes showed minimal change from baseline or between groups. Change from baseline in fibrinogen differed between groups (P = 0.019) but effect size was small (Smoking reduction group: mean 383 mg/dL at baseline, 367 at 18m; Usual care group: 384 at baseline, 352 at 18m) | Not reported | No differences between groups in quality of life at any time point | No differences between groups in frequency of angina at any time point |
Comparison 2 NRT combined with counselling to assist smoking reduction versus brief cessation advice, Outcome 4 Other outcomes ‐ health markers.
Comparison 3 Nicotine patches versus placebo for temporary abstinence, Outcome 1 Cessation at long‐term follow‐up.
Comparison 4 Bupropion to assist smoking reduction versus placebo, Outcome 1 Outcomes at long‐term follow‐up.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Hatsukami 2004a | Reduction in mean CPD from baseline to 3m: Bupropion group 6.5, placebo group 6.3. Proportion with 50% reduction in CPD from baseline statistically significant at 6m (16% vs 9%, P = 0.02) but not at 3m (28% vs 17%, P = 0.41) or 12m (5% vs 7%, P = 0.55) | In ITT analysis, mean urinary cotinine decrease from baseline greater in bupropion group than in placebo group (mean decrease approximately 340 ng/ml vs 130 ng/ml, P = 0.008) but difference at 12m not statistically significant (mean decrease 82 ng/mL vs 28 ng/ml, P = 0.25). Similar conclusion for % of participants achieving 50% reduction in urine cotinine | Not reported | ‐ |
Comparison 4 Bupropion to assist smoking reduction versus placebo, Outcome 2 Other outcomes ‐ consumption markers.
Comparison 5 Varenicline to assist smoking reduction versus placebo, Outcome 1 Outcomes at long‐term follow‐up.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Hughes 2011 | Reduction in CPD was higher in varenicline group than in control group (reduction from baseline 5.8 (29%) vs 3.2 (17%), P = 0.003) | Not reported | Not reported | ‐ |
Comparison 5 Varenicline to assist smoking reduction versus placebo, Outcome 2 Other outcomes ‐ consumption markers.
Comparison 6 Ecigarettes to assist smoking reduction versus placebo, Outcome 1 Outcomes at long‐term follow‐up.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Caponnetto 2013 | Significant differences in CPD between groups (with higher CPD in the no‐nicotine group) were reported at 2, 6 and 8 wks, but not at other intermediate time points, nor at the end of the study (52 wks, median CPD 12 ‐ 14 in all groups) | Saliva cotinine levels at wk 6 and wk 12 were near zero in the no‐nicotine group, and not significantly different between the other 2 study groups (median (ng/ml) 42.5 (wk 6) and 91.0 (wk 12) in the 7.2 mg nicotine group; 67.8 (wk 6) and 69.8 (wk 12) in the 5.4 mg nicotine group) | Significant difference in CO between groups was reported at wk 6 (P = 0.01) but at none of the other 7 time points during follow‐up (at 52 wks, median CO was 15 ‐ 17 ppm in all groups) | ‐ |
Comparison 6 Ecigarettes to assist smoking reduction versus placebo, Outcome 2 Other outcomes ‐ consumption markers.
| Study | Lipoproteins | Haematological markers | Pulmonary function | Quality of life | Other health markers |
| Caponnetto 2013 | Not reported | Not reported | No significant changes in resting heart rate, SBP or DBP over time or between groups | Not reported | No significant changes in weight over time or between groups |
Comparison 6 Ecigarettes to assist smoking reduction versus placebo, Outcome 3 Other outcomes ‐ health markers.
Comparison 7 Snus to reduce and replace smoking versus placebo, Outcome 1 Outcomes at long‐term follow‐up.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Joksić 2011 | At 48 wks, CPD had decreased to around ⅓ of baseline in each group (mean 7.6 (snus group), 8.6 (placebo group)), difference between groups not statistically significant | Reduction from baseline in plasma cotinine was similar in both groups (snus group: mean 98.9 ng/ml (baseline), 66.1 (48 wks); placebo group: 101.2 (baseline), 69.1 (48 wks)) | Reduction from baseline in exhaled CO was similar in both groups (snus group: mean 23.5 ppm (baseline), 11.5 (48 wks); placebo group: 23.5 (baseline), 12.1 (48 wks)) | ‐ |
Comparison 7 Snus to reduce and replace smoking versus placebo, Outcome 2 Other outcomes ‐ consumption markers.
| Study | Lipoproteins | Haematological markers | Pulmonary function | Quality of life | Other health markers |
| Joksić 2011 | No changes in total, LDL or HDL cholesterol over time or differences between groups. | No changes in WBC, CRP or fibrinogen over time or differences between groups. | No changes in FEV1.0, FVC or FEV% over time or differences between groups. | Not reported | No changes in SBP, DBP, weight or BMI over time or differences between groups. |
Comparison 7 Snus to reduce and replace smoking versus placebo, Outcome 3 Other outcomes ‐ health markers.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Benowitz 2012 | Small but statistically significant differences between control and reduced‐nicotine groups in change in CPD from baseline to 26 wks, and from 14 wks to 26 wks (mean CPD: control 19 (baseline), 21 (14 wks), 22 (26 wks); reduced‐nicotine 22 (baseline), 24 (14 wks), 20 (26 wks)) | For plasma cotinine, larger reductions from baseline to 14 wks and 26 wks follow‐up in reduced‐nicotine group (mean (ng/ml) 256 (baseline), 240 (26 wks)) than in control group (mean 256 (baseline), 113 (26 wks)) (P < 0.001), with greatest decline in the reduced‐nicotine group occurring between 6 and 18 wks | No differences between groups at any time point (mean CO (ppm): control 20 (baseline), 24 (14 wks), 20 (26 wks); reduced‐nicotine 21 (baseline), 25 (14 wks), 23 (26 wks)) | Pattern of plasma nicotine was similar to that seen for cotinine (greater decline in reduced‐nicotine group than in control group). Significantly greater reduction between 14 wks and 26 wks in reduced‐nicotine group than in control group. No difference between groups in sum of phens, 2‐naphthol, sum of fluors or 1‐hydroxypyrene |
| Mendes 2008 | Mean CPD at baseline; short‐term phase; long‐term phase: MFF group: 19.7; "between 19.1 and 19.7"; 26.3 ML group: 20.3; "between 20.0 and 20.5"; 26.8 MUL group: 19.8; "between 18.6 and 19.8"; 30.3 | Statistically significantly lower during the short‐term phase in MUL group (mean 230 ng/mL) than in MFF group. No difference between ML group and MFF group | Not reported | Mean urine nicotine equivalents over the whole study was lower in MUL group (mean 13.1 mg/24 hrs) in MFF group (16.8) (P = 0.02) but similar between MFF group and ML group (15.4) (P = 0.76). A similar pattern was observed in the short‐term phase (first 8 days), when levels were slightly higher in all groups. Overall urine total NNAL was lower in MUL group than in MFF group in the short‐term phase (P = 0.05); differences in long‐term phase not significant. Urine total 1‐OHP lower in MUL group than in MFF group during both phases. Urine mutagenicity: differences between groups not significant. COHb tended to be lowest in MUL group and highest in ML group. Some evidence that urine S‐PMA was lower in MUL group than MFF group in long‐term phase (P = 0.05). 3‐HPMA decreased from baseline in all groups. Mean values of the Fagerström Test for Nicotine Dependence "were between 5.4 and 5.8 on a scale of 0–9 and did not change during the study". |
| Roethig 2008 | Mean CPD increased from 24.3 (baseline) to 63.4 (52 wks) in EHCSS group (a 95% increase) and from 23.3 (baseline) to 36.6 in CC group (a 27% increase) (P < 0.001 for difference between groups) | Over 12m, mean plasma cotinine decreased by 16% in EHCSS group and increased by 5% in CC group (P = 0.018) | Not reported | Over 12m, urine nicotine equivalents decreased by 18% in EHCSS group and increased by 0.1% in CC group (P = 0.014). Also greater and statistically significant reductions in the EHCSS group than in the CC group in total NNAL, total 1‐OHP, urine mutagenicity, 4‐ABP Hb adducts, COHb AUC(7 ‐ 23 hrs) and 3‐HPMA (all P < 0.001) |
| Sarkar 2008 | In different study groups, mean CPD was between 17.5 and 19.1 at baseline and increased to between 24.6 and 35.1 at 24 wks (differences between groups not statistically significant) | Not reported | Not reported | For most time points in both short‐ and long‐term follow‐up, MHBMA, 3‐HPMA and S‐PMA were all statistically significantly lower in the test cigarette groups than in the conventional cigarette groups. At most follow‐up times, differences between groups in nicotine equivalents, total NNAL, total 1‐OHP were not statistically significant |
Comparison 8 PREPs to assist smoking reduction versus smoking as usual, Outcome 1 Other outcomes ‐ consumption markers.
Comparison 8 PREPs to assist smoking reduction versus smoking as usual, Outcome 2 Cessation at long‐term follow‐up.
| Study | Lipoproteins | Haematological markers | Pulmonary function | Quality of life | Other health markers |
| Benowitz 2012 | No significant changes in any group for HDL cholesterol | No significant changes in any group for WBC, haemoglobin or fibrinogen | Not reported | Not reported | Average weight gain among compliant smokers in the reduced nicotine group was 2 kg (statistically significant), but no difference between control and reduced‐nicotine group overall. No significant changes in any group for blood pressure or |
| Roethig 2008 | Greater % increase for HDL cholesterol in EHCSS group than in CC group (P = 0.008), Differences between groups in LDL cholesterol not statistically significant | % reduction from baseline to 12m was greater in EHCSS group than in CC group for haemoglobin, haematocrit, RBC, WBC, neutrophils, lymphocytes and urine 11‐dehydrothromboxane B2 (P < 0.02 in each case). DIfferences between groups in CRP, fibrinogen and urine 8‐epi‐prostaglandin F2α not statistically significant | Not reported | Not reported | Not reported |
| Sarkar 2008 | Differences between groups in HDL cholesterol, LDL cholesterol and triglycerides not statistically significant | Differences between groups in urine microalbumin, 11‐dehydrothromboxane B2, 8‐epi‐prostaglandin F2α, fibrinogen, von Willebrand factor and CRP not statistically significant, with the exception of urine microalbumin in a single group | Not reported | Not reported | Not reported |
Comparison 8 PREPs to assist smoking reduction versus smoking as usual, Outcome 3 Other outcomes ‐ health markers.
Comparison 9 Computerized programme to assist smoking reduction versus self‐help reduction guide, Outcome 1 Outcomes at long‐term follow‐up.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Riley 2002 | A mean reduction of approximately 10 CPD between pretreatment to post‐treatment in both groups, which was essentially maintained over 1 year. Differences in % reduction from pre‐treatment to 6m (N = 60; 32% for CSGR; 25% for SER) and to 12m (N = 57; 38% for CSGR; 35% for SER) were not significant | Not reported | Overall reduction in mean CO from 22.6 to 19.6 ppm (P < 0.01) from pre‐ to post‐treatment, but no significant effect of treatment | |
Comparison 9 Computerized programme to assist smoking reduction versus self‐help reduction guide, Outcome 2 Other outcomes ‐ consumption markers.
Comparison 10 Behavioural reduction advice to assist smoking reduction versus health mailings, Outcome 1 Outcomes at long‐term follow‐up.
| Study | CPD | Cotinine/Thiocyanate | CO | Other consumption markers |
| Glasgow 2009 | No difference between groups in CPD at 3m (Intervention mean (SD) 17.2 (9.6); Control 17.3 (8.7)) or at 12m (15.8 (10.3); 15.3 (9.2)), but both groups had showed "modest change from baseline" (21.2 (9.4); 20.1 (8.9)) | Not reported | Mean (SD) CO levels At baseline: Intervention (n = 164) 29.8 (13.9); Control (n = 156) 29.8 (14.5) At 12m: Intervention (n = 164) 24.9 (14.0); Control (n = 156) 24.3 (13.8). No significant between‐group difference in the change from baseline | ‐ |
Comparison 10 Behavioural reduction advice to assist smoking reduction versus health mailings, Outcome 2 Other outcomes ‐ consumption markers.
| Interventions to reduce the harms caused by continued smoking | ||||||
| Patient or population: Smokers who cannot or do not want to quit smoking | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Quality of the evidence | Comments | |
| Risk with control | Risk with harm reduction aid | |||||
| Long‐term change in health status | We found no studies that reported this primary outcome | Not applicable | (0 RCTs) | Not applicable | ||
| Cessation: NRT vs placebo | Study population | RR 1.87 | 3081 | ⊕⊕⊝⊝ | ||
| 5 per 100 | 10 per 100 | |||||
| Cessation: Bupropion vs. placebo | Study population | RR 1.27 | 594 | ⊕⊕⊝⊝ | ||
| 5 per 100 | 7 per 100 | |||||
| Cessation: Varenicline vs placebo | Study population | RR 1.95 | 218 | ⊕⊕⊝⊝ | ||
| 7 per 100 | 14 per 100 | |||||
| Cessation: Ecigs vs placebo | Study population | RR 2.75 | 300 | ⊕⊕⊝⊝ | ||
| 4 per 100 | 11 per 100 | |||||
| Cessation: Snus vs placebo | Study population | RR 3.06 | 319 | ⊕⊕⊝⊝ | ||
| 2 per 100 | 6 per 100 | |||||
| Cessation: Low‐nicotine cigarettes vs regular cigarettes | Study population | RR 1.38 | 135 | ⊕⊝⊝⊝ | ||
| 2 per 100 | 3 per 100 | |||||
| Cessation: Behavioural reduction advice vs health mailings | Study population | RR 1.49 | 320 | ⊕⊝⊝⊝ | ||
| 4 per 100 | 7 per 100 | |||||
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded two levels due to imprecision. Small number of events (< 300), and wide confidence intervals. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Reduction in cigarettes/day of > 50% of baseline or cessation Show forest plot | 8 | 3081 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [1.44, 2.13] |
| 1.1 Choice of NRT type versus placebo | 2 | 848 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [1.11, 1.75] |
| 1.2 Nicotine gum versus placebo | 4 | 1404 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.50 [1.57, 4.00] |
| 1.3 Nicotine inhaler versus placebo | 2 | 829 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.39 [1.70, 6.77] |
| 2 Cessation at long‐term follow‐up (subgroups by type of NRT) Show forest plot | 8 | 3081 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.87 [1.43, 2.44] |
| 2.1 Choice of NRT type versus placebo | 2 | 848 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [1.04, 2.33] |
| 2.2 Nicotine gum versus placebo | 4 | 1404 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.38 [1.46, 3.89] |
| 2.3 Nicotine inhaler versus placebo | 2 | 829 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.90 [1.13, 3.20] |
| 3 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| 4 Other outcomes ‐ health markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Reduction in cigarettes/day of > 50% of baseline or cessation Show forest plot | 2 | 1306 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [1.26, 2.43] |
| 1.1 Nicotine gum, or patch, combined with counselling | 2 | 1306 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.75 [1.26, 2.43] |
| 2 Cessation at long‐term follow‐up Show forest plot | 2 | 1306 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.89, 2.50] |
| 2.1 Nicotine gum, or patch, combined with counselling | 2 | 1306 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.49 [0.89, 2.50] |
| 3 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| 4 Other outcomes ‐ health markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Cessation at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Outcomes at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Reduction in cigarettes/day of > 50% of baseline or cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Outcomes at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Outcomes at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Reduction in cigarettes/day of > 50% of baseline or cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| 3 Other outcomes ‐ health markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Outcomes at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Reduction in cigarettes/day of > 50% of baseline or cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| 3 Other outcomes ‐ health markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| 2 Cessation at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3 Other outcomes ‐ health markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Outcomes at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Reduction in cigarettes/day of > 50% of baseline or cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Outcomes at long‐term follow‐up Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 1.1 Reduction in cigarettes/day of > 50% of baseline or cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Cessation | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Other outcomes ‐ consumption markers Show forest plot | Other data | No numeric data | ||
