topical fluoride for caries prevention 2013 update - full manuscript

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Topical fluoride for caries prevention

Full report of the updated clinical recommendations and supporting systematic review

A Report of the Council on Scientific Affairs November 2013

This report is intended to assist practitioners with decision-making about the use of topical-fluoride caries preventive agents to prevent caries. The recommendations in this document are not intended to define a standard of care and rather should be integrated with a practitioners professional judgment and a patients needs and preferences.

2103 ADA Center for Evidence-Based Dentistry. All rights reserved.

Background. A panel of experts convened by the American Dental Association (ADA) Council on Scientific Affairs presents evidence-based clinical recommendations on professionally-applied and prescription-strength, home-use topical fluoride agents for caries prevention. These recommendations are an update of the 2006 ADA recommendations regarding professionally applied topical fluoride, and were developed by using a new process that includes conducting the systematic review of primary studies.

Types of studies reviewed. The authors conducted a search of MEDLINE and the Cochrane Library for clinical trials of professionally-applied and prescription-strength topical fluoride agents including mouthrinses, varnishes, gels, foams, and pastes with caries increment outcomes published in English through October 2012.

Results. The panel included 71 trials in 82 articles in its review and assessed the efficacy of various topical fluoride caries-preventive agents. The panel makes recommendations for further research.

Clinical Implications. The panel recommends the following for people at risk of developing dental caries: 2.26% fluoride varnish or 1.23% fluoride (APF) gel, or a prescription-strength, home-use 0.5% fluoride gel or paste or 0.09% fluoride mouthrinse for 6 years or older. Only 2.26% fluoride varnish is recommended for children younger than 6 years. The strengths of the recommendations for the recommended products varied from in favor to expert opinion for. As part of the evidence-based approach to care, these clinical recommendations should be integrated with the practitioners professional judgment and the patients needs and preferences.

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Authors and acknowledgments

Authors

Robert J. Weyant, DMD, DrPH; Sharon L. Tracy, PhD; Theresa (Tracy) Anselmo, MPH, BSDH, RDH;

Eugenio D. Beltrn-Aguilar, DMD, MPH, MS, DrPH; Kevin J. Donly, DDS, MS; William A. Frese, MD;

Philippe P. Hujoel, MSD, PhD; Timothy J. Iafolla, DMD, MPH; William Kohn, DDS; Jayanth Kumar,

DDS, MDH; Steven M. Levy, DDS, MPH; Norman Tinanoff, DDS, MS; J. Timothy Wright, DDS, MS;

Domenick Zero DDS, MS; Krishna Aravamudhan, BDS, MS; Julie Frantsve-Hawley RDH, PhD; Daniel

M. Meyer, DDS; for the American Dental Association Council on Scientific Affairs Expert Panel on

topical fluoride caries preventive agents

Robert J. Weyant is Professor and Chair, Department of Dental Public Health, School of Dental Medicine,

University of Pittsburgh, Pittsburgh, PA. He was the chair of the panel.

Sharon L. Tracy is Assistant Director, Center for Evidence-Based Dentistry, Division of Science, American Dental

Association, Chicago. Address reprint requests to Dr. Tracy.

Theresa Anselmo is the Oral Health Program Manager, San Luis Obispo Health Agency, San Luis Obispo, CA.

She represented the American Dental Hygienists Association on the panel.

Eugenio D. Beltrn-Aguilar is Senior Epidemiologist and Advisor to the Director, Division of Oral Health, Centers

for Disease Control and Prevention, Atlanta, GA. He represented the Centers for Disease Control and Prevention

on the panel.

Kevin J. Donly is Professor and Chair, Pediatric Dentistry at the University of Texas Health Science Center San

Antonio, San Antonio, TX. He represented the American Academy of Pediatric Dentistry on the panel.

William A. Frese is Assistant Professor of Pediatrics at the University of Illinois at Chicago, Chicago, IL. He

represented the American Academy of Pediatrics on the panel.

Philippe P. Hujoel is Professor of Periodontics, Department of Dental Public Health Sciences, School of Dentistry,

University of Washington, Seattle, WA.

Timothy J. Iafolla is a Public Health Analyst, Office of Science Policy and Analysis, National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health, Bethesda, MD. He represented NIDCR on the panel.

William Kohn is vice president of dental science and policy, Delta Dental Plans Association, Oak Park, IL.

Jayanth Kumar is Director, Oral Health Surveillance and Research, Bureau of Dental Health, New York State Department of Health, Albany, NY and Associate Professor, School of Public Health, University at Albany.

Steven M. Levy is the Wright-Bush-Shreves Endowed Professor of Research, Department of Preventive and

Community Dentistry, College of Dentistry, and a professor, Department of Epidemiology, College of Public

Health, University of Iowa, Iowa City, IA.

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Norman Tinanoff is Professor and Division Chief, Pediatric Dentistry, School of Dentistry, University of Maryland,

Baltimore, MD.

J. Timothy Wright is Professor and Chair, Department of Pediatric Dentistry, School of Dentistry, University of

North Carolina, Chapel Hill, NC

Domenick Zero is Professor and Chair, Department of Preventive and Community Dentistry, Director, Oral Health

Research Institute, Associate Dean for Research, Indiana University, School of Dentistry, Indianapolis, IN.

Krishna Aravamudhan is Senior Manager, Office of Quality Assessment and Improvement, Division of Dental

Practice, American Dental Association, 211 E. Chicago Ave., Chicago, IL 60611, e-mail

[email protected].

Julie Frantsve-Hawley is Senior Director, Center for Evidence-based Dentistry, Division of Science, American

Dental Association, Chicago.

Daniel M. Meyer is Senior Vice President, Science/Professional Affairs, American Dental Association, Chicago.

Acknowledgments

The panel would like to acknowledge the efforts of the following individuals and their commitment in

helping complete this project.

Dr. Rocky Napier, ADA Council on Access, Prevention, and Interprofessional Relations (CAPIR)

Liaison; Ms. Jane McGinley, Manager, Fluoridation and Preventive Health Activities, ADA CAPIR Staff

Liaison; Dr. Douglas B. Torbush, ADA Council on Dental Practice (CDP) Liaison; Dr. C. Rieger Wood,

ADA Council on Dental Benefit Programs (CDBP) Liaison; Dr. William F. Robinson, ADA Council on

Dental Education and Licensure (CDEL) Liaison; Mr. Antanas Rasymas, ADA Library; Mr. Tom Wall,

ADA Health Policy Resources Center; Mr. Sam Cole, ADA Health Policy Resources Center.

The panel would like to thank the following individuals and organizations whose valuable input during

external peer review helped improve this report: Dr. Elliot Abt, Advocate Illinois Masonic Medical

Center; Dr. James Bader, University of North Carolina School of Dentistry; Dr. William H. Bowen,

University of Rochester School of Medicine and Dentistry; Dr. Albert Kingman, National Institute of

Dental and Craniofacial Research Center for Clinical Research; Dr. Stephen J. Moss, New York

University College of Dentistry; Dr. David G. Pendrys, University of Connecticut School of Dental

Medicine; Dr. Philip A. Swango, private dental consultant; Dr. Gary M. Whitford, Georgia Health

Sciences University School of Dentistry; Dr. Helen Worthington, Cochrane Oral Health Group,

University of Manchester School of Dentistry; the American Association for Dental Research (AADR);

the American Academy of Pediatric Dentistry (AAPD); the American Dental Hygienists Association

(ADHA); the National Institute of Dental and Craniofacial Research (NIDCR); the ADA Council on

Access, Prevention and Interprofessional Relations; the ADA Council on Communications; the ADA

Council on Dental Practice.

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The panel would like to thank the following individuals whose valuable input helped improve Table 1

and the chairside guide: Dr. Paul Fischl, Dr. Bob Kaspers, Dr. Dave Lewis, Dr. Dave McWhinnie, Dr.

Peter Neuhaus, and Dr. Maria Simon.

CDC Disclaimer: The work of the American Dental Association Council on Scientific Affairs Expert

Panel on Topical Fluoride Agents was supported in part by the U. S. Centers for Disease Control and

Prevention, Atlanta, GA. The findings and conclusions in this report are those of the authors and do not

necessarily represent the official position of the Centers for Disease Control and Prevention.

Disclosures: Robert J. Weyant, DMD, DrPH did not report any conflicts; Theresa (Tracy) Anselmo, MPH, BSDH, RDH served on the Council on Public Health for the American Dental Hygienists' Association ending in June 2012; Eugenio D. Beltrn-Aguilar, DMD, MPH, MS,

DrPH is the Director of the American Board of Dental Public Health; Kevin J. Donly, DDS, MS is a Pediatric Dentistry Commissioner to the

ADA Commission on Dental Accreditation; William A. Frese, MD is the American Academy of Pediatrics Section VII Oral Health liaison and

also an advocate of oral health for the Illinois Oral Health Chapter of the American Academy of Pediatrics; Philippe P. Hujoel, MSD, PhD is a

Consultant to Delta Dental; Timothy Iafolla, DMD, MPH did not report any disclosures; William Kohn, DDS holds material financial interest in

a business that furnishes or is seeking to furnish goods or services to the ADA and publically represents Delta Dental Plans Association at

various meetings and events; Jayanth Kumar, DDS, MDH is the ASTDD Perinatal Committee Chair (2010 to present); Steven M. Levy, DDS,

MPH was the President of the American Board of Dental Public Health during the development of this report; Norman Tinanoff, DDS, MS is

on the Board of Trustees of the Dentaquest Foundation, an organization with a mission to improve access to oral health care, and receives no

compensation and occasionally does advocacy work for the University of Maryland Dental Action Coalition regarding oral health issues; J.

Timothy Wright, DDS, MS serves as a consultant to Edimer, which is a company working on ectodermal dysplasia protein therapy;

Domenick Zero, DDS, MS serves on the Johnson & Johnson Oral Care Advisory Board, receives compensation from Unilever for moderating

a symposium at the 2011 IADR Annual Meeting and consults on an ad hoc basis for GSK, Colgate, and P&G; Krishna Aravamudhan, BDS,

MS; Sharon L. Tracy, PhD; Julie Frantsve-Hawley RDH, PhD; Daniel M. Meyer, DDS have no disclosures.

Dr. Rocky Napier, ADA Council on Access, Prevention, and Interprofessional Relations (CAPIR) Liaison is a private practice dentist in Aiken,

South Carolina. He is also a member of the ADA Dental Practice Council, a mentor/local facilitator for the SC AAPD/OHS Head Start Dental

Home Initiative, a member of the Executive Board of the South Carolina Society of Pediatric Dentistry and a Liaison to the South Carolina

Dental Association. He is the Coordinator of the Aiken County Schools Dental Screening Program, and has been involved in several other

local dentistry-related organizations.

Dr. Douglas B. Torbush, ADA Council on Dental Practice Liaison is a Board Member of Fisher Foundation, which provides educational

loans/scholarships/grants to dental students and dental hygiene students in Georgia. He is also involved with Georgia Dental Associates

Legislative Awareness (LAW) Program, which lobbies Georgia Representatives on behalf of the patients of Georgia.

Dr. C. Rieger Wood, ADA Council on Dental Benefit Programs Liaison is the Dental Director of St. John Hospital Sapulpa and a part-time

Clinical Instructor at the University of Oklahoma College of Dentistry, Department of Operative Dentistry.

Dr. William F. Robinson, ADA Council on Dental Education and Licensure Liaison is a consultant for the Florida Board of Dentistry and the

Florida Department of Health.

Funding source: The ADA Council on Scientific Affairs commissioned this work and the Centers for

Disease Control and Prevention (CDC) partly funded this project.

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Introduction ...............................................................................................................................................................7

Clinical considerations and recommendations ....................................................................................................8

Balancing benefits with potential harms ...........................................................................................................9

Clinical Recommendations .............................................................................................................................. 10

Systematic review methods ................................................................................................................................ 12

Literature search ............................................................................................................................................... 12

Critical appraisal of included studies ............................................................................................................. 14

Data synthesis and meta-analysis ................................................................................................................. 15

Process for developing evidence statements ............................................................................................... 18

Deviations from the protocol ........................................................................................................................... 19

Methods for developing clinical recommendations .......................................................................................... 19

Results .................................................................................................................................................................... 22

Varnish: 2.26% and 0.1% fluoride .................................................................................................................. 23

Varnish (2.26% fluoride) .............................................................................................................................. 23

Evidence profiles: 2.26% fluoride varnish ................................................................................................. 26

Varnish (0.1% fluoride) ................................................................................................................................ 28

Evidence profiles: 0.1% fluoride varnish ................................................................................................... 30

APF gel (1.23% fluoride).................................................................................................................................. 31

General summary of results ........................................................................................................................ 31

Evidence statements .................................................................................................................................... 33

Evidence profiles: APF gel (1.23% fluoride) ............................................................................................. 34

APF foam (1.23% fluoride) .............................................................................................................................. 35



Evidence profiles: APF foam (1.23% fluoride) ......................................................................................... 35

Prophylaxis pastes containing fluoride .......................................................................................................... 37



Evidence profiles: prophylaxis pastes containing fluoride ...................................................................... 38

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Is prophylaxis prior to professional application of topical fluoride necessary? ........................................ 40



Evidence profiles: Prophylaxis prior to APF gel (1.23% fluoride) application ...................................... 41

Prescription-strength, home-use (0.5% fluoride) gel/paste agents ........................................................... 43



Evidence profiles: Prescription-strength, home-use (0.5% fluoride) gel/paste agents ...................... 45

Prescription-strength, home-use (0.09% fluoride) mouthrinse .................................................................. 47



Evidence profiles: Prescription-strength, home-use (0.09% fluoride) mouthrinse .............................. 50

Stannous fluoride .............................................................................................................................................. 51

Erupting teeth .................................................................................................................................................... 51

Systematic review conclusions ........................................................................................................................... 51

Limitations .............................................................................................................................................................. 52

Regarding the evidence ................................................................................................................................... 52

Regarding this systematic review ................................................................................................................... 53

Future research ..................................................................................................................................................... 53

References ............................................................................................................................................................. 55

Appendix 1 Clinical Recommendations detailed presentation ................................................................ 61

Appendix 2 Literature searches ...................................................................................................................... 62

Appendix 3 Excluded studies at full-text stage ............................................................................................. 64

Appendix 4 Study characteristics, bias scores, and outcomes data tables .............................................. 81

Appendix 5 - Pragmatic calculations for interpreting summary estimates clinically ................................. 118

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Introduction In 2006, the Council on Scientific Affairs (CSA) of the American Dental Association (ADA) published

recommendations for the use of professionally-applied topical fluorides for caries prevention.1 Fluoride

is the primary agent available for caries prevention. The local availability of fluoride to the tooth surface

has been shown to prevent caries by primarily three mechanisms2, 3: 1) inhibiting demineralization of

tooth enamel; 2) enhancing remineralization of tooth enamel prior to lesion progression; and 3)

inhibiting the enzyme activity of cariogenic bacteria.

The objective of this report is to update the evidence at the 5-year interval according to ADA policy and

address additional questions related to the use of prescription-strength, home-use topical fluorides. In

this review the authors evaluated sodium, stannous, and acidulated phosphate fluoride for professional

and prescription home use, including varnishes, gels, foams, rinses and prophylaxis pastes. Not

included in this report are: over-the-counter products, slow release delivery devices, dental materials

that release fluorides and products based on sodium monofluorophosphate (MFP), silver diamine

fluoride, and titanium tetrafluoride. Sodium monofluorophosphate is primarily a non-prescription, daily

use fluoride product. Silver diamine fluoride and titanium tetrafluoride are not currently available in any

products in the U.S. For the remainder of this manuscript, the term topical fluoride(s) will be used to

include professionally-applied as well as prescription-strength, home-use products.

This report is intended to assist practitioners with decision-making about the use of topical fluoride

caries preventive agents. The panel notes that lack of clinical data, changes in formulations across

time, and a wide variety of products can hamper decision-making. The recommendations in this

document do not purport to define a standard of care, but rather should be integrated with each

practitioners professional judgment and each patients needs and preferences.

The authors addressed three clinical questions:

1. In primary and permanent teeth, does the use of a topical fluoride compared to no topical

fluoride reduce the incidence of new lesions, or arrestA or reverseA existing coronal and/or root

caries?

A Although the original clinical questions asked about arresting and reversing coronal and/or root caries,

insufficient data were found to answer the question; therefore, these outcomes are not addressed in these clinical recommendations.

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2. For primary and permanent teeth, is one topical fluoride agent more effective than another in

reducing the incidence of, or arrestingA or reversingA coronal and/or root caries?

3. Does the use of prophylaxis before application of topical fluoride reduce the incidence of caries

to a greater extent than topical fluoride application without prophylaxis?

Although improved clinical outcomes such as reduced need for treatment, enhanced quality of life,

increased function, decreased pain and tooth loss, and improved esthetics are the ultimate goal of

preventive interventions, outcomes such as reductions in incidence and progression (arrests or

reversals)A of caries are commonly reported outcomes for topical fluorides and thus are the a priori

outcomes measures chosen for these clinical recommendations.

The panel notes that clinical trials generally test the efficacy of an intervention, which results in the best

possible outcome for the intervention because of the controlled nature of the trial and strict

inclusion/exclusion criteria for participants. These results do not necessarily equate to effectiveness of

an intervention, i.e. how the intervention works in routine practice, which typically includes patients with

comorbidities who may be taking multiple medications. The efficacy is almost always higher than the

effectiveness because of the presence of idealized conditions. Several different topical fluoride

modalities, including those planned for home use, have been reviewed in this document. Practitioners

can expect different compliance with treatment plans incorporating home-use products compared to

products applied by the practitioner. Cost, efficacy, and/or effectiveness related to the intended usage

environment also may vary.

Clinical considerations and recommendations The grading system4 used in this report is adapted from the United States Preventive Service Task

Force (USPSTF) system5 and differs markedly from the system used originally in the 2006 Clinical

Recommendations.1 The difference is that current clinical recommendations are based on synthesis of

primary evidence collected via a de novo systematic review; whereas the previous clinical

recommendations were primarily based on published systematic reviews, with additional studies

included if published after the most recent systematic review. Another difference is that these

recommendations are based on the net benefit of the intervention, i.e. a balance of benefits to potential

harms, in conjunction with the level of certainty in the evidence, whereas the previous

recommendations were based solely on the design6 of studies on benefits. This has resulted in some

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modifications to the strength assigned to the individual recommendations for products reviewed in this

report compared to the 2006 Clinical Recommendations.

The current grading system includes the use of expert opinion as a means of making clinical

recommendations or not making clinical recommendations when evidence was lacking, contradictory,

or judged to be at high risk of bias, so that the panel could not reliably estimate the net benefit of the

intervention. Practitioners should note the strength of the recommendations and endeavor to

understand the level of certainty in the underlying evidence, as well as the balance of benefits to

potential harms. They should discuss uncertainties in evidence with their patients, providing awareness

that there is usually some level of uncertainty in the evidence used for clinical decision-making.

A practitioner should consider a patients risk of experiencing disease when developing an optimal

caries prevention plan. Part of a patients risk includes whether the patient lives in an optimally

fluoridated community and uses fluoridated toothpaste. Patients at low risk for caries may not need

additional fluoride interventions, whereas caries in very high risk individuals appears at times to be

largely refractory to additional intensive preventive interventions.7, 8

Professional judgment is required to interpret the clinical relevance of all effect measures to the

individual patient. The combination of the patients caries risk status, the practitioners professional

judgment, and a patients needs and preferences should guide decision-making. Patient education,

assessment of readiness for change, dietary advice, other preventive modalities, and periodic clinical

examinations should be considered as a part of the caries prevention plan. In public health settings,

additional considerations include the feasibility and cost of the proposed intervention. The panel did not

include these issues in providing its clinical recommendations.

Balancing benefits with potential harms

When considering any intervention, the practitioner and patient must balance the potential benefits with

the potential harms. The panel considered harms reported by included articles as well as known

potential harms of fluoride use. Potential harms of topical fluorides include, but may not be limited to,

the following:

1. Nausea and vomiting associated with the ingestion of topical fluorides.9

2. Dental fluorosis (an esthetic concern) while tooth enamel is developing until about age 6, due to

daily ingestion of topical fluoride, such as from toothpaste or from prescription home use gels.

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There is less of a concern with professionally-applied topical fluorides that have much longer

intervals between applications.10 Additionally, fluoride varnish has less potential for harms than

other forms of high concentration topical fluoride because the amount of fluoride that is placed in

the mouth with fluoride varnish is approximately one-tenth that of other professionally-applied

products.11

The panel judged that the benefits outweighed the potential for harms for all professionally-applied or

prescription-strength topical fluorides and age groups except for children under age 6, where the risk of

swallowing and associated events (particularly nausea and vomiting) outweighed the potential benefits

for all professionally-applied or prescription-strength topical fluorides except 2.26% fluoride varnish.

Clinical Recommendations

For individuals at elevated risk of developing dental caries, the panel made clinical recommendations

for the use of specific topical fluoride agents (as shown in Table 1); these recommendations are based

on the evidence statements and the balance of benefits with potential harm. The panel recommends

topical fluoride agents only for people at elevated risk for dental caries. Further details of the strength of

the clinical recommendations for each form of topical fluoride and age group are available in Appendix

1.

The panel recommends the following for people at risk of developing dental caries: 2.26% fluoride

varnish or 1.23% fluoride (APF) gel, or a prescription-strength, home-use 0.5% fluoride gel or paste or

0.09% fluoride mouthrinse for patients 6 years or older. Only 2.26% fluoride varnish is recommended

for children younger than 6 years. The strengths of the recommendations for the recommended

products varied from in favor to expert opinion for.

The panel judged that the benefits outweighed the potential for harm for all professionally applied and

prescription-strength, home-use topical fluoride agents and age groups except for children younger

than 6 years. In these children, the risk of experiencing adverse events (particularly nausea and

vomiting) associated with swallowing professionally applied topical fluoride agents outweighed the

potential benefits of using all of the topical fluoride agents except for 2.26 percent fluoride varnish.

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Table 1. Clinical recommendations for use of Professionally-applied or prescription-strength, home-use topical fluoride agents for caries

prevention in patients at elevated risk of developing caries

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Systematic review methods The authors represent a multidisciplinary panel of subject matter experts convened by the American Dental

Association (ADA) Council on Scientific Affairs (CSA). The panel conducted a comprehensive search of the

biomedical literature, screened the results of the search according to inclusion/exclusion criteria, critically

appraised the included studies, synthesized the data through meta-analyses where appropriate, evaluated the

level of certainty in the evidence regarding the magnitude of effect, and used a standardized process to

develop clinical recommendations. The supplemental materials (Appendices 2-4) contain further detailed

information for the interested reader as follows: Appendix 2 - search methods; Appendix 3 - detailed list of

excluded studies; and Appendix 4 - key information, risk of bias assessments, and extracted data from the

included studies.

Literature search

Two authors (KA and JF) used the strategy as presented in Appendix 2 to search MEDLINE through PubMed

and the Cochrane Library. In addition, two authors (KA and ST) hand-searched references of relevant recent

systematic reviews12-14 and other selected articles in order to include studies that might have been missed

through the electronic sources.

Figure 1 shows the process and results of the literature screening process. MEDLINE (through PubMed) was

searched from 1965 through March 4, 2011 resulting in 5,009 articles. An additional search of MEDLINE

(through PubMed) to identify articles on prescription-strength toothpaste was conducted on October 5, 2011 for

articles published since 1965 inclusive, which identified 23 articles. A second electronic database (The

Cochrane Library) was also searched from 1965 through March 4, 2011 resulting 1,281 articles. The electronic

database searches were all updated on August 30, 2012 resulting in 260 unique hits, for a total of 6,547

articles found. Through a hand-searching process, another 47 articles were identified for consideration.

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Two authors (KA and JF) independently screened the titles and abstracts using the inclusion and exclusion

criteria as shown in Table 2 and selected 402 articles for full-text review. One author (KA) reviewed the

manuscripts in full and identified articles for exclusion as reported in Appendix 3. Two members of the expert

panel (NT and TW) reviewed the reasons for exclusion and approved the final exclusion list. When a reviewer

was uncertain, she referred the papers to the expert panel members (NT and TW) for decision. Discrepancies

between reviewers were resolved by a third expert panel member and Chair of this workgroup (RW).

Figure 1: Flow diagram of the literature search and screening process

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Table 2. Inclusion/exclusion criteria

Inclusion criteria: Prospective human controlled clinical studies (randomized or non-randomized)

Fluoride agents requiring professional application or prescription

Studies that report caries incidence, arrest or reversal as outcomes

Exclusion criteria: Studies irrelevant to the topic

in vitro and animal studies

in situ studies using material surrogates (e.g., studies with removable appliances hosting enamel slabs)

Studies where the only reported outcome was increased salivary flow or reduction in Streptococcus mutans

Split-mouth designs

Cross-over design

Studies in which the experimental arm had other co-interventions (fluorides/OH instruction etc.) in which the control arm did not. (e.g., Exp: CHX + F; Control: F)

Studies that have sealants or toothpaste as the control group, except for studies that evaluated home use products

Studies reporting on fluoride-releasing dental materials

Studies reporting on slow release devices

Baseline caries data not reported

Abstracts only

Non English

Post-treatment results and effect of cessation of intervention

Products that are commercially available as OTC

APF Varnish

Studies that do not report the concentration of fluoride

Short-term (less than 1 year) studies unless the study reported frank cavitation in less than a year

Studies on products that are not commercially available in the U.S.

Critical appraisal of included studies: The grading system4 used in this report was adapted from the

United States Preventive Service Task Force (USPSTF) system5. The panel assessed the following four key

elements in their critical appraisal process: Randomization, allocation concealment, blinding and losses to

follow-up. All panel members participated in an orientation through a conference call to standardize the

application of the critical appraisal criteria. Each panel member received five to seven studies to review, along

with a standardized data abstraction form. Independent from the panel members, one of three authors (KA, JF,

or ST) duplicated the review and critical appraisal of all included studies independently and blinded to the

panels review. This ensured appraisal by two independent and blinded reviewers and standardized application

of the criteria by all reviewers. During a three-day face-to-face panel meeting, all panel members reviewed and

extensively discussed results from each study.

Each included trial was critically appraised according to the criteria displayed in Table 3, which are formatted

such that a yes response indicates low risk of bias. The number of yes answers was counted to provide a

risk of bias score. The numerical values of the risk of bias score generally can be interpreted as: 9-11 = low

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risk of bias; 7-8 = moderate risk of bias; and 0-6 = high risk of bias. Note that studies were assessed based on

the methods they reported, sometimes without certain knowledge of the methods actually used.

Table 3. Criteria for assessment of individual study risk of bias

Data synthesis and meta-analysis

Choice of outcome measures. Caries increment was the primary outcome measure, which is the number of

newly decayed, missing and/or filled surfaces or teeth experienced by each participant per year compared to

baseline. Caries increment is derived from longitudinal and not cross-sectional studies. The panel adapted a

set of rules published in a Cochrane review of caries trials15 to select outcome data from each study for

subsequent analysis. Specifically, the panel chose data for "all surface types combined" over data for specific

types (surfaces)" only; data for "all erupted and erupting teeth combined" over data for "erupted" only, and this

over data for "erupting only"; data from "clinical and radiological examinations combined" over data from

"clinical" only, and this over "radiological" only; DMFS (dmfs) scores over DFS (dfs) or DS (ds); netB caries

B Net caries increment is obtained by subtracting the number of reversals (negative increments) from the number of

positive caries increments (Broadbent and Thomson 2005). 16. Broadbent J. M., Thomson WM. For debate: problems with the DMF index pertinent to dental caries data analysis. Community Dent Oral Epidemiol 2005;33(6):400-9.

Were patients in both study arms recruited from the same

population at the same time?

Randomization reported (random sequence generation)?

Randomization procedure described?

Allocation concealment claimed?

Blinding (examiner, patient and statistician)?

Rate of losses to follow-up similar between treatment

groups?

Baseline caries status of those lost to follow-up similar to

those remaining?

Baseline caries status similar between treatment groups at

end of study or adjustment for confounding?

Sample size estimated a priori (to ensure sufficient power)?

Intention to treat* used?

Conflict of interest absent?

*As defined by study author(s)

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increment data over crudeC (observed) increment data; and follow-up nearest to three years (often the one at

the end of the treatment period) over all other lengths of follow-up.

When data on both the tooth surface-level and tooth-level were available, the panel extracted data for both.

Similarly, the panel extracted data for dentinal/cavitated caries lesions, as well as for "all stages" (these data

are presented in Appendix 3). The panel also extracted data for primary and permanent teeth separately.

Imputing variances. When needed and possible, the panel imputed non-reported standard deviations using a

linear regression equation. 15

Adjusting for cluster-randomization. Some studies used group randomization (groups such as schools or

classes as opposed to individuals receiving the same intervention). In some of these studies, the results were

not adequately adjusted for the unit of analysis being the cluster rather than the individual. Standard statistical

procedures for adjustment for clustering depend on the number of clusters and the intracluster correlation

coefficient (ICC).17 The ICC ranges from 0 to 1, with the smaller number indicating the smaller cluster effect

and vice versa; however, it is often not reported, thus requiring estimation. 17,18 The standardized mean

differenceD (SMD) for three ICC values (0, 0.1, and 0.2) were calculated, and the resulting effects on the SMD

are presented, when applicable.

Effect estimates. Individual study results were combined by meta-analysis when multiple papers using

comparable methods were included for the same fluoride agent, with the objective of obtaining a more powerful

estimate of the true effect size. The SMD between the treatment and control arms was used as the effect

estimate, since it indicates whether the intervention is effective (i.e., works or does not work) and allows

measures on a variety of scales to be combined.

Data on cavitated surfaces were used in the meta-analysis calculations when both surface- and tooth-level

cavitated data were extracted. When only all stages data were reported, those data were also included in the

C Crude caries increment is obtained by comparing the baseline and follow-up status of each surface (on a surface-by-

surface basis). It does not allow for reversals. (Broadbent and Thomson 2005).16. Ibid.

D Standardized mean difference is the difference in means divided by a standard deviation. The standard deviation is the

pooled standard deviation of outcomes. The SMD value does not depend on the measurement scale, so it is a useful metric when outcomes are measured on different scales. What it actually measures is the number of standard deviations between the means. [Cochrane Handbook, Meta-analysis of continuous data, http://www.cochrane-net.org/openlearning/html/modA1-4.htm.]

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meta-analysis with cavitated data. When only tooth-level cavitated data were reported, the data were

summarized separately.

For individual studies judged to be too clinically heterogeneousE to combine into a meta-analysis, SMD

between the treatment and control arms in each study was used as the summary estimate. Individual study

results (as SMD), if present, are shown in a table along with the meta-analysis results, and not presented

graphically in a forest plot. All analyses were designed to assess superiority, not equivalence.

Clinical interpretation issues. Other systematic reviews on topical fluorides12-14 presented prevented fraction

(PF), number needed to treat (NNT), and SMD as their effect estimates. The panel chose a pragmatic

approach to summarize and interpret the data, which was to summarize one effect estimate (SMD), and then

provide conversions of that estimate into both PF and NNT for those more familiar with these effect estimates.

The methods are described in Appendix 5, and the results are presented in each topical fluoride section. The

methods originate from the observation14 that the character of DMFS data (that mean caries increments are

similar to their standard deviations) implies that meta-analysis of SMD (the difference between two means

divided by an estimate of the within-group standard deviation) is similar in magnitude to PF (the difference in

mean caries increments between the treatment and control groups divided by the mean increment of the

control group). The panel notes that the regression equation used to convert SMD to PF in Appendix 5 was

derived from studies on topical fluorides reviewed in this report and is not generalizable beyond this report. In

addition, the NNT in this report was based on an annual caries increment of 1 DMFS in the control group.

Generating forest plots. Random-effects meta-analyses were conducted throughout to generate forest plots

using Review Manager (RevMan) 5.1 software19 when there were two or more combinable trials. The random

effects method (rather than the fixed effect method) is recommended when trial data are taken from the

literature and likely do not represent the same population.20 The random effects model is more conservative in

that the variance is composed of both the within-study and between-studies sampling errors. Individual study

and summary effect estimates were weighted by the inverse of the variance according to standard methods.21

Statistical heterogeneity. Heterogeneity in study results typically arises from differences in study methodology

and/or differences in the clinical aspects of the trial, such as populations, time period of the study, and/or

E Clinical heterogeneity arises from variability in participants, interventions, and outcomes studied. [Cochrane Handbook

for Systematic Reviews of Interventions, Version 5.1.0 (updated March 2011), Editors: Julian PT Higgins and Sally Green.]

18

topical fluoride dose.22 The panel assessed heterogeneity from the forest plots based on the I2 statistic

generated by Review Manager19 software. The statistical heterogeneity was interpreted as23: I2

19

Low

More information could allow a reliable estimation of effects on health outcomes.

The available evidence is insufficient to support the statement or the statement is based on extrapolation from the best available evidence. Evidence is insufficient or the reliability of estimated effects is limited by factors such as:

the limited number or size of studies;

important flaws in study design or methods leading to high risk of bias;

inconsistency** of findings across individual studies;

gaps in the chain of evidence;

findings not applicable to the populations of interest; or

a lack of information on important health outcomes.

*Adapted from the United States Preventive Services Task Force system **Inconsistency of findings is a concept incorporating direction of effect, similarity of point estimates, overlapping of confidence intervals, and statistical heterogeneity. Statistical heterogeneity (I

2) is interpreted as

23: I

2

20

The panel used the criteria displayed in Table 5 to combine the Level of Certainty with the Net Benefit Rating

to arrive at the strength of the recommendation (Strong, In Favor, Weak, Expert Opinion For, Expert Opinion

Against, or Against). Table 6 shows the definitions of these strengths of recommendations.

Table 5. Balancing Level of Certainty and Net Benefit Rating to arrive at recommendation strength

Level of Certainty

Net Benefit Rating

Benefits outweigh

potential harms

Benefits balanced with

potential harms

No benefit or potential harms

outweigh benefits

High Strong In Favor Against

Moderate In favor Weak Against

Low Expert Opinion For or Expert Opinion Against

The USPSTF system defines this category as insufficient evidence and makes I-Statements. They do not make recommendations when the level of certainty in the

evidence is low.

Table 6. Definitions for the strength of recommendation:*

Recommendation strength

Definition

Strong Evidence strongly supports providing this intervention

In Favor Evidence favors providing this intervention

Weak Evidence suggests implementing this intervention after alternatives have been considered.

Expert Opinion For Evidence is lacking; the level of certainty is low. Expert Opinion guides this recommendation

Expert Opinion Against Evidence is lacking; the level of certainty is low. Expert Opinion suggests not implementing this intervention

Against Evidence suggests not implementing this intervention or discontinuing ineffective procedures

*Adapted from the USPSTF system The USPSTF system defines this category as insufficient evidence and makes I-Statements. They do not make recommendations when the level of

certainty in the evidence is low.

21

Note that as described in Table 4 for Low level of certainty (when evidence is insufficient or reliability of

estimated effects is limited) and Table 5, the expert panel can still make a recommendation based on their

collective judgment, based on the available evidence. Upon agreement that the level of certainty in the effect

was low, and when the panel decided to make a clinical recommendation, the language of that

recommendation was discussed and amended until a majority of the panel was satisfied, as assessed by vote.

A summary of the steps the panel took to translate the evidence into clinical recommendation strength levels is

presented at the end of each treatment section (subdivided by age/dentition) with the subheading Evidence

Profiles.24 The bulleted list includes: 1) the level of certainty in the effect estimate (column 1 in Table 5); 2) the

benefit of the treatment presented in three formats (standardized mean difference [SMD], prevented fraction

[PF], and number needed to treat [NNT]); 3) potential harms associated with the treatment; 4) the panels

judgment of the benefit-to-potential-harm balance (net benefit rating, columns 2 through 4 in Table 5); and 5)

the resulting strength of the recommendation from Table 5. By making the judgments explicit, the panel hopes

the reader can understand the reasoning behind the clinical judgments that were made to develop the clinical

recommendations. The panels judgments are based on the best available data. Some topical fluorides could

perform better than others in various situations. The panel notes that mean effects are just that, i.e., average

results; and some patients could experience a very large effect, while others experience little effect. Similarly,

small effects for an individual patient can have large public health effects if they apply to a large part of the

population.25

The panel approved clinical recommendations by a simple majority vote. The panel sought comments on this

report from other subject matter experts, methodologists, epidemiologists and end-users before finalizing the

recommendations. The ADA Council on Scientific Affairs approved the final report for publication.

22

Results The panel included 71 trials in 82 published papersF to assess the efficacy of various topical fluoride agents for

preventing caries. When possible, data from the studies were combined through a meta-analysis. Results of

the quality assessment and the data synthesis are presented below. Table 7 presents the fluoride

concentrations of each topical fluoride agent evaluated, both as concentration of fluoride ion and concentration

of sodium fluoride.

Table 7. Fluoride ion and sodium fluoride concentrations of topical fluoride agents

Topical Fluoride Agent % F- ion % NaF

Professionally-applied

2.26% fluoride varnish 2.26 5.0

0.1% fluoride varnish 0.1 N/A*

Acidulated phosphate fluoride (APF) gel (with 0.1 M phosphoric acid)

1.23 2.7

Acidulated phosphate fluoride (APF) foam (with 0.1 M phosphoric acid)

1.23** 2.7**

Prophylaxis paste containing fluoride (most as APF) 1.23 2.7

Prescription-strength, home-use

Prescription-strength gels/pastes with or without acidulation (0.1M phosphoric acid)

0.5 1.1

Prescription-strength mouthrinses 0.09 0.2

*0.09% difluorsilane **Concentration of fluoride before dispensed. When delivered as foam by combining gel with air, the total amount of fluoride in the foam product is reduced.

Some general considerations to take into account in reviewing the evidence include: First, some of the studies

were done before the 1970s, when dental caries rates among children were higher,26 the percentage of the

population receiving fluoridated water was substantially lower,27 and the percentage of people using fluoridated

dentifrice was much lower28. Second, some studies were conducted in countries with different levels of

background fluoride exposure, other caries preventive efforts, and caries prevalence. Lastly, the study

populations often could not be categorized in terms of caries risk and the panel could not extrapolate to the risk

categories as defined today. Therefore, caution is advised when extrapolating the results to todays high-risk

populations, such as children at high risk for early childhood caries.

F Note that there are several cases where one study was cited by several papers. All papers are cited for each study in

these cases.

23

Varnish: 2.26% and 0.1% fluoride

There are over 30 fluoride-containing varnish products on the market today, with varying compositions

(including resin, solvent, and presence of tricalcium phosphate [TCP]) and delivery systems. These

compositional differences lead to widely variable pharmacokinetics, the effects of which remain largely

untested clinically. Through its literature search process, the panel found clinical trials on four brand name

products and decided to summarize the results based on the percentage of fluoride, which was either 2.26% or

0.1%. Further research revealed that products identified with an identical brand name (Fluor Protector) had a

compositional change in 1987 from 0.7% fluoride to 0.1% fluoride29. Since the 0.7% fluoride product is no

longer available commercially, these trials30-34 were not eligible for inclusion in this review. Therefore, the data

are subdivided by 2.26% and 0.1% fluoride varnish.

Varnish (2.26% fluoride)

General summary of results

The panel identified 17 randomized and five non-randomized clinical trials that evaluated 2.26% fluoride

varnish. There were six randomized31-33, 35-39 and two non-randomized40, 41 clinical trials concerning the primary

dentition, 11 randomized31-33, 42-52 and two non-randomized53, 54 clinical trials concerning the permanent

dentition, and one controlled55 clinical trial that combined results for both dentitions. The control groups were

no treatment, oral health counseling, or placebo varnish. The studies were carried out in populations with

various levels of dental caries. The studies were conducted in many countries (Brazil, Canada, Hong Kong,

India, Kuwait, Netherlands, Poland, Spain, Sweden, U.K. and U.S.), with and without additional fluoride use or

other fluoride exposures (although most studies were in low fluoride areas), and with and without prior

prophylaxis. The ages of the children at baseline varied from 6 months to 8 years for studies of the primary

teeth; and 5 to 15 years for studies of the permanent teeth. The panel identified two studies50, 51 of root caries.

The age range in these two studies was 44 to 79 years. The varnish was professionally applied every 3 to 12

months, with the majority of studies applying varnish every 6 months.

The study characteristics, bias scores, and the extracted outcomes data are presented in Tables A through C

in Appendix 4. The bias scores ranged from 2 to 11 for the studies on primary and permanent teeth.

The panel combined the surface-level data for studies comparing varnish application to placebo or no

treatment into two meta-analyses, one each for the primary and permanent dentitions. These meta-analyses

are shown in Figures 2 and 3. Some studies were not included in the meta-analysis because the results for

primary and permanent teeth were combined55, only tooth-level data were reported53, and only data on the

occlusal surfaces of the first permanent molars were reported45.

24

The results of two root caries studies50, 51 were combined in a separate meta-analysis (Figure 4).

Table 8 summarizes the SMD from all the studies, separated into those results generated via meta-analysis

and those of individual studies (not included in the meta-analysis).

Figure 2. Standardized mean differences from meta-analysis of 2.26% fluoride varnish studies on

primary teeth [d(e/m)fs]

Notes: 1) Adjustment for cluster randomized trials (Grodzka) at ICC=0.1: -0.20 [-0.32, -0.08], I2=58%; at ICC=0.2: -0..20 [-0.32, -0.08], I

2=57%; 2) For

Clark, used Cochrane regression equation for imputing SD; 3) For Autio-Gold and Gugwad, calculated the change between baseline and final

measurements, assuming r=0.5 for SD calculation; 4) For Weintraub, ITT data used combining both treatment arms; 4) For Hardman, converted SE to

SD; 5) For Lawrence, used adjusted means for aboriginal only data, and converted SE (2.04) to SD using the adjusted difference according to SD =

SE/(sqrt(1/832+1/328)).


permanent teeth [DMFS]

Notes: 1) Koch-SE converted to SD using the adjusted difference according to SD = SE/(sqrt(1/60+1/61)); 2) Moder-mean prevalence at 3 years adding

Decayed 03 plus Filled data; and used Cochrane regression equation for imputing SD; 3) For Clark, used Cochrane regression equation for imputing

SD; 4) Tewari converted SE to SD using the same approach as for Koch SE; 5) Bravo added fissured and non-fissured means for total surface mean;

not cluster adjusted in this figure; used Cochrane regression equation for imputing SD; 6) Milsom used Total DFS increment - Mean of cluster

summaries data with the number of clusters used as the sample size.

Sensitivity analysis: Adjustment for cluster randomized trials (Bravo) at ICC=0.1: -0.37 [-0.52, -0.23], I2=65%; at ICC=0.2: -0.37 [-0.51, -0.22], I

2=64%

25


decayed root caries surfaces

Table 8. Summary of standardized mean differences from meta-analysis and individual studies for 2.26% fluoride varnish studies

Outcome Measures Number

and type* of studies

Number of participants**

Standardized Mean Difference [95% Confidence Interval]

(negative favors intervention, positive favors control)

Meta-analysis results: Primary teeth

d(e/m)fs, increment or incidence

6 RCT31-33, 35-39 and 2 CCT40, 41

3,409** -0.19 [-0.31, -0.08]

Meta-analysis results: Permanent teeth

D(M)FS, increment or incidence

8 RCT31-33, 42-44, 46-49, 52

and 1 CCT54 2,574 -0.38 [-0.53, -0.24]

Root caries, meta-analysis results

Root caries increment 2 RCT50, 51 132 -0.67 [-1.14, -0.20]

Individual study results

Combined dentition 1 CCT55 390 DMFS + dmfs: -1.47 [-1.70, -1.25] DMFT + dmft: -1.15 [-1.37, -0.94]

DMFT 1 CCT53 77 -0.13 [-0.58, 0.32]

DS occlusal surfaces 1 RCT45 79 -0.54 [-1.06, -0.03] Notes: * RCT = randomized controlled trial; CCT = controlled clinical trial (non-randomized); **Including all participants (not using cluster-adjusted number of participants or numbers of clusters);

all stages used if cavitated data not available; parentheses indicate that component was included in

some of the combined results and not others

The results of the meta-analyses for primary teeth (Figure 2) indicate that the application of 2.26% fluoride

varnish has a statistically significant effect (SMD -0.19 [95% CI: -0.31, -0.08]) on caries prevention as

measured by increment or incidence using surface-level data.

The results of the meta-analyses for permanent teeth (Figure 3) indicate that 2.26% fluoride varnish has a

statistically significant effect (SMD= -0.38 [95% CI: -0.53, -0.24]) on caries prevention as measured by

increment or incidence using surface-level data. Several studies provided data that could not be included in the

meta-analysis, the results of which are summarized in Table 8.

26

In addition, two RCTs on root caries indicated a statistically significant improvement in root caries prevention

as shown in Figure 4.

Evidence statements

The panel concluded with moderate certainty that there is a benefit of 2.26% fluoride varnish application

at least twice per year for caries prevention in the primary teeth among children aged 6 months to 8

years. This statement is based on meta-analysis of seven studies that ranged from low to high risk of bias and

included over 3,000 participants; however, it is noted that there was moderate statistical heterogeneity

(I2=58%) and inconsistency among the results of the studies.

The panel concluded with moderate certainty that there is a benefit of 2.26% fluoride varnish application

at least twice per year for caries prevention in the permanent teeth among children aged 5 to 15 years.

This statement is based on meta-analysis of nine studies that ranged from low to high risk of bias and included

over 4,500 participants; however, it is noted that there was moderate statistical heterogeneity (I2=68%) and

some inconsistency among the results of the studies.

The panel concluded with low certainty that there is a benefit of 2.26% fluoride varnish application at

least twice per year for root caries prevention in adults with root caries. This statement is based on meta-

analysis of two studies with low to moderate risk of bias that included only 132 participants, but there was low

statistical heterogeneity (I2=28%), showing a consistent effect between the two studies.

The panel identified no studies of the effect on coronal caries of 2.26% fluoride varnish on the permanent teeth

of adults over the age of 18.

Evidence profiles: 2.26% fluoride varnish

Primary teeth (children under age 6):

Level of certainty: Moderate

Benefit: Yes (smaller caries increment or incidence with topical fluoride use). o SMD=-0.19 [-0.31, -0.08] o PF=0.22 o NNT for control rate of 1 dmfs per year = 4

Adverse events or harms: Little potential for harms if swallowed

Benefit-harm assessment (Net benefit rating): Benefits outweigh potential harms

Strength of clinical recommendation: In favor

Permanent teeth (children):


Benefit: Yes (smaller caries increment or incidence with topical fluoride use). o SMD=-0.38 [-0.53, -0.24] o PF=0.36

27

o NNT for control rate of 1 DMFS per year = 3

Adverse events or harms: None if used as manufacturers recommend


Strength of clinical recommendation: In favor Permanent teeth coronal caries (adults):

Level of certainty: No certainty (no studies)

Benefit: Unknown, but extrapolated from permanent teeth of children data



Strength of clinical recommendation: Expert opinion for use Permanent teeth - root caries (adults):

Level of certainty: Low

Benefit: Yes (smaller caries increment or incidence with topical fluoride use). o SMD=-0.67 [-1.14, -0.20] o PF=0.58 o NNT for control rate of 1 DMFS per year = 2



Strength of clinical recommendation: Expert opinion for use

28

Varnish (0.1% fluoride)


The panel identified two non-randomized clinical trials56, 57 that evaluated 0.1% fluoride varnish on the

primary dentition and one randomized clinical trial58 on the permanent dentition. The control groups

received oral hygiene instruction or no treatment. The studies were carried out in Germany and Sweden

in populations with various baseline levels of dental caries. The ages of the children at baseline varied

from 4 to 5 years for primary dentition and 9 to 12 years for permanent dentition. The varnish was

professionally applied every 6 months for the primary dentition and every 4 months for the permanent

dentition. Additional fluoride use or other fluoride exposure was variable, and all studies included prior

prophylaxis.

The study characteristics, bias scores, and extracted outcomes data are presented in Tables D through

F in Appendix 4. The bias scores were 2 for the two clinical trials and 6 for the RCT.

The panel compared varnish application to no treatment in one meta-analysis for the primary dentition

as shown in Figure 5. Table 9 summarizes the meta-analysis results and also lists the single-study

results for the permanent dentition.

Figure 5. Standardized mean differences from meta-analysis of studies of 0.1% fluoride varnish

applied twice a year to primary teeth [d(e/m)fs]

Notes: Twetman and Petersson not cluster adjusted in figure.

Sensitivity analysis: Adjustment for cluster randomized trials (Twetman and Petersson) at ICC=0.1: -0.05 [-0.30, 0.20], I2=0%; at ICC=0.2: -0.05

[-0.40, 0.29], I2=0%

29

Table 9. Summary of standardized mean differences from meta-analysis and individual studies for 0.1% fluoride varnish

Outcome Measures

Number and type* of studies




Primary teeth, meta-analysis results

dfs increment or incidence

2 CCT56, 57 4,977 -0.11 [-0.27, 0.06]

Permanent teeth, individual study results

DMFS increment 1 RCT58 318 -0.15 [-0.37, 0.08] Notes: * RCT = randomized controlled trial; CCT = controlled clinical trial (non-randomized); **Including all participants (not using cluster-adjusted number of participants)

The estimate of effect of 0.1% fluoride varnish applied twice per year on the primary teeth shows no

statistically significant effect, as shown in Figure 5.

The estimate of effect of 0.1% fluoride varnish applied at least once per year on the permanent dentition

is not statistically significant, as shown in Table 9.

Evidence statement

The panel concluded with moderate certainty that there is no benefit of 0.1% fluoride varnish

application twice per year for caries prevention of primary teeth among children less than 6

years old. This statement is based on meta-analysis of two studies at high risk of bias with almost 5,000

participants; however, the results were inconsistent with high statistical heterogeneity (I2=79% without

cluster adjustment). Furthermore, when adjusted for clustering, the statistical heterogeneity was

eliminated (I2=0%).

The panel concluded with low certainty that there is no benefit of 0.1% fluoride varnish application

three times per year for caries prevention of permanent teeth among children aged 6-14 years

old. This statement is based on one study at high risk of bias with 318 participants.

The panel identified no studies on the effect of 0.1% fluoride varnish on coronal or root caries on the

permanent teeth of adults over the age of 18.

30

Evidence profiles: 0.1% fluoride varnish



Benefit: No

Adverse events or harms: Little potential for harms if swallowed

Benefit-harm assessment (Net benefit rating): No benefit

Strength of clinical recommendation: Against



Benefit: No



Strength of clinical recommendation: Expert opinion against use Permanent teeth coronal caries (adults):





Strength of clinical recommendation: Expert opinion against use Permanent teeth root caries (adults):


Benefit: Unknown


Benefit-harm assessment (Net benefit rating): Unknown

Strength of clinical recommendation: Panel unable to make a recommendation

31

APF gel (1.23% fluoride)


The panel identified 11 randomized59-70 and four non-randomized 55, 71-75 clinical trials that evaluated APF gel

(1.23% fluoride as Acidulated Phosphate Fluoride [APF], 0.1 M phosphoric acid) quarterly, semiannually,

annually or biennually (one application observed after 2 years). The comparison groups received no treatment,

placebo, prophylaxis, or non-fluoride placebo gel. All studies except one71 were on permanent teeth. All

studies applied fluoride gel for four minutes.

The study characteristics, bias scores, and the extracted outcomes data are presented in Tables G through I in

Appendix 4. All studies were conducted on school-aged children (between 3 and 16 years old) except for

one69. One study69 was conducted on non-institutionalized adults at least 60 years of age and reported on root

caries. Ten studies were conducted in the U.S. and five elsewhere (India55 70, U.K.66, China65 and Canada67).

The bias scores of eight55, 59-61, 64, 66, 69, 71, 75 of the studies ranged from 3 to 6, and seven55, 56, 58, 60, 61 70, 72-74, 76

were rated as 7. Although most studies used blinded assessment of outcomes, these bias scores were driven

primarily by lack of reporting of the randomization procedure, allocation concealment, and use of intention-to-

treat analysis.

The panel combined the results of 12 studies on permanent teeth through a meta-analysis that was grouped by

frequency of application. Three of the studies were excluded from the meta-analysis because of clinical

heterogeneity (the participants were older adults and the outcome was root caries increment)69 and because of

non-comparable outcomes measures (results combined for primary and permanent teeth55; and primary teeth

only71). Figure 6 presents the results of the meta-analysis.

32

Figure 6. Standardized mean differences from meta-analysis of studies of APF gel (1.23% fluoride)

applied on permanent teeth [DMFS] grouped by frequency of application

Notes: Jiang not cluster-adjusted in figure because ICC is not known, but adjustment at ICC=0.1: -0.25 [-0.34, -0.17], I2=42%; and at ICC=0.2: -0.26 [-

0.35, -0.17], I2=42%.

The meta-analysis (Figure 6) shows statistically significant reduction of dental caries in permanent teeth with

professionally-applied 1.23% APF gel at 3- to 24-month intervals compared to no treatment, placebo, or

prophylaxis. All application frequencies had statistically significant overall effects.

Table 10 summarizes the standardized mean differences from all the studies, separated into those generated

via meta-analysis and those of individual studies (not included in the meta-analysis).

33

Table 10. Summary of standardized mean differences from meta-analysis and individual studies for professionally-applied APF gel (1.23% fluoride)

Outcome Measures Number and

Type* of studies Number of

participants**



Meta-analysis results:

D(M)FS, increment or incidence, all frequencies

10 RCT59-68, 70 / 2 CCT72-75

4,023 -0.25 [-0.33, -0.16]

Individual trial results:

dmfs increment 1 CCT71 255 -1.51 [-1.79, -1.23]

DMFS + dmfs increment, all stages

1 CCT55 390 -0.84 [-1.05, -0.63]

Root caries DMFS increment, adults older

than 60 1 RCT69 318 -0.22 [-0.44, -0.00]

Notes:* RCT = randomized controlled trial; CCT = controlled clinical trial; **Using non-cluster-adjusted participant numbers;

All stages used if cavitated

data not available

Professionally-applied APF gel was shown to have a statistically significant effect on caries increment for the

mixed dentition55, as well as primary teeth71; however, the effect on root caries in adults older than 60 was

marginally statistically significant.69

Evidence statements

The panel concluded with low certainty that there is a benefit of APF gel (1.23% fluoride) application up

to every three months for 4G minutes for caries prevention in the primary dentition. This statement is

based on one study with a high bias score that included 255 participants.

The panel concluded with moderate certainty that there is a benefit of APF gel (1.23% fluoride)

application up to every three months for 4G minutes for caries prevention in the permanent teeth of 6-

14 year olds. This statement is based on meta-analysis of 12 studies with moderate to high bias scores and

including over 4,000 participants; although there was some inconsistency, there was low statistical

heterogeneity (I2=43) between the studies.

The panel concluded with low certainty that there is a benefit of APF gel (1.23% fluoride) application 2

times per year for 4G minutes to prevent root caries. This statement is based on one study with a high bias

score including 318 participants.

G No studies were found on professionally-applied fluoride APF gels with an application time of less than 3 minutes.

34

The panel identified no studies on the effect of 2% NaF gel meeting study criteria. In addition, the panel

identified no studies of APF gel (1.23% fluoride) on the coronal surfaces of permanent teeth of adults over the

age of 18.

Evidence profiles: APF gel (1.23% fluoride)



Benefit: Yes (smaller caries increment or incidence with topical fluoride use). o SMD=-1.51 [-1.79, -1.23]

Adverse events or harms: Potential harms if swallowed

Benefit-harm assessment (Net benefit rating): Potential harms could outweigh benefits

Strength of clinical recommendation: Expert opinion against use



Benefit: Yes (smaller caries increment or incidence with topical fluoride use). o SMD=-0.25 [-0.33, -0.16] o PF=0.27 o NNT for control rate of 1 DMFS per year = 4



Strength of clinical recommendation: In favor Permanent teeth coronal caries (adults):





Strength of clinical recommendation: Expert opinion for use Permanent teeth - root caries (adults):


Benefit: Yes (smaller caries increment or incidence with topical fluoride use) o SMD=-0.22 [-0.44, 0] o PF=0.24 o NNT for control rate of 1 DMFS per year = 4



Strength of clinical recommendation: Expert opinion for use

35

APF foam (1.23% fluoride)


The panel identified two randomized clinical trials65, 77 that evaluated APF foam (1.23% fluoride) in children

aged 3-7 years at baseline, one in the primary and the other in the permanent dentition. The comparison group

received either no treatment or placebo. Both studies were done in China.

The panel judged the bias score of one77 of the studies to be 9, while the other65 was judged to be 7. The study

characteristics, bias scores, and the extracted outcomes data are presented in Tables J through L in Appendix

4. The results for each study are shown in Table 11.

Table 11. Summary of standardized mean differences from individual studies for APF foam (1.23% fluoride)

Outcome Measures





dmfs increment 1 RCT77 318 -1.26 [-1.50, -1.02]

DMFS increment 1 RCT65 412 -0.14 [-0.34, 0.04] Notes:* RCT = randomized controlled trial; CCT = controlled clinical trial (non-randomized); **Using non-cluster adjusted numbers of participants; Adjustment for cluster randomized trials (Jiang and Tai) at ICC=0.1: -1.26 [-1.68, -0.84]; at ICC=0.2: -1.25 [-1.79, -0.71]

Adjustment for cluster randomized trials (Jiang and Bian) at ICC=0.1: -0.14 [-0.59, 0.31]; at ICC=0.2: -0.14 [-0.75, 0.48]

Evidence statements

The panel concluded with low certainty that there is a benefit of APF foam (1.23% fluoride) application 2

times per year for 4H minutes for caries prevention in the primary dentition. This statement is based on

one study with a low bias score including 318 participants.

The panel concluded with low certainty that there is no benefit of APF foam (1.23% fluoride) application 2

times per year for 4H minutes for caries prevention in the permanent dentition of children. This

statement is based on one study with a moderate bias score including 412 participants.

Evidence profiles: APF foam (1.23% fluoride)



Benefit: Yes (smaller caries increment or incidence with topical fluoride use). o SMD=-1.26 [-1.50, -1.02]

Adverse events or harms: Potential for harm if swallowed


Strength of clinical recommendation: Expert opinion against use

H Both studies on professionally-applied fluoride APF foams used an application time of 4 minutes.

36



Benefit: No



Strength of clinical recommendation: Expert opinion against use Permanent teeth coronal caries (adults):





Strength of clinical recommendation: Expert opinion against use Permanent teeth - root caries (adults):


Benefit: Unknown




37

Prophylaxis pastes containing fluoride


The panel identified three randomized78-80 and three non-randomized81-83 clinical trials that evaluated the

annual or semiannual application of prophylaxis pastes, most containing 1.23% fluoride as APF, for caries

prevention. These studies were all conducted in the 1960s-1970s. The comparison groups received pumice

prophylaxis or placebo paste. All studies except one83 (on children 3-5 years old at baseline) were on the

permanent teeth of children 8-16 years old at baseline.

The study characteristics, bias scores, and the extracted outcomes data are presented in Tables M through O

in Appendix 4. All of the studies were conducted in the U.S. The panel judged five of the studies to have bias

scores ranging from 3 to 5, and one with a bias score of 7.78 These judgments of quality were primarily driven

by lack of randomization; and if randomized, lack of reporting of the randomization procedure, allocation

concealment, and/or use of intention-to-treat analysis.

The panel combined the results of five of the studies through a meta-analysis. One of the studies83 was

excluded from the meta-analysis because of clinical heterogeneity (primary teeth). Two studies80, 81 reported

the results of two examiners separately; to be conservative, the data from the examiner with the largest

standard deviation were used. Standard deviations were imputed for two studies.82, 83 Figure 7 presents the

results of the meta-analysis on cavitated lesions of decayed surfaces. Table 12 summarizes the standardized

mean differences for both primary (one study) and permanent (5 studies) teeth.

Figure 7. Summary of standardized mean differences from meta-analysis of studies of prophylaxis

pastes containing fluoride on permanent teeth (DMFS)

38

Table 12. Summary of standardized mean differences from meta-analysis and individual studies of

prophylaxis pastes containing fluoride

Outcome Measures


Number of participants



Individual study results of primary teeth data

defs increment, cavitated lesions

1 CCT83 40 0.14 [-0.48, 0.76]

Meta-Analysis results of permanent teeth data

DMFS increment, cavitated lesions

3 RCT78-80 and 2 CCT81, 82

2,297 -0.08 [-0.18, 0.02]

Notes:* RCT = randomized controlled trial; CCT = controlled clinical trial (non-randomized)

Evidence statements

The panel concluded with low certainty that there is no benefit from prophylaxis paste containing

fluoride application for 4 minutes twice per year for caries prevention in the primary teeth of 3-5-year-

olds. This statement is based on one small study of 40 participants with a high bias score.

The panel concluded with moderate certainty that there is no benefit from prophylaxis paste containing

fluoride application for 4 minutes twice per year for caries prevention in the permanent teeth of 8-16-

year-olds. This statement is based on meta-analysis of six studies with moderate-to-high bias scores including

almost 2,300 participants that showed low statistical heterogeneity (I2=35%) but inconsistent beneficial effects.

No studies were identified that tested fluoride prophylaxis pastes on adult populations for caries preventive

effect.

Evidence profiles: prophylaxis pastes containing fluoride



Benefit: No

Adverse events or harms: Potential for harm if swallowed


Strength of clinical recommendation: Expert opinion against use Permanent teeth (children):


Benefit: No



Strength of clinical recommendation: Against

39

Permanent teeth coronal caries (adults): Level of certainty: No certainty (no studies)




Strength of clinical recommendation: Expert opinion against use Permanent teeth - root caries (adults):


Benefit: Unknown




40

Is prophylaxis prior to professional application of topical fluoride necessary?


The panel identified two randomized84-86 and one non-randomized 87 clinical trials to assess whether

prophylaxis prior to professional application of topical fluoride impacts efficacy. All studies were of North

American children from 6-14 years of age at baseline. All studies reported data on permanent teeth, and one84

also reported data on primary teeth. All studies reported results on prophylaxis prior to APF gel (1.23%

fluoride) application.

The study characteristics, bias scores, and the extracted outcomes data are presented in Tables P through R

in Appendix 4. Two of the studies were judged to have bias scores of 3 and 685-87 and the other84 was 7. These

judgments of quality were primarily driven by lack of randomization; and if randomized, lack of reporting of the

randomization procedure, allocation concealment, blinding, and use of intention-to-treat analysis.

The panel combined the results on permanent teeth in a meta-analysis as shown in Fig. 8. Table 13

summarizes the standardized mean differences for both the primary (one study) and permanent (3 studies)

teeth.

Figure 8. Summary of standardized mean differences from meta-analysis of studies of prophylaxis

prior to professional application of APF gel (1.23% fluoride) on pe

topical fluoride for caries prevention 2013 update - full manuscript

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