Enjuague bucal con clorhexidina como tratamiento adyuvante para la salud gingival
Resumen
Antecedentes
La gingivitis asociada con la placa dental es un trastorno inflamatorio reversible causado por la acumulación y la persistencia de biocapas microbianas (placa dental) en los dientes. Se caracteriza por el enrojecimiento y la inflamación del gingivae (encías) y una tendencia a que el gingivae sangre fácilmente. En los individuos susceptibles, la gingivitis puede dar lugar a la periodontitis y a la pérdida de las partes blandas y del soporte óseo para el diente. Se cree que el enjuague bucal con clorhexidina puede reducir la acumulación de placa y de ese modo reducir la gingivitis.
Objetivos
Evaluar la efectividad de enjuague bucal con clorhexidina usado como un complemento de los procedimientos mecánicos de higiene bucodental para el control de la gingivitis y la placa en comparación con los procedimientos mecánicos de higiene bucodental solos o los procedimientos mecánicos de higiene bucodental más placebo/enjuague bucal de control. Los procedimientos mecánicos de higiene bucodental fueron el cepillado de dientes con/sin hilo dental o la ayuda a la limpieza interdental y podían incluir la limpieza de los dientes por parte de profesionales / tratamiento periodóntico.
Determinar si el efecto del enjuague bucal con clorhexidina está influido por la concentración de clorhexidina, o la frecuencia del enjuague (una vez al día versus dos veces al día).
Informar y describir cualquier efecto adverso asociado con el uso de enjuague bucal con clorhexidina a partir de los ensayos incluidos.
Métodos de búsqueda
El especialista en información del Grupo Cochrane de Salud Oral (Cochrane Oral Health's Information Specialist) buscó en las siguientes bases de datos: Registro de ensayos del Grupo Cochrane de Salud Oral (Cochrane Oral Health Group) (hasta el 28 septiembre 2016); Registro Cochrane Central de Ensayos Controlados (Cochrane Central Register of Controlled Trials (CENTRAL; 2016, número 8) en la Cochrane Library (búsqueda 28 septiembre 2016); MEDLINE Ovid (1946 hasta 28 septiembre 2016); Embase Ovid (1980 hasta 28 septiembre 2016); y en CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 hasta 28 septiembre 2016). Se hicieron búsquedas de ensayos en curso en ClinicalTrials.gov y en la World Health Organization International Clinical Trials Registry Platform. No se impusieron restricciones de idioma ni fecha de publicación en la búsqueda en las bases de datos electrónicas.
Criterios de selección
Se incluyeron ensayos controlados aleatorios que evaluaban los efectos del enjuague bucal con clorhexidina usado como un complemento de los procedimientos mecánicos de higiene bucodental durante al menos cuatro semanas en niños y adultos con gingivitis. Los procedimientos mecánicos de higiene bucodental fueron el cepillado de los dientes con/sin uso de hilo dental o ayudas de limpieza interdental y podían incluir limpieza de los dientes por parte de profesionales / tratamiento periodóntico. Se incluyeron ensayos en los que los participantes tenían gingivitis o periodontitis, en los que los participantes eran sanos y en los que algunos o todos los participantes presentaban trastornos médicos o necesidades de atención especiales.
Obtención y análisis de los datos
Dos autores de la revisión, de forma independiente, examinaron los resultados de la búsqueda, extrajeron los datos y evaluaron el riesgo de sesgo de los estudios incluidos. Cuando fue posible, se intentó establecer contacto con los autores de los estudios para obtener los datos faltantes o aclaraciones. Para los resultados continuos, se utilizaron las medias y las desviaciones estándar para obtener la diferencia de medias (DM) y el intervalo de confianza (IC) del 95%. Se combinaron las DM cuando los estudios usaban la misma escala y las diferencias de medias estandarizadas (SME) cuando los estudios usaban diferentes escalas. Para los resultados dicotómicos, se informaron los cocientes de riesgos (CR) y los IC del 95%. Debido a la heterogeneidad prevista se utilizaron los modelos de efectos aleatorios para todos los metanálisis.
Resultados principales
Se incluyeron 51 estudios que analizaron un total de 5345 participantes. Un estudio se evaluó como en riesgo poco claro de sesgo, y los 50 restantes como en alto riesgo de sesgo, sin embargo, este hecho no afectó la calidad de las evaluaciones para la gingivitis y la placa debido a que se cree que es muy improbable que la investigación adicional cambie la confianza en el cálculo del efecto.
Gingivitis
Después de cuatro a seis semanas de uso, el enjuague bucal con clorhexidina redujo la gingivitis (escala de 0 a 3 del Gingival Index [GI]) en un 0,21 (IC del 95%: 0,11 a 0,31) en comparación con placebo, control o ningún enjuague bucal (10 ensayos, 805 participantes con inflamación gingival leve [puntuación media de 1 en la escala del GI] analizados, evidencia de alta calidad). Se encontró un tamaño del efecto similar para la reducción de la gingivitis a los seis meses. No hubo datos suficientes para determinar la reducción de la gingivitis asociada con el uso de enjuague bucal con clorhexidina en los individuos con puntuaciones medias en el GI de 1,1 a 3 (niveles moderados o graves de inflamación gingival).
Placa
La placa fue medida con diferentes índices y la DME a las cuatro a seis semanas fue de 1,45 (IC del 95%: 1,00 a 1,90) desviaciones estándar inferior en el grupo de clorhexidina (12 ensayos, 950 participantes analizados, evidencia de alta calidad), lo cual indica una reducción grande de la placa. Se encontró una reducción grande similar para el uso de enjuague bucal con clorhexidina a los seis meses.
Tinción extrínseca de los dientes
Se produjo un aumento grande de la tinción extrínseca de los dientes en los participantes que utilizaron enjuague bucal con clorhexidina a las cuatro a seis semanas. La DME fue de 1,07 (IC del 95%: 0,80 a 1,34) desviaciones estándar mayor (ocho ensayos, 415 participantes analizados, evidencia de calidad moderada) en el grupo de enjuague bucal con clorhexidina. Se produjo también un aumento grande de la tinción extrínseca de los dientes en los participantes que utilizaron enjuague bucal con clorhexidina a las siete a 12 semanas y a los seis meses.
Sarro
Los resultados para el efecto del enjuague bucal con clorhexidina sobre la formación de sarro fueron no concluyentes.
Efecto de la concentración y la frecuencia del enjuague
No hubo datos suficientes para determinar si había una diferencia en el efecto para la concentración de clorhexidina o la frecuencia del enjuague.
Otros efectos adversos
Los efectos adversos informados con más frecuencia en los estudios incluidos fueron trastorno/alteración del gusto (informado en 11 estudios), efectos sobre la mucosa oral que incluyeron dolor, irritación, descamación leve y ulceración/erosiones de la mucosa (informado en 13 estudios) y una sensación de ardor general o ardor en la lengua o ambos (informado en nueve estudios).
Conclusiones de los autores
Hay evidencia de alta calidad proveniente de los estudios que informaron el Löe and Silness Gingival Index de una reducción de la gingivitis en los individuos con inflamación gingival leve en promedio (puntuación media de 1 en la escala del GI de 0 a 3) que no se consideró relevante desde el punto de vista clínico. Hay evidencia de alta calidad de una reducción grande en la placa dental con el enjuague bucal con clorhexidina usado como un complemento de los procedimientos mecánicos de higiene bucodental para las cuatro a seis semanas y los seis meses. No hay evidencia de que una concentración del enjuague de clorhexidina sea más efectiva que otra. Hay evidencia insuficiente para determinar la reducción de la gingivitis asociada con el uso de enjuague bucal con clorhexidina en los individuos con puntuaciones medias en el GI de 1,1 a 3 que indican niveles moderados o graves de inflamación gingival. El enjuague bucal con clorhexidina durante cuatro semanas o más causa la tinción extrínseca de los dientes. Además, los estudios incluidos informaron otros efectos adversos como acumulación de sarro, trastorno transitorio del gusto y efectos sobre la mucosa oral.
PICO
Resumen en términos sencillos
Enjuague bucal con clorhexidina para reducir la gingivitis y la acumulación de placa
Pregunta de la revisión
¿El uso de enjuague bucal con clorhexidina (un antiséptico de amplio espectro) además de otro tipo de limpieza convencional de los dientes ayuda a controlar y a mejorar la gingivitis (inflamación de las encías)? ¿La frecuencia del enjuague o la concentración de la solución afectan el resultado y hay efectos secundarios no deseados?
Antecedentes
La gingivitis es un trastorno reversible en el que las encías presentan enrojecimiento, inflamación y pueden sangrar con facilidad. La gingivitis también es muy común ‐ los estudios sugieren que hasta un 50% a 90% de los adultos en el Reino Unido y los EE.UU. sufren este trastorno. En los pacientes susceptibles la gingivitis puede dar lugar a periodontitis, que es no reversible. En la periodontitis la inflamación es acompañada por la pérdida de los ligamentos y el hueso que sostiene los dientes. Si no se trata con el tiempo puede dar lugar a la pérdida de los dientes. La periodontitis grave es la sexta enfermedad más difundida a nivel global.
Se reconoce que el mantenimiento de un estándar alto de higiene bucodental es importante para la prevención y el tratamiento de la gingivitis. El cepillado de dientes es el método principal para mantener una higiene bucodental adecuada. Otros métodos de limpieza utilizados comúnmente incluyen hilo dental, cepillos interdentales y raspaje y pulido realizado por un dentista profesional. Algunas personas tienen dificultad para controlar la acumulación de placa y prevenir la gingivitis mediante solo la limpieza convencional de los dientes. Por lo tanto, los pacientes a veces usan enjuagues bucales que contienen clorhexidina además de la limpieza convencional de los dientes. Estos enjuagues bucales pueden obtenerse fácilmente sin prescripción; en general no se requirieren prescripciones fuera de los EE.UU..
Características de los estudios
Se incluyeron 51 estudios que analizaron a un total de 5345 participantes. La evidencia incluida en esta revisión está actualizada hasta el 28 de septiembre de 2016. En general, los participantes de los estudios eran niños y adultos que tenían gingivitis o periodontitis, podían usar los métodos habituales de limpieza de los dientes y eran sanos. No se excluyeron los estudios en los que algunos o todos los participantes presentaban trastornos médicos o necesidades de atención especiales debido que se consideró que el uso de enjuagues bucales con clorhexidina es particularmente relevante a ellos. Los estudios incluidos evaluaron los efectos del enjuague bucal con clorhexidina utilizado durante al menos cuatro semanas además de la limpieza convencional de los dientes sobre la gingivitis en niños y adultos.
Resultados clave
Hay evidencia de alta calidad de que el uso de enjuague bucal que contiene clorhexidina además del cepillado de los dientes y la limpieza habitual durante cuatro a seis semanas o seis meses da lugar a una reducción grande en la acumulación de placa. También hay evidencia de alta calidad de una reducción moderada de la gingivitis en los pacientes con un nivel leve de este trastorno, aunque debido a que el nivel de la enfermedad ya era bajo, este hecho no se considera clínicamente importante. La naturaleza de las pruebas disponibles no permite determinar el nivel de la reducción de la gingivitis en los pacientes con niveles moderados a graves del trastorno.
No hubo evidencia de que una concentración o potencia del enjuague de clorhexidina fuese más efectiva que otra.
El enjuague durante cuatro semanas o más causa la tinción de los dientes, lo cual requiere el raspaje y el pulido realizado por un dentista profesional. Se han informado otros efectos secundarios, que incluyen acumulación de sarro, trastorno temporal del gusto y descamación/daño temporal del recubrimiento de la boca.
Calidad de la evidencia
Un estudio se evaluó como en riesgo incierto de sesgo, y los 50 restantes en alto riesgo de sesgo, sin embargo este hecho no afectó las evaluaciones de la calidad para la gingivitis y la placa debido a que se cree que es muy poco probable que la investigación adicional cambie la confianza en el cálculo del efecto.
Authors' conclusions
Summary of findings
| Chlorhexidine mouthrinse compared with placebo/control mouthrinse/no mouthrinse for gingival health | ||||||
|---|---|---|---|---|---|---|
| Patient or population: adults and children with gingivitis Settings: any Intervention: chlorhexidine mouthrinse Comparison: placebo/control mouthrinse or no mouthrinse | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Chlorhexidine | |||||
| Gingival Index 4 to 6 weeks (Löe and Silness Gingival Index) (0 to 3 on an increasing scale) | The mean gingivitis scores ranged across control groups from 0.17 to 1.401 | The mean gingivitis score in the chlorhexidine group was 0.21 lower (0.11 to 0.31 lower) | 805 (10 trials) | ⊕⊕⊕⊕2,3 | The effect size at 6 months was similar Insufficient evidence for differences in effect size for different chlorhexidine concentration or frequency of use Insufficient evidence to determine the effect size in individuals with moderate or severe levels of gingival inflammation on average (mean GI scores 1.1 to 3) | |
| Plaque 4 to 6 weeks (various increasing scales including Plaque Index (0 to 3 scale) and Turesky Modification of the Quigley and Hein Index (0 to 5 scale)) | Plaque Index ranged from 0.75 to 1.06 Turesky Modification of the Quigley and Hein Index ranged from 1.2 to 3.3 | The SMD was 1.45 lower in the chlorhexidine group indicating a large reduction in plaque from 1.00 to 1.90 standard deviations | 950 (12 trials) | ⊕⊕⊕⊕2,3 | The effect for the Plaque Index (4 trials; 223 participants) was 0.58 (95% CI 0.39 to 0.78) lower The effect for the Turesky Modification of the Quigley and Hein Index (5 trials; 546 participants) was 0.78 (95% CI 0.70 to 0.85) lower There were also large effects for the plaque at 6 months | |
| Tooth staining 4 to 6 weeks (various increasing scales) | The mean tooth staining score was measured on different scales | The SMD for tooth staining in the chlorhexidine group was | 415 (8 trials) | ⊕⊕⊕⊝4 | Data have not been converted to original scale as many different scales are used. The SMD effect size is considered large There were also 2 trials presenting dichotomous data showing large significant effect RR 5.41 (95% CI 2.03 to 14.47) There was also a large effect for tooth staining for chlorhexidine at 7 to 12 weeks and 6 months | |
| Other adverse effects | 22 trials reported at least 1 adverse effect apart from extrinsic tooth staining and calculus formation in the chlorhexidine rinse arms. The adverse effects most commonly reported were taste disturbance/alteration (reported in 11 trials), effects on the oral mucosa including mucosal irritation, soreness, mild desquamation, mucosal ulceration/erosions, oral mucosal lesions (reported in 13 trials) and a general burning sensation and/or a burning tongue (reported in 9 trials) | |||||
| *The basis for the assumed risk (e.g. the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) 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 | ||||||
| 1The mean gingivitis score for the control group was 0.93 (median is 1.0). | ||||||
Background
Description of the condition
Plaque‐associated periodontal disease involves the inflammation of the gingivae (gums) and the supporting structures of the teeth. The first stage of the disease is plaque‐associated gingivitis (inflammation of the gingivae), which is a reversible inflammatory condition characterised by redness and swelling of the gingivae and a tendency for the gingivae to bleed easily. It is caused by the accumulation and persistence of microbial biofilms (dental plaque) on the teeth (Löe 1965). Gingivitis is very common with studies suggesting that as many as 50% to 90% of adults in the UK and USA suffer from gingivitis (NICE 2012). In susceptible individuals, gingivitis may lead to the second stage of periodontal disease, periodontitis. Periodontitis is an irreversible condition, where inflammation of the gingivae is accompanied by connective tissue destruction and loss of the periodontal ligament and alveolar bone supporting the tooth. If untreated, periodontitis may ultimately lead to tooth loss. Severe periodontitis is the sixth most prevalent disease of man with a global age‐standardised prevalence of 11.2% (Kassebaum 2014). It has a negative impact on oral‐health‐related quality of life (Al‐Harthi 2013; Marcenes 2013; Needleman 2004; Tonetti 2015), affecting both physical function and social interaction (Cunha‐Cruz 2007; Ng 2006). The response of the individual to gingival irritation by the microbial biofilm is modulated by local, systemic and genetic factors, and it is recognised that gingivitis will only progress to periodontitis in some individuals and at some sites. However as the microbial biofilm is a prerequisite for both conditions, gingival inflammation is considered a key risk factor in the initiation of periodontitis (Chapple 2015; Lang 2009). Indeed, consistent inflammation of the gingivae and gingival bleeding are predictive of future attachment loss and tooth loss (Schatzle 2004).
Although it is not possible to identify those individuals who will go on to develop severe periodontitis, the importance of maintaining a high standard of oral hygiene in the prevention and treatment of periodontal diseases is well recognised (Axelsson 2004; Ohrn 2009; van der Weijden 2011). Furthermore, the most important predictor of periodontal diseases, regardless of age is poor oral hygiene (Abdellatif 1987). Thus, the population approach to prevention of periodontal diseases should promote adequate plaque control and removal of the microbial biofilm for all individuals.
Description of the intervention
Mechanical disruption and removal of the microbial biofilm is commonly achieved by toothbrushing and interdental cleaning (Berchier 2008). However, adequate removal of the microbial biofilm with mechanical methods alone can be difficult for some, with many individuals finding it difficult to maintain an effective level of plaque control (Marsh 1992; Salzer 2015; Slot 2012; van der Weijden 2005; van der Weijden 2011; van der Weijden 2015). For these individuals, the level of plaque control that is achieved by regular mechanical cleaning alone may not be sufficient to prevent the onset or recurrence of periodontal diseases (Serrano 2015).Therefore chemical methods of removing the microbial biofilm such as antimicrobial mouthrinses have been recommended for use as either an adjunct to, or in some limited situations, a replacement for mechanical removal of the microbial biofilm.
Chlorhexidine is a broad spectrum bisbiguanide antiseptic which was first introduced into clinical medicine in 1953 in the form of an antiseptic cream (Eley 1999; Foulkes 1973). It is a strong base and is practically insoluble in water (Karpinski 2015). In clinical medicine its water soluble salts, in particular chlorhexidine digluconate, are most commonly used (Foulkes 1973; Karpinski 2015). In dentistry, chlorhexidine is used in a variety of formulations and vehicles, such as mouthrinses, gels, sprays and varnishes. Problems can be encountered when delivering chlorhexidine as a gel or a toothpaste as the chlorhexidine may bind to ingredients in the products reducing its activity (Eley 1999). Although considerable advances have been made in recent years in the formulation of these and other chlorhexidine vehicles, mouthrinses have the advantage of having a long history of use for oral health. They are already accepted as part of a normal oral hygiene regimen, used following normal mechanical tooth cleaning (van der Weijden 2015). Chlorhexidine‐containing mouthrinses are marketed worldwide under a number of trade names and are in widespread use for chemical plaque control. This family of rinses are mainly indicated for use as adjuncts to mechanical cleaning, in specific clinical situations where mechanical oral hygiene is difficult, such as postsurgery, in individuals with intermaxillary fixation, in fixed appliance orthodontic therapy and in individuals with intellectual and physical disabilities (Addy 1986). Chlorhexidine mouthrinse is mainly available in concentrations of 0.1%, 0.12% or 0.2% chlorhexidine digluconate as well as in low concentration (≤ 0.06%) rinse. The effect of chlorhexidine on the microbial biofilm is dose‐dependant (Keijser 2003). The optimum dose of chlorhexidine in a mouthrinse is considered to be 20 mg twice daily (Löe 1970) equivalent to 10 mL of 0.2% chlorhexidine mouthrinse (20 mg) or 15 mL of 0.12% chlorhexidine mouthrinse (18 mg) (Eley 1999; Keijser 2003). A rinse time of 30 seconds appears to be effective and acceptable although 60‐second rinse times are also advocated (Bonesvoll 1974; Keijser 2003).
How the intervention might work
The action of chlorhexidine mouthrinse as a treatment adjunct in managing inflammation of the gingivae involves its antimicrobial properties, which reduce the bacterial load of the microbial biofilm and should therefore reduce levels of inflammation and help prevent primary and secondary plaque‐associated periodontal disease. Chlorhexidine digluconate has the ability to kill a wide variety of micro‐organisms including gram‐positive and gram‐negative bacteria (aerobes and anaerobes) (Emilson 1977) as well as fungi including yeasts (Greenstein 1986; Puig Silla 2008). When chlorhexidine mouthrinse is used, the positively charged (cationic) chlorhexidine molecule binds to the negatively charged microbial cell wall and interferes with the osmotic equilibrium of the micro‐organism. Depending on the dose, chlorhexidine can have a bacteriostatic or bacteriocidal effect. At low concentrations, chlorhexidine is bacteriostatic causing leakage of low molecular weight substances from the microbial cell and inhibiting reproduction. At higher concentrations chlorhexidine is bacteriocidal and causes cell death by precipitating the cytoplasmic contents of the microbial cell (Greenstein 1986; Puig Silla 2008). This ability of chlorhexidine to adsorb and adhere to negatively charged surfaces is central to its success as an antimicrobial agent. The chlorhexidine molecule has the ability to adsorb to anionic (negatively charged) substrates such as hydroxyapatite, pellicle, salivary glycoproteins and mucous membranes exerting an immediate bacteriocidal effect. When slowly released over time from the pellicle‐coated enamel surface, it provides a prolonged bacteriostatic effect in vivo (Bonesvoll 1974; Bonesvoll 1974a; Bonesvoll 1978; Jenkins 1988; Rolla 1971). This property of chlorhexidine is known as its substantivity and is what sets chlorhexidine apart from many other antimicrobial agents.
Chlorhexidine mouthrinse use is associated with a number of local adverse effects the most common being the formation of brown staining on the teeth and oral tissues, particularly the tongue (Addy 1986). Several theories have been put forward to explain the cause of this characteristic staining, however most evidence points to the staining being a result of precipitation of anionic dietary chromogens (e.g. from tea, coffee, tannins from wine) onto adsorbed chlorhexidine cations (Addy 1985; Addy 1985a; Watts 2001). Other less common local adverse effects have also been reported including supragingival calculus accumulation (Eley 1999; Mandel 1994; Van Strydonck 2012), oral mucosal lesions (Addy 1986; Flotra 1971; Van Strydonck 2012), and altered taste perception (Addy 1986; Eley 1999; Marinone 2000; Van Strydonck 2012). The occurrence of side effects tends to be reduced with lower chlorhexidine concentrations (Addy 1986; Cumming and Löe 1973; Flotra 1971; Keijser 2003). With the exception of extrinsic staining of the teeth and calculus accumulation which require removal by professional tooth cleaning, the adverse effects are transient and resolve once chlorhexidine mouthrinse use has ceased (Flotra 1971; Greenstein 1986). These local adverse effects limit the use of chlorhexidine to short or moderate term use in specific clinical circumstances (van der Weijden 2015). Chlorhexidine is poorly absorbed by the oral tissues and the gastrointestinal tract and is considered to have very low toxicity (Foulkes 1973; Greenstein 1986). Parotid gland swelling has been reported following chlorhexidine mouthrinse use (Addy 1986; Eley 1999; van der Weijden 2010). There have been rare reports of type 1 hypersensitivity reactions to chlorhexidine used in the mouth or on the lips (Pemberton 2012) but severe reactions such as anaphylaxis do not appear to have occurred as a result of using chlorhexidine mouthrinse to maintain periodontal health.
Why it is important to do this review
Chlorhexidine mouthrinse is readily available and a prescription is generally not required outside the USA (Moran 2008). Its efficacy in controlling plaque and gingivitis in humans in the absence of active oral hygiene was first demonstrated over 40 years ago by Harald Löe and colleagues (Löe 1970). Nowadays chlorhexidine mouthrinse is mostly used as an adjunct to regular mechanical oral hygiene and is commonly regarded as the gold standard against which other antiplaque agents are measured (Jones 1997; Marsh 1992). The last decade has seen the publication of two meta‐analyses (Gunsolley 2006; Gunsolley 2010) and a number of systematic reviews (including one metareview) of the effectiveness of chlorhexidine mouthrinse (Boyle 2014; Serrano 2015; van der Weijden 2015; Van Strydonck 2012). In most of these publications chlorhexidine mouthrinse was one of a number of antiplaque chemical agents under review. The one dedicated review of the effectiveness of chlorhexidine mouthrinse compared to placebo, control or regular oral hygiene employed slightly different inclusion criteria to this review but included tooth staining as an outcome in addition to gingivitis and plaque (Van Strydonck 2012). However, the search for this review was conducted in April 2011 and adverse effects other than extrinsic tooth staining were not prespecified outcomes in the review.
Given the numerous clinical indications for the use of chlorhexidine mouthrinse for gingivitis and plaque control, and the ready availability of chlorhexidine mouthrinse over‐the‐counter in many parts of the world, it is important to conduct a Cochrane systematic review of chlorhexidine mouthrinse as an adjunctive treatment for gingival health in order to provide, rigorous, up‐to‐date evidence for patients, oral health practitioners and policy makers. This should take into account the risk of bias of the studies that have been conducted, as well as assessing the possible adverse effects of the chlorhexidine mouthrinse.
Objectives
To assess the effectiveness of chlorhexidine mouthrinse used as an adjunct to mechanical oral hygiene procedures for the control of gingivitis and plaque compared to mechanical oral hygiene procedures alone or mechanical oral hygiene procedures plus placebo/control mouthrinse. Mechanical oral hygiene procedures were toothbrushing with/without the use of dental floss or interdental cleaning aids and could include professional tooth cleaning/periodontal treatment.
To determine whether the effect of chlorhexidine mouthrinse is influenced by chlorhexidine concentration, or frequency of rinsing (once/day versus twice/day).
To report and describe any adverse effects associated with chlorhexidine mouthrinse use (reporting of adverse effects is limited to those detailed in the included trials).
Methods
Criteria for considering studies for this review
Types of studies
We included parallel‐group randomised controlled trials (RCTs) irrespective of language or publication status where the duration of mouthrinsing was at least 4 weeks.The minimum duration of rinsing was selected to reflect the 'real life' use of chlorhexidine as a short‐term adjunct to mechanical oral hygiene procedures. Studies where the duration of mouthrinsing was less than 4 weeks were excluded. Cross‐over studies were excluded due to concerns that chlorhexidine could exert an effect beyond the washout period. It would not be possible to conduct a split‐mouth study of mouthrinse use, however split‐mouth studies comparing different scaling and root planing regimens and different periodontal surgical techniques often incorporate a chlorhexidine and placebo/control comparison. Such study designs were considered inappropriate to answer the question posed by this review and were excluded. We would have included properly designed cluster‐RCTs if any such studies had met the inclusion criteria.
Types of participants
We included RCTs involving children or adults with gingivitis or periodontitis provided they were capable of performing normal mechanical oral hygiene procedures (in accordance with other Cochrane reviews, we classified all participants aged 16 years or less as children and those older than 16 years as adults). We included trials where some or all of the participants had medical conditions or special care needs as we considered the intervention to be particularly relevant to these individuals/groups.
Types of interventions
Experimental intervention: chlorhexidine mouthrinse (used at any concentration, volume, frequency or duration of rinsing) used in conjunction with mechanical oral hygiene procedures (toothbrushing with/without the use of dental floss or interdental cleaning aids and could include professional tooth cleaning/periodontal treatment).
Comparator interventions: mechanical oral hygiene alone (toothbrushing with/without the use of dental floss or interdental cleaning aids and could include professional tooth cleaning/periodontal treatment), or mechanical oral hygiene used in conjunction with placebo/control mouthrinse.
We included studies:
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where the chlorhexidine mouthrinse also contained fluoride;
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where gum care or antigingivitis dentifrices (that did not contain chlorhexidine) were used for mechanical oral hygiene provided that they were used in both experimental and comparator arms;
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with and without baseline prophylaxis (scale and polish) but all study arms had to have the same treatment.
We excluded studies:
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where chlorhexidine mouthrinse was used as a monotherapy in the absence of mechanical oral hygiene procedures;
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where the chlorhexidine mouthrinse formed part of a combined intervention with other agents (such as other chlorhexidine vehicles, e.g. dentifrice‐containing chlorhexidine, or other antimicrobial agents (e.g. cetylpyridinium chloride (CPC)) that the comparator arm/s did not receive because we would have been unable to separate the effect of the chlorhexidine from the effect of the other active agents;
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where the mechanical oral hygiene procedures were not the same in both the chlorhexidine mouthrinse and the comparator arms e.g. studies or study arms where experimental or comparator arms received more intensive or more frequent professional mechanical cleaning or used additional mechanical cleaning aids e.g. dental floss as part of the intervention that was different from the other study arms;
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where chlorhexidine mouthrinse was applied locally e.g. with a brush or via subgingival irrigation.
Types of outcome measures
Primary outcomes
Gingivitis measured using any appropriate index/scale.
Only trials that reported gingivitis as an outcome were considered for inclusion in the review. The clinical features of gingivitis can be assessed non‐invasively by visual assessment of colour, contour and gingival bleeding or invasively using an instrument to provoke bleeding or both (Lorenz 2009). The Gingival Index of Löe and Silness (GI) utilises both visual assessment and assessment of bleeding on provocation. It can be measured at specific sites using six index teeth (Löe and Silness 1963) or all teeth (Löe 1967). Each site is scored on a 0 to 3 increasing scale and an average score can be calculated for each tooth assessed. The mean score for an individual represents an average score for the areas examined. The Modified Gingival Index (MGI) (Lobene 1986) can be used as a full‐mouth index or applied to selected teeth and is measured non‐invasively on a 0 to 4 increasing scale i.e. there is no attempt to use pressure to elicit bleeding. Many indices measure gingivitis solely by assessing bleeding on provocation but the techniques used to elicit bleeding can vary between indices. The Gingival Bleeding Index (Ainamo and Bay 1975) uses a blunt pocket probe to gently probe the orifice of the gingival crevice. If bleeding occurs within about 10 seconds after testing, a positive finding is recorded. The percentage of sites with gingival bleeding are calculated for the individual.
It is not uncommon for multiple measures of gingivitis to be presented within one study. Therefore the following hierarchy was developed to simplify data extraction.
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Where gingival inflammation and gingival bleeding were reported within the same study we extracted data on both outcomes.
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Where gingival inflammation was reported using more than one index within a study, the GI (Löe and Silness 1963; Löe 1967) was chosen over other indices and the MGI (Lobene 1986) was chosen next if the gingival index was not reported.
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Where gingival bleeding was reported within a study as bleeding on probing (BOP) (Ainamo and Bay 1975) and the proportion of sites with BOP using the GI (i.e. GI scores 2 or 3) (Löe and Silness 1963; Löe 1967), BOP was chosen over the proportion of sites with BOP (GI scores 2 or 3).
Within the gingival index, the severity (the average extent of the disease) was considered a measure of gingival inflammation and occurrence (the proportion of sites with BOP i.e. GI scores 2 or 3) was considered a measure of gingival bleeding.
Outcome data at 4 to 6 weeks, 7 to 12 weeks, 13 weeks to 6 months and greater than 6 months were collected and reported but the primary analysis of the gingivitis data was concerned with short‐term use (4 to 6 weeks), along with a longer term measure at 6 months.
Secondary outcomes
Data on the following secondary outcomes were extracted from eligible trials that also reported gingivitis as an outcome.
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Dental plaque measured using any appropriate index/scale. Although dental plaque can be measured using a variety of different indices, the Plaque Index (Silness and Löe 1964) and the Turesky modification of the Quigley and Hein index (TQH) (Turesky 1970) are commonly used to measure dental plaque. Both use an increasing scale to quantify the amount of plaque present. The Plaque Index uses a 0 to 3 increasing scale to quantify the amount of plaque on each surface (buccal, lingual, mesial and distal) of six index teeth. An average score for each tooth and for the individual can then be calculated. The TQH uses a 0 to 5 increasing scale to quantify the amount of plaque on the buccal and lingual surfaces of the teeth. An average score for the individual can then be calculated. Where dental plaque was measured using more than one index within a study; the Plaque Index (Silness and Löe 1964) was chosen over other indices and the TQH (Turesky 1970) was chosen next if the Plaque Index was not reported.
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Calculus measured using any appropriate index/scale.
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Tooth staining measured using any appropriate index/scale.
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Adverse effects (e.g. mucosal desquamation, taste disturbances, allergic reactions).
Search methods for identification of studies
Electronic searches
Cochrane Oral Health's Information Specialist conducted systematic searches in the following databases for randomised controlled trials and controlled clinical trials without language or publication status restrictions:
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Cochrane Oral Health's Trials Register (searched 28 September 2016) (Appendix 1);
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Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 28 September 2016) (Appendix 2);
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MEDLINE Ovid (1946 to 28 September 2016) (Appendix 3);
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Embase Ovid (1980 to 28 September 2016) (Appendix 4);
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CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 28 September 2016) (Appendix 5).
Subject strategies were modelled on the search strategy designed for MEDLINE Ovid. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying randomised controlled trials and controlled clinical trials as described in the Cochrane Handbook for Systematic Reviews of Interventions Chapter 6 (Lefebvre 2011).
Searching other resources
We searched the following trial registries for ongoing studies:
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov; searched 28 September 2016) (Appendix 6);
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 28 September 2016) (Appendix 7).
We searched the reference lists of included studies and relevant systematic reviews for further studies. We attempted to contact companies that manufacture chlorhexidine mouthrinse (Colgate Palmolive (Periogard), 3M (Peridex), GlaxoSmithKline (Corsodyl)) and companies that manufacture other types of mouthrinse (Johnson & Johnson (Listerine), P&G (Oral B brand)) to identify unpublished and ongoing studies.
We did not perform a separate search for adverse effects of interventions. Only the adverse effects that were described in the included studies were considered.
Data collection and analysis
Selection of studies
Two review authors independently and in duplicate screened the titles and abstracts of the list of studies identified by the searching process against the inclusion criteria for the review to identify eligible and potentially eligible studies. We obtained full‐text copies of all the potentially eligible studies, and also of studies with insufficient information in the title/abstract to make a decision on eligibility. The review authors were not blinded to the journal name, authors, institution, results or sources of funding when assessing eligibility of the identified studies. Two review authors independently and in duplicate assessed the full‐text copies to identify those that met the inclusion criteria. We contacted study authors for clarification or missing information relating to eligibility where necessary and feasible. We linked multiple reports of the same study together under one single study title. We resolved any disagreements on eligibility through discussion but, if this was not possible, an experienced member of the Cochrane Oral Health editorial team (H Worthington) was consulted to achieve consensus. We recorded any studies failing to meet the inclusion criteria, along with reasons for exclusion.
The eligibility of the non‐English language reports were assessed by two review authors independently and in duplicate. Relevant sections of the reports were translated with the assistance of Cochrane Oral Health. Non‐English language reports that met the inclusion criteria for the review were translated in full.
This process is summarised in the 'Study flow diagram' (Figure 1).
Study flow diagram.
Data extraction and management
Two review authors independently and in duplicate extracted data from the included studies using a customised Excel spreadsheet that was piloted on a small sample of studies. We contacted study authors for clarification or missing information where necessary and feasible. We resolved any disagreements through discussion and where agreement could not be reached, an experienced member of the Cochrane Oral Health editorial team (H Worthington) was consulted to achieve consensus.
We recorded the following data for each included study, which were then tabulated in the 'Characteristics of included studies' tables.
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Trial design, location/setting, number of centres, study duration.
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Details of the participants including demographic characteristics, criteria for inclusion and exclusion, and relevant information on gingivitis levels at baseline, numbers randomised to each study arm, and numbers analysed in each arm.
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Details of the type of experimental/comparator intervention, concentration and volume of mouthrinse, frequency and duration of rinsing, baseline prophylaxis (scale and polish), details of oral hygiene instruction (OHI), supervision of mouthrinsing, timing of mouthrinsing in relation to toothbrushing and postrinsing instructions.
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Details of the outcomes reported, including method and timing of assessment.
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Sample size calculations, source of study funding, information about adverse effects, proportion of smokers in the studies/study arms and declarations/conflicts of interest.
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Outcome data: For gingivitis and plaque we extracted outcome data from the end point of each study with the exception of studies where the duration of rinsing was longer than 6 months. In this situation interim data for gingivitis and plaque at 6 months were extracted in addition to data at the end point of the study. We considered interim data on extrinsic tooth staining and calculus formation important in determining the time of onset of these adverse effects. Therefore, where they were reported, data on extrinsic tooth staining and calculus formation were extracted at interim time points as well as at the end point of each study. Outcome data were grouped according the following time intervals: 4 to 6 weeks, 7 to 12 weeks, 13 weeks to 6 months and greater than 6 months. Where data on extrinsic tooth staining or calculus were reported twice within one time interval, the later results were data extracted. Where an outcome was measured after rinsing has ceased, we considered the time point that rinsing ceased as the primary end point. Studies that measured gingivitis and plaque outcomes only after cessation of rinsing were included in a separate analysis of the long‐term effects of rinsing with chlorhexidine mouthrinse on gingivitis and plaque. We did not extract extrinsic tooth staining and calculus data reported after rinsing had ceased.
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Where studies reported mean scores for the Gingival Index at 4 to 6 weeks or 6 months but did not report a measure of variance and a measure of variance could not be obtained from the authors of the studies, the variance was estimated from the standard deviations reported in similar trials that used the same index at the same time point as described in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Where mean scores and measures of variance were reported only in graphs and the data could not be obtained from the authors of the studies, data were estimated by reading the data off the graphs in the published report for inclusion in meta‐analyses. The graphs were enlarged and the data were estimated independently and in duplicate. Any disagreements were resolved by discussion. A sensitivity analysis was conducted to gauge the effects of estimating these outcome data on the overall results.
Assessment of risk of bias in included studies
Two review authors assessed the risk of bias of all included studies, independently and in duplicate, using Cochrane's domain‐based, two‐part tool as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We contacted study authors for clarification or missing information where necessary and feasible. We tried to resolve any disagreements on risk of bias through discussion but, if this was not possible, an experienced member of the Cochrane Oral Health editorial team (H Worthington) was consulted to achieve consensus. A 'Risk of bias' table was completed for each included study. For each domain of risk of bias, we first described what was reported to have happened in the study in order to provide a rationale for the second part, which involved assigning a judgement of 'low risk' of bias, 'high risk' of bias, or 'unclear risk' of bias.
For each included study, we assessed the following seven domains of risk of bias.
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Random sequence generation (selection bias): use of simple randomisation (e.g. random number table, computer‐generated randomisation, central randomisation by a specialised unit), restricted randomisation (e.g. random permuted blocks), stratified randomisation and minimisation were assessed as at low risk of bias. Other forms of simple randomisation, such as repeated coin tossing, throwing dice or dealing cards, were also considered as at low risk of bias. If a study report used the phrase 'randomised' or 'random allocation' but with no further information, and if randomisation could not be confirmed, we assessed it as unclear for this domain.
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Allocation concealment (selection bias): use of centralised/remote allocation, pharmacy‐controlled randomisation (i.e. allocation of sequentially numbered mouthrinse containers of identical appearance) and sequentially numbered, sealed, opaque envelopes were assessed as at low risk of bias. If a study report did not mention allocation concealment, we assessed it as unclear for this domain.
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Blinding of participants and personnel (performance bias): if blinding was not mentioned, we assessed this domain as at unclear risk of bias. We only considered personnel blinding for studies with supervised mouthrinsing. If a study was described as double blind, we assumed that the intention was for participants and outcome assessors to be blinded to group allocation, however due to the propensity for chlorhexidine to stain the teeth and oral tissues and the association of its use with visible adverse effects such as mucosal desquamation and mucosal lesions, we considered the potential effect of these on blinding as follows.
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Where tooth staining/adverse effects were reported narratively or measured using a scale (where relevant) and were higher in the chlorhexidine rinse arm/s, we considered that participants could have worked out which study arm they were in and this could have affected their oral health behaviours and hence the outcome and assessed this domain as at high risk of bias irrespective of whether participant blinding was indicated.
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Where tooth staining/adverse effects were reported narratively or measured using a scale (where relevant) but were not higher in the chlorhexidine rinse arm/s and participant blinding was also indicated, we assessed this domain as at low risk of bias.
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Where tooth staining/adverse effects were not reported, although we considered it likely in this situation that tooth staining or other visible adverse effects could have occurred and been noticeable in the chlorhexidine rinse arm/s after 4 weeks or more of rinsing, we assessed this domain as unclear as there was not enough information upon which to base a judgement.
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Where it was not possible to blind participants and personnel due to differences in the experimental and comparator interventions this domain was assessed as at high risk of bias.
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Blinding of outcome assessment (detection bias): if blinding was not mentioned, we assessed this domain as at unclear risk of bias. If a study was described as double blind, we assumed that the intention was for participants and outcome assessors to be blinded to group allocation, however due to the propensity for chlorhexidine to stain the teeth and oral tissues and the association of its use with visible adverse effects such as mucosal desquamation and mucosal lesions, we considered the potential effect of these on blinding as follows.
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Where tooth staining/adverse effects such as mucosal desquamation and mucosal lesions that could be visible to the outcome assessor were reported narratively or measured using a scale (where relevant) and were higher in the chlorhexidine arm/s, we considered that outcome assessors could have worked out which study arm participants were in and therefore could not be adequately blinded. In this situation we assessed this domain as at high risk of bias irrespective of whether blinding of outcome assessment was indicated.
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Where tooth staining/adverse effects such as mucosal desquamation and mucosal lesions that could be visible to the outcome assessor were reported narratively or measured using a scale (where relevant) but were not higher in the chlorhexidine arm/s and blinding of outcome assessment was also indicated, we assessed this domain as at low risk of bias.
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Where tooth staining/adverse effects such as mucosal desquamation and mucosal lesions that could be visible to the outcome assessor were not reported, although we considered it likely that tooth staining or other visible adverse effects could have occurred and been noticeable in the chlorhexidine arm/s after 4 weeks of more of rinsing, we assessed this domain as unclear as there was not enough information upon which to base a judgement.
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Incomplete outcome data (attrition bias): if 10% or less of randomised participants were excluded from the analysis, we assessed this as at low risk of bias. However, when attrition was greater than 10%, assuming the missing participants in one group had a higher mean (e.g. gingivitis score) than those in the other group, as the attrition rate increased, so would the mean difference (MD) between groups, as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). This situation led to a judgement of high risk of bias if we believed that the attrition was high enough to have resulted in a distortion of the true intervention effect, or if there was considerably greater attrition in one group than another. If attrition was greater than 10%, but with the additional factors of not being reported by group and insufficient reporting of reasons for attrition, this led to a judgement of unclear risk of bias. If it was not clear from the study report how many participants were randomised into each group, we assessed it as at unclear risk of bias for this domain.
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Selective reporting (reporting bias): if the study either reported outcomes not stated a priori in the methods section or the study protocol (if available) or did not report outcomes stated in the methods section, we assessed this as at high risk of bias. If gingivitis and plaque outcomes were reported with insufficient information to allow us to use the outcome data in a meta‐analysis (e.g. no information on variance), we assessed it as at high risk of bias. We considered the reporting of adverse effects associated with the use of chlorhexidine mouthrinse to be important outcomes. For an assessment of low risk of bias we required either a statement that there were no adverse effects associated with the chlorhexidine rinse or if present, that adverse effects be reported by group. Where tooth staining was not reported or was measured using an index but insufficient data were reported to allow us to use the data in a meta‐analysis we assessed it as at high risk of bias. Where tooth staining was not measured using an index but its presence/absence was reported we assessed this as at low risk of bias, provided that the information was reported for all participants by group.
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Other bias: any other potential source of bias that may feasibly alter the magnitude of the effect estimate (e.g. baseline imbalances in potentially important prognostic factors between intervention groups and differential diagnostic activity by outcome assessors).
We summarised the risk of bias as follows.
| Risk of bias | Interpretation | In outcome | In included studies |
|---|---|---|---|
| Low risk of bias | Plausible bias unlikely to seriously | Low risk of bias for all key domains | Most information is from studies at low risk of bias |
| Unclear risk of bias | Plausible bias that raises some | Unclear risk of bias for one or more key domains | Most information is from studies at low or unclear risk of bias |
| High risk of bias | Plausible bias that seriously weakens confidence in the results | High risk of bias for one or more key domains | The proportion of information from studies at high risk of bias is sufficient to affect the interpretation of results |
Measures of treatment effect
We used the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We combined mean differences (MDs) where studies used the same scale and standardised mean differences (SMDs) where studies used different scales for continuous outcomes. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals.
Unit of analysis issues
The participant was the unit of analysis. We were unable to use data from studies that reported number of sites rather than number of individuals in the meta‐analyses, as failure to take the clustering into account could lead to an overestimate of effect, with narrower confidence intervals and smaller P values. Had we included cluster‐RCTs we would have analysed the results taking account of the clustering present in the data, otherwise we would have used the methods outlined in Section 16.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions in order to perform an approximately correct analysis (Higgins 2011).
Dealing with missing data
We attempted, where feasible, to contact the authors of studies to obtain missing data or for clarification. Where appropriate, we used the methods outlined in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions in order to estimate missing standard deviations for the main outcome only (gingivitis) (Higgins 2011). We did not use any further statistical methods or carry out any further imputation to account for missing data. Where mean scores and measures of variance were only reported in graphs and could not be obtained from the authors of the studies, data were estimated by reading the data off the graphs in the published report for inclusion in meta‐analyses. The graphs were enlarged and the data were estimated independently and in duplicate. Any disagreements were resolved by discussion.
Assessment of heterogeneity
If meta‐analyses were performed, we assessed the possible presence of heterogeneity visually by inspecting the point estimates and confidence intervals on the forest plots; if the confidence intervals had poor overlap then heterogeneity was considered to be present. We also assessed heterogeneity statistically using a Chi2 test, where a P value < 0.1 indicated statistically significant heterogeneity. Furthermore, we quantified heterogeneity using the I2 statistic. A guide to interpretation of the I2 statistic given in Section 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions is as follows (Higgins 2011):
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0% to 40%: might not be important;
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30% to 60%: may represent moderate heterogeneity;
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50% to 90%: may represent substantial heterogeneity;
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75% to 100%: considerable heterogeneity.
Assessment of reporting biases
Assessment of reporting bias within studies has already been described in the section Assessment of risk of bias in included studies.
Reporting biases can occur when reporting (or not reporting) research findings is related to the results of the research (e.g. a study that did not find a statistically significant difference/result may not be published). Reporting bias can also occur if ongoing studies are missed (but that may be published by the time the systematic review is published), or if multiple reports of the same study are published, or if studies are not included in a systematic review due to not being reported in the language of the review authors. We attempted to limit reporting bias in the first instance by conducting a detailed, sensitive search, including searching for ongoing studies, and any studies not reported in English were translated. If there were more than 10 studies included in a meta‐analysis for the primary outcome (gingivitis), we assessed the possible presence of reporting bias by testing for asymmetry in a funnel plot. We carried out statistical analysis using the methods described by Egger 1997 for continuous outcomes.
Data synthesis
We carried out a meta‐analysis only where studies of similar comparisons reported the same outcomes at the same time interval. We combined mean differences (MDs) where studies used the same scale and standardised mean differences (SMDs) where studies used different scales for continuous outcomes. For dichotomous outcomes, we reported risk ratios (RR) and 95% confidence intervals. Due to anticipated heterogeneity we used random‐effects models for all meta‐analyses.
We reported the results from studies not suitable for inclusion in a meta‐analysis both in the results and in additional tables.
Subgroup analysis and investigation of heterogeneity
Where there were sufficient studies, we carried out the following subgroup analyses.
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Baseline prophylaxis (scale and polish) versus none.
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Children versus adults.
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Different chlorhexidine concentrations.
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Initial levels of gingivitis.
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Gingivitis only versus gingivitis + periodontitis.
Sensitivity analysis
In order to ensure our conclusions were robust, we carried out sensitivity analyses (where there were sufficient studies for each outcome) by excluding studies where outcome data were read from graphs, studies where standard deviations were estimated and studies where periodontal treatment was conducted during the study.
We would have carried out sensitivity analyses by excluding studies at high and unclear risk of bias, however this was not possible as apart from one study at unclear risk of bias, all of the included studies were at high risk of bias.
Summary of findings and assessment of the quality of the evidence
We produced a 'Summary of findings' table for chlorhexidine mouthrinse compared to placebo/control mouthrinse or no mouthrinse for the following outcomes: gingivitis measured using the Gingival Index at 4 to 6 weeks, plaque at 4 to 6 weeks, tooth staining at 4 to 6 weeks and other adverse effects. We used GRADE methods (GRADE 2004), and the GRADEpro GDT online tool for developing 'Summary of findings' tables (www.guidelinedevelopment.org). We assessed the quality of the body of evidence for each outcome by considering the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, and the risk of publication bias. We categorised the quality of each body of evidence as high, moderate, low, or very low.
Results
Description of studies
Results of the search
The searches resulted in 1520 references after de‐duplication. Two review authors screened the titles against the inclusion criteria for this review, independently and in duplicate, discarding 1424 references in the process. We obtained full‐text copies of the remaining 96 references (94 studies) and examined them independently and in duplicate, excluding 38 studies at this stage. A further four studies are awaiting assessment of their eligibility to be included in the review and one study is ongoing. Therefore, fifty‐one studies (53 records) met the inclusion criteria for this review. This process is presented diagrammatically in Figure 1.
Included studies
Characteristics of the trial designs and settings
Fifty‐one studies met the inclusion criteria for this review. All studies were of parallel‐group design. Sixteen studies had two study arms and compared chlorhexidine rinse with placebo rinse. However, thirty‐five studies had multiple study arms and not all study arms were relevant to this review. Twenty‐two studies had three arms; 10 had four arms and two had five arms. One of the studies with four study arms (Flotra 1972) had three chlorhexidine rinse groups and one placebo rinse group but presented data only for two groups: the three chlorhexidine study arms combined and the placebo group. One additional study (Feres 2012) had three main therapeutic arms which were each divided into chlorhexidine rinse and placebo rinse groups using a 2 x 3 factorial design.
Sixteen studies were conducted in the USA, six in Brazil, five in the UK, four in Germany, three in India, three in Sweden, two in each of the following countries: Canada, Mexico and Spain, and one in each of the following countries: Argentina, China, Iran, Italy, Norway, Switzerland, the Netherlands and Turkey. The settings of the studies were diverse and often poorly reported. Twenty‐seven studies were conducted in a dental school/university setting and an additional three studies were assumed, based on the information provided, to have been conducted in a dental school/university setting (Emling 1992; Pereira 2011; Van Strydonck 2008). Two studies were conducted under "dental office conditions" (Grossman 1986; Grossman 1989), two in general dental practices (Eaton 1997; Fine 1985) and one in a private practice limited to periodontics (Sanz 1989). Three studies were conducted in a school setting (de la Rosa 1988; de la Rosa 1988b; Jayaprakash 2007). The remaining studies were conducted in military garrisons (Flotra 1972; Hase 1998); pensioners/nursing homes (Lopez‐Jornet 2012; Weitz 1992); a bone marrow transplant unit (Ferretti 1987) and a knitting factory (Corbet 1997). Three studies were conducted at what we assumed were clinical research facilities (Charles 2004; Jose 2015; Stookey 2005) and in four studies the setting of the study was not clear (Flemmig 1990; Hase 1995; Sanz 1994; Taller 1993). The numbers of centres involved in the studies was often unclear but it appeared that all but two of the studies were conducted at a single centre. One study (Eaton 1997) was conducted at five suburban dental practices in Southern England and another study (Jose 2015) was conducted at two sites (Manchester and Wirral) in the UK.
In 19 studies direct support from industry was explicitly stated. Nine studies received support from P&G; three from GSK; two from Teledyne and one from each of the following companies: GABA, J&J, Oral B, Smithkline Beecham and Warner Lambert. Three studies that did not appear to be funded directly by industry explicitly stated that oral care products used in the study had been provided by industry (Anderson 1997; Sanz 1994; Stookey 2005). Three studies (Hase 1995; Hase 1998; Lang 1998) were associated with Biosurface Pharma AB through authorship and another study was associated with 'Dental Products Testing' and Pfizer through authorship (Charles 2004). Of the remaining studies that reported a source of support, two appeared to be funded by universities (Rahmani 2006; Taller 1993); six appeared to be funded by research grants (Anauate‐Netto 2014; Bajaj 2011; Corbet 1997; Faveri 2006; Feres 2009; Feres 2012); and in 17 studies there was no statement regarding funding or support. Only one study (Zimmer 2015) stated that the conduct of the research and final decisions regarding the study report were independent of the funder (GSK).
Only 13 of the studies described a sample size calculation. For six of these studies (Faveri 2006; Feres 2009; Feres 2012; Graziani 2015; Turkoglu 2009; Van Strydonck 2008) the sample size required was reported and achieved but for three of these studies the sample size was based on pocket probing depth (PPD) (Faveri 2006; Feres 2012) and clinical attachment loss (CAL) (Feres 2009) rather than gingivitis. Two studies reported the sample size calculation and number of participants required in each group but the minimum sample size was not achieved at the end of the studies (Hase 1998; Lang 1998). Five of the studies (Axelsson 1987; Brightman 1991; Charles 2004; Eaton 1997; Zimmer 2015) described the sample size calculation but not the required sample size so we were unable to determine if the required sample size was achieved. In one study the sample size calculation was not described but the required sample size was reported and achieved (Bhat 2014).
Characteristics of the participants
A total of 6995 participants provided data for the included studies. The total number of participants providing data for the study arms relevant to this review (excluding the irrelevant study arms) was 5345 with the numbers analysed in each study ranging from 20 to 852.
Six studies involved children and adolescents (Anderson 1997; Bajaj 2011; Brightman 1991; de la Rosa 1988; de la Rosa 1988b; Jayaprakash 2007). The age range of the children was 8 to 16 and three of these studies also included some young adults aged 17 and 18 (Brightman 1991; de la Rosa 1988; de la Rosa 1988b). Four studies while predominantly focused on adults, included children and adolescents among the participants: in Axelsson 1987 participants were aged 16 to 50 years old; in Fine 1985no participants under the age of 12 were included; and in Navarro 1998 the age range of participants was 14 to 35 years old. In Ferretti 1987, a study involving individuals undergoing bone marrow transplantation and chemoradiotherapy, the age range was 5 to 51 years old. The remaining forty‐one studies involved adults. The age range of adult participants was 17 to 94 years with the mean age ranging from 20 to 83.
Twenty‐two studies had a greater proportion of females than males and in four studies, the proportion of males was greater (Lang 1998; Southern 2006; Stookey 2005; Taller 1993). In five studies there was an equal balance of males to females (Bhat 2014; Graziani 2015; Pereira 2011; Turkoglu 2009; Zimmer 2006). Five studies involved male participants only (de la Rosa 1988; de la Rosa 1988b; Hase 1995; Hase 1998; Navarro 1998) and in the remaining 15 studies, the proportion of males to females was not reported. Eight studies included smokers among the participants (Charles 2004; Eaton 1997; Ernst 2005; Jose 2015; Joyston‐Bechal 1993; Overholser 1990; Zimmer 2006; Zimmer 2015) with the proportion of smokers in each study ranging from 11% to 41%. 10 studies excluded smokers and in the remaining 33 studies, the smoking status of the participants was not reported.
Twenty‐four studies reported gingivitis at baseline using the Gingival Index of Löe and Silness (Löe and Silness 1963; Löe 1967). In one study involving dental students (Lucas 1999) where normal gingiva were obtained in a pre‐experimental phase by scaling and polishing and twice daily brushing, the mean baseline gingivitis score was zero. In two other studies (Navarro 1998; Jayaprakash 2007) gingivitis at baseline was particularly low, mean gingival index scores were 0.049 and 0.057 respectively. In the remaining 21 studies the mean gingival index ranged from 0.53 to 1.87 with an overall mean of 1.09.
In many of the included studies, the periodontal status of the participants was not explicitly described. In 15 studies, the participants appeared to have gingivitis but no periodontitis whereas in nine studies, the participants had periodontitis of varying severity in addition to gingivitis (Chaves 1994; Corbet 1997; Ernst 2005; Faveri 2006; Feres 2009; Feres 2012; Graziani 2015; Rahmani 2006; Sanz 1989). In three of these studies the periodontitis was untreated at baseline (Faveri 2006; Feres 2009; Feres 2012) and in one study the participants required osseous periodontal surgery (Sanz 1989). In 16 studies it was unclear whether the participants had periodontitis in addition to gingivitis but it was deemed likely that at least some of the participants in these studies had periodontitis; two studies involved older adults (Lopez‐Jornet 2012 (aged > 65 years) and Weitz 1992 (mean age 83)) and in the remaining 14 studies, the inclusion criteria allowed for the participants to have deep pockets and clinical attachment loss but the periodontal status of the people actually included in the study was not described. In 11 studies the participants clearly had gingivitis at baseline, but it was unclear whether the participants also had periodontitis.
Characteristics of the interventions
Nine studies compared chlorhexidine rinse and mechanical oral hygiene with mechanical oral hygiene alone.Two of these studies had additional chlorhexidine mouthrinse arms that were also included in the analysis (Jose 2015; Zimmer 2015). All of these studies except Jose 2015 also had additional arms that were not relevant to this review. Forty‐two studies compared chlorhexidine rinse with placebo or control rinse. Six of these studies had additional chlorhexidine mouthrinse arms. Data from five of these six studies were included in the analysis (Flotra 1972; Graziani 2015; Hoffmann 2001; Jayaprakash 2007; Overholser 1990; Segreto 1986). We could not include data from the three separate chlorhexidine arms for Flotra 1972 because the authors combined the three arms into one experimental group. Twenty of these 42 studies comparing chlorhexidine rinse with placebo or control rinse also had additional arms that were not relevant to this review.
Of the studies with one concentration of chlorhexidine mouthrinse, 10 evaluated 0.2% chlorhexidine mouthrinse; 29 evaluated 0.12% chlorhexidine mouthrinse; two evaluated 0.1% chlorhexidine mouthrinse (Bajaj 2011; Ernst 2005) and four evaluated 0.05% or 0.06% chlorhexidine mouthrinse (Jayaprakash 2007; Joyston‐Bechal 1993; Zimmer 2006; Zimmer 2015). Four studies had additional arms evaluating different chlorhexidine concentrations (Axelsson 1987; Flotra 1972; Hoffmann 2001; Segreto 1986) and in two studies, the concentration of the chlorhexidine rinse was not reported (Fine 1985; Turkoglu 2009).
Most of the studies evaluating 0.2% chlorhexidine mouthrinse used a volume of 10 mL twice daily for one minute whereas most of the studies evaluating 0.1% or 0.12% chlorhexidine mouthrinse used a volume of 15 mL twice daily. Duration of rinsing for the studies of 0.1% and 0.12% chlorhexidine mouthrinse varied from 30 seconds to 1 minute but most of the studies employed a 30‐second rinse. The studies of 0.05% and 0.06% chlorhexidine mouthrinse predominantly used a volume of 10 mL once or twice a day for 30 seconds. In some studies with multiple arms different volumes of rinse were used in different arms: in three studies the placebo/control arms and other non‐chlorhexidine active rinse groups rinsed with 20 mL while the chlorhexidine arms rinsed with 10 mL (Axelsson 1987) or 15 mL (Charles 2004; Overholser 1990); in another study the 0.1% chlorhexidine arm rinsed with 15 mL while the two 0.06% chlorhexidine arms used 10 mL of rinse (Hoffmann 2001).
In six studies the volume of rinse used by participants was not reported. In three of these studies participants rinsed twice daily but rinse volume and duration were not reported (Chaves 1994; Rahmani 2006; Sanz 1994). In two of the studies, participants rinsed once a day for 30 seconds with an unknown volume of rinse (Fine 1985; Zimmer 2006). In another study rinse volume, frequency and duration were not reported (Emling 1992).
Of the nine studies that compared chlorhexidine rinse and mechanical oral hygiene with mechanical oral hygiene alone, six involved regular mechanical cleaning using a toothbrush and toothpaste (Chaves 1994; Flemmig 1990; Jose 2015; Taller 1993; Zimmer 2006; Zimmer 2015). In one study floss and wood points were also used by participants (Fine 1985). In another study participants underwent conventional ultrasonic debridement (Rahmani 2006) and were given interdental cleaning aids, and participants in a further study used a toothbrush and no toothpaste (Van Strydonck 2008).
Thirty‐five of the 51 studies compared chlorhexidine mouthrinse with placebo and seven studies compared chlorhexidine mouthrinse with control. The control rinses were 5% hydroalcohol solution (Charles 2004); coloured and flavoured 5% hydroalcohol solution (Overholser 1990); 0.5% benzene alcohol (Flotra 1972); saline (Bhat 2014; Graziani 2015) and water (Bajaj 2011; Hoffmann 2001). In one of these studies comparing 0.2% chlorhexidine mouthrinse with placebo rinse, participants were instructed to brush without toothpaste before using the mouthrinse (Hase 1995). In another study comparing 0.12% chlorhexidine mouthrinse with placebo rinse, all participants used a gum care dentifrice (Blend‐a‐med) (Sanz 1994).
Thirty‐six studies reported a baseline prophylaxis to remove plaque and thus assess the potential for chlorhexidine mouthrinse to inhibit plaque accumulation and its ability to reduce gingivitis. In two of the studies that reported a baseline prophylaxis, an additional prophylaxis was also provided 2 weeks before baseline (Brecx 1993; Hoffmann 2001). In another study the baseline prophylaxis was conducted during the first week of the study (Stookey 2005). Participants in eight of the nine studies in which some or all of the participants had periodontitis at baseline either had professional prophylaxis at baseline (Chaves 1994; Ernst 2005; Graziani 2015), or adjunctive professional non‐surgical (Faveri 2006; Feres 2009; Feres 2012; Rahmani 2006) or surgical periodontal treatment (Sanz 1989) during the study. In the three studies where the participants with periodontitis had a professional prophylaxis at baseline only, scaling and polishing was supragingival (Graziani 2015) or the extent of the professional cleaning was not clear (Chaves 1994; Ernst 2005).
Participants in six studies did not have a baseline prophylaxis. These studies were thus designed to assess the potential for chlorhexidine mouthrinse to reduce plaque and gingivitis in individuals who do not obtain professional tooth cleaning or scaling prior to commencing mouthrinse use (Corbet 1997; Jayaprakash 2007; Jenkins 1993; Lopez‐Jornet 2012; Southern 2006; Weitz 1992). One of these studies included participants with untreated periodontitis (Corbet 1997). Participants in this study received no professional prophylaxis and no oral hygiene instructions. In seven studies it was not clear whether a baseline prophylaxis had been carried out (Anauate‐Netto 2014; Bajaj 2011; Bhat 2014; Emling 1992; Taller 1993; Turkoglu 2009; Zimmer 2015). In one study (Zimmer 2006), the screening examination was followed by calculus removal in the lower front teeth only. In another study, where it was not clear whether the participants had periodontitis in addition to gingivitis, there was no prophylaxis at baseline but supragingival scaling was performed at week 9 and subgingival scaling was performed after 13 weeks (Flotra 1972).
Twenty‐two studies reported that participants received some form of oral hygiene instruction. Where details were reported about the oral hygiene instruction, it usually involved instruction about toothbrushing technique. In two studies, oral hygiene instruction included instruction in the use of interdental cleaning aids (i.e. interdental brushes or dental floss or both) (Chaves 1994; Graziani 2015) and in another three studies participants were given interdental cleaning aids; presumably instruction in their use was included in the oral hygiene instruction but this not clear from the text (Fine 1985; Rahmani 2006; Taller 1993). In two studies participants were advised on duration and frequency of brushing but not technique (Pereira 2011; Van Strydonck 2008) and in another study, participants were given brief instruction about using the toothbrush they were given but were not given any instructions about duration or technique of toothbrushing (Zimmer 2006).
The participants in 27 studies did not receive any oral hygiene instruction. In 18 of these studies participants were advised to continue their usual oral hygiene practices throughout the duration of the studies. The participants in one of these 18 studies (Ferretti 1987) were undergoing bone marrow transplant and chemoradiotherapy and their usual oral hygiene regimen involved oral cleaning with a foam rubber toothbrush substitute and saline solution irrigations. In another of these studies where continuation of usual oral hygiene practices was advised, it was explicitly stated that use of interproximal cleaning devices was permitted if they were part of participants' usual oral hygiene routine (Zimmer 2015). In two studies it was not clear whether participants received oral hygiene instruction (Bajaj 2011; Stookey 2005). In one of these studies toothbrushing was supervised Monday to Friday in the mornings but it is not clear if oral hygiene instructions were provided to participants (Stookey 2005).
In 38 studies mouthrinsing was unsupervised. Mouthrinsing was fully supervised in only three studies, all conducted in a school setting (de la Rosa 1988; de la Rosa 1988b; Jayaprakash 2007). In 10 studies mouthrinsing was partially supervised for practical reasons. In five of the studies mouthrinsing was fully supervised on weekdays only (Axelsson 1987; Bajaj 2011; Bhat 2014; Lang 1998; Overholser 1990); in another two studies, mouthrinsing was supervised once a day on weekdays only (Charles 2004; Stookey 2005). In another three studies the mouthrinsing was supervised except for two weeks during the Chinese New Year (Corbet 1997); after participants were discharged from hospital (Ferretti 1987) and when participants were at military training (Hase 1998).
Thirty studies reported instructing participants to use the mouthrinse after toothbrushing. Three of these studies specified waiting 30 minutes after toothbrushing before using the mouthrinse (Feres 2012; Turkoglu 2009; Zimmer 2015). One of these studies specified waiting five timed minutes before mouthrinsing (Jose 2015). One study reported instructing participants to use mouthrinse at a separate time to toothbrushing (Charles 2004). In the remaining 20 studies the timing of mouthrinsing in relation to toothbrushing was not reported.
In most of the studies the duration of the intervention (mouthrinsing with chlorhexidine) was 6 months or less broken down as follows: 4 to 6 weeks (15 studies); 2 months (9 studies); 10 weeks (1 study); 3 months (9 studies); 4 months (2 studies) or 6 months (13 studies). In two studies the duration of the intervention was longer than 6 months; one study of 9 months' duration (Bajaj 2011) and another of 24 months' duration (Banting 1989).
In most studies the final follow‐up assessment was at the end of the intervention phase. However in four studies participants ceased mouthrinsing before the final outcome assessment. In these studies the final assessment of the outcomes was carried out 4 weeks (Faveri 2006; Ferretti 1987), 4 months (Feres 2009) and 10 months (Feres 2012) after mouthrinsing had ceased. For this review, we considered the time that mouthrinsing ceased to be the primary end point for data extraction.
Characteristics of the outcomes
Gingivitis
Gingival inflammation
Thirty‐eight studies included gingival inflammation as an outcome. The most commonly used index for measuring gingival inflammation was the Gingival Index of Löe and Silness (GI) (Löe and Silness 1963; Löe 1967). The following indices were also used to measure gingival inflammation: the Modified Gingival Index (MGI) (Lobene 1986), the Papillary Bleeding Score (PBS) (Loesche 1979), and the Papillary Marginal Gingival Index (PMGI) (de la Rosa and Sturzenberger 1976). Thirty‐one studies measured gingival inflammation using the GI; two studies used the MGI (Eaton 1997; Overholser 1990); one study used the PBS (Anauate‐Netto 2014); and four studies used the PMGI (de la Rosa 1988; de la Rosa 1988b; Ferretti 1987; Segreto 1986). In one of these studies (Segreto 1986), the PMGI was measured with visual inspection only (no probing) in addition to the GI. One study reported a total mean score for a non‐specific gingival inflammation index (Fine 1985).
Gingival bleeding
Thirty‐four studies included gingival bleeding as an outcome. The following indices were used to measure gingival bleeding: the GI (Löe and Silness 1963; Löe 1967) scores 2 and 3, the Gingival Bleeding Index of Ainamo and Bay (Ainamo and Bay 1975), the Eastman Interdental Bleeding Index (Caton and Polson 1985), the Bleeding Index/Bleeding on Marginal Probing (Saxton and van der Ouderaa 1989; van der Weijden 1994), a modification of the method described by Cowell et al (Cowell 1975), Papillary Bleeding Score (PBS) (proportion of sites with a PBS ≥ 2) (Loesche 1979) and the Papillary Bleeding Index (Muhlemann 1977; Saxer 1975).
Thirteen studies reported gingival bleeding using scores 2 and 3 from the GI. One of these studies (Southern 2006) also reported bleeding on probing after 15 seconds. Another two studies (Hase 1998; Lang 1998) measured bleeding on probing and the method used suggests that it was based on scores 2 and 3 of the GI. Three studies (Graziani 2015; Pereira 2011; Rahmani 2006) measured gingival bleeding using the Gingival Bleeding Index of Ainamo and Bay. Two studies (Brightman 1991; Overholser 1990) used the Eastman Interdental Bleeding Index. Two studies (Ernst 2005; Van Strydonck 2008) reported the Bleeding Index/Bleeding on Marginal Probing. One study (Joyston‐Bechal 1993) used a modification of the method described by Cowell et al. One study (Anauate‐Netto 2014) reported the proportion of sites with a PBS ≥ 2 and three studies (Turkoglu 2009; Zimmer 2006; Zimmer 2015) used the Papillary Bleeding Index. A further seven studies measured the proportion of sites with bleeding on probing but were not specific about the index used (Chaves 1994; Faveri 2006; Feres 2009; Feres 2012; Flemmig 1990; Hase 1995; Taller 1993); three of these studies also reported the mean proportion of sites with gingival bleeding but were not specific about the index used (Faveri 2006; Feres 2009; Feres 2012).
Plaque
Forty‐eight studies included plaque as an outcome. The majority of the studies measured dental plaque accumulation using the Plaque Index of Silness and Lӧe (Silness and Löe 1964) or the Turesky modification of the Quigley and Hein Index (TQH) (Turesky 1970). The following indices were also used to measure plaque: Soparker's modification of the TQH (Lobene 1982), the Modified Proximal Plaque Index (MPPI) (Zimmer 2005), the Quigley and Hein Plaque Index (Quigley 1962), the Approximal Plaque Index (API) (Lange 1977), a full‐mouth plaque score (FMPS) (O'Leary 1972), and the method described by Greene and Vermilion (Greene and Vermillion 1964).
Twenty‐one studies reported using the Plaque Index of Silness and Lӧe. Nineteen studies reported using TQH. One of these studies (Jose 2015) used Soparker's modification of the TQH, and one of these studies (Zimmer 2015) reported the MPPI in addition to TQH. Two studies in the same report that used the TQH (de la Rosa 1988; de la Rosa 1988b) did not report any outcome data for plaque. One study (Zimmer 2006) reported both the MPPI and the Quigley and Hein Plaque Index. The following indices were reported in one study each: the Quigley and Hein Plaque Index (Turkoglu 2009), the API (Ernst 2005), FMPS (Graziani 2015), and the method described by Greene and Vermilion (Lucas 1999). Three studies (Faveri 2006; Feres 2009; Feres 2012) measured the presence or absence of plaque accumulation but were not specific about the index used.
Adverse effects
Calculus
Twelve studies reported calculus as an outcome. Seven studies (Banting 1989; Charles 2004; Emling 1992; Flemmig 1990; Hase 1998; Overholser 1990; Sanz 1994) reported using the Volpe‐Manhold Calculus Index (Manhold 1965; Volpe 1965). Two studies (Corbet 1997; Lang 1998) reported using the Calculus Surface Index (CSI) (Ennever 1961). One study (Anderson 1997) reported using the Retention Index (Björby and Löe 1966; Löe 1967). One study (Turkoglu 2009) used a calculus index described in the National Institutes of Health (NIH) report 'Oral health of United States adults' (report not available online) and in one study the index used was not specified (Grossman 1986). In two additional studies accumulation of calculus in the chlorhexidine rinse groups was noted but not measured using an index or scale (de la Rosa 1988; de la Rosa 1988b).
Extrinsic tooth staining
Twenty‐one studies included extrinsic tooth staining as an outcome but this was measured and reported in a variety of different ways. In 16 studies, the following indices were used to measure extrinsic tooth staining: the Discolouration Index (Lobene 1968), the Discolouration Index of Lang and Räber (Lang and Räber 1981), the Shaw and Murray Index (Shaw 1977), the Gingival Modification of the Lobene Stain Index (GMSI) (Grundemann 2000; Lobene 1968), and Meckels stain grading method (Lang 1982). Seven studies (Axelsson 1987; Charles 2004; Emling 1992; Ernst 2005; Joyston‐Bechal 1993; Navarro 1998; Overholser 1990) reported the Lobene Discolouration Index. Five studies (Anderson 1997; Brecx 1993; Corbet 1997; Hoffmann 2001; Lang 1998) reported the Discolouration Index of Lang and Räber. One study (Hase 1998) reported the Shaw and Murray Index and another (Jenkins 1993) a modification of the Shaw and Murray Index. One study (Van Strydonck 2008) reported the GMSI and one study (Ferretti 1987) used Meckels stain grading method.
One study (Brightman 1991) reported using the Mean Stain Severity Index that was created at the Case Western Reserve University school of dentistry, to record intensity and area of stain. Another study (Graziani 2015) reported dividing the buccal surfaces of the eight central incisors into three areas: incisal, approximal and gingival according to Lobene 1968 and Grundemann 2000 and using a Staining Index (SI) to record the dichotomous presence or absence of staining in each area and to calculate the percentage of the total area showing staining. Three studies (Flemmig 1990; Grossman 1989; Sanz 1994) described their method of measuring tooth staining but did not specify a particular index.
Sixteen of the other included studies described information regarding tooth staining/discolouration/pigmentation reported by study participants (Anauate‐Netto 2014; Bhat 2014; Feres 2009; Hase 1995; Pereira 2011); noted by the clinicians during the clinical examination but not measured using an index or scale (de la Rosa 1988; de la Rosa 1988b; Flotra 1972; Grossman 1986; Lopez‐Jornet 2012; Turkoglu 2009; Zimmer 2006; Zimmer 2015); or listed as a reason for participant withdrawal from the studies (Banting 1989; Eaton 1997). In one study (Sanz 1989) the presence or absence of tooth staining was assessed from clinical photographs of the mandibular facial anterior teeth. We included information regarding tooth staining from these studies in meta‐analyses where possible but were unable to include participant‐reported data, data where staining of teeth were reported combined with tongue staining or denture staining or where tooth staining was reported grouped with other adverse effects.
Other adverse effects
Fourteen studies did not report any adverse effects apart from extrinsic staining of teeth or oral tissues alone or both (Brecx 1993; Brightman 1991; Ferretti 1987; Grossman 1989; Hoffmann 2001; Joyston‐Bechal 1993; Lopez‐Jornet 2012; Overholser 1990; Van Strydonck 2008; Zimmer 2015) or with calculus (Corbet 1997; Flemmig 1990; Grossman 1986; Sanz 1994). Twenty‐two studies reported at least one adverse effect relating to the chlorhexidine mouthrinse use apart from extrinsic tooth staining/staining of the oral tissues and calculus. Three studies (Chaves 1994; Feres 2009; Segreto 1986) mentioned a bitter or unacceptable taste associated with the chlorhexidine mouthrinse and no other adverse effects, except for one of the studies (Feres 2009) which also mentioned tooth staining. Adverse effects were not mentioned in six studies (Bajaj 2011; Fine 1985; Jayaprakash 2007; Rahmani 2006; Southern 2006; Weitz 1992). The remaining six studies that did not report any adverse effects or issues with acceptability of the chlorhexidine rinse indicated that there were no oral mucosal lesions (Charles 2004); no severe/serious adverse effects/events (Faveri 2006; Stookey 2005); or adverse reaction/effect (Feres 2012); no irreversible pathology (Lucas 1999); or pathology related to the chlorhexidine mouthrinse use (Taller 1993).
Excluded studies
We excluded 38 studies from the review (see 'Characteristics of excluded studies' table). Below is a summary of the reasons for excluding these studies.
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In seven studies it was not clear whether the studies were randomised and attempts to contact the authors for clarification were unsuccessful (Bay 1975; Goutham 2013; Lang 1982; Ousehal 2011; Paknejad 2006; Todkar 2012; Vechis‐Bon 1989).
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In four studies the mechanical oral hygiene procedures were not the same in the chlorhexidine rinse and comparator arms (Bouwsma 1992; Brown 2002; Madden 2008; Subhash 1985).
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In 11 studies the comparison was with another active rinse and there was no placebo/control or mechanical oral hygiene only group (Biswas 2014; CTRI 2014; Ernst 1998; Eshwar 2016; Haffajee 2009; McKenzie 1992; NCT01750801; NCT02546804; Persson 1991; Priya 2015; Radafshar 2017).
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Four studies were excluded because the chlorhexidine arm included another active agent that the comparator arms did not have. We would have been unable to separate the effect of the chlorhexidine rinse from the effect of the other active agent (Cortelli 2015; Luoma 1978; Quirynen 2005; Quirynen 2006).
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In one study the chlorhexidine arm received a more intensive intervention including cognitive behavioural education (2 hours) compared to the control arm who received standard care (Persson 1998). In another study (Caton 1993) the chlorhexidine arm received oral hygiene instructions but the control arm did not. The mechanical oral hygiene procedures were potentially not the same in both arms in these two studies.
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One study was unpublished and we were unable to obtain a copy of the study despite following up several lines of enquiry (Segreto 1993).
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In one study, it was not clear from the published report whether the study was a randomised trial. Additional information obtained from the contact author indicated quasi‐randomisation (participants were assigned to groups according to the order that they came to the University) (Leyes Borrajo 2002).
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One study was reported in an abstract. The authors were contacted but they did not have access to the data (Saltini 1988).
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One study compared chlorhexidine, zinc and placebo mouthrinses but each rinse arm was further split into those who received a professional prophylaxis prior to the start of the study and those that did not. The study outcomes were not reported in a format that could be used in the review and the authors of the study were unable to provide any additional data (Fischman 1975).
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In one study (Nadkerny 2015) the duration of rinsing was only 15 days and this was not apparent until the full text of the paper was reviewed.
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In three studies we had concerns about the duplication of outcome data in different studies from the same research group (Gupta 2014; Gupta 2015; Karim 2014) and contact with the authors failed to provide an adequate explanation or reassurance. Another study from this research group was excluded due to these concerns (Gupta 2015a).
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One study was excluded because the chlorhexidine mouthrinse was not used as an adjunct to regular mechanical oral hygiene (Yates 2002).
Risk of bias in included studies
Allocation
Random sequence generation
Nineteen studies reported sufficient details of the method of random sequence generation to allow us to assign a judgement of low risk of bias. The remaining 32 studies either stated that participants were randomised to groups, with no further details, or gave an inadequate description of the method. For these studies, we assigned a judgement of unclear risk of bias.
Allocation concealment
Eleven studies described various methods of allocation concealment which implied that the random sequence was adequately protected and administered as it was generated, thus we assigned a judgement of low risk of bias. Two studies were rated as being at high risk of bias because personnel involved in the studies used a random number table to assign participants to groups, and could have foreseen upcoming assignments (Faveri 2006; Fine 1985). The remaining 38 studies did not report sufficient information on the randomisation process to allow a judgement of either low or high risk of bias, so we assigned a judgement of unclear risk of bias to them.
Overall, seven studies had a rating of low risk of bias for the two above domains, and therefore were at low risk of selection bias. The two studies that had a rating of high risk of bias for allocation concealment were therefore at high risk of selection bias. The remaining 42 studies were at unclear risk of bias.
Blinding
The majority of studies contained a placebo arm with the intention of blinding participants and personnel. However, we considered blinding unlikely to be successful due to the propensity for chlorhexidine to stain the teeth and oral tissues and the association of its use with clinically apparent adverse effects such as mucosal desquamation and mucosal lesions.
Blinding of participants and personnel (performance bias)
Forty‐one studies were assigned a judgement of high risk of bias either because staining or adverse events were reported at a higher rate in the chlorhexidine arms, or because a placebo comparison was not used and therefore no blinding was attempted. In these studies, participants could be aware of their allocated intervention and this could have affected their motivation and oral health behaviour. Two studies were assigned a judgement of low risk of bias as there was no difference in staining between the groups, so the blinding appeared to have been maintained (Ferretti 1987; Lopez‐Jornet 2012). In the remaining eight studies, blinding was intended through the use of placebo but staining was not reported, so there was insufficient information on which to base a judgement. We rated these studies as being at unclear risk of bias.
Blinding of outcome assessment (detection bias)
Thirty‐three studies were assigned a judgement of high risk of bias because the outcomes assessors could have noticed the higher rates of staining or adverse events or both in the chlorhexidine arms. Five studies were rated as having low risk of bias. Two of these studies showed no difference in staining between groups (Axelsson 1987; Lopez‐Jornet 2012). Two studies used masking strategies (whereby a subset of participants were assessed with and without plastic tooth covers and painting of the tongue with food dyes) which revealed that measurements of gingivitis were no different when an examiner thought the participant had received chlorhexidine or not (Grossman 1986; Grossman 1989). One study performed a sensitivity analysis on participants with no visible side effects, which showed no difference to the analysis including all participants, and we judged that bias had not affected the results (Zimmer 2006). We rated the remaining 13 studies at unclear risk of bias because extrinsic tooth staining was not reported. These studies either implied that the outcome assessors were blinded, or did not discuss it, but in any case it was not possible to judge whether or not any blinding could have been successful.
Incomplete outcome data
We did not have any concerns regarding attrition bias in 23 studies, so we rated them as at low risk of bias. Nineteen studies were assigned a judgement of high risk of bias due to either a high overall proportion of attrition, differences in the proportion of attrition between groups, or because the reasons for attrition differed between groups and were linked to the intervention. The remaining nine studies were rated as unclear because the numbers per group at either baseline or evaluation were not reported, thus preventing us from calculating the attrition.
Selective reporting
Fourteen studies adequately reported all expected and planned outcomes, so we rated them as having low risk of bias. The remaining 37 studies were rated at high risk of bias, mainly due to lack of reporting of measures of variance along with the means for each group, and no reporting of tooth staining and other adverse effects.
Other potential sources of bias
Eleven studies were assigned a judgement of low risk of bias. Three studies were assigned a judgement of high risk of bias due to baseline imbalances between groups in important prognostic factors or outcomes of the review or both (Bajaj 2011; Graziani 2015; Sanz 1989). The remaining 37 studies were rated as unclear due to a lack of reporting of details of either calibration of outcome assessment or baseline measurements, meaning that we were unable to assess the potential for differential measurement of outcomes or baseline imbalances respectively.
Overall risk of bias
Fifty studies were at high risk of bias overall as they had at least one domain rated at high risk of bias. One study was rated at unclear risk of bias overall as it had at least one domain rated at unclear risk of bias, but with no domains rated at high risk of bias (Lopez‐Jornet 2012). A summary of the risk of bias of the included studies is presented in Figure 2.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Effects of interventions
See: Summary of findings 1 Summary of findings
Chlorhexidine rinse versus placebo/control rinse or no intervention
Gingivitis
Gingival Index of Löe and Silness
At 4 to 6 weeks, eight studies analysing 466 participants (seven at high and one at unclear risk of bias) comparing chlorhexidine rinse with placebo or control rinse and two studies analysing 339 participants (both at high risk of bias) comparing chlorhexidine with no rinse, presented data using the Gingival Index (GI) of Löe and Silness (Löe 1967; Löe and Silness 1963) (Analysis 1.1). The mean GI score across the control groups ranged from 0.17 to 1.4 with a mean of 0.93 and a median of 1. There was no clear difference between the placebo/control and no rinse control subgroups (P = 0.33). The pooled effect estimate of the comparison for all trials showed a reduction in gingivitis in favour of chlorhexidine rinse (mean difference (MD) ‐0.21, 95% confidence interval (CI) ‐0.31 to ‐0.11, P < 0.0001) demonstrating a moderate effect (GI on 0 to 3 increasing scale). There was substantial heterogeneity between the studies (P = 0.001; I2 = 67%).
There was no clear difference between the different control group subgroups at 6 months (P = 0.11). The overall effect estimate showed a reduction in gingivitis in favour of the chlorhexidine rinse (MD ‐0.20, 95% CI ‐0.30 to ‐0.11, P < 0.0001, 13 high risk of bias studies, 2616 participants) (Analysis 1.2). The mean GI score across the control groups ranged from 0.1 to 1.25 with a mean of 0.8 and a median of 0.7. There was considerable heterogeneity (P < 0.00001; I2 = 96%).
There were insufficient data to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with higher mean GI scores of 1.1 to 3 (moderate or severe levels of gingival inflammation).
Investigation of heterogeneity
We undertook an investigation of the reasons for heterogeneity for the GI scores, at both 4 to 6 weeks and 6 months, for the following subgroups: adults compared to children; baseline gingivitis alone compared to gingivitis and periodontitis at baseline; prophylaxis/scale and polish at baseline compared to none; baseline mean gingivitis score < 1 versus scores ≥ 1, by undertaking metaregression in Stata version 14 (Stata 2015) (Additional Table 1; Table 2). The only subgroup analysis that was significant (P = 0.045) was for prophylaxis or not at 6 months, where the trials including a prophylaxis had a lesser effect for the chlorhexidine rinse than those without. This may explain some of the heterogeneity at 6 months.
| Characteristic | Number of studies | Slope estimate | 95% CI | Slope interpretation | P value |
|---|---|---|---|---|---|
| Adults versus children | 10 ‐ no studies with just children | ||||
| Gingivitis alone versus gingivitis with perio | 8 | 0.12 | ‐0.14 to 0.38 | Increase in GI effect estimate for gingivitis and perio | 0.30 |
| Prophylaxis or not | 9 | 0.05 | ‐0.22 to 0.32 | Increase in GI effect estimate for prophylaxis | 0.66 |
| Baseline gingivitis < 1 versus > 1 | 9 | 0.02 | ‐0.25 to 0.30 | Increase in GI effect estimate for higher baseline score | 0.84 |
CI = confidence interval.
| Characteristic | Number of studies | Slope estimate | 95% CI | Slope interpretation | P value |
|---|---|---|---|---|---|
| Adults versus children | 13 | ‐0.17 | ‐0.42 to 0.09 | Increase in GI effect estimate for adults | 0.185 |
| Gingivitis alone versus gingivitis with perio | 9 | 0.15 | ‐0.14 to 0.44 | Increase in GI effect estimate for gingivitis and perio | 0.25 |
| Prophylaxis or not | 11 | ‐0.13 | ‐0.25 to ‐0.004 | Increase in GI effect estimate for no prophylaxis | 0.045 |
| Baseline gingivitis < 1 versus > 1 | 9 | ‐0.05 | ‐0.39 to 0.30 | Decrease in GI effect estimate for higher baseline score | 0.75 |
CI = confidence interval.
Chlorhexidine concentration and frequency of rinsing
At 4 to 6 weeks there was no difference between the studies with concentrations of 0.2% and 0.1%/0.12% chlorhexidine, and there was an insufficient number of studies in the concentration subgroups at 6 months to undertake the analysis (Additional Table 3). Participants in one study included in the meta‐analysis for 4 to 6 weeks for the GI rinsed once a day, participants in the other studies rinsing twice per day so we were unable to undertake an analysis. Participants in two studies at 6 months rinsed once per day compared with 11 rinsing twice but there was no difference between these subgroups (P = 0.56, Additional Table 4).
| Outcome (index) | Time | Chlorhexidine concentration | Studies (participants) | MD/SMD 95% CI | Effect P value | Subgroup P value |
|---|---|---|---|---|---|---|
| Gingival inflammation (Gingival Index) | 4 to 6 weeks | 0.2 | 6 (552) | MD ‐0.27 (‐0.46 to ‐0.09) | 0.003 favours CHX | 0.41 |
| 0.1 and 0.12 | 5 (253) | MD ‐0.19 (‐0.27 to ‐0.10) | < 0.0001 favours CHX | |||
| Gingival inflammation (Gingival Index) | 6 months | 0.2 | 1 (86) | MD ‐0.12 (‐0.20 to ‐0.04) | 0.005 | Too few studies in subgroup |
| 0.1 and 0.12 | 10 (2352) | MD ‐0.22 (‐0.33 to ‐0.11) | < 0.00001 favours CHX | |||
| 0.05 | 1 (150) | MD ‐0.04 (‐0.11 to 0.03) | 0.28 | |||
| Gingival bleeding | 4 to 6 weeks | 0.2 | 4 (472) | SMD ‐0.71 (‐0.90 to ‐0.51) | < 0.00001 favours CHX | 0.18 |
| 0.1 and 0.12 | 3 (127) | SMD ‐0.32 (‐0.85 to 0.21) | 0.23 | |||
| Gingival bleeding | 6 months | 0.2 | 2 (155) | SMD ‐1.20 (‐2.48 to 0.08) | 0.07 | 0.34 |
| 0.12 | 6 (977) | SMD ‐0.57 (‐0.79 to ‐0.36) | < 0.00001 favours CHX | |||
| Plaque | 4 to 6 weeks | 0.2 | 8 (685) | SMD ‐1.75 (‐2.45 to ‐1.04) | < 0.00001 favours CHX | 0.04 |
| 0.1 and 0.12 | 4 (215) | SMD ‐0.95 (‐1.23 to ‐0.66) | < 0.00001 favours CHX | |||
| Plaque | 6 months | 0.2 | 2 (149) | SMD ‐1.26 (‐1.61 to ‐0.90) | < 0.00001 favours Chx | 0.65 |
| 0.1 and 0.12 | 8 (1898) | SMD ‐1.38 (‐1.75 to ‐1.00) | < 0.00001 favours CHX | |||
| Calculus | 4 to 6 weeks | 0.12 | 1 (52) | MD 0.01 (‐0.21 to 0.23) | 0.93 | |
| Calculus | 7 to 12 weeks | 0.2 | 2 (159) | SMD ‐0.03 (‐0.43 to 0.36) | 0.86 | 0.05 |
| 0.12 | 4 (266) | SMD 0.52 (0.13 to 0.91) | 0.10 | |||
| Calculus | 6 months | 0.2 | 2 (149) | SMD 0.41 (0.09 to 0.74) | 0.01 | 0.005 |
| 0.12 | 2 (174) | SMD 1.17 (0.76 to 1.59) | < 0.00001 favours control | |||
| Tooth staining | 4 to 6 weeks | 0.2 | 2 (116) | SMD 1.45 (1.04 to 1.87) | < 0.00001 favours control | 0.05 |
| 0.1 and 0.12 | 6 (299) | SMD 0.96 (0.68 to 1.24) | < 0.00001 favours control | |||
| Tooth staining | 7 to 12 weeks | 0.2 | 3 (181) | SMD 1.38 (1.05 to 1.71) | < 0.00001 favours control | 0.10 |
| 0.12 | 7 (361) | SMD 1.2 (0.96 to 1.45) | < 0.00001 favours control | |||
| 0.05 | 1 (39) | SMD 0.59 (‐0.05 to 1.24) | 0.07 | |||
| Tooth staining | 6 months | 0.2 | 2 (149) | SMD 1.79 (1.41 to 2.17) | < 0.00001 favours control | 0.08 |
| 0.12 | 2 (174) | SMD 1.33 (1.00 to 1.66) | < 0.00001 favours control |
CHX = chlorhexidine; CI = confidence interval; MD = mean difference; SMD = standardised mean difference.
Studies where the concentration of the chlorhexidine mouthrinse was not reported (Turkoglu 2009) and where data relate to a combination of different chlorhexidine concentrations (Flotra 1972) were excluded from this analysis. Therefore, in certain analyses, the number of studies and participants presented in the table are different from the data presented in the main analysis.
| Outcome (index) | Time | Chlorhexidine frequency | Studies (participants) | MD/SMD 95% CI | Effect P value | Subgroup P value |
|---|---|---|---|---|---|---|
| Gingival inflammation (Gingival Index) | 4 to 6 weeks | Twice per day | 9 (785) | MD ‐0.22 (‐0.33 to ‐0.11) | < 0.0001 | Too few studies in subgroup |
| Once per day | 1 (20) | MD ‐0.13 (‐0.31 to 0.06) | 0.18 | |||
| Gingival inflammation (Gingival Index) | 6 months | Twice per day | 11 (1614) | MD ‐0.17 (‐0.20 to ‐0.13) | < 0.0001 | 0.56 |
| Once per day | 2 (1002) | MD ‐0.34 (‐0.93 to 0.25) | 0.26 | |||
| Gingival bleeding | 4 to 6 weeks | Twice per day | 8 (649) | SMD ‐0.56 (‐0.79 to ‐0.33) | < 0.0001 | ‐ |
| Gingival bleeding | 6 months | Twice per day | 8 (1132) | SMD ‐0.72 (‐1.02 to ‐0.42) | < 0.0001 | ‐ |
| Plaque | 4 to 6 weeks | Twice per day | 11 (930) | SMD ‐1.49 (‐1.97 to ‐1.02) | < 0.0001 | Too few studies in subgroup |
| Once per day | 1 (20) | SMD ‐0.92 (‐1.86 to 0.02) | 0.05 | |||
| Plaque | 6 months | Twice per day | 10 (1223) | SMD ‐1.34 (‐1.66 to ‐1.03) | < 0.0001 | Too few studies in subgroup |
| Once a day | 1 (852) | SMD ‐2.10 (‐2.27 to ‐1.93) | < 0.0001 | |||
| Calculus | 4 to 6 weeks | Twice per day | 1 (50) | MD 0.03 (‐0.11 to 0.17) | 0.70 | ‐ |
| Calculus | 7 to 12 weeks | Twice per day | 5 (373) | SMD 0.33 (‐0.11 to 0.77) | 0.14 | ‐ |
| Calculus | 6 months | Twice per day | 4 (323) | SMD 0.80 (0.33 to 1.26) | 0.0007 | ‐ |
| Tooth staining | 4 to 6 weeks | 3 times per day | 1 (33) | SMD 1.55 (0.76 to 2.34) | < 0.0001 | Too few studies in subgroup |
| Twice per day | 5 (310) | SMD 1.18 (0.93 to 1.44) | < 0.0001 | |||
| Once per day | 1(20) | SMD 0.39 (‐0.5 to 1.28) | 0.39 | |||
| Tooth staining | 7 to 12 weeks | 3 times per day | 1 (33) | SMD 0.77 (0.06 to 1.48) | 0.03 | Too few studies in subgroup |
| Twice per day | 9 (496) | SMD 1.26 (1.04 to 1.49) | < 0.0001 | |||
| Tooth staining | 6 months | Twice per day | 4 (323) | SMD 1.54 (1.22 to 1.86) | < 0.0001 | ‐ |
CI = confidence interval; MD = mean difference; SMD = standardised mean difference.
Other data
Meta‐analyses of studies comparing chlorhexidine rinse with placebo or control rinse after 7 to 12 weeks and > 6 months of rinsing (all at high risk of bias), using the GI of Löe and Silness (Löe 1967; Löe and Silness 1963), showed an effect size similar to the 4 to 6 weeks and 6 month studies (MD ‐0.47, 95% CI ‐0.76 to ‐0.18 and MD ‐0.50, 95% CI ‐1.11 to 0.11 respectively). The uncertainty around the effect estimate at > 6 months (two studies of 9 and 24 months duration) is reflected in the 95% CI. Furthermore, there was considerable heterogeneity in both meta‐analyses (P < 0.0001, I2 = 86%; P < 0.0001, I2 = 99% respectively) (Additional Table 5).
| Outcome (index) | Time | Chlorhexidine conc (%) | Studies (participants) | MD/SMD 95% CI | Effect P value | Heterogeneity |
|---|---|---|---|---|---|---|
| Results for studies with no rinse control arms | ||||||
| Gingival bleeding | 7 to 12 weeks | < 0.1 | 2 (196) | MD ‐0.07 (‐0.16 to 0.02) | 0.13 favours CHX | P = 0.19, I2 = 40% |
| Plaque | 7 to 12 weeks | < 0.1 | 2 (196) | SMD ‐0.77 (‐1.07 to ‐0.47) | < 0.00001 favours CHX | P = 0.61, I2 = 0% |
| Results for studies with placebo/control rinse arms | ||||||
| Gingival inflammation (Gingival Index) | 7 to 12 weeks | 0.2 and 0.12 | 4 (144) | MD ‐0.47 (‐0.76 to ‐0.18) | 0.001 favours CHX | P < 0.0001, I2 = 86% |
| Gingival inflammation (Gingival Index) | > 6 months | 0.1 and 0.12 | 2 (1124) | MD ‐0.50 (‐1.11 to 0.11) | 0.11 favours CHX | P < 0.0001, I2 = 99% |
| Gingival bleeding | 7 to 12 weeks | 0.12 and < 0.1 | 5 (182) | SMD ‐1.29 (‐1.85 to ‐0.72) | < 0.00001 favours CHX | P = 0.02, I2 = 64% |
| Gingival bleeding | Long term | 0.12 | 3 (99) | MD ‐0.12 (‐0.2 to ‐0.04) | 0.003 favours CHX | P = 0.33, I2 = 11% |
| Plaque | 7 to 12 weeks | 0.2, 0.12 and < 0.1 | 10 (423) | SMD ‐1.74 (‐2.51 to ‐0.98) | < 0.00001 favours CHX | P < 0.00001, I2 = 91% |
| Plaque | > 6 months | 0.1 | 1 (852) | MD ‐1.55 (‐1.79 to ‐1.31) | < 0.00001 favours CHX | N/A |
| Plaque | Long term | 0.12 | 4 (132) | SMD ‐1.10 (‐1.18 to ‐0.40) | < 0.002 favours CHX | P = 0.02, I2 = 71% |
CHX = chlorhexidine; CI = confidence interval; conc = concentration; MD = mean difference; N/A = not applicable; SMD = standardised mean difference.
There were no subgroup differences between the different chlorhexidine concentrations, therefore the overall effect for all concentrations combined is reported.
One 4‐week study (Anauate‐Netto 2014) at high risk of bias that was not included in the meta‐analysis found no statistically significant differences in Papillary Bleeding Score (Loesche 1979) between the chlorhexidine (0.12%) and placebo group. Three studies (Fine 1985; Hoffmann 2001; Overholser 1990) at high risk of bias, reporting gingival inflammation at 4 to 6 months were not included in the meta‐analysis. Two of the three studies found a reduction in the GI (P = 0.043) (Hoffmann 2001) and the modified GI (P < 0.001) (Overholser 1990) for the 0.1% and 0.12% chlorhexidine groups respectively compared to the control rinse (Additional Table 6). Results for 7 to 12 weeks studies not included in meta‐analyses are supportive of a reduction in gingival inflammation associated with chlorhexidine mouthrinse use (Additional Table 6).
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Anauate‐Netto 2014 | CHX 0.12% vs placebo | PBS | 0.9 (0.6) | 0.7 (0.4) | 40 | Did not report GI. Quote: "..no statistically significant differences were detected among groups" |
| 7 to 12 weeks | Anderson 1997 | CHX 0.12% vs placebo | GI | 0.345 | 0.895 | 28 | Reported mean GI by surface + SD. No overall SD. We calculated overall mean. Quote: "The means of the …gingival indices did not show any significant differences (P<0.05) 1 or 2 months after baseline. However there were significant differences (P<0.05) in the changes recorded at 30 and 60 days at all sites in…..the experimental group" |
| de la Rosa 1888b | CHX 0.12% vs placebo | PMGI severity (mean score of all sites graded) | 0.1413 | 0.2902 | 92 | Did not report GI or a SD. Quote: "..the effect of the chlorhexidine rinse on the occurrence and severity of gingivitis amounted to a 51% reduction of the disease compared to the placebo rinse…differences were statistically significant" | |
| de la Rosa 1988a | CHX 0.12% vs placebo | PMGI severity (mean score of all sites graded) | 0.2892 | 0.4526 | 99 | Did not report GI or a SD. Quote: "..the gingivitis reductions were 34% and 36% for occurrence and severity respectively…differences were statistically significant" | |
| Eaton 1997 | CHX 0.12% vs placebo | mGI | 0.42 (0.383) | 0.55 (0.382) | 98 | Did not report GI. Quote: "..the pooled mean mGI score improved by 25% from 0.56 at baseline to 0.42 at 12 weeks in the ChD (CHX) group but showed no change (0.54 to 0.55) in the placebo group" | |
| Ferretti 1987 | CHX 0.12% vs placebo | PMGI | 0.8 | 1.94 | 33 | Did not report GI and SD depicted in graph but not reported. Quote: "Significant reductions in …gingivitis scores were seen on days 33 (P<0.0001) and 60… (P<0.001) for those patients using chlorhexidine rinse" | |
| Segreto 1986 | 0.2% vs 0.12% vs placebo | GI | 0.4112/0.3640 | 0.5039 | 454 | Did not report a SD. Quote: "Gingivitis severity by the GI method was… significantly lower at 3 months for both chlorhexidine groups compared to the placebo group. Differences ranged from 28‐46% and averaged 37% for the 0.12% group. Differences ranged from 18‐40% for the 0.20% group and averaged 29%" | |
| Weitz 1992 | CHX 0.12% vs placebo | GI | 1.69 | 1.86 | 36 | Did not report a SD. Quote: "…the active (CHX) groups had significantly lower… gingivitis scores than the respective control groups. Overall, the active group had a 10.27% reduction in the gingival index…compared to insignificant changes in the control groups" | |
| 6 months | Fine 1985 | CHX+OH vs OH | Not clear. Quote: "a gingival inflammation Index" | NR | NR | 83 | Outcomes reported in graphs which are difficult to decipher. Quote: "Whilst there was a general improvement in all… groups of patients, no one group was statistically significantly different from the other…" |
| Hoffmann 2001 | CHX 0.1%, CHX 0.06%, CHX 0.06%+F vs control | GI | Median 0.15/0.29/0.34 | Median 0.45 | 58 | No SD. At 3 months "..only the 0.1% CHX was different from the control". At 6 months "…the 0.1% CHX showed significant differences…in the GI…when compared to the 0.06% CHX/F" (P = 0.043) | |
| Overholser 1990 | CHX 0.12% vs control | mGI | 0.81 (SE 0.065) | 1.166 (SE 0.063) | 83 | Did not report a SD. Quote: "PX (CHX) inhibited gingivitis development by 26.8% (P<0.001) at 3 months and by 30.5% (P<0.001) at 6 months, compared to the control" |
CHX = chlorhexidine; F = fluoride; NR = not reported; OH = oral hygiene; SD = standard deviation; SE = standard error.
Total n is the number of participants analysed in the study arms relevant to the review.
PBS (Papillary Bleeding Score, Loesche 1979) is measured on a 0‐5 increasing scale.
GI (Gingival Index, Löe 1967; Löe and Silness 1963) is measured on a 0‐3 increasing scale.
PMGI (Papillary Marginal Gingivitis Index, de la Rosa and Sturzenberger 1976) is measured on a 0‐3 increasing scale.
mGI (modified Gingival Index, Lobene 1986) is measured on a 0‐4 increasing scale.
Gingival bleeding
A variety of different indices were used to measure gingival bleeding, therefore standardised mean differences (SMD) are presented. There was no clear difference between the placebo/control and the no rinse subgroups at either 4 to 6 weeks or 6 months (Analysis 1.3; Analysis 1.4). At 4 to 6 weeks, eight studies analysing 649 participants (all at high risk of bias) comparing chlorhexidine rinse with placebo/control or with no rinse that reported gingival bleeding were combined in a meta‐analysis. The overall effect estimate for all studies, both placebo/control and no rinse controls, was moderate at 4 to 6 weeks (SMD ‐0.56, 95% CI ‐0.79 to ‐0.33) showing a reduction in gingival bleeding in favour of the chlorhexidine rinse (P < 0.00001). There was evidence of moderate heterogeneity (P = 0.16; I2 = 34%).
At 6 months, eight studies analysing 1132 participants (all at high risk of bias) reported gingival bleeding and were combined in a meta‐analysis. The overall effect estimate for all studies was also moderate at 6 months (SMD ‐0.72, 95% CI ‐1.02 to ‐0.42), showing a reduction in gingival bleeding in favour of the chlorhexidine rinse (P < 0.00001). There was evidence of considerable heterogeneity between the studies at 6 months (P < 0.00001; I2 = 81%).
Chlorhexidine concentration and frequency of rinsing
No statistically significant differences were found between the subgroups with different chlorhexidine concentrations, at 4 to 6 weeks and 6 months (Additional Table 3). At both 4 to 6 weeks and 6 months all participants in the included studies for gingival bleeding were instructed to rinse twice per day, so no analysis for the effect of frequency of rinsing could be undertaken (Additional Table 4).
Other data
A meta‐analysis of two studies (both at high risk of bias) analysing 196 participants comparing chlorhexidine rinse with no rinse controls using the Papillary Bleeding Index (Muhlemann 1977; Saxer 1975) after 8 weeks of rinsing showed no evidence of a difference in gingival bleeding (MD ‐0.07, 95% CI ‐0.16 to 0.02) (Additional Table 5).
Another meta‐analysis of five studies (all at high risk of bias) analysing 182 participants comparing chlorhexidine rinse with placebo rinse using a variety of different gingival bleeding indices after 7 to 12 weeks of rinsing showed a strong effect in favour of the chlorhexidine rinse (SMD ‐1.29, 95% CI ‐1.85 to ‐0.72, P < 0.00001). There was evidence of substantial heterogeneity (P = 0.02; I2 = 64%) (Additional Table 5).
Three studies analysing 99 participants (all at high risk of bias) comparing chlorhexidine rinse with placebo rinse, using bleeding on probing, presented longer‐term data 1, 4 and 10 months after chlorhexidine mouthrinsing had ceased and were combined in a meta‐analysis that showed a small retained effect in favour of chlorhexidine (MD ‐0.12, 95% CI ‐0.20 to ‐0.04) (Additional Table 5).
Three studies (Axelsson 1987; Graziani 2015; Sanz 1989) at high risk of bias reporting gingival bleeding at 4 to 6 weeks were not included in the meta‐analysis (Additional Table 7). All three studies reported a reduction in gingival bleeding for 0.1%, 0.12% and 0.2% chlorhexidine rinses compared to placebo or control rinse.
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Axelsson 1987 | CHX 0.2% vs CHX 0.1% vs placebo | Mean % of gingival units with GI score 2 or 3 | 12%/11% | 25% | 64 | Did not report a SD. Quote: "In all…study groups, the % of gingival units scored GI 2+3 was reduced between baseline..and end of trial" |
| Graziani 2015 | CHX 0.2%+Alc vs CHX 0.2% no Alc vs CHX+ADS vs control rinse | FMBS /BOP | Not clear | 13.47% | 70 | Partial reporting of outcome data. Quote: "Statistically significant decreases in mean full‐mouth scores of gingival inflammation were noted for all experimental study groups at day 35 compared to baseline. Between‐group changes in FMBS…were statistically significant only when CHX2 (mean difference of 43.4 ± 22.4, P = 0.05) and CHX 3 (mean difference of 46.1 ± 23.1, P = 0.05) were compared to the CTRL group" (note: CHX 2 = CHX no Alc, CHX 3 = CHX + ADS) | |
| Sanz 1989 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 18.78% | 31.31% | 38 | Did not report a SD. Quote: "Beginning at 4 weeks of rinsing, gingival bleeding was significantly lower in the CHX group compared to the placebo group by an average of 41.6% (P < 0.05). At 6 weeks that reduction was 40%, (P < 0.05)" | |
| 7 to 12 weeks | Corbet 1997 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 27%(anterior) 42%(posterior) | 52%(anterior) 75%(posterior) | 36 | Did not report a SD. Quote: "The difference between the mean percentage of GB of the test and control groups at 3 months was highly significant (P < 0.001)" |
| Segreto 1986 | CHX 0.2% vs CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | Examiner A: 3.4%/2% Examiner B: 7.2%/6.2% | Examiner A: 3.81% Examiner B: 14.9% | 454 | Did not report a SD. O.2% Quote: "Bleeding was 31% lower (range 11‐52%) compared to the placebo group" (P > 0.05) 0.12% Quote: "..gingival bleeding was significantly lower by an average of 53% for both examiners (range 48‐59%)" (P ≤ 0.05) | |
| 6 months | Banting 1989 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 2.41% | 4.12% | 383 | Did not report a SD. Regarding outcomes at 6 months to 2 years: Quote: "Subjects in the treatment group…displayed between 42% and 51% fewer sites with moderate to severe gingivitis (GI scores of 2 or 3) compared with subjects in the control group" (P < 0.0001) |
| Charles 2004 | CHX 0.12% vs control | Mean % sites GI score 2 and 3 | 11.01% | 20.65% | 1156 sites | % of bleeding sites in each group is presented. There is a unit of analysis error (number of sites rather than number of subjects). Quote: "There was a considerable reduction in percent bleeding sites in the chlorhexidine…groups at 6 months compared with both control and baseline" | |
| Lucas 1999 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 1% | 4.2% | 20 | Did not report a SD. Quote: "Although the percentage of bleeding surfaces in the chlorhexidine group was less than in the placebo group on days 90 (33%) and 180 (76%), the differences were not significant" (P = 0.07) | |
| Sanz 1994 | CHX 0.12% vs placebo | % sites GI score 2 and 3 | Graph | Graph | 130 | % bleeding sites reported incompletely in text and also in a graph. Did not report a SD. Quote: "At 6 months…the positive control group had significantly fewer bleeding sites than the control group (.. 23%...)" | |
| Gingival bleeding > 6 months | Banting 1989 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 4.41% | 8.88% | 272 | Did not report a SD. Regarding outcomes at 6 months to 2 years: Quote: "Subjects in the treatment group…displayed between 42% and 51% fewer sites with moderate to severe gingivitis (GI scores of 2 or 3) compared with subjects in the control group" (P < 0.0001) |
ADS = antidiscolouration system; Alc = alcohol; BOP = bleeding on probing; CHX = chlorhexidine; FMBS = Full‐Mouth Bleeding Score; GI = Gingival Index; SD = standard deviation.
Total n is the number of participants analysed in the study arms relevant to the review.
Four studies (Banting 1989; Charles 2004; Lucas 1999; Sanz 1994) at high risk of bias reporting gingival bleeding at 6 months were not included in the meta‐analysis (Additional Table 7). Three of these studies reported a reduction in gingival bleeding for 0.12% chlorhexidine rinse compared to placebo or control rinse. Banting 1989 demonstrated a reduction in gingival bleeding at 2 years for 0.12% chlorhexidine compared to placebo (P < 0.0001). Results for 7 to 12 weeks studies not included in meta‐analyses are supportive of a reduction in gingival bleeding associated with chlorhexidine mouthrinse use (Additional Table 7).
Plaque
A variety of different indices were used to measure plaque, therefore SMDs are presented. There was no difference between the placebo/control or no rinse control subgroups for plaque at 4 to 6 weeks (P = 0.93) (Analysis 1.5). The overall effect was based on 12 trials analysing 950 participants, 11 at high and one at unclear risk of bias, and showed a large effect in favour of chlorhexidine rinse (SMD ‐1.45, 95% CI ‐1.90 to ‐1.00). Four of these trials analysing 223 participants reported the Plaque Index (0 to 3 increasing scale) (Silness and Löe 1964) and showed a reduction in plaque in favour of chlorhexidine rinse (MD ‐0.58, 95% CI ‐0.78 to ‐0.39) (Analysis 1.6); five of these trials analysing 546 participants reported the Turesky modification of the Quigley Hein Index (0 to 5 increasing scale) (Turesky 1970) and also showed a reduction in plaque in favour of chlorhexidine rinse (MD ‐0.78, 95% CI ‐0.85 to ‐0.70) (Analysis 1.7).
At 6 months, although both subgroups showed a reduction in plaque favouring the chlorhexidine rinse (Analysis 1.8), there was a difference between the size of the effect estimates for the placebo/control and no rinse subgroups (P = 0.02). The higher estimate for the chlorhexidine rinse compared to placebo/control rinse based on nine trials analysing 1933 participants (all at high risk of bias) with a large effect (SMD ‐1.59, 95% CI ‐1.89 to ‐1.29) is compared with a moderate effect for the chlorhexidine rinse compared to no rinse control groups based on 2 trials analysing 142 participants (both at high risk of bias) (SMD ‐0.68, 95% CI ‐1.35 to ‐0.01). There was substantial heterogeneity among the studies in each subgroup (P < 0.00001; I2 = 84%; P = 0.06; I2 = 72% for placebo/control and no rinse subgroups respectively). Five studies analysing 1108 participants reported data for the Plaque Index at 6 months. There was no clear difference between the placebo/control and no rinse subgroups, and the overall effect was ‐0.62 (95% CI ‐1.12 to ‐0.12) (Analysis 1.9). Six trials, all with placebo/no treatment controls, analysing 967 participants reported the Turesky modification of the Quigley Hein Index at 6 months and also showed a reduction in plaque in favour of chlorhexidine rinse (MD ‐0.73, 95% CI ‐0.88 to ‐0.57) (Analysis 1.10).
Chlorhexidine concentration and frequency of rinsing
No differences were found between the subgroups with different chlorhexidine concentrations (Additional Table 3). At 4 to 6 weeks the participants in one trial were instructed to rinse once per day compared with twice a day in the other 11 trials so no analysis for the effect of frequency of rinsing could be undertaken. Similarly at 6 months the participants in one trial were instructed to rinse once per day compared with twice a day in the other 10 trials so no analysis for the effect of frequency of rinsing could be undertaken (Additional Table 4).
Other data
Meta‐analyses of studies that compared chlorhexidine mouthrinse with placebo (10 studies all at high risk of bias analysing 423 participants) or no rinse control (two studies both at high risk of bias analysing 196 participants) at 7 to 12 weeks showed a reduction in plaque (using various indices) in favour of chlorhexidine rinse (SMD ‐1.74, 95% CI ‐2.51 to ‐0.98 and SMD ‐0.77, 95% CI ‐1.07 to ‐0.47 respectively, Additional Table 5) both indicating a strong effect. There was considerable heterogeneity among the 10 placebo‐controlled studies P < 0.00001; I2 = 91%.
One large 9‐month study (at high risk of bias) (Bajaj 2011) analysing 852 participants comparing 0.1% chlorhexidine rinse with distilled water found a large reduction in plaque (0 to 3 increasing scale) in the chlorhexidine rinse group (MD ‐1.55, 95% CI ‐1.79 to ‐1.31, Additional Table 5).
Four studies analysing 132 participants (all at high risk of bias) comparing chlorhexidine rinse with placebo rinse presented data 1, 4 and 10 months after rinsing had ceased, using a variety of indices, and were combined in a meta‐analysis that showed a large retained effect in favour of chlorhexidine (SMD ‐1.10, 95% CI ‐1.18 to ‐0.40, Additional Table 5). However, there was substantial heterogeneity between the studies (P = 0.02; I2 = 71%).
One study (Sanz 1989) at high risk of bias reporting a plaque outcome at 6 weeks that was not included in the meta‐analysis showed a reduction in plaque for 0.12% chlorhexidine rinse compared to placebo rinse (Additional Table 8).
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Sanz 1989 | CHX 0.12% vs placebo | PI | 0.452 | 0.9907 | 38 | Did not report a SD |
| 7 to 12 weeks | Anderson 1997 | CHX 0.12% vs placebo | PI | 0.3175* | 0.8425* | 28 | Mean GI by surface + SD reported. We calculated the overall mean. No overall SD |
| de la Rosa 1888b | CHX 0.12% vs placebo | TQH | NR | NR | 92 | Quote: "The reductions in dental plaque were not statistically significant.." | |
| de la Rosa 1988a | CHX 0.12% vs placebo | TQH | NR | NR | 99 | Quote: "The reductions in dental plaque were not statistically significant.." | |
| Segreto 1986 | 0.2% vs 0.12% vs placebo | TQH | 1.14/1.01 | 1.58 | 451 | Did not report a SD | |
| Weitz 1992 | CHX 0.12% vs placebo | PI | 1.84 | 2.21 | 36 | Did not report a SD | |
| 6 months | Banting 1989 | CHX 0.12% vs placebo | TQH | Graph | Graph | 383 | Data presented in a graph. Did not report a SD. Quote: "Subjects in the treatment group had significantly lower mean plaque scores than those in the control group at six months, and at one and two years. The difference between the groups ranged from 35% to 46%" |
| Hoffmann 2001 | CHX 0.1%/CHX 0.06%/CHX 0.06%+F vs control rinse | PI | Median 0.13/0.25/0.27 | Median 0.72 | 58 | Median only. Did not report a SD | |
| Jayaprakash 2007 | CHX 0.05%/ CHX 0.05%+F vs placebo | PI | 0.0813/0.0459 | 0.1189 | 100 | Did not report a SD | |
| Lucas 1999 | CHX 0.12% vs placebo | OHI‐S | 0.33 | 0.59 | 20 | Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | PI | Graph | Graph | 130 | Data presented in a graph. Did not report a SD. Quote: "…reductions in Plaque Index...were statistically significant for the positive control group…compared with the reduction obtained with the control group.. These reductions were 41% (positive control)…after 3 months and 35%..after 6 months.." | |
| Plaque > 6 months | Banting 1989 | CHX 0.12% vs placebo | TQH | Graph | Graph | 272 | Data presented in a graph. Did not report a SD. Quote: "Subjects in the treatment group had significantly lower mean plaque scores than those in the control group at six months, and at one and two years. The difference between the groups ranged from 35% to 46%" |
CHX = chlorhexidine; F = Fluoride; NR = not reported; SD = standard deviation.
Total n is the number of participants analysed in the study arms relevant to the review.
PI (Plaque Index, Silness and Löe 1964) is measured on a 0‐3 increasing scale.
TQH (Turesky modification of the Quigley and Hein Index, Turesky 1970) is measured on a 0‐5 increasing scale.
OHI‐S (Simplified Oral Hygiene Index, Greene and Vermillion 1964) is measured on a 0‐3 increasing scale.
Five studies at high risk of bias reporting a plaque outcome at 6 months that were not included in the meta‐analysis also showed a reduction in plaque for 0.12%, 0.1%, 0.05% and 0.06% chlorhexidine rinse compared to placebo or control rinse (Banting 1989; Hoffmann 2001; Jayaprakash 2007; Lucas 1999; Sanz 1994) (Additional Table 8).
Banting 1989, which was not included in the meta‐analysis demonstrated a reduction in plaque at 2 years for 0.12% chlorhexidine compared to placebo. Results for 7 to 12 weeks studies not included in meta‐analyses were generally supportive of a reduction in plaque associated with chlorhexidine mouthrinse use (Additional Table 8).
Adverse effects
Calculus
Two studies analysing 102 participants, both at high risk of bias, and with placebo/control rinses, presented data on calculus at 4 to 6 weeks. There was insufficient evidence to determine whether using chlorhexidine rinse for 4 to 6 weeks was associated with increased calculus formation (SMD 0.02, 95% CI ‐0.09 to 0.14) (Analysis 1.11).
At 7 to 12 weeks, five studies (all high risk of bias) analysing 330 participants, with a placebo/control rinse presented calculus data, along with one study analysing 95 participants with a no rinse control also at high risk of bias (Analysis 1.12). There was a difference between the subgroups for control type, with there being insufficient evidence to determine an effect on calculus for chlorhexidine rinse compared to placebo/control rinse (SMD 0.14, 95% CI ‐0.08 to 0.36). The single study in the no rinse control group, however, showed more calculus in the chlorhexidine rinse group compared to the no rinse control group (SMD 1.02, 95% CI 0.59 to 1.45) demonstrating a large effect. There was evidence of substantial heterogeneity (P =0.004; I2 = 71%).
At 6 months there was a difference between the subgroups for control type. There was only one study (at high risk of bias), analysing 91 participants, with a no rinse control group which showed an increase in calculus in the chlorhexidine rinse group (SMD 1.39, 95% CI 0.93 to 1.85) demonstrating a large effect (Analysis 1.13). The pooled result for the three studies (at high risk of bias) analysing 232 participants with placebo/control rinses showed an increase in calculus associated with chlorhexidine rinse (SMD 0.60, 95% CI 0.24 to 0.96) demonstrating a moderate effect. There was evidence of moderate heterogeneity (P = 0.16; I2 = 46%).
Chlorhexidine concentration and frequency of rinsing
No statistically significant difference was found between the subgroups with different chlorhexidine concentrations at 7 to 12 weeks, however the data at 6 months indicated a larger effect (increased calculus formation in the chlorhexidine rinse group) for the lower concentration chlorhexidine mouthrinse (Additional Table 3). Participants in all the included trials with calculus data at 4 to 6, 7 to 12 weeks and 6 months were asked to use the mouthrinse twice a day, so no analysis of frequency could be undertaken (Additional Table 4).
Other data
Five studies at high risk of bias reporting interim and end scores for calculus at various time points from 4 weeks to 2 years (Anderson 1997; Banting 1989; Charles 2004; Grossman 1986; Sanz 1994) that were not included in the meta‐analysis all found increased supragingival calculus in the 0.12% chlorhexidine rinse groups compared to the placebo and control rinse groups (Additional Table 9). Increased calculus was noted in two other studies but not measured using an index or scale (de la Rosa 1988; de la Rosa 1988b).
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Anderson 1997 | CHX 0.12% vs placebo | RI | 0.1075 | 0.0475 | 29 | Mean RI by surface + SD reported. We calculated overall mean. No overall SD |
| 7 to 12 weeks | Anderson 1997 | CHX 0.12% vs placebo | RI | 0.0875 | 0.0525 | 28 | Mean RI by surface + SD reported. We calculated overall mean. No overall SD |
| Charles 2004 | CHX 0.12% vs control | VM | 0.37 (SD NR) | 0.11 (SD NR) | 74 | Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | VM | Graph | Graph | 130 | Data presented in graph. Did not report a SD. Quote: "All groups developed calculus after the initial cleaning at baseline. This increase was only statistically significant for the positive control group compared with the control group at 6 months" | |
| Calculus 6 months | Banting 1989 | CHX 0.12% vs placebo | VM | NR | NR | 383 | Results reported at 24 months only. See results at > 6 months below |
| Charles 2004 | CHX 0.12% vs control | VM | 0.45 (SD NR) | 0.21 (SD NR) | 73 | Did not report a SD | |
| Grossman 1986 | CHX 0.12% vs placebo | Not specified | NR | NR | 380 | Quote: "Supragingival calculus was higher in the group using chlorhexidine but this increase in calculus did not diminish the therapeutic effects of chlorhexidine since subjects with significant increases in calculus also had significant decreases in gingivitis" | |
| Sanz 1994 | CHX 0.12% vs placebo | VM | Graph | Graph | 130 | Data presented in a graph. Did not report a SD. Quote: "All groups developed calculus after the initial cleaning at baseline. This increase was only statistically significant for the positive control group compared with the control group at 6 months" | |
| Calculus > 6 months | Banting 1989 | CHX 0.12% vs placebo | VM | NR | NR | 272 | At 24 months subjects in the treatment group had higher mean supragingival calculus scores, but at the same time more subjects were free of subgingival calculus |
CHX = chlorhexidine; NR = not reported; SD = standard deviation.
Total n is the number of participants analysed in the study arms relevant to the review.
RI (Retention Index, Björby and Löe 1966) is measured on a 0‐3 increasing scale.
VM (Volpe‐Manhold Calculus Index, Manhold 1965; Volpe 1965) measures calculus present on the lingual surface of the lower 6 anterior teeth. Calculus is measured in 3 planes using a standard periodontal probe.The greatest value allowed for any 1 plane is 3 units, therefore the maximum score per tooth is 9 units or 54 units per subject. The mean per subject score is obtained by dividing the total calculus score by the number of lower anterior teeth. A mean calculus score for the group is then calculated.
Extrinsic tooth staining
Different dichotomous and continuous indices were used to measure tooth staining. At 4 to 6 weeks both the dichotomous data (two studies at high risk of bias, 156 participants) and the continuous data (eight studies at high risk of bias, 415 participants) showed more tooth staining in the chlorhexidine rinse group. A large effect estimate was found for both the dichotomous data (risk ratio (RR) 5.41, 95% CI 2.03 to 14.47, Analysis 1.14) and continuous data (SMD 1.07, 95% CI 0.80 to 1.34, Analysis 1.16). There was no strong evidence of heterogeneity between the trials reporting continuous data (P = 0.14, I2 = 36%).
Only one study, analysing 118 participants, reported dichotomous data for tooth staining at 7 to 12 weeks, with more tooth staining in the chlorhexidine group (RR 2.50, 95% CI 1.29 to 4.83) (Analysis 1.15). Eleven studies, analysing 581 participants (at high risk of bias) reported data on different continuous scales showing an increase in tooth staining associated with chlorhexidine rinse at 7 to 12 weeks (SMD 1.19, 95% CI 0.98 to 1.40), demonstrating a large effect (Analysis 1.17).
Four studies analysing 323 participants, at high risk of bias, reported continuous data at 6 months using different tooth staining indices. The pooled effect estimate indicated a large effect for tooth staining due to the chlorhexidine rinse (SMD 1.54, 95% CI 1.22 to 1.86) (Analysis 1.18). There was no strong evidence of heterogeneity (P = 0.19; I2 = 36%).
Chlorhexidine concentration and frequency of rinsing
Subgroup comparisons for chlorhexidine concentration were not significant (Additional Table 3). In one study providing tooth staining data at both 4 to 6 weeks and 7 to 12 weeks, participants rinsed three times a day, and in one of the studies at 4 to 6 weeks participants rinsed only once per day, whereas in all the other studies participants rinsed twice per day (Additional Table 4). There were insufficient studies in the subgroups to make a meaningful comparison on frequency at any time point.
Other data
Thirteen studies reported information about tooth staining that could not be included in meta‐analyses. Eight studies that reported data on extrinsic tooth staining could not be included in meta‐analyses because no measure of variance was reported (Charles 2004; Flotra 1972; Grossman 1989; Hoffmann 2001; Sanz 1994), no outcome data were reported (Grossman 1986) or because the mean value in the control groups was zero (Axelsson 1987; Graziani 2015). All of these studies reported higher levels of extrinsic tooth staining in the chlorhexidine compared to control arms at 4 to 6 weeks (Axelsson 1987; Flotra 1972; Graziani 2015); 7 to 12 weeks (Charles 2004; Grossman 1989); and at 6 months (Charles 2004; Grossman 1986; Grossman 1989; Hoffmann 2001; Sanz 1994). In five other studies tooth staining was reported combined with either denture staining (Lopez‐Jornet 2012), discolouration of oral tissues (Hase 1995; Turkoglu 2009; Zimmer 2006) or was reported as 'discolouration' and it was not clear whether this related to teeth, oral tissues or both (Bhat 2014). In four of these five studies staining/discolouration was higher in the chlorhexidine rinse groups at 4 to 6 weeks (Bhat 2014; Hase 1995; Turkoglu 2009; Zimmer 2006) and 7 to 12 weeks (Zimmer 2006) (Additional Table 10).
| Time | Study ID | Comparison | Index | CHX mean (SD/SE) or n (%) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Axelsson 1987 | CHX 0.2%/0.1% vs control | DI (Lobene) | 0.1171 (0.297) | 0 | 64 | Not included in meta‐analysis as control mean is 0. We combined data from the 0.2% and 0.1% CHX groups |
| Bhat 2014 | CHX 0.2% vs control | Reported number and proportion of participants with mild or moderate 'discolouration' in text | 20 (91%) | 0 | 44 | Not clear whether discolouration relates to teeth or oral tissues or both | |
| Flotra 1972 & 1971 (4‐month study that reports this outcome at 4 weeks) | CHX 0.2%/0.1%/0.1% (acetate) vs control | No index Reported narratively | 12% of tooth surfaces without fillings 62% of silicate fillings | NR | 48 (at 4 weeks) | Quote: "..12% of the tooth surfaces without fillings became discolored within the first 4 weeks of the experiment…this happened more frequently on the interproximal surfaces than on the labial surfaces (ratio2:1). Sixty‐two per cent of the silicate fillings in these areas were discolored.." | |
| Graziani 2015 | CHX 0.2% vs control | SI | 0.2228 (0.18) | 0 | 70 | Not included in meta‐analysis as control mean is 0. We combined data from the 3 CHX groups | |
| Hase 1995 | CHX 0.2% vs placebo | Subjective of participants regarding staining of teeth and/or tongue using VAS | 38 (SE 7) | 9 (SE 1) | 39 | Teeth and/or tongue staining reported together. Data estimated from a graph | |
| López‐Jornet 2012 | CHX 0.2% vs placebo | Registration of side effects including denture/dental staining (n and %) | 2 (5.71%) | 3 (8.57%) | 70 | Denture and dental staining reported together | |
| Turkoglu 2009 | CHX (conc not reported) vs placebo | No index Reported narratively | 14 (56%) | Assumed 0 | 50 | Quote: "Of the 25 subjects who rinsed their mouth with CHX mouthrinse..14 showed discolouration of teeth and/or tongue" | |
| Zimmer 2006 | CHX 0.06%+F+OH vs OH | Staining of teeth and tongue registered at final examination (n) | 4 | 0 | 78 | Stain on teeth/tongue reported together. If more than 1 side effect was present, only the most relevant was listed i.e. side effects were reported with no double counting | |
| 7 to 12 weeks | Charles 2004 | CHX 0.12% vs control | DI (Lobene) | 1.61 (SD NR) | 0.01 (SD NR) | 74 | Did not report a SD |
| Grossman 1989 | CHX 0.12% vs placebo | Not specified Quote: "Photographs of facial surfaces of the 12 anterior teeth (maxillary and mandibular, cuspid to cuspid) were graded for stain intensity and coverage" | 4.66 (SD NR) | 2.59 (SD NR) | 246 | Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | Not specified | NR | NR | 130 | Data presented in a graph at 6 months only See 6‐month results below | |
| Zimmer 2006 | CHX 0.06% +F+OH vs OH | Staining of teeth and tongue registered at final examination (n) | 6 | 0 | 78 | Stain on teeth/tongue reported together. If more than 1 side effect was present, only the most relevant was listed i.e. side effects were reported with no double counting | |
| 6 months | Charles 2004 | CHX 0.12% vs control | DI (Lobene) | 2.08 (SD NR) | 0.01 (SD NR) | 73 | Did not report a SD |
| Grossman 1986 | CHX 0.12% vs placebo | Not specified | NR | NR | 380 | Outcome data not reported. Quote: "Some extrinsic tooth staining was observed in the chlorhexidine group" | |
| Grossman 1989 | CHX 0.12% vs placebo | Not specified Quote: "Photographs of facial surfaces of the 12 anterior teeth (maxillary and mandibular, cuspid to cuspid) were graded for stain intensity and coverage" | 5.15 (SD NR) | 2.75 (SD NR) | 246 | Did not report a SD | |
| Hoffmann 2001 | CHX 0.1%/ 0.06%/0.06%+F vs control | DI (Lang and Räber) | 1.13/1.02/1.06 (SD NR) | 0.38 (SD NR) | 58 | Median only. Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | Not specified Quote: "Photographs of facial surfaces of the 12 anterior teeth (maxillary and mandibular, cuspid to cuspid) were graded for stain intensity and coverage" | Graph | Graph | 130 | Data presented in graph Did not report a SD Quote: "Statistically significant more overall staining, more intense staining and stain coverage per tooth were detected for the positive control group…compared with the control group" |
CHX = chlorhexidine; conc = concentration; F = fluoride; NR = not reported; OH = oral hygiene; SD = standard deviation; SE = standard error; VAS = visual analogue scale.
Total n is the number of participants analysed in the study arms relevant to the review.
DI (Discolouration Index, Lobene 1968): gingival and body regions of the tooth are scored for intensity (0‐3 increasing scale) and severity (0‐3 increasing scale).
DI (Discolouration Index, Lang and Räber 1981) is measured on a 0‐3 increasing scale.
SI (Staining Index): the buccal surfaces of the 8 central incisors were divided into 3 areas: incisal, approximal and gingival according to Lobene 1968 and Grundemann 2000 and a SI was used to record the dichotomous presence or absence of staining in each area and to calculate the percentage of the total area showing staining.
In five additional studies, increased tooth staining (de la Rosa 1988; de la Rosa 1988b; Feres 2009), 'pigmentation' (Pereira 2011) and 'yellow teeth' (Anauate‐Netto 2014) were reported in relation to the chlorhexidine rinse arms. In two studies staining of teeth in the chlorhexidine rinse arm was listed as a reason for participant withdrawal from the studies (Banting 1989; Eaton 1997).
Other adverse effects
Twenty‐two studies reported at least one adverse effect apart from extrinsic tooth staining and calculus formation in the chlorhexidine rinse arms. Apart from extrinsic tooth staining, the adverse effects most commonly reported in the chlorhexidine rinse arms of the included studies were taste disturbance/alteration (reported in 11 studies), effects on the oral mucosa (reported in 13 studies) and a general burning sensation or a burning tongue or both (reported in nine studies).
Taste disturbance/alteration was reported in 11 studies (Anauate‐Netto 2014; Bhat 2014; Ernst 2005; Graziani 2015; Hase 1998; Jenkins 1993; Jose 2015; Lang 1998; Pereira 2011; Turkoglu 2009; Zimmer 2006). The proportion of participants experiencing taste disturbance/alteration was reported in eight of these studies and was consistently higher in the chlorhexidine rinse arms (3% to 30%) than in the placebo/control/oral hygiene (OH) only arms (0% to 7%) with one exception (Bhat 2014) where a higher proportion of participants in the saline control arm experienced taste disturbances (45.4% versus 63.6%).
A general burning sensation (Anderson 1997; Bhat 2014; Emling 1992; Hase 1995; Sanz 1989; Zimmer 2006) and/or a burning tongue (Anauate‐Netto 2014; Jose 2015; Lang 1998) was reported in the chlorhexidine rinse arms in nine studies. The proportion of participants affected was reported in four of the nine studies (Anderson 1997; Bhat 2014; Jose 2015; Zimmer 2006) and ranged from 4.6% to 50% in the chlorhexidine arms compared to 0% in the placebo/control/OH only arms. Hase 1995 reported 'burning sensation' rated by participants on a visual analogue scale from none (0) to 100 (very much). The mean visual analogue scale score for the chlorhexidine rinse arm was approximately 18 compared to 8 for the placebo arm.
Effects on the oral mucosa of participants in the chlorhexidine rinse arms were reported in 13 studies. Specific effects were described as mucosal irritation (Anauate‐Netto 2014; Emling 1992), sensitivities of the oral mucosa (Ernst 2005), mucosal soreness (Jenkins 1993), mild desquamation (de la Rosa 1988; de la Rosa 1988b; Navarro 1998), mucosal ulceration (Hase 1995; Turkoglu 2009), mucosal erosions (Jenkins 1993), soft tissue conditions (Banting 1989), oral mucosal lesions (Axelsson 1987; Flotra 1972) and adverse mucosal reaction (Eaton 1997). Where it was reported, the proportion of participants experiencing effects on the oral mucosa was generally low. For example, clinically apparent mucosal ulceration was reported in 12% (n = 3) of participants in the chlorhexidine rinse arm of one study (Turkoglu 2009) and mucosal erosions affected 4% (n = 2) of participants in the chlorhexidine rinse arm of another study (Jenkins 1993). However one study reported a high proportion of oral mucosal lesions in participants in the chlorhexidine (0.2%) rinse arm (25%, n = 6) (Axelsson 1987).
Discolouration/pigmentation of the oral soft tissues was reported in seven studies and was consistently higher in the chlorhexidine rinse arms ranging from 9% to 88% compared to 0% to 7% in the placebo/control/OH only arms (Graziani 2015; Pereira 2011; Hase 1995; Hase 1998; Lang 1998; Turkoglu 2009; Zimmer 2006). Coated tongue was reported as an adverse effect in one study (Jose 2015).
Less commonly reported adverse effects included transient anaesthetic sensation, hypoaesthesia and paraesthesia; affecting 5% to 18% of participants in the chlorhexidine rinse arms (Hase 1995; Hase 1998; Jenkins 1993; Jose 2015; Lang 1998; Zimmer 2006).
Lastly, in relation to acceptability, an unacceptable or unpleasant taste was reported by participants in the chlorhexidine rinse arms of eight studies (Anauate‐Netto 2014; Chaves 1994; Eaton 1997; Feres 2009; Hase 1995; Jenkins 1993; Sanz 1989; Segreto 1986).
Sensitivity analysis
We undertook a sensitivity analysis for the GI at both 4 to 6 weeks and 6 months, excluding trials where we had to estimate the standard deviation from similar studies, or had to read the data from graphs. The pooled estimate for 4 to 6 weeks (excluding Jenkins 1993 and Sanz 1989) was: MD ‐0.23 (95% CI ‐0.36 to ‐0.10), and at 6 months (excluding Banting 1989; Chaves 1994; Jayaprakash 2007; Lucas 1999; Sanz 1994) MD ‐0.25 (95% CI ‐0.39 to ‐0.10). These estimates are similar to those for the overall pooling of the studies.
We undertook a sensitivity analysis for the GI at both 4 to 6 weeks and 6 months excluding trials where professional periodontal treatment was carried out during the study (i.e. Faveri 2006; Feres 2009; Feres 2012; Flotra 1972; Rahmani 2006; Sanz 1989). The pooled estimate for 4 to 6 weeks (excluding Rahmani 2006 and Sanz 1989 ) was: MD ‐0.21 (95% CI ‐0.32 to ‐0.10), and at 6 months (excluding Flotra 1972) MD ‐0.19 (95% CI ‐0.29 to ‐0.10). These estimates are similar to those for the overall pooling of the studies.
Assessment of reporting biases
The meta‐analysis for GI at 4 to 6 weeks included 10 trials. Testing for asymmetry in a funnel plot using the methods described by Egger 1997, using "metabias" command in Stata (P = 0.019), although significant, the estimate of bias was negative indicating that the bias was lack of large studies (not small studies). The meta‐analysis for GI at 6 months included 13 trials, and there was no evidence of publication bias from the funnel plot and this was confirmed by testing for asymmetry in a funnel plot using the same methods (P = 0.95). Two of the plaque meta‐analyses at 4 to 6 weeks and 6 months had more than 10 studies but funnel plots cannot be investigated when SMD models are used. All the other meta‐analyses had less than 10 trials, so we were unable to assess reporting bias for these.
Discussion
Summary of main results
There was high‐quality evidence that using chlorhexidine mouthrinse as an adjunct to regular mechanical oral hygiene procedures for 4 to 6 weeks and 6 months results in a moderate reduction in gingivitis compared to placebo, control or mechanical oral hygiene alone. This reduction in gingivitis, in individuals with mild gingival inflammation on average (mean score of 1 on the 0 to 3 Gingival Index (GI) scale) is not considered to be clinically important. Heterogeneity was considerable in the meta‐analyses at 4 to 6 weeks and 6 months and subgroup analysis was only able to explain some of the heterogeneity at 6 months, due to whether or not a prophylaxis or scale and polish was conducted at the start of the study. The standardised mean differences (SMDs) for gingival bleeding at 4 to 6 weeks and 6 months also indicate that chlorhexidine mouthrinse has a moderate effect on gingival bleeding compared to placebo, control or mechanical oral hygiene alone. There was insufficient evidence to determine the reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with mean GI scores of 1.1 to 3 indicating moderate or severe levels of gingival inflammation.
There was also high‐quality evidence that chlorhexidine mouthrinse reduces plaque at 4 to 6 weeks and 6 months. SMDs for plaque for both control subgroups at 4 to 6 weeks and at 6 months indicate a large effect. The four studies that used the Plaque Index (0 to 3 increasing scale) and the four studies that used the Turesky Modification of the Quigley and Hein Index (0 to 5 increasing scale) at 4 to 6 weeks indicate a reduction in plaque in favour of the chlorhexidine mouthrinse.
There was no evidence that one concentration of chlorhexidine rinse was more effective than another in reducing gingivitis and plaque. Participants in most of the studies included in the meta‐analyses used a rinse frequency of twice daily, limiting our ability to analyse the effect of rinse frequency on gingivitis and plaque. We were only able to evaluate the effect of rinse frequency for gingivitis measured at 6 months using the GI, however, no difference in effect was observed.
There was moderate‐quality evidence that chlorhexidine rinse causes a large amount of extrinsic tooth staining when used for periods of 4 weeks or longer. Comparison of subgroups with different chlorhexidine concentrations was not statistically significant.
There was insufficient evidence to determine whether using chlorhexidine rinse for 1 to 3 months was associated with increased calculus formation. There was some evidence of increased calculus formation related to rinsing with chlorhexidine mouthrinse for a period of 6 months. However, overall evidence for the effect of chlorhexidine mouthrinse on calculus formation was inconclusive.
Twenty‐two of the 51 studies included in this review reported at least one adverse effect apart from extrinsic tooth staining and calculus formation in the chlorhexidine rinse arms. The adverse effects most commonly reported in the chlorhexidine rinse arms of the included studies were taste disturbance/alteration (reported in 11 studies), effects on the oral mucosa including mucosal irritation, soreness, mild desquamation, mucosal ulceration/erosions and oral mucosal lesions (reported in 13 studies) and a general burning sensation or a burning tongue or both (reported in nine studies).
Overall completeness and applicability of evidence
Chlorhexidine mouthrinse is effective in reducing gingivitis and plaque when used as an adjunct to regular mechanical oral hygiene procedures for 4 weeks or longer. The consistency of effect for chlorhexidine mouthrinse on gingivitis and plaque across studies included in this review was remarkable though not surprising considering that chlorhexidine mouthrinse has long been regarded as the gold standard of antimicrobial mouthrinses.The primary outcome of this review was gingivitis which can be measured using a variety of different indices. The clinical features of gingivitis can be assessed non‐invasively by visual assessment of colour, contour and gingival bleeding or invasively using an instrument to provoke bleeding or both (Lorenz 2009). Our review clearly demonstrates the many different indices that can be used to measure gingivitis. While these many indices were developed to provide a standardised reproducible method of quantifying gingivitis for descriptive or comparative purposes in epidemiology and clinical trials respectively, the subjectivity involved in their use remains problematic. The presence/absence of bleeding on provocation would appear to be the more objective approach (Ciancio 1986; Lorenz 2009; Polson and Caton 1985). However, the probing technique, the depth to which the instrument is inserted, the force with which it is applied, the time allowed to elapse between applying the stimulus and recording the outcome and even the angulation of the instrument can have an effect on the bleeding response (Lorenz 2009; Polson and Caton 1985; van der Weijden 1994). Moreover, calibration of examiners and demonstrating inter‐ and intraexaminer reliability are hampered by the inability to obtain the same response upon repeated application of the stimulus to provoke gingival bleeding at the same site (Lorenz 2009; Polson and Caton 1985). In synthesising the evidence from primary research studies evaluating chlorhexidine mouthrinse as an adjunctive treatment for gingival health, the many different approaches to measuring gingivitis, particularly gingival bleeding, presented difficulties in combining the study results to produce a summary of the effect of the mouthrinse.
To facilitate the analysis, we grouped the indices into those that measured principally gingival inflammation visually and invasively (e.g. the Gingival Index (Löe 1967; Löe and Silness 1963)) or visually only (e.g. the Modified Gingival Index (Lobene 1986)) and those that measured gingival bleeding (e.g. bleeding on probing (BOP) (Ainamo and Bay 1975) or the Eastman Interdental Bleeding Index (Caton and Polson 1985)). We endeavoured to include both types of index for measuring gingivitis in the review, therefore where both were reported within a study, both were data extracted. Our main analysis was based on the studies that reported gingival inflammation using the Gingival Index (Löe 1967; Löe and Silness 1963) at 4 to 6 weeks and 6 months to reflect both the short‐ and long‐term effect of chlorhexidine mouthrinse. Our results showed that after 4 to 6 weeks of use, chlorhexidine mouthrinse reduced gingivitis by a mean of 0.21 of a unit on the Gingival Index (GI) scale when compared to a placebo/control mouthrinse or mechanical oral hygiene alone. Based on these studies, a reduction in gingivitis of 0.11 to 0.31 of a unit on the GI scale could be expected with use of chlorhexidine mouthrinse for a period of 4 to 6 weeks in individuals with mild gingival inflammation on average (mean score of 1 on the 0 to 3 GI scale). A similar mean effect size of 0.20 of a unit reduction on the GI scale was found for gingivitis at 6 months also in individuals with mild gingival inflammation on average.
The GI is measured on a 0 to 3 increasing scale with 0 indicating normal gingivae. However, each one unit increase on the scale does not indicate the same proportionate deterioration in gingival condition and a low mean GI score could mask the presence of a small number of sites with moderate or severe levels of gingival inflammation. With this in mind, depending on the average gingivitis level in an individual, a one unit reduction could indicate a shift from severe inflammation and a tendency for spontaneous bleeding to moderate inflammation and BOP or from moderate inflammation and BOP to mild inflammation but no BOP. As previously mentioned, the participants who contributed data to the meta‐analyses of the GI at 4 to 6 weeks had a low mean gingival index score at baseline. The clinical relevance of a mean reduction of one fifth of a unit on the GI scale is therefore not clear. Our results for gingival bleeding indicate that using chlorhexidine mouthrinse for 4 to 6 weeks or 6 months has a moderate effect on gingival bleeding. Although these meta‐analyses included some studies where participants appeared to have a high proportion of sites with BOP at baseline, the variety of different gingival bleeding indices employed meant that we were unable to determine the mean reduction in gingivitis associated with chlorhexidine mouthrinse use in individuals with moderate or severe levels of gingival inflammation. When the SMDs for gingival bleeding were expressed in the units of the bleeding aspect of the GI (GI ≥ 2) the effect size was equivalent to a 7% reduction in the percentage of sites with BOP at 4 to 6 weeks and a 4% reduction in the percentage of sites with BOP at 6 months. Use of chlorhexidine mouthrinse was associated with a large reduction in plaque at 4 to 6 weeks and 6 months. The mean reduction in plaque associated with chlorhexidine mouthrinse use at 4 to 6 weeks was equivalent to approximately half a unit on the 0 to 3 Plaque Index scale (Silness and Löe 1964) or three quarters of a unit on the 0 to 5 Turesky modification of the Quigley and Hein Index (TQH) scale (Turesky 1970).
Statistical heterogeneity was evident in many of our meta‐analyses and was likely due to variation in the characteristics of the individual included studies. Investigation of the observed heterogeneity was conducted for our main outcome, measured using the GI at 4 to 6 weeks and 6 months using prespecified characteristics. There was a decrease in the effect estimate for the GI at 6 months when a prophylaxis or scale and polish was conducted at the start of the study compared to studies where no prophylaxis or scale and polish was undertaken. This is not consistent with our knowledge of the mechanism of action of chlorhexidine mouthrinse which would appear to be more effective in preventing plaque accumulation when applied to a clean tooth surface than reducing pre‐existing plaque (Eley 1999). Nonetheless, the results indicate that some of the heterogeneity for the GI at 6 months was due to whether or not a prophylaxis or scale and polish was conducted at the beginning of the study. We have presented all of the meta‐analyses despite the high heterogeneity due to the remarkable consistency of the direction of effect across the different analyses.
We included studies that evaluated chlorhexidine mouthrinse use in individuals with gingivitis only or gingivitis and periodontitis. Where it was reported, the level of gingivitis in the included studies at baseline was generally low. The majority of the studies that evaluated chlorhexidine mouthrinse use in individuals with periodontitis evaluated its effect as an adjunct to surgical or non‐surgical periodontal treatment. In a small number of the studies that evaluated chlorhexidine mouthrinse use in individuals with periodontitis, it was difficult to ascertain whether the professional tooth cleaning provided was appropriate for the level of disease present. For example, in two of these studies it was reported that professional cleaning was undertaken at baseline but no further details were provided (Chaves 1994; Ernst 2005). In another study where 17% to 50% of participants in the study groups were diagnosed with periodontitis, supragingival scaling and polishing only was provided at baseline (Graziani 2015). In one study a proportion of the participants clearly had periodontitis and abundant calculus, however no professional treatment or oral hygiene instructions were provided to the participants (Corbet 1997). The inclusion of these studies could be criticised because antimicrobials such as chlorhexidine have limited capacity to penetrate subgingivally and are therefore suggested for use as an adjunct to mechanical debridement rather than as an alternative therapy (Greenstein 1986; Ohrn 2009). Furthermore, self‐medication with an effective antimicrobial agent such as chlorhexidine mouthrinse "may mask more serious underlying periodontal disease" (Tonetti 2015). It is well recognised that control of supragingival plaque alone will not be sufficient to treat periodontitis (Eley 1999; Hull 1980), disruption of the subgingival plaque by mechanical debridement will also be required (Kornman 1986; Ohrn 2009).
We would have liked to investigate how the effect of chlorhexidine mouthrinse on gingival health varies depending on the level of underlying periodontal disease. However, the periodontal status of the participants in the included studies often was not clearly reported at baseline. In many cases, the inclusion criteria allowed for individuals to have pocket probing depths and clinical attachment loss consistent with periodontitis but the periodontal status of the people actually enrolled in the study was not described. Furthermore, where participants were advised to continue their regular oral hygiene practices during the study, no information about their frequency of toothbrushing or their use of interdental cleaning aids was reported. Therefore, our ability to explore the effect of the adjunctive use of chlorhexidine mouthrinse on gingivitis in individuals with different levels of periodontal disease at baseline and in individuals with treated and untreated periodontitis was hampered both by the small number of studies available at each time point and by poor reporting of the relevant information in the included studies.
We were able to conduct a metaregression analysis of 4 to 6 week and 6‐month studies where participants had gingivitis only compared to studies where participants had gingivitis and periodontitis (both treated and untreated during the study). The results did not disclose any statistically significant difference in the effect of the chlorhexidine mouthrinse on the gingival index at either time point, however only eight studies were included in the metaregression at 4 to 6 weeks and only nine studies were included in the metaregression at 6 months. We cannot specifically comment on the effect of chlorhexidine used adjunctively during periodontal treatment on periodontal outcomes such as pocket probing depth and clinical attachment loss because the focus of this review was gingivitis and therefore periodontal outcomes were outside the scope of the review.
Retention of chlorhexidine in the oral cavity is key to its effectiveness as an antimicrobial agent (Bonesvoll 1974; Bonesvoll 1974a; Bonesvoll 1978; Jenkins 1988; Rolla 1971) and is dependant on a number of different factors including concentration and duration of application (Tomás 2010). In relation to concentration, the effect of chlorhexidine on plaque is dose‐dependant and a similar effect can be achieved with larger volumes of lower concentration solutions providing the optimal dose of approximately 20 mg twice a day is delivered (Bonesvoll 1978). All but four of the included studies evaluated either 0.2%, 0.12% or 0.1% chlorhexidine mouthrinse and only two of these studies provided data for 0.2% compared to 0.1% (Axelsson 1987) or 0.12% (Segreto 1986) chlorhexidine mouthrinse within the same study. Most of the studies that evaluated 0.2% chlorhexidine mouthrinse employed a rinse volume of 10 mL twice a day while most of the studies that evaluated 0.12% or 0.1% chlorhexidine mouthrinse employed a rinse volume of 15 mL twice a day. Therefore regardless of the concentration of chlorhexidine mouthrinse used, the dose of chlorhexidine was effectively the same in the majority of the studies and corresponded to the optimal dose of 18 mg to 20 mg twice a day. It has been demonstrated that increasing the duration of rinsing with 0.12% or 0.2% chlorhexidine mouthrinse from 30 to 60 seconds results in greater substantivity of the rinse (Tomás 2010). The longer duration of rinsing employed by most of the studies in this review that evaluated 0.2% chlorhexidine mouthrinse could be expected to translate into greater retention of chlorhexidine in these studies and hence a greater effect on gingivitis and plaque. However, 75% of the chlorhexidine that is retained after rinsing for 60 seconds with 0.2% chlorhexidine rinse is retained after the first 30 seconds of rinsing (Bonesvoll 1974) and a rinse duration of 30 seconds for 0.12% chlorhexidine mouthrinse has been shown to be both effective and acceptable (Keijser 2003). Therefore, most of the studies included in this review used the optimal dose of chlorhexidine for at least 30 seconds which may partly explain why we did not find any difference in effect between the different concentration rinses. The two included studies that provided data for a direct comparison between 0.2% and 0.1%/0.12% chlorhexidine rinse found no difference in effect between the different concentration rinses used with the same volume and duration of rinsing (Axelsson 1987; Segreto 1986).
Studies that evaluated the effectiveness of chlorhexidine mouthrinse on gingivitis using a cross‐over study design were excluded from this review. This was due to concerns that the duration of the washout phase between the trial periods might not be sufficient to rule out a carry‐over effect due to chlorhexidine mouthrinse. Carry‐over can threaten the internal validity of a cross‐over study and is of particular concern in studies involving chlorhexidine mouthrinse due to the established substantivity or prolonged effect of chlorhexidine mouthrinse. Evidence‐based guidance on the appropriate duration of washout phase is absent from the literature and the washout periods commonly used appear to range from 2 days to 3 weeks (Berchier 2010; Newcombe 1995). The very limited data we have in this review regarding gingivitis and plaque outcomes recorded after cessation of chlorhexidine mouthrinsing suggest a residual effect on these outcomes weeks or months after rinsing with chlorhexidine has ceased. Although no firm conclusions can be drawn regarding the appropriateness of using a cross‐over study design when the study includes a chlorhexidine mouthrinse arm, the uncertainty surrounding carry‐over in relation to chlorhexidine mouthrinse warrants further investigation.
Low concentration (0.05%/0.06%) chlorhexidine mouthrinses are currently marketed for long‐term daily use. Side‐effects associated with chlorhexidine mouthrinse use are dose‐dependant and tend to decrease when the concentration is lowered (Cumming and Löe 1973; Flotra 1971). Therefore in lowering the concentration of chlorhexidine, it is hoped that side effects will be reduced while maintaining the effect on gingivitis and plaque (Keijser 2003). Only five studies that evaluated chlorhexidine concentrations less than 0.1% met the inclusion criteria for this review. Two studies evaluated 0.05% (Jayaprakash 2007; Joyston‐Bechal 1993) and three studies evaluated 0.06% chlorhexidine mouthrinse (Hoffmann 2001; Zimmer 2006; Zimmer 2015). Although all of these studies demonstrated a reduction in plaque, the effect on gingivitis was not clear. This might be explained by the lower concentration rinses having a mainly bacteriostatic action that may produce an effect below the threshold required to produce a corresponding reduction in gingivitis. Despite the reduced concentration of chlorhexidine, extrinsic tooth staining occurred in all four studies of low concentration chlorhexidine mouthrinse that reported a staining outcome (Hoffmann 2001; Joyston‐Bechal 1993; Zimmer 2006; Zimmer 2015). There has been some debate about the mechanism by which chlorhexidine mouthrinse produces extrinsic tooth staining. However, it is currently understood to be a result of precipitation of anionic dietary chromogens onto adsorbed chlorhexidine cations (Watts 2001) and thus the mechanism by which chlorhexidine mouthrinse produces extrinsic tooth staining appears to be closely linked to its mechanism of action. Therefore lack of staining is likely to indicate lack of effectiveness (Addy 2005; Eley 1999). Some degree of tooth staining can therefore be expected to feature even with low chlorhexidine concentration rinses. However, with the exception of Zimmer 2006, there were no reports of other adverse effects relating to the low concentration chlorhexidine mouthrinse apart from staining of the teeth and oral tissues.
Use of chlorhexidine mouthrinse is associated with a number of adverse effects, the most common being extrinsic staining of the teeth and oral soft tissues (Addy 1986). In many of the studies included in this review, adverse effects were inadequately reported or not reported at all. It is important that adverse effects due to chlorhexidine mouthrinse use are reported alongside evidence for effectiveness with enough detail to allow health professionals and the public to make an informed decision about recommending, prescribing or using the mouthrinse.
From our included studies it was clear that rinsing with any concentration of chlorhexidine mouthrinse for 4 weeks or longer was associated with an increase in extrinsic tooth staining. A number of the included studies reported higher levels of calculus in the chlorhexidine rinse arms but the meta‐analyses were inconclusive. Other adverse effects such as taste disturbance/alteration, burning sensation and pigmentation of the oral soft tissues were also reported in a number of included studies. Effects on the oral mucosa such as mucosal ulceration, lesions or erosions and a transient anaesthetic sensation, hypoaesthesia and paraesthesia were also reported in a number of included studies and can be considered more severe but the proportion of participants experiencing these adverse effects in any study tended to be low. While extrinsic tooth staining and calculus build‐up due to chlorhexidine mouthrinse use must be removed by professional tooth cleaning incurring the costs associated with a visit to a dental professional, the other associated adverse effects are known to be transient in nature and to resolve once mouthrinsing ceases (Flotra 1971; Greenstein 1986). However, these adverse effects, although transient, can be severe and development of extrinsic tooth staining with short‐term use of the mouthrinse is an obvious deterrent to using chlorhexidine mouthrinse.
Quality of the evidence
Although all the included studies were randomised controlled trials (RCTs), 50 of the 51 included studies were assessed as at high risk of bias overall, as they had at least one domain rated at high risk of bias. The reason many of the studies were assessed as at high risk of bias was due to problems with the blinding of participants, personnel, and outcome assessors. The majority of studies contained a placebo arm with the intention of blinding participants and personnel. However, we considered blinding unlikely to be successful due to the propensity for chlorhexidine to stain the teeth and oral tissues and the association of its use with clinically visible adverse effects such as mucosal desquamation and mucosal lesions. This also applied to the blinding of outcome assessors, in trials with either a placebo, control, or mechanical oral hygiene alone. This was not the fault of the investigators who in many studies went to great lengths to try to ensure blinding. Consequently we assessed 42 (82%) studies as at high risk of bias for either sort of blinding bias (performance bias or detection bias).
Thirty‐seven studies were rated at high risk of selective reporting bias, mainly due to lack of reporting of measures of variance along with the means for each group, and no reporting of tooth staining and other adverse effects.
It is worth mentioning that 22 of the included studies were published prior to the first publication of the first iteration of the CONSORT Statement in 1996 (Begg 1996) and their quality was therefore partly judged according to reporting standards that did not exist at the time of their publication. An additional nine studies were published prior to the publication of the revised CONSORT Statement in 2001 (Moher 2001). However, disappointingly, instances of poor reporting were not confined to the studies that predated widespread awareness of the CONSORT Statement.
Despite most studies included in the meta‐analyses being assessed as at high risk of bias we did not downgrade the GRADE assessments for gingivitis and plaque for this reason. This is because we believe that further research is very unlikely to change our confidence in the estimate of effect for these outcomes. The grade assessments for the body of evidence for chlorhexidine mouthrinse compared with placebo, control or mechanical oral hygiene alone for gingivitis measured using the Löe and Silness Gingival Index and for plaque measured using various indices were therefore rated as high quality. Although there was high heterogeneity for some of these meta‐analyses we did not downgrade for this due to consistency of the direction of effect.
Over half of the included studies were either funded directly, received support for the study or were affiliated in some way with industry. Although a high level of industry funding is far from ideal, the reality is that without industry funding few trials evaluating the effectiveness of chlorhexidine mouthrinse would have been conducted. However, it is noteworthy that of the 19 included studies funded directly by industry, only one study (Zimmer 2015) stated that the conduct of the research and final decisions regarding the study report were independent of the company funding the research.
Potential biases in the review process
In order to prevent judgements about the eligibility criteria for studies being influenced by prior knowledge of the study results, the methods to be used in the review should be established and documented in advance of the review being undertaken (Higgins 2011). We made a number of changes to the protocol in relation to the types of studies and types of participants to be included in the review. We also clarified additional criteria for the inclusion of studies based on type of intervention that were implicit but not explicitly stated in the protocol. We amended the assessment of the blinding domains in the 'Risk of bias' tool to allow studies to obtain a judgement of 'low' or 'unclear' risk of bias in certain circumstances compared to the blanket judgement of high risk of bias that was stated in the published protocol.
A hierarchy to guide data extraction for gingivitis and plaque data was developed to facilitate data extraction and analysis. The main analysis however, was based on the main prespecified gingivitis index: the Gingival Index of Löe and Silness (Löe 1967; Löe and Silness 1963). Full details of the changes to the protocol are described in the Differences between protocol and review section. It is acknowledged that it may not always be appropriate to adhere to the published protocol (Higgins 2011). Therefore, while these changes to the protocol could introduce a risk of bias, the changes were made in the early stages of the review before any analyses of the results were undertaken and are therefore considered unlikely to have been influenced by knowledge of the study results or the results of the review. Furthermore, each decision was appropriately justified and was made to improve the scientific quality and clinical applicably of the review.
We estimated the standard deviations for four studies that measured the Gingival Index at 6 months (Banting 1989; Jayaprakash 2007; Lucas 1999; Sanz 1994) and one study that measured the Gingival Index at 4 to 6 weeks (Sanz 1989) using data from the same outcomes measured at the same time point in other similar studies so that we could include these data in meta‐analyses. Where mean scores or measures of variance of the mean scores or both were not reported in the text or in tabular form, and could not be obtained from the authors of the studies, data were estimated by reading them off the graphs in the published report for inclusion in meta‐analyses for six studies (Brecx 1993; Brightman 1991; Chaves 1994; Ferretti 1987; Jenkins 1993; Joyston‐Bechal 1993). The graphs were enlarged and the data were estimated independently and in duplicate. A sensitivity analysis for the Gingival Index at both 4 to 6 weeks and 6 months, excluding trials where we had to estimate the standard deviation from similar studies, or had to read the data from graphs, showed that the effect estimates were similar to those for the overall pooling of the studies.
Agreements and disagreements with other studies or reviews
Van Strydonck 2012 conducted a comprehensive review of the effect of chlorhexidine mouthrinse on plaque, gingival inflammation and tooth staining in studies of 4 weeks or longer. This review was very similar to our review but slight differences in the inclusion criteria and the dates of the literature searches meant that a slightly different group of studies were reviewed by Van Strydonck et al. The review focused on healthy adults only, considered chlorhexidine mouthrinse used as a monotherapy or as an adjunct, and excluded patients with periodontitis or dentures as well as orthodontic and implant patients. In addition, apart from tooth staining, adverse effects although reported in the review, were not prespecified outcomes. Of the 30 studies included in this review, 27 are common to our review. The results of the meta‐analysis of studies reporting the GI at all time points included data from seven studies, six of which were included in our meta‐analyses at either 4 to 6 weeks, 7 to 12 weeks or 6 months. The weighted mean difference for the GI in this review was ‐0.32 which is similar to the mean difference for the GI reported in our review. Extrinsic tooth staining, increased calculus formation and change of taste sensation were also noted to have frequently occurred in the included studies. Considerable heterogeneity in the design, study duration and rinse regimen were also noted to be present.
Boyle 2014 systematically reviewed the evidence relating to the efficacy of the most frequently used mouthrinses for the control of supragingival plaque and gingivitis. Both the scope of the literature search and the inclusion criteria were narrower than in our review. Of the 17 trials involving chlorhexidine mouthrinse included in this review 16 are common to our review. The reported 'summary relative differences' facilitated comparison between the different mouthrinse preparations being reviewed. Results for the chlorhexidine mouthrinse studies are supportive of the effectiveness of chlorhexidine mouthrinse primarily for the control of both gingivitis and plaque relative to control but also relative to other active mouthrinse preparations.
A systematic review by Serrano 2015 evaluated the effectiveness of adjunctive antiplaque chemical agents including chlorhexidine mouthrinse in RCTs of at least 6 months duration. The review included 14 studies evaluating chlorhexidine mouthrinse. Due to differences in inclusion criteria, 12 of these studies are common to our review. The authors reported a significant benefit for rinsing with 0.1% to 0.2% chlorhexidine mouthrinse based on a meta‐analysis of four studies (weighted mean difference on the GI ‐0.185) but a non‐significant effect for chlorhexidine mouthrinse at concentrations of ≤ 0.06%. In common with our review was the presence of high heterogeneity which made it difficult to pool the data and was an acknowledged limitation of the review.
Gunsolley 2006 conducted a meta‐analysis of 6‐month mouthrinse studies for the control of gingivitis and plaque. Six of the included studies evaluated the effect of 0.12% chlorhexidine mouthrinse using the GI and all six were common to our review. The analysis indicated a moderate effect for gingivitis and a large effect for plaque. A subsequent metareview also conducted by Gunsolley drew on the data from the earlier meta‐analysis and found a weighted mean percentage reduction of 28.7% for the GI and 40.4% for the Plaque Index (Gunsolley 2010) based on the same six studies.
The efficacy of 0.12% chlorhexidine mouthrinse compared to 0.2% on plaque and periodontal parameters was systematically reviewed by Berchier 2010. The review included eight studies with rinse duration from 3 days to 3 months that directly compared 0.12% with 0.2% chlorhexidine mouthrinse. The review found no difference in the effect on gingivitis between the two concentrations of chlorhexidine. The small significant difference in plaque inhibition in favour of 0.2% chlorhexidine was thought to be of negligible clinical relevance. Our review included two studies that provided data for a direct comparison between 0.2% and 0.1%/0.12% chlorhexidine rinse (Axelsson 1987; Segreto 1986), one of which was also included in the Berchier review (Segreto 1986). There was no difference in effect between the different concentration rinses used with the same volume and duration of rinsing in these two studies. Similarly our subgroup analysis found no evidence that one concentration of chlorhexidine rinse was more effective than another in reducing gingivitis and plaque.
van der Weijden 2015 conducted a metareview of the evidence regarding the efficacy and safety of chemical agents in mouthrinses to manage gingivitis and plaque. The evidence for chlorhexidine mouthrinse was drawn from the systematic reviews (Serrano 2015; Van Strydonck 2012) and meta‐analyses (Gunsolley 2006; Gunsolley 2010) described above. Berchier 2010 contributed data for the comparison of active ingredients. This review reaffirmed the effectiveness of chlorhexidine mouthrinse for reducing plaque and gingivitis. The body of evidence resulting from these three reviews was rated as 'strong'. Due to the heterogeneity in the meta‐analyses, the authors advised caution in interpreting the difference of means as it "may not provide an exact measure of the results" (van der Weijden 2015). Although the authors concluded that chlorhexidine is the "first choice", they also acknowledged that the development of taste disturbance, tooth staining and calculus formation prohibit long‐term adjunctive use of the mouthrinse.
Study flow diagram.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 1: Gingival Index (0‐3) 4‐6 weeks
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 2: Gingival Index (0‐3) 6 months
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 3: Gingival bleeding 4‐6 weeks
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 4: Gingival bleeding 6 months
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 5: Plaque 4‐6 weeks
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 6: Plaque 4‐6 weeks PI (0‐3)
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 7: Plaque 4‐6 weeks TQH (0‐5)
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 8: Plaque 6 months
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 9: Plaque 6 months PI (0‐3)
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 10: Plaque 6 months TQH (0‐5)
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 11: Calculus 4‐6 weeks
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 12: Calculus 7‐12 weeks
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 13: Calculus 6 months
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 14: Tooth staining 4‐6 weeks dichotomous
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 15: Tooth staining 7‐12 weeks dichotomous
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 16: Tooth staining 4‐6 weeks
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 17: Tooth staining 7‐12 weeks
Comparison 1: CHX versus placebo/control mouthrinse or no mouthrinse, Outcome 18: Tooth staining 6 months
| Chlorhexidine mouthrinse compared with placebo/control mouthrinse/no mouthrinse for gingival health | ||||||
|---|---|---|---|---|---|---|
| Patient or population: adults and children with gingivitis Settings: any Intervention: chlorhexidine mouthrinse Comparison: placebo/control mouthrinse or no mouthrinse | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | Number of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Control | Chlorhexidine | |||||
| Gingival Index 4 to 6 weeks (Löe and Silness Gingival Index) (0 to 3 on an increasing scale) | The mean gingivitis scores ranged across control groups from 0.17 to 1.401 | The mean gingivitis score in the chlorhexidine group was 0.21 lower (0.11 to 0.31 lower) | 805 (10 trials) | ⊕⊕⊕⊕2,3 | The effect size at 6 months was similar Insufficient evidence for differences in effect size for different chlorhexidine concentration or frequency of use Insufficient evidence to determine the effect size in individuals with moderate or severe levels of gingival inflammation on average (mean GI scores 1.1 to 3) | |
| Plaque 4 to 6 weeks (various increasing scales including Plaque Index (0 to 3 scale) and Turesky Modification of the Quigley and Hein Index (0 to 5 scale)) | Plaque Index ranged from 0.75 to 1.06 Turesky Modification of the Quigley and Hein Index ranged from 1.2 to 3.3 | The SMD was 1.45 lower in the chlorhexidine group indicating a large reduction in plaque from 1.00 to 1.90 standard deviations | 950 (12 trials) | ⊕⊕⊕⊕2,3 | The effect for the Plaque Index (4 trials; 223 participants) was 0.58 (95% CI 0.39 to 0.78) lower The effect for the Turesky Modification of the Quigley and Hein Index (5 trials; 546 participants) was 0.78 (95% CI 0.70 to 0.85) lower There were also large effects for the plaque at 6 months | |
| Tooth staining 4 to 6 weeks (various increasing scales) | The mean tooth staining score was measured on different scales | The SMD for tooth staining in the chlorhexidine group was | 415 (8 trials) | ⊕⊕⊕⊝4 | Data have not been converted to original scale as many different scales are used. The SMD effect size is considered large There were also 2 trials presenting dichotomous data showing large significant effect RR 5.41 (95% CI 2.03 to 14.47) There was also a large effect for tooth staining for chlorhexidine at 7 to 12 weeks and 6 months | |
| Other adverse effects | 22 trials reported at least 1 adverse effect apart from extrinsic tooth staining and calculus formation in the chlorhexidine rinse arms. The adverse effects most commonly reported were taste disturbance/alteration (reported in 11 trials), effects on the oral mucosa including mucosal irritation, soreness, mild desquamation, mucosal ulceration/erosions, oral mucosal lesions (reported in 13 trials) and a general burning sensation and/or a burning tongue (reported in 9 trials) | |||||
| *The basis for the assumed risk (e.g. the median control group risk across trials) is provided in footnotes. The corresponding risk (and its 95% CI) 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 | ||||||
| 1The mean gingivitis score for the control group was 0.93 (median is 1.0). | ||||||
| Characteristic | Number of studies | Slope estimate | 95% CI | Slope interpretation | P value |
|---|---|---|---|---|---|
| Adults versus children | 10 ‐ no studies with just children | ||||
| Gingivitis alone versus gingivitis with perio | 8 | 0.12 | ‐0.14 to 0.38 | Increase in GI effect estimate for gingivitis and perio | 0.30 |
| Prophylaxis or not | 9 | 0.05 | ‐0.22 to 0.32 | Increase in GI effect estimate for prophylaxis | 0.66 |
| Baseline gingivitis < 1 versus > 1 | 9 | 0.02 | ‐0.25 to 0.30 | Increase in GI effect estimate for higher baseline score | 0.84 |
| CI = confidence interval. | |||||
| Characteristic | Number of studies | Slope estimate | 95% CI | Slope interpretation | P value |
|---|---|---|---|---|---|
| Adults versus children | 13 | ‐0.17 | ‐0.42 to 0.09 | Increase in GI effect estimate for adults | 0.185 |
| Gingivitis alone versus gingivitis with perio | 9 | 0.15 | ‐0.14 to 0.44 | Increase in GI effect estimate for gingivitis and perio | 0.25 |
| Prophylaxis or not | 11 | ‐0.13 | ‐0.25 to ‐0.004 | Increase in GI effect estimate for no prophylaxis | 0.045 |
| Baseline gingivitis < 1 versus > 1 | 9 | ‐0.05 | ‐0.39 to 0.30 | Decrease in GI effect estimate for higher baseline score | 0.75 |
| CI = confidence interval. | |||||
| Outcome (index) | Time | Chlorhexidine concentration | Studies (participants) | MD/SMD 95% CI | Effect P value | Subgroup P value |
|---|---|---|---|---|---|---|
| Gingival inflammation (Gingival Index) | 4 to 6 weeks | 0.2 | 6 (552) | MD ‐0.27 (‐0.46 to ‐0.09) | 0.003 favours CHX | 0.41 |
| 0.1 and 0.12 | 5 (253) | MD ‐0.19 (‐0.27 to ‐0.10) | < 0.0001 favours CHX | |||
| Gingival inflammation (Gingival Index) | 6 months | 0.2 | 1 (86) | MD ‐0.12 (‐0.20 to ‐0.04) | 0.005 | Too few studies in subgroup |
| 0.1 and 0.12 | 10 (2352) | MD ‐0.22 (‐0.33 to ‐0.11) | < 0.00001 favours CHX | |||
| 0.05 | 1 (150) | MD ‐0.04 (‐0.11 to 0.03) | 0.28 | |||
| Gingival bleeding | 4 to 6 weeks | 0.2 | 4 (472) | SMD ‐0.71 (‐0.90 to ‐0.51) | < 0.00001 favours CHX | 0.18 |
| 0.1 and 0.12 | 3 (127) | SMD ‐0.32 (‐0.85 to 0.21) | 0.23 | |||
| Gingival bleeding | 6 months | 0.2 | 2 (155) | SMD ‐1.20 (‐2.48 to 0.08) | 0.07 | 0.34 |
| 0.12 | 6 (977) | SMD ‐0.57 (‐0.79 to ‐0.36) | < 0.00001 favours CHX | |||
| Plaque | 4 to 6 weeks | 0.2 | 8 (685) | SMD ‐1.75 (‐2.45 to ‐1.04) | < 0.00001 favours CHX | 0.04 |
| 0.1 and 0.12 | 4 (215) | SMD ‐0.95 (‐1.23 to ‐0.66) | < 0.00001 favours CHX | |||
| Plaque | 6 months | 0.2 | 2 (149) | SMD ‐1.26 (‐1.61 to ‐0.90) | < 0.00001 favours Chx | 0.65 |
| 0.1 and 0.12 | 8 (1898) | SMD ‐1.38 (‐1.75 to ‐1.00) | < 0.00001 favours CHX | |||
| Calculus | 4 to 6 weeks | 0.12 | 1 (52) | MD 0.01 (‐0.21 to 0.23) | 0.93 | |
| Calculus | 7 to 12 weeks | 0.2 | 2 (159) | SMD ‐0.03 (‐0.43 to 0.36) | 0.86 | 0.05 |
| 0.12 | 4 (266) | SMD 0.52 (0.13 to 0.91) | 0.10 | |||
| Calculus | 6 months | 0.2 | 2 (149) | SMD 0.41 (0.09 to 0.74) | 0.01 | 0.005 |
| 0.12 | 2 (174) | SMD 1.17 (0.76 to 1.59) | < 0.00001 favours control | |||
| Tooth staining | 4 to 6 weeks | 0.2 | 2 (116) | SMD 1.45 (1.04 to 1.87) | < 0.00001 favours control | 0.05 |
| 0.1 and 0.12 | 6 (299) | SMD 0.96 (0.68 to 1.24) | < 0.00001 favours control | |||
| Tooth staining | 7 to 12 weeks | 0.2 | 3 (181) | SMD 1.38 (1.05 to 1.71) | < 0.00001 favours control | 0.10 |
| 0.12 | 7 (361) | SMD 1.2 (0.96 to 1.45) | < 0.00001 favours control | |||
| 0.05 | 1 (39) | SMD 0.59 (‐0.05 to 1.24) | 0.07 | |||
| Tooth staining | 6 months | 0.2 | 2 (149) | SMD 1.79 (1.41 to 2.17) | < 0.00001 favours control | 0.08 |
| 0.12 | 2 (174) | SMD 1.33 (1.00 to 1.66) | < 0.00001 favours control | |||
| CHX = chlorhexidine; CI = confidence interval; MD = mean difference; SMD = standardised mean difference. Studies where the concentration of the chlorhexidine mouthrinse was not reported (Turkoglu 2009) and where data relate to a combination of different chlorhexidine concentrations (Flotra 1972) were excluded from this analysis. Therefore, in certain analyses, the number of studies and participants presented in the table are different from the data presented in the main analysis. | ||||||
| Outcome (index) | Time | Chlorhexidine frequency | Studies (participants) | MD/SMD 95% CI | Effect P value | Subgroup P value |
|---|---|---|---|---|---|---|
| Gingival inflammation (Gingival Index) | 4 to 6 weeks | Twice per day | 9 (785) | MD ‐0.22 (‐0.33 to ‐0.11) | < 0.0001 | Too few studies in subgroup |
| Once per day | 1 (20) | MD ‐0.13 (‐0.31 to 0.06) | 0.18 | |||
| Gingival inflammation (Gingival Index) | 6 months | Twice per day | 11 (1614) | MD ‐0.17 (‐0.20 to ‐0.13) | < 0.0001 | 0.56 |
| Once per day | 2 (1002) | MD ‐0.34 (‐0.93 to 0.25) | 0.26 | |||
| Gingival bleeding | 4 to 6 weeks | Twice per day | 8 (649) | SMD ‐0.56 (‐0.79 to ‐0.33) | < 0.0001 | ‐ |
| Gingival bleeding | 6 months | Twice per day | 8 (1132) | SMD ‐0.72 (‐1.02 to ‐0.42) | < 0.0001 | ‐ |
| Plaque | 4 to 6 weeks | Twice per day | 11 (930) | SMD ‐1.49 (‐1.97 to ‐1.02) | < 0.0001 | Too few studies in subgroup |
| Once per day | 1 (20) | SMD ‐0.92 (‐1.86 to 0.02) | 0.05 | |||
| Plaque | 6 months | Twice per day | 10 (1223) | SMD ‐1.34 (‐1.66 to ‐1.03) | < 0.0001 | Too few studies in subgroup |
| Once a day | 1 (852) | SMD ‐2.10 (‐2.27 to ‐1.93) | < 0.0001 | |||
| Calculus | 4 to 6 weeks | Twice per day | 1 (50) | MD 0.03 (‐0.11 to 0.17) | 0.70 | ‐ |
| Calculus | 7 to 12 weeks | Twice per day | 5 (373) | SMD 0.33 (‐0.11 to 0.77) | 0.14 | ‐ |
| Calculus | 6 months | Twice per day | 4 (323) | SMD 0.80 (0.33 to 1.26) | 0.0007 | ‐ |
| Tooth staining | 4 to 6 weeks | 3 times per day | 1 (33) | SMD 1.55 (0.76 to 2.34) | < 0.0001 | Too few studies in subgroup |
| Twice per day | 5 (310) | SMD 1.18 (0.93 to 1.44) | < 0.0001 | |||
| Once per day | 1(20) | SMD 0.39 (‐0.5 to 1.28) | 0.39 | |||
| Tooth staining | 7 to 12 weeks | 3 times per day | 1 (33) | SMD 0.77 (0.06 to 1.48) | 0.03 | Too few studies in subgroup |
| Twice per day | 9 (496) | SMD 1.26 (1.04 to 1.49) | < 0.0001 | |||
| Tooth staining | 6 months | Twice per day | 4 (323) | SMD 1.54 (1.22 to 1.86) | < 0.0001 | ‐ |
| CI = confidence interval; MD = mean difference; SMD = standardised mean difference. | ||||||
| Outcome (index) | Time | Chlorhexidine conc (%) | Studies (participants) | MD/SMD 95% CI | Effect P value | Heterogeneity |
|---|---|---|---|---|---|---|
| Results for studies with no rinse control arms | ||||||
| Gingival bleeding | 7 to 12 weeks | < 0.1 | 2 (196) | MD ‐0.07 (‐0.16 to 0.02) | 0.13 favours CHX | P = 0.19, I2 = 40% |
| Plaque | 7 to 12 weeks | < 0.1 | 2 (196) | SMD ‐0.77 (‐1.07 to ‐0.47) | < 0.00001 favours CHX | P = 0.61, I2 = 0% |
| Results for studies with placebo/control rinse arms | ||||||
| Gingival inflammation (Gingival Index) | 7 to 12 weeks | 0.2 and 0.12 | 4 (144) | MD ‐0.47 (‐0.76 to ‐0.18) | 0.001 favours CHX | P < 0.0001, I2 = 86% |
| Gingival inflammation (Gingival Index) | > 6 months | 0.1 and 0.12 | 2 (1124) | MD ‐0.50 (‐1.11 to 0.11) | 0.11 favours CHX | P < 0.0001, I2 = 99% |
| Gingival bleeding | 7 to 12 weeks | 0.12 and < 0.1 | 5 (182) | SMD ‐1.29 (‐1.85 to ‐0.72) | < 0.00001 favours CHX | P = 0.02, I2 = 64% |
| Gingival bleeding | Long term | 0.12 | 3 (99) | MD ‐0.12 (‐0.2 to ‐0.04) | 0.003 favours CHX | P = 0.33, I2 = 11% |
| Plaque | 7 to 12 weeks | 0.2, 0.12 and < 0.1 | 10 (423) | SMD ‐1.74 (‐2.51 to ‐0.98) | < 0.00001 favours CHX | P < 0.00001, I2 = 91% |
| Plaque | > 6 months | 0.1 | 1 (852) | MD ‐1.55 (‐1.79 to ‐1.31) | < 0.00001 favours CHX | N/A |
| Plaque | Long term | 0.12 | 4 (132) | SMD ‐1.10 (‐1.18 to ‐0.40) | < 0.002 favours CHX | P = 0.02, I2 = 71% |
| CHX = chlorhexidine; CI = confidence interval; conc = concentration; MD = mean difference; N/A = not applicable; SMD = standardised mean difference. There were no subgroup differences between the different chlorhexidine concentrations, therefore the overall effect for all concentrations combined is reported. | ||||||
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Anauate‐Netto 2014 | CHX 0.12% vs placebo | PBS | 0.9 (0.6) | 0.7 (0.4) | 40 | Did not report GI. Quote: "..no statistically significant differences were detected among groups" |
| 7 to 12 weeks | Anderson 1997 | CHX 0.12% vs placebo | GI | 0.345 | 0.895 | 28 | Reported mean GI by surface + SD. No overall SD. We calculated overall mean. Quote: "The means of the …gingival indices did not show any significant differences (P<0.05) 1 or 2 months after baseline. However there were significant differences (P<0.05) in the changes recorded at 30 and 60 days at all sites in…..the experimental group" |
| de la Rosa 1888b | CHX 0.12% vs placebo | PMGI severity (mean score of all sites graded) | 0.1413 | 0.2902 | 92 | Did not report GI or a SD. Quote: "..the effect of the chlorhexidine rinse on the occurrence and severity of gingivitis amounted to a 51% reduction of the disease compared to the placebo rinse…differences were statistically significant" | |
| de la Rosa 1988a | CHX 0.12% vs placebo | PMGI severity (mean score of all sites graded) | 0.2892 | 0.4526 | 99 | Did not report GI or a SD. Quote: "..the gingivitis reductions were 34% and 36% for occurrence and severity respectively…differences were statistically significant" | |
| Eaton 1997 | CHX 0.12% vs placebo | mGI | 0.42 (0.383) | 0.55 (0.382) | 98 | Did not report GI. Quote: "..the pooled mean mGI score improved by 25% from 0.56 at baseline to 0.42 at 12 weeks in the ChD (CHX) group but showed no change (0.54 to 0.55) in the placebo group" | |
| Ferretti 1987 | CHX 0.12% vs placebo | PMGI | 0.8 | 1.94 | 33 | Did not report GI and SD depicted in graph but not reported. Quote: "Significant reductions in …gingivitis scores were seen on days 33 (P<0.0001) and 60… (P<0.001) for those patients using chlorhexidine rinse" | |
| Segreto 1986 | 0.2% vs 0.12% vs placebo | GI | 0.4112/0.3640 | 0.5039 | 454 | Did not report a SD. Quote: "Gingivitis severity by the GI method was… significantly lower at 3 months for both chlorhexidine groups compared to the placebo group. Differences ranged from 28‐46% and averaged 37% for the 0.12% group. Differences ranged from 18‐40% for the 0.20% group and averaged 29%" | |
| Weitz 1992 | CHX 0.12% vs placebo | GI | 1.69 | 1.86 | 36 | Did not report a SD. Quote: "…the active (CHX) groups had significantly lower… gingivitis scores than the respective control groups. Overall, the active group had a 10.27% reduction in the gingival index…compared to insignificant changes in the control groups" | |
| 6 months | Fine 1985 | CHX+OH vs OH | Not clear. Quote: "a gingival inflammation Index" | NR | NR | 83 | Outcomes reported in graphs which are difficult to decipher. Quote: "Whilst there was a general improvement in all… groups of patients, no one group was statistically significantly different from the other…" |
| Hoffmann 2001 | CHX 0.1%, CHX 0.06%, CHX 0.06%+F vs control | GI | Median 0.15/0.29/0.34 | Median 0.45 | 58 | No SD. At 3 months "..only the 0.1% CHX was different from the control". At 6 months "…the 0.1% CHX showed significant differences…in the GI…when compared to the 0.06% CHX/F" (P = 0.043) | |
| Overholser 1990 | CHX 0.12% vs control | mGI | 0.81 (SE 0.065) | 1.166 (SE 0.063) | 83 | Did not report a SD. Quote: "PX (CHX) inhibited gingivitis development by 26.8% (P<0.001) at 3 months and by 30.5% (P<0.001) at 6 months, compared to the control" | |
| CHX = chlorhexidine; F = fluoride; NR = not reported; OH = oral hygiene; SD = standard deviation; SE = standard error. Total n is the number of participants analysed in the study arms relevant to the review. PBS (Papillary Bleeding Score, Loesche 1979) is measured on a 0‐5 increasing scale. GI (Gingival Index, Löe 1967; Löe and Silness 1963) is measured on a 0‐3 increasing scale. PMGI (Papillary Marginal Gingivitis Index, de la Rosa and Sturzenberger 1976) is measured on a 0‐3 increasing scale. mGI (modified Gingival Index, Lobene 1986) is measured on a 0‐4 increasing scale. | |||||||
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Axelsson 1987 | CHX 0.2% vs CHX 0.1% vs placebo | Mean % of gingival units with GI score 2 or 3 | 12%/11% | 25% | 64 | Did not report a SD. Quote: "In all…study groups, the % of gingival units scored GI 2+3 was reduced between baseline..and end of trial" |
| Graziani 2015 | CHX 0.2%+Alc vs CHX 0.2% no Alc vs CHX+ADS vs control rinse | FMBS /BOP | Not clear | 13.47% | 70 | Partial reporting of outcome data. Quote: "Statistically significant decreases in mean full‐mouth scores of gingival inflammation were noted for all experimental study groups at day 35 compared to baseline. Between‐group changes in FMBS…were statistically significant only when CHX2 (mean difference of 43.4 ± 22.4, P = 0.05) and CHX 3 (mean difference of 46.1 ± 23.1, P = 0.05) were compared to the CTRL group" (note: CHX 2 = CHX no Alc, CHX 3 = CHX + ADS) | |
| Sanz 1989 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 18.78% | 31.31% | 38 | Did not report a SD. Quote: "Beginning at 4 weeks of rinsing, gingival bleeding was significantly lower in the CHX group compared to the placebo group by an average of 41.6% (P < 0.05). At 6 weeks that reduction was 40%, (P < 0.05)" | |
| 7 to 12 weeks | Corbet 1997 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 27%(anterior) 42%(posterior) | 52%(anterior) 75%(posterior) | 36 | Did not report a SD. Quote: "The difference between the mean percentage of GB of the test and control groups at 3 months was highly significant (P < 0.001)" |
| Segreto 1986 | CHX 0.2% vs CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | Examiner A: 3.4%/2% Examiner B: 7.2%/6.2% | Examiner A: 3.81% Examiner B: 14.9% | 454 | Did not report a SD. O.2% Quote: "Bleeding was 31% lower (range 11‐52%) compared to the placebo group" (P > 0.05) 0.12% Quote: "..gingival bleeding was significantly lower by an average of 53% for both examiners (range 48‐59%)" (P ≤ 0.05) | |
| 6 months | Banting 1989 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 2.41% | 4.12% | 383 | Did not report a SD. Regarding outcomes at 6 months to 2 years: Quote: "Subjects in the treatment group…displayed between 42% and 51% fewer sites with moderate to severe gingivitis (GI scores of 2 or 3) compared with subjects in the control group" (P < 0.0001) |
| Charles 2004 | CHX 0.12% vs control | Mean % sites GI score 2 and 3 | 11.01% | 20.65% | 1156 sites | % of bleeding sites in each group is presented. There is a unit of analysis error (number of sites rather than number of subjects). Quote: "There was a considerable reduction in percent bleeding sites in the chlorhexidine…groups at 6 months compared with both control and baseline" | |
| Lucas 1999 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 1% | 4.2% | 20 | Did not report a SD. Quote: "Although the percentage of bleeding surfaces in the chlorhexidine group was less than in the placebo group on days 90 (33%) and 180 (76%), the differences were not significant" (P = 0.07) | |
| Sanz 1994 | CHX 0.12% vs placebo | % sites GI score 2 and 3 | Graph | Graph | 130 | % bleeding sites reported incompletely in text and also in a graph. Did not report a SD. Quote: "At 6 months…the positive control group had significantly fewer bleeding sites than the control group (.. 23%...)" | |
| Gingival bleeding > 6 months | Banting 1989 | CHX 0.12% vs placebo | Mean % sites GI score 2 and 3 | 4.41% | 8.88% | 272 | Did not report a SD. Regarding outcomes at 6 months to 2 years: Quote: "Subjects in the treatment group…displayed between 42% and 51% fewer sites with moderate to severe gingivitis (GI scores of 2 or 3) compared with subjects in the control group" (P < 0.0001) |
| ADS = antidiscolouration system; Alc = alcohol; BOP = bleeding on probing; CHX = chlorhexidine; FMBS = Full‐Mouth Bleeding Score; GI = Gingival Index; SD = standard deviation. Total n is the number of participants analysed in the study arms relevant to the review. | |||||||
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Sanz 1989 | CHX 0.12% vs placebo | PI | 0.452 | 0.9907 | 38 | Did not report a SD |
| 7 to 12 weeks | Anderson 1997 | CHX 0.12% vs placebo | PI | 0.3175* | 0.8425* | 28 | Mean GI by surface + SD reported. We calculated the overall mean. No overall SD |
| de la Rosa 1888b | CHX 0.12% vs placebo | TQH | NR | NR | 92 | Quote: "The reductions in dental plaque were not statistically significant.." | |
| de la Rosa 1988a | CHX 0.12% vs placebo | TQH | NR | NR | 99 | Quote: "The reductions in dental plaque were not statistically significant.." | |
| Segreto 1986 | 0.2% vs 0.12% vs placebo | TQH | 1.14/1.01 | 1.58 | 451 | Did not report a SD | |
| Weitz 1992 | CHX 0.12% vs placebo | PI | 1.84 | 2.21 | 36 | Did not report a SD | |
| 6 months | Banting 1989 | CHX 0.12% vs placebo | TQH | Graph | Graph | 383 | Data presented in a graph. Did not report a SD. Quote: "Subjects in the treatment group had significantly lower mean plaque scores than those in the control group at six months, and at one and two years. The difference between the groups ranged from 35% to 46%" |
| Hoffmann 2001 | CHX 0.1%/CHX 0.06%/CHX 0.06%+F vs control rinse | PI | Median 0.13/0.25/0.27 | Median 0.72 | 58 | Median only. Did not report a SD | |
| Jayaprakash 2007 | CHX 0.05%/ CHX 0.05%+F vs placebo | PI | 0.0813/0.0459 | 0.1189 | 100 | Did not report a SD | |
| Lucas 1999 | CHX 0.12% vs placebo | OHI‐S | 0.33 | 0.59 | 20 | Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | PI | Graph | Graph | 130 | Data presented in a graph. Did not report a SD. Quote: "…reductions in Plaque Index...were statistically significant for the positive control group…compared with the reduction obtained with the control group.. These reductions were 41% (positive control)…after 3 months and 35%..after 6 months.." | |
| Plaque > 6 months | Banting 1989 | CHX 0.12% vs placebo | TQH | Graph | Graph | 272 | Data presented in a graph. Did not report a SD. Quote: "Subjects in the treatment group had significantly lower mean plaque scores than those in the control group at six months, and at one and two years. The difference between the groups ranged from 35% to 46%" |
| CHX = chlorhexidine; F = Fluoride; NR = not reported; SD = standard deviation. Total n is the number of participants analysed in the study arms relevant to the review. PI (Plaque Index, Silness and Löe 1964) is measured on a 0‐3 increasing scale. TQH (Turesky modification of the Quigley and Hein Index, Turesky 1970) is measured on a 0‐5 increasing scale. OHI‐S (Simplified Oral Hygiene Index, Greene and Vermillion 1964) is measured on a 0‐3 increasing scale. | |||||||
| Time | Study ID | Comparison | Index | CHX mean (SD) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Anderson 1997 | CHX 0.12% vs placebo | RI | 0.1075 | 0.0475 | 29 | Mean RI by surface + SD reported. We calculated overall mean. No overall SD |
| 7 to 12 weeks | Anderson 1997 | CHX 0.12% vs placebo | RI | 0.0875 | 0.0525 | 28 | Mean RI by surface + SD reported. We calculated overall mean. No overall SD |
| Charles 2004 | CHX 0.12% vs control | VM | 0.37 (SD NR) | 0.11 (SD NR) | 74 | Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | VM | Graph | Graph | 130 | Data presented in graph. Did not report a SD. Quote: "All groups developed calculus after the initial cleaning at baseline. This increase was only statistically significant for the positive control group compared with the control group at 6 months" | |
| Calculus 6 months | Banting 1989 | CHX 0.12% vs placebo | VM | NR | NR | 383 | Results reported at 24 months only. See results at > 6 months below |
| Charles 2004 | CHX 0.12% vs control | VM | 0.45 (SD NR) | 0.21 (SD NR) | 73 | Did not report a SD | |
| Grossman 1986 | CHX 0.12% vs placebo | Not specified | NR | NR | 380 | Quote: "Supragingival calculus was higher in the group using chlorhexidine but this increase in calculus did not diminish the therapeutic effects of chlorhexidine since subjects with significant increases in calculus also had significant decreases in gingivitis" | |
| Sanz 1994 | CHX 0.12% vs placebo | VM | Graph | Graph | 130 | Data presented in a graph. Did not report a SD. Quote: "All groups developed calculus after the initial cleaning at baseline. This increase was only statistically significant for the positive control group compared with the control group at 6 months" | |
| Calculus > 6 months | Banting 1989 | CHX 0.12% vs placebo | VM | NR | NR | 272 | At 24 months subjects in the treatment group had higher mean supragingival calculus scores, but at the same time more subjects were free of subgingival calculus |
| CHX = chlorhexidine; NR = not reported; SD = standard deviation. Total n is the number of participants analysed in the study arms relevant to the review. RI (Retention Index, Björby and Löe 1966) is measured on a 0‐3 increasing scale. VM (Volpe‐Manhold Calculus Index, Manhold 1965; Volpe 1965) measures calculus present on the lingual surface of the lower 6 anterior teeth. Calculus is measured in 3 planes using a standard periodontal probe.The greatest value allowed for any 1 plane is 3 units, therefore the maximum score per tooth is 9 units or 54 units per subject. The mean per subject score is obtained by dividing the total calculus score by the number of lower anterior teeth. A mean calculus score for the group is then calculated. | |||||||
| Time | Study ID | Comparison | Index | CHX mean (SD/SE) or n (%) | Control mean (SD) | Total n | Notes |
|---|---|---|---|---|---|---|---|
| 4 to 6 weeks | Axelsson 1987 | CHX 0.2%/0.1% vs control | DI (Lobene) | 0.1171 (0.297) | 0 | 64 | Not included in meta‐analysis as control mean is 0. We combined data from the 0.2% and 0.1% CHX groups |
| Bhat 2014 | CHX 0.2% vs control | Reported number and proportion of participants with mild or moderate 'discolouration' in text | 20 (91%) | 0 | 44 | Not clear whether discolouration relates to teeth or oral tissues or both | |
| Flotra 1972 & 1971 (4‐month study that reports this outcome at 4 weeks) | CHX 0.2%/0.1%/0.1% (acetate) vs control | No index Reported narratively | 12% of tooth surfaces without fillings 62% of silicate fillings | NR | 48 (at 4 weeks) | Quote: "..12% of the tooth surfaces without fillings became discolored within the first 4 weeks of the experiment…this happened more frequently on the interproximal surfaces than on the labial surfaces (ratio2:1). Sixty‐two per cent of the silicate fillings in these areas were discolored.." | |
| Graziani 2015 | CHX 0.2% vs control | SI | 0.2228 (0.18) | 0 | 70 | Not included in meta‐analysis as control mean is 0. We combined data from the 3 CHX groups | |
| Hase 1995 | CHX 0.2% vs placebo | Subjective of participants regarding staining of teeth and/or tongue using VAS | 38 (SE 7) | 9 (SE 1) | 39 | Teeth and/or tongue staining reported together. Data estimated from a graph | |
| López‐Jornet 2012 | CHX 0.2% vs placebo | Registration of side effects including denture/dental staining (n and %) | 2 (5.71%) | 3 (8.57%) | 70 | Denture and dental staining reported together | |
| Turkoglu 2009 | CHX (conc not reported) vs placebo | No index Reported narratively | 14 (56%) | Assumed 0 | 50 | Quote: "Of the 25 subjects who rinsed their mouth with CHX mouthrinse..14 showed discolouration of teeth and/or tongue" | |
| Zimmer 2006 | CHX 0.06%+F+OH vs OH | Staining of teeth and tongue registered at final examination (n) | 4 | 0 | 78 | Stain on teeth/tongue reported together. If more than 1 side effect was present, only the most relevant was listed i.e. side effects were reported with no double counting | |
| 7 to 12 weeks | Charles 2004 | CHX 0.12% vs control | DI (Lobene) | 1.61 (SD NR) | 0.01 (SD NR) | 74 | Did not report a SD |
| Grossman 1989 | CHX 0.12% vs placebo | Not specified Quote: "Photographs of facial surfaces of the 12 anterior teeth (maxillary and mandibular, cuspid to cuspid) were graded for stain intensity and coverage" | 4.66 (SD NR) | 2.59 (SD NR) | 246 | Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | Not specified | NR | NR | 130 | Data presented in a graph at 6 months only See 6‐month results below | |
| Zimmer 2006 | CHX 0.06% +F+OH vs OH | Staining of teeth and tongue registered at final examination (n) | 6 | 0 | 78 | Stain on teeth/tongue reported together. If more than 1 side effect was present, only the most relevant was listed i.e. side effects were reported with no double counting | |
| 6 months | Charles 2004 | CHX 0.12% vs control | DI (Lobene) | 2.08 (SD NR) | 0.01 (SD NR) | 73 | Did not report a SD |
| Grossman 1986 | CHX 0.12% vs placebo | Not specified | NR | NR | 380 | Outcome data not reported. Quote: "Some extrinsic tooth staining was observed in the chlorhexidine group" | |
| Grossman 1989 | CHX 0.12% vs placebo | Not specified Quote: "Photographs of facial surfaces of the 12 anterior teeth (maxillary and mandibular, cuspid to cuspid) were graded for stain intensity and coverage" | 5.15 (SD NR) | 2.75 (SD NR) | 246 | Did not report a SD | |
| Hoffmann 2001 | CHX 0.1%/ 0.06%/0.06%+F vs control | DI (Lang and Räber) | 1.13/1.02/1.06 (SD NR) | 0.38 (SD NR) | 58 | Median only. Did not report a SD | |
| Sanz 1994 | CHX 0.12% vs placebo | Not specified Quote: "Photographs of facial surfaces of the 12 anterior teeth (maxillary and mandibular, cuspid to cuspid) were graded for stain intensity and coverage" | Graph | Graph | 130 | Data presented in graph Did not report a SD Quote: "Statistically significant more overall staining, more intense staining and stain coverage per tooth were detected for the positive control group…compared with the control group" | |
| CHX = chlorhexidine; conc = concentration; F = fluoride; NR = not reported; OH = oral hygiene; SD = standard deviation; SE = standard error; VAS = visual analogue scale. Total n is the number of participants analysed in the study arms relevant to the review. DI (Discolouration Index, Lobene 1968): gingival and body regions of the tooth are scored for intensity (0‐3 increasing scale) and severity (0‐3 increasing scale). DI (Discolouration Index, Lang and Räber 1981) is measured on a 0‐3 increasing scale. SI (Staining Index): the buccal surfaces of the 8 central incisors were divided into 3 areas: incisal, approximal and gingival according to Lobene 1968 and Grundemann 2000 and a SI was used to record the dichotomous presence or absence of staining in each area and to calculate the percentage of the total area showing staining. | |||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1.1 Gingival Index (0‐3) 4‐6 weeks Show forest plot | 10 | 805 | Mean Difference (IV, Random, 95% CI) | ‐0.21 [‐0.31, ‐0.11] |
| 1.1.1 CHX versus no rinse | 2 | 339 | Mean Difference (IV, Random, 95% CI) | ‐0.13 [‐0.31, 0.05] |
| 1.1.2 CHX versus placebo/control rinse | 8 | 466 | Mean Difference (IV, Random, 95% CI) | ‐0.23 [‐0.34, ‐0.13] |
| 1.2 Gingival Index (0‐3) 6 months Show forest plot | 13 | 2616 | Mean Difference (IV, Random, 95% CI) | ‐0.20 [‐0.30, ‐0.11] |
| 1.2.1 CHX versus no rinse | 2 | 142 | Mean Difference (IV, Random, 95% CI) | ‐0.12 [‐0.18, ‐0.05] |
| 1.2.2 CHX versus placebo/control rinse | 11 | 2474 | Mean Difference (IV, Random, 95% CI) | ‐0.22 [‐0.33, ‐0.11] |
| 1.3 Gingival bleeding 4‐6 weeks Show forest plot | 8 | 649 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.56 [‐0.79, ‐0.33] |
| 1.3.1 CHX versus no rinse | 4 | 459 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.69 [‐0.89, ‐0.50] |
| 1.3.2 CHX versus placebo/control rinse | 4 | 190 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.36 [‐0.77, 0.06] |
| 1.4 Gingival bleeding 6 months Show forest plot | 8 | 1132 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.72 [‐1.02, ‐0.42] |
| 1.4.1 CHX versus no rinse | 2 | 142 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.49 [‐0.83, ‐0.16] |
| 1.4.2 CHX versus placebo/control rinse | 6 | 990 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.79 [‐1.16, ‐0.41] |
| 1.5 Plaque 4‐6 weeks Show forest plot | 12 | 950 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.45 [‐1.90, ‐1.00] |
| 1.5.1 CHX versus no rinse | 3 | 433 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.43 [‐2.39, ‐0.47] |
| 1.5.2 CHX versus placebo/control rinse | 9 | 517 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.48 [‐2.07, ‐0.89] |
| 1.6 Plaque 4‐6 weeks PI (0‐3) Show forest plot | 4 | 223 | Mean Difference (IV, Random, 95% CI) | ‐0.58 [‐0.78, ‐0.39] |
| 1.6.1 CHX versus no rinse | 2 | 114 | Mean Difference (IV, Random, 95% CI) | ‐0.59 [‐0.94, ‐0.24] |
| 1.6.2 CHX versus placebo/control rinse | 2 | 109 | Mean Difference (IV, Random, 95% CI) | ‐0.50 [‐0.97, ‐0.04] |
| 1.7 Plaque 4‐6 weeks TQH (0‐5) Show forest plot | 5 | 546 | Mean Difference (IV, Random, 95% CI) | ‐0.78 [‐0.85, ‐0.70] |
| 1.7.1 CHX versus no rinse | 1 | 319 | Mean Difference (IV, Random, 95% CI) | ‐0.83 [‐1.00, ‐0.66] |
| 1.7.2 CHX versus placebo/control rinse | 4 | 227 | Mean Difference (IV, Random, 95% CI) | ‐0.76 [‐0.85, ‐0.68] |
| 1.8 Plaque 6 months Show forest plot | 11 | 2075 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.43 [‐1.76, ‐1.10] |
| 1.8.1 CHX versus no rinse | 2 | 142 | Std. Mean Difference (IV, Random, 95% CI) | ‐0.68 [‐1.35, ‐0.01] |
| 1.8.2 CHX versus placebo/control rinse | 9 | 1933 | Std. Mean Difference (IV, Random, 95% CI) | ‐1.59 [‐1.89, ‐1.29] |
| 1.9 Plaque 6 months PI (0‐3) Show forest plot | 5 | 1108 | Mean Difference (IV, Random, 95% CI) | ‐0.62 [‐1.12, ‐0.12] |
| 1.9.1 CHX versus no rinse | 2 | 142 | Mean Difference (IV, Random, 95% CI) | ‐0.30 [‐0.42, ‐0.18] |
| 1.9.2 CHX versus placebo/control rinse | 3 | 966 | Mean Difference (IV, Random, 95% CI) | ‐0.86 [‐1.46, ‐0.25] |
| 1.10 Plaque 6 months TQH (0‐5) Show forest plot | 6 | 967 | Mean Difference (IV, Random, 95% CI) | ‐0.73 [‐0.88, ‐0.57] |
| 1.10.1 CHX versus placebo/control rinse | 6 | 967 | Mean Difference (IV, Random, 95% CI) | ‐0.73 [‐0.88, ‐0.57] |
| 1.11 Calculus 4‐6 weeks Show forest plot | 2 | Mean Difference (IV, Random, 95% CI) | Subtotals only | |
| 1.11.1 CHX versus placebo/control rinse | 2 | 102 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.09, 0.14] |
| 1.12 Calculus 7‐12 weeks Show forest plot | 6 | 425 | Std. Mean Difference (IV, Random, 95% CI) | 0.32 [‐0.04, 0.69] |
| 1.12.1 CHX versus no rinse | 1 | 95 | Std. Mean Difference (IV, Random, 95% CI) | 1.02 [0.59, 1.45] |
| 1.12.2 CHX versus placebo/control rinse | 5 | 330 | Std. Mean Difference (IV, Random, 95% CI) | 0.14 [‐0.08, 0.36] |
| 1.13 Calculus 6 months Show forest plot | 4 | 323 | Std. Mean Difference (IV, Random, 95% CI) | 0.80 [0.33, 1.26] |
| 1.13.1 CHX versus no rinse | 1 | 91 | Std. Mean Difference (IV, Random, 95% CI) | 1.39 [0.93, 1.85] |
| 1.13.2 CHX versus placebo/control rinse | 3 | 232 | Std. Mean Difference (IV, Random, 95% CI) | 0.60 [0.24, 0.96] |
| 1.14 Tooth staining 4‐6 weeks dichotomous Show forest plot | 2 | 156 | Risk Ratio (M‐H, Random, 95% CI) | 5.41 [2.03, 14.47] |
| 1.14.1 CHX versus no rinse | 1 | 118 | Risk Ratio (M‐H, Random, 95% CI) | 4.44 [1.43, 13.80] |
| 1.14.2 CHX versus placebo/control rinse | 1 | 38 | Risk Ratio (M‐H, Random, 95% CI) | 9.88 [1.37, 71.44] |
| 1.15 Tooth staining 7‐12 weeks dichotomous Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Subtotals only | |
| 1.15.1 CHX versus no rinse | 1 | 118 | Risk Ratio (M‐H, Random, 95% CI) | 2.50 [1.29, 4.83] |
| 1.16 Tooth staining 4‐6 weeks Show forest plot | 8 | 415 | Std. Mean Difference (IV, Random, 95% CI) | 1.07 [0.80, 1.34] |
| 1.16.1 CHX versus no rinse | 1 | 94 | Std. Mean Difference (IV, Random, 95% CI) | 1.54 [1.08, 2.00] |
| 1.16.2 CHX versus placebo/control rinse | 7 | 321 | Std. Mean Difference (IV, Random, 95% CI) | 0.97 [0.73, 1.22] |
| 1.17 Tooth staining 7‐12 weeks Show forest plot | 11 | 581 | Std. Mean Difference (IV, Random, 95% CI) | 1.19 [0.98, 1.40] |
| 1.17.1 CHX versus no rinse | 1 | 95 | Std. Mean Difference (IV, Random, 95% CI) | 1.32 [0.88, 1.77] |
| 1.17.2 CHX versus placebo/control rinse | 10 | 486 | Std. Mean Difference (IV, Random, 95% CI) | 1.17 [0.93, 1.41] |
| 1.18 Tooth staining 6 months Show forest plot | 4 | 323 | Std. Mean Difference (IV, Random, 95% CI) | 1.54 [1.22, 1.86] |
| 1.18.1 CHX versus no rinse | 1 | 91 | Std. Mean Difference (IV, Random, 95% CI) | 1.18 [0.73, 1.62] |
| 1.18.2 CHX versus placebo/control rinse | 3 | 232 | Std. Mean Difference (IV, Random, 95% CI) | 1.69 [1.38, 1.99] |
