Accepted Article

Article Type: Supplement Article

TITLE: Efficacy of adjunctive anti-plaque chemical agents in managing gingivitis. A systematic review and meta-analysis.

RUNNING TITLE: Adjunctive chemical plaque control and gingivitis.

AUTHORS: Jorge Serrano Marta Escribano Silvia Roldán Conchita Martín David Herrera

ETEP (Etiology and Therapy of Periodontal Diseases) Research Group, University Complutense, Madrid, Spain.

ADDRESS David Herrera Facultad de Odontología – Ciudad Universitaria Plaza Ramón y Cajal, s/n. 28040 Madrid

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jcpe.12331 This article is protected by copyright. All rights reserved.

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SPAIN e-mail: [email protected] fax: 34-91-394-19-10

ABSTRACT

Aim: The aim of this systematic review was to evaluate the efficacy of anti-plaque chemical formulations for managing gingivitis, in 6-month, home-use, randomised clinical trials (RCT). Material and Methods: A protocol was designed, including inclusion and exclusion criteria to identify RCTs assessing gingival and/or bleeding indices. Electronic and hand-searches identified relevant papers, which were screened and evaluated for inclusion. Full-papers were retrieved and relevant information was extracted (including plaque indices), including quality and risk of bias. Mean treatment effects were calculated to obtain weighted mean differences (WMD) and 95% confidence intervals. Results: After the process of screening and selection, 87 articles with 133 comparisons, were included in the review. The additional effects of the tested products were statistically significant in terms of Löe & Silness gingival index (46 comparisons, WMD -0.217), modified gingival index (n=23, -0.415), gingivitis severity index (n=26, -14.939%) or bleeding index (n=23, -7.626%), with significant heterogeneity. For plaque, additional effects were found for Turesky (66 studies, WMD -0.475), Silness & Löe (n=26, -0.109), and plaque severity (n=12, -23.4%) indices, with significant heterogeneity. Conclusion: Within the limitations of the present study, formulations with specific agents for chemical plaque control provide statistically significant improvements in terms of gingival, bleeding and plaque indices.

Key Words: systematic review, gingivitis, antiseptics, plaque, bleeding

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CLINICAL RELEVANCE

Scientific rationale for study: Chemical plaque control might be necessary in those subjects who are not capable of properly controlling supragingival biofilms using conventional mechanical procedures. The use of chemical formulations (especially antiseptics) to control levels of plaque and gingivitis has been widely evaluated. The efficacy of different formulations has been reported in several systematic reviews. However, none of the available systematic reviews have included all available of agents. Most of them just focused on a specific agent or a limited group of agents. Principal findings: Dentifrices, mouthrinses or the combination of both, containing specific agents for gingivitis and/ or plaque control, provide statistically significant improvements in terms of gingival, bleeding and plaque indices. Practical implications: There is weak but consistent evidence that the adjunctive use (to mechanical plaque control) of specific agents administered as dentifrices, mouthrinses or the combination, helps to control gingival inflammation and plaque levels.

Conflict of Interest and Sources of Funding Statement The authors declare that they have no conflict of interests. This work was self-funded by the ETEP (Etiology and Therapy of Periodontal Diseases) Research Group, University Complutense, Madrid, Spain.

Efficacy of adjunctive anti-plaque chemical agents in managing gingivitis. A systematic review and meta-analysis.

Bacteria present in oral biofilms are responsible for the most prevalent diseases of mankind: caries and periodontal diseases. Therefore, control of oral biofilms becomes essential in the prevention of these diseases. Prevention of periodontal diseases is based on supragingival biofilm control, by means of mechanical and/or chemical oral hygiene products, that are able

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to limit gingivitis onset (Baehni & Takeuchi 2003); prevention of periodontitis assumes that a healthy periodontium (without gingivitis) will not develop periodontitis.

In order to control biofilms in the oral cavity, different oral hygiene products have been developed and marketed. Physical disruption and elimination of dental biofilm can be effectively accomplished with the use of mechanical devices. Their efficacy in supragingival biofilm and gingivitis control has been widely demonstrated (van der Weijden & Slot 2011). However, different studies (Addy et al. 1986, Albandar & Buischi 1995, Hugoson & Jordan 2004, Lavstedt et al. 1982, Rugg-Gunn & MacGregor 1978) and a systematic review (van der Weijden & Hioe 2005) have shown that mechanical control alone may not be sufficient to prevent the onset or recurrence of periodontal diseases in a wide proportion of the population. Different explanations have been advocated to justify this fact, including: limited time of usage (Beals et al. 2000); limited use of interdental cleaning (Lang et al. 1995, MacGregor et al. 1998, Stewart et al. 1997); tendency to return to baseline plaque levels in patients instructed in oral hygiene procedures (Stewart et al. 1997) or in patients enrolled in oral hygiene studies (Claydon et al. 1996, Emilson & Fornell 1976, Lie & Enersen 1986, Rosling et al. 1997, Yates et al. 1993); lack of mechanical control of other oral biofilms different from dental plaque (Greenstein 2002, Greenstein 2004, Quirynen et al. 1995).

The adjunctive use of chemical plaque control may be required in those subjects who are not able to effectively remove supragingival biofilms by the sole use of mechanical procedures which, in addition, reduce the amount of biofilm and disrupt its structure. The latter allows for a more effective action of the chemical formulation (F.D.I. Commission 2002). Their use (especially antiseptics) to control plaque and gingivitis levels has been widely evaluated. The efficacy of different formulations has been reported in several systematic reviews (Addy et al. 2007, Afennich et al. 2011, Gunsolley 2006, Gunsolley 2010, Hioe & van der Weijden 2005, Hossainian et al. 2011, Paraskevas & van der Weijden 2006, Sahrmann et al. 2010, Stoeken et al. 2007). However, none of the available systematic reviews have analysed a wide variety of agents. Most of them just focused on one specific agent or a limited group of agents.

There is a general consensus that plaque inhibitory and antiplaque activities of a given formulation must be proven in the long-term (at least 6 months), home-use, randomised

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clinical trials (RCT), together with the evidence of its safety primarily shown by the lack of relevant side effects. In these studies, the use of the tested formulations should be adjunctive to mechanical plaque control. The characteristics of these types of trials, in order to obtain valid conclusions, have been approved (Council of Dental Therapeutics 1986), and include double blindness, presence of a control group, a minimum duration of 6 months, a microbiological evaluation, and the selection of a representative population.

Based on the previous information, the present systematic review focused on those studies providing the higher level of evidence, and therefore, its main purpose was to evaluate the efficacy of adjunctive chemical plaque control in managing gingivitis, based on the data provided by home-use, 6-month, RCTs.

Material and methods

Protocol development A detailed protocol was designed according to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-analysis) statement (Liberati et al. 2009, Moher et al. 2009).

The systematic review was designed to answer the following focused question: in humans with gingivitis (Patients), what is the efficacy of chemical plaque control formulations used adjunctively to mechanical oral hygiene measures, with or without previous professional prophylaxis (Intervention), as compared to subjects using a negative control adjunctive to mechanical oral hygiene (Comparison), in terms of changes, with a minimum follow up of 6 months, in gingivitis or bleeding indices, with plaque levels as secondary outcome variable (Outcome).

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Eligibility criteria Inclusion criteria •

RCTs, at least 6 months of follow-up.



Gingivitis or bleeding indices among the outcome variables.



In systemically healthy patients.



With some degree of gingivitis at baseline.



Test products administered in mouthrinses, dentifrices or gels, adjunctively to mechanical oral hygiene (including tooth brushing).

Exclusion criteria •

Additional periodontal mechanical therapy, before or after baseline, excluding professional prophylaxis or tooth polishing.



Patients wearing fixed or removable orthodontic appliances.



Studies assessing abutment teeth of fixed or removable prosthesis.



Lack of a negative control.



Not systemically healthy patients, or chronically medicated with drugs that may affect gingivitis.



Untreated or uncontrolled periodontitis patients.

Information sources and search An electronic search was conducted on PubMed CENTRAL up to and including 17th May 2014. The strategy is detailed in Appendix 1 (available as online supplement). References of retrieved papers and, especially, of previously published systematic reviews, were hand searched.

Study selection and data collection Eligibility assessment was performed through title and abstract analysis and full-text analysis. Two reviewers (JS, ME) screened titles and abstracts for possible inclusion in the review,

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according to the inclusion criteria. Reviewers were first trained and calibrated (un-weighted kappa [k] scores) for study screening against another reviewer (SR) with experience in conducting systematic reviews, with four rounds of screening (20 papers each), before conducting the final search: the percentage of agreement and corresponding k for each round were: 100%, k=1.00; 95%, k=0.86; 80% k=0.59; 90%, k=0.67. References with unclear or no abstract were included in the full-text analysis.

Full-texts of potentially relevant studies were independently assessed by the same reviewers. Any disagreement was solved by discussion between reviewers.

Data items Data were extracted by two reviewers (JS, ME) under the supervision of a third reviewer (DH), including primary outcome measures (gingivitis and/or bleeding indices), secondary outcomes (plaque indices), and other relevant data (study design, sample characteristics…).

Risk of bias in individual studies Risk of bias was evaluated, firstly, by assessing the quality of methods of each RCT according to a checklist with items suggested by the Cochrane reviewers’ handbook (Higgins et al. 2011) and the CONSORT statement (Moher et al. 2012): sequence generation, allocation concealment, blinding of personnel and outcome assessors, and incomplete outcome data. In addition, funding of the study and independency of authors was also evaluated. Secondly, a quality of reporting analysis was performed, as well as an evaluation of specific methods for oral hygiene product studies, generating an overall score for quality of methods and reporting for each individual study (Graziani et al. 2012). The assessed items included registration, statistical analyses, outcome assessment, characteristics of the population and oral hygiene. Each item was scored according to its adequateness and then the percentage of items positively qualified, for both methods and reporting, was calculated.

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Summary measures and synthesis of the results Tables were created to summarize all the previously mentioned items. Outcomes were summarized as means and standard deviation (SD) or error (SE) (if SD were not provided), both for baseline and 6-month values. To compare the selected studies, a mean treatment effect (baseline-6 months) was calculated and the results were pooled and analysed using weighted mean differences (WMD) and 95% confidence intervals (CI). When 6-month data was available, independently of the study length, 6-month data was extracted and used (n=77). When it was not available, 7-month (n=7) (Bruhn et al. 2002, Garcia-Godoy et al. 1990, Kocher et al. 2000, Schaeken et al. 1996, Svatun et al. 1993a, Svatun et al. 1993b, Zimmermann et al. 1993), 9month (n=1) (Mengel et al. 1996), or 12-month (n=1) (Spets-Happonen et al. 1991) data were used.

The statistical heterogeneity among studies was assessed using the Q-test according to DerSimonian & Laird (1986). As a complement to the Q test, the I2 index (Higgins et al. 2003) was calculated in order to know the percentage of variation in the global estimate that was attributable to heterogeneity.

The study-specific estimates were pooled using both the fixed effect model (I-V, MantelHaenzel-Peto test) and the random effect model (D+L, DerSimonian-Laird test). If significant heterogeneity was found, the random effect model results were presented. Meta-analyses with considerable statistical heterogeneity (I2>75%) were not considered for the conclusions.

Forest Plots were created to illustrate the effects in the meta-analysis of the global estimation and the different sub-analyses, with STATA® 11.1 (StataCorp LP, Lakeway Drive, College Station, Texas, USA). Statistical significance was defined as a p-value

Efficacy of adjunctive anti-plaque chemical agents in managing gingivitis: a systematic review and meta-analysis.

The aim of this systematic review was to evaluate the efficacy of anti-plaque chemical formulations for managing gingivitis, in 6-month, home-use, ran...
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