Protocol and Registration

This study protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO - CRD42015015564) and followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for report.³²

Information Sources and Search Strategy

The controlled vocabulary (MeSH terms) and free keyword in the search strategy were defined based on the following PICOS question:

• 1

  Population (P): adult patients that underwent vital tooth bleaching.

• 2

  Intervention (I): in-office bleaching.

• 3

  Comparison (C): dentist-supervised at-home bleaching.

• 4

  The outcome (O): risk and intensity of tooth sensitivity during dental bleaching; color change in shade guide units (ΔSGU) and in in terms of color difference measured with a spectrophotometer (ΔE*) will be the secondary outcomes.

• 5

  Study design (S): randomized clinical trials (RCTs).

To identify trials to be included for this review, the electronic databases such as MEDLINE via PubMed, Scopus, Web of Science, Latin American and Caribbean Health Sciences Literature database (LILACS), Brazilian Library in Dentistry (BBO), and Cochrane Library (Table 1) were searched. The reference lists of all primary studies were hand searched for additional relevant publications and the related articles link of each primary study in the PubMed database without restrictions to publication date or languages.

Table 1 Electronic Database and Search Strategy

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Other sources were also used to identify more articles. The abstracts of the annual conference of the International Association for Dental Research and their regional divisions (1990-2014) were searched. The grey literature using the database System for Information on Grey Literature in Europe and dissertations and theses using the ProQuest Dissertations and Theses Full text database, as well as the Periódicos Capes Theses database, were explored.

To locate unpublished and ongoing trials related to the review question, the following clinical trials registries were searched: Current Controlled Trials (www.controlled-trials.com), International Clinical trials registry platform (http://apps.who.int/trialsearch/), ClinicalTrials.gov (www.clinicaltrials.gov), Rebec (www.rebec.gov.br), and EU Clinical Trials Register (https://www.clinicaltrialsregister.eu).

Eligibility Criteria

Parallel and split-mouth RCTs that compared in-office vs at-home bleaching in adult patients of any age group were included. No controlled clinical trials, editorial letters, pilot studies, historical reviews, in vitro studies, cohort, and observational and descriptive studies, such as case reports and case series, were excluded.

Additionally, RCT studies were excluded if 1) studies compared only in-office or only at-home bleaching treatments; 2) studies whose participants took analgesics or anti-inflammatory drugs before or during bleaching treatment; 3) studies that always used desensitizers before and after bleaching; and 4) studies in which the at-home protocol was performed with over-the-counter products.

Study Selection and Data Collection Process

Initially, the articles were selected by title and abstracts according to the previously described search strategy. Articles that appeared in more than one database were considered only once. Full-text articles were also obtained when the title and abstract presented insufficient information to make a clear decision. Subsequently two reviewers classified those that met the inclusion criteria. To handle such a large number of studies, a study ID for each eligible study was used, combining first author and year of publication. Relevant information about the study design, participants, interventions, and outcomes were extracted using customized extraction forms by three authors.

If there were multiple reports of the same study (ie, reports with different follow-ups), data from all reports were extracted directly into a single data collection form to avoid overlapping data. When data were not reported in the studies, authors were contacted by email at least twice to request the missing information.

When data from multiple bleaching sessions were provided, an average of the figures for each bleaching protocol was obtained. When more than one bleaching agent from the same bleaching protocol was included in the study, their values were merged to make a single entry. Concerning color change, the data that represented the immediate result (up to three months after bleaching) were used.

Risk of Bias in Individual Studies

Quality assessments of the selected trials were carried out by two independent reviewers, using the Cochrane Collaboration's tool for assessing risk of bias in randomized trials.³³ The assessment criteria contain six items: sequence generation, allocation concealment, blinding of the outcome assessors, incomplete outcome data, selective outcome reporting, and other possible sources of bias. During data selection and quality assessment, any disagreements between the reviewers were solved through discussion, and if needed, by consulting a third reviewer.

For each aspect of the quality assessment, the risk of bias was scored following recommendations as described in the Cochrane Handbook for Systematic reviews of Interventions 5.1.0 (http://handbook.cochrane.org). At domain level, the judgment for each entry involved recording “yes,” indicating low risk of bias, “no,” indicating high risk of bias, and “unclear,” indicating either lack of information or uncertainty over the potential for bias. At the study level, the study was considered to be at “low” risk of bias if all key domains for each outcome were at low risk of bias. If one or more key domains (see below) were judged as “unclear” or at “high” risk of bias, the study as a whole was considered at high risk of bias. When the study was judged as unclear in its key domains, authors were contacted to obtain more information and to allow a definitive yes or no judgment.

For the patient-centered outcomes (risk and intensity of tooth sensitivity) and for color change in ΔE*, studies were considered to be at low risk of bias if there were adequate sequence generation and allocation concealment (key domains). Patient blinding was not considered a key domain as patients could easily identify the different bleaching protocols. Examiner blinding was not essential for evaluation of color in ΔE* as the previous knowledge of the treatment would not affect the results produced by the instrument. However, examiner blinding was considered to be essential in the subjective color assessment performed with shade guide units. Therefore, for color change in ΔSGU, three items of the Cochrane tool as key domains were considered: adequate sequence generation, allocation concealment, and examiner blinding.

Summary Measures and Synthesis of Results

Data were analyzed using Revman 5 (Review Manager Version 5, The Cochrane Collaboration, Copenhagen, Denmark). Data from eligible studies were either dichotomous (absolute risk of tooth sensitivity) or continuous (intensity of tooth sensitivity, ΔSGU, and ΔE*).

Only studies classified at low risk of bias in the key domains were used in the meta-analysis. The outcomes were summarized by calculating the Hedge's g standardized mean difference for the continuous data and the odds ratio along with the 95% confidence interval for the dichotomous data.

When matched data were available (split-mouth and crossover designs), an external correlation of 0.5 was imputed among data from both groups, as this information was not available in any of the studies. Sensitivity analyses using lower (0.1) and higher (0.9) external correlations were performed to check the impact of such imputation in all meta-analysis.

The random-effects models were used. Heterogeneity was assessed using the Cochran Q test and I² statistics. All analyses were conducted using CMA software (version 3, Biostat, Englewood, New Jersey, USA). No subgroup analysis was performed. Sensitivity analyses were also conducted to investigate the reasons for high heterogeneity whenever detected.

Study Selection

After the database screening and removal of duplicates, 1139 studies were identified (Figure 1). After title screening, 29 studies remained, and this number was reduced to 12 after careful examination of the abstracts.

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Characteristics of Included Articles

The characteristics of the 12 studies selected are listed in Table 2. The parallel study design was predominantly used in these studies.^{7,13,27,30,34-36} Some of the studies used the split-mouth design.^4,5,28,31,37

Table 2 Summary of the Studies Selected for This Systematic Review

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Six of the 12 studies used a 0-10 visual analog scale for pain evaluation,^{4,5,13,28,34,35} and 3 studies used a 0-4 numeric rating scale.^7,27,30 One study just evaluated the risk of tooth sensitivity.³⁷ Two studies did not evaluate tooth sensitivity.^31,36

For color evaluation, ten studies used a shade guide.^{4,5,7,27,28,30,31,34,36,37} Six of these 12 studies added an objective instrument (spectrophotometer or colorimeter) for color assessment.^{4,5,27,28,31,36} Color slide photography was used in one study³⁴ and photography in two others.^27,37 Two studies did not evaluate the color.^13,35

The number of patients per group included in these studies ranged from 10 to 30. In 2 of the 12 articles, most participants were male^5,31; in 3 articles, females predominated.^7,28,30 Seven studies did not report this information.

Regarding the bleaching protocol (Table 2), nine studies used 10% carbamide peroxide for at-home bleaching.^{4,5,7,13,27,30,31,34,37} Carbamide peroxide with different concentrations, such as 15%,²⁸ 16%,³⁵ 20%,⁷ and 32%,³⁶ was also used for at-home bleaching. For in-office bleaching, the majority of studies used 35% hydrogen peroxide.^{4,7,13,27,30,34,35,37} Only three studies used 38% hydrogen peroxide for this bleaching modality.^7,28,31 Two studies used 25% hydrogen peroxide for this technique.^5,36

The daily time use of the at-home bleaching gel varied from 3 to 10 minutes, and the number of days varied from 6 to 28 days. The application protocol of the in-office bleaching was quite variable. Most of the studies applied the product for 20-45 minutes in each clinical session.^{4,7,13,27,28,30,31,35,37} However, variations in this protocol were observed, with applications lasting 15³⁴ or 60 minutes^5,36 in each session (Table 2). Half of the studies performed two to three bleaching sessions,^{4,7,13,27,30,37} with some exceptions. Some studies performed only one in-office bleaching session,^{5,28,31,35,36}and another study performed a variable number of clinical sessions to reach the patient's satisfaction³⁴ (Table 2).

Assessment of the Risk of Bias

The selected studies risk of bias is presented in Figure 2. Few full-text studies reported the method of randomization, allocation concealment, and whether or not the examiner was blinded during color assessment in shade guide units.

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E-mails were sent to authors of nine studies^{4,5,7,13,27,34-37} to request further information. Responses were obtained from the authors of eight studies.^{4,5,7,13,27,34-36}

In summary, from the 12 studies, 3^13,36,37 were considered to be at high/unclear risk of bias in the key domains of the Cochrane risk of bias tool, yielding 9 studies^{4,5,7,27,28,30,31,34,35} that met the best requirement features (randomization and allocation concealment) for meta-analysis of risk and intensity of tooth sensitivity and color change in ΔE*.

From the 12 studies, 4^13,35-37 were considered to be at high/unclear risk of bias in the key domains of the Cochrane risk of bias tool, yielding 8 studies^{4,5,7,27,28,30,31,34} that met the best requirement features (randomization, allocation concealment, and blinding) for meta-analysis of ΔSGU. Although the study of Giachetti and others³¹ was classified at low risk of bias, the authors did not evaluate color change in shade guide units or ΔE*, which is the reason why the study was not included in the meta-analyses of color change. Additionally, this study did not evaluate bleaching-induced tooth sensitivity; therefore, it was not included in the meta-analyses of tooth sensitivity.

Meta-analysis

All meta-analysis was performed on studies classified as low risk of bias in the key domains and from which the information about the outcome could be extracted.

Risk of Tooth Sensitivity

This analysis was based on five studies.^4,5,7,28,30 The odds ratio was 2.186, with a 95% confidence interval of 0.63-7.53 (p=0.215). Based on these studies, a significant statistical difference between the groups could not be identified (Figure 3). Data were heterogeneous (χ² test, p<0.001; I²=87.8%; Figure 3), which means that all studies included in the analysis did not share a common effect size. Through a sensitivity analysis, the high heterogeneity of this outcome was caused by the study of Basting and others.⁷ By removing this study from the present meta-analysis, the heterogeneity was seen not to be significant, and the overall odds ratio was shown as significant, with a lower chance of tooth sensitivity for the at-home bleaching protocol (data not shown).

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Intensity of Tooth Sensitivity

This analysis was based on five studies.^4,7,30,34,35 The Hedge's g standardized difference in means was 0.823, with a confidence interval varying from −0.42 to 2.09 (p=0.193). This provides evidence that there is no difference in the intensity of tooth sensitivity between the two bleaching protocols (Figure 4). Data were heterogeneous (χ² test, p<0.001; I²=95.6%; Figure 4), which means that all studies included in the analysis did not share a common effect size. Through a sensitivity analysis, no study that was responsible for such high heterogeneity was identified, and the reduced number of studies prevented us from performing meta-regression or subgroup analysis.

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Color Change in ΔSGU

This analysis was based on four studies.^4,7,27,30 The Hedge's g standardized difference in means was −0.184, with a confidence interval varying from −0.66 to 0.29 (p=0.451). This showed that there was no difference in the color change measured in shade guide units (Figure 5). Data were heterogeneous (χ² test, p=0.01; I²=72%; Figure 5), which means that all studies included in the analysis did not share a common effect size. Through a sensitivity analysis, no study that was responsible for such high heterogeneity could be identified.

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Color Change in ΔE*

This analysis was based on four studies.^4,5,27,28 The Hedge's g standardized difference in means was −0.260, with a confidence interval varying from −0.77 to 0.22 (p=0.292). This showed that there was no difference in the color change measured with a spectrophotometer (Figure 6). Data were heterogeneous (χ² test, p=0.05; I²=62.8%; Figure 6), which means that all studies included in the analysis did not share a common effect size.

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