Is there an Advantage in Using Triclosan containing Dentifrice?Group 1Agustin, Andres, Aquitania, Aradanas, Asama, Austria, Bagasan, Bantegui, Bare, Bondoc, Borlagon, Buyawe, Cabrera, Cheung

TRICLOSAN

Triclosan (2,4,4-trichloro-2-hydroxydiphenyl ether)- Broad-spectrum, non-ionic, anti-bacterial/antimicrobial agent incorporated in soaps and cosmetics.

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Triclosan Toothpastes versus Fluoride Toothpastes: Are they Different?Ragy et. al, 2001

OBJECTIVEDetermine whether Triclosan Toothpastes could be shown to be more effective than conventional fluoride toothpaste when utilized in a twice daily home use for two months.

Effect of Triclosan/copolymer-containing Toothpaste on the Association between Plaque and Gingival Bleeding: a Randomized Controlled Clinical TrialMuller et. al, 2006

OBJECTIVETo study longitudinal associations between plaque and gingival bleeding and multilevel variance/covariance structures after introducing triclosan-containing toothpaste.

The Effectiveness of a Toothpaste containing Triclosan and Polyvinyl-methyl ether maleic acid copolymer in Improving Plaque Control and Gingival HealthDavies et. al, 2004

OBJECTIVETo compare the effectiveness of triclosan/copolymer and fluoride dentifrices in improving plaque control and gingival health.

METHODOLOGY

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METHODOLOGY

Muller et alRagy et alInclusion CriteriaFemaleMild plaque-induced gingival disease (slight gingival edema and redness in certain areas)Minimum amounts of supragingival calculus (CLS)A participant must demonstrate clinical signs of gingivitisBaseline mean erythrosine disclosed plaque score of >1.5 (Quigley and Hein plaque index)Mean gingivitis score of >1.0 (Loe and Sillness gingival index)

METHODOLOGY

METHODOLOGY

Muller et alRagy et alExperimental DesignSimple randomization was accompanied by assigning computer generated random numbers to volunteers by an independent periodontist (E.K.). Divided randomly into 3 groups of 10TRICLOSAN TOOTHPASTES1. Group A: Colgate total (triclosan- 0.3%, NaF- 0.33%, Gantrez copolymer, 2%)2. Group B: Gingilacer (triclosan 0.3%, zinc citrate 0.5%, Na MFP 1.13g 1500ppm)FLUORIDE TOOTHPASTE3. Group C:Colgate regular (NaF 0.1% w/w, and MFP 0.76% w/w, dicalcium phosphate)

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Muller et alRagy et alClinical ExaminationThe principal investigator carried out all examinationsClinical periodontal examinations were recorded at six sites of every tooth presentPeriodontal probing depth (PPD) and clinical attachment level (CAL) were measured with a pressure-controlled probe to the nearest millimetre Scoring indices were performed by a single clinical examiner 4 surfaces per tooth (buccal, mesio-buccal, lingual, mesio-lingual) Williams #11 round graduated periodontal probe

METHODOLOGY

METHODOLOGY

METHODOLOGY

Muller et alRagy et alStatistical AnalysisPrimary outcome variable was the association between plaque amount and BOP in a steady-state plaque environment.Null hypothesis was that triclosan-containing toothpaste doesnt change the associationEcological analysis of correlation between bleeding and PLIMultivariate multilevel modelsCovariance Analysis: to determine if there was any overall treatment effect; baseline=covariateNo further pairwise comparisons (overall treatment P value was>10 for both plaque and gingival indices

RESULTS

Ragy et. al., 2001Baseline averages of the whole mouth plaque index scores were initially very similar to each other ranging from 2.65-2.73. At the end of the 8th week mean values were 2.45, 2.33 and 2.5 for Col. Total, gingilacer and Col. regular respectivelyTable 1: summary of the whole mouth plaque index scores (mean+/- SD)

Col. Total

Gingilacer

Col. Regular

Baseline

2.73+/- 0.23

2.65+/-0.31

2.71+/-0.32

4 weeks

2.46+/- 0.29

2.37+/-0.25

2.5+/-0.41

8 weeks

2.45+/- 0.34

2.33+/-0.33

2.5+/-0.38

There were no statistically significant differences in plaque scores between groups at either the 4th or 8th weeksTable 2: Least square means of plaque index scores

Week

Treatment

95% Confidence interval

mean

lower

upper

P-value

4

Col. Total

2.42

2.32

2.52

> 0.2

Gingilacer

2.40

2.30

2.30

Col. Regular

2.49

2.39

2.39

8

Col. Total

2.44

2.30

2.30

> 0.2

Gingilacer

2.37

2.27

2.27

Col. Regular

2.43

2.34

2.34

The gingival index for the whole mouth showed no difference between products during the 4th and 8th weeks

Table 3: Summary of the whole mouth gingival index scores (mean +/-SD) 3:

Col. Total

Gingilacer

Col. Regular

Baseline

1.62+/-0.26

1.76+/-0.40

1.63+/-0.34

4 Weeks

1.09+/-0.34

1.15+/-0.37

1.11+/-0.37

8 Weeks

1.05+/-0.30

1.04+/-0.31

1.06+/-0.38

There was no significant statistical difference in gingivitis score between the groups at either 4 or 8 weeksTable 4:Least square means of gingival index scores

Week

Treatment

95% Confidence interval

mean

lower

upper

P-value

4

Col. Total

1.11

1.0

1.21

> 0.2

Gingilacer

1.04

0.95

1.15

Col. Regular

1.07

0.97

1.18

8

Col. Total

1.08

0.97

1.16

> 0.2

Gingilacer

0.97

0.86

1.08

Col. Regular

0.04

0.93

1.16

Although the difference in plaque scores among the three groups was not found to be statistically significant, there was a decrease in plaque scores for all three groups between the baseline and 4th week. A similar pattern was observed in the gingival index of all three groups. No statistical significance was noted, but a decrease in gingival index was observed for all three groups from baseline to week 4.

Muller et. al., 2006Volunteers: 34 32 (due to examination stress after week 4)Volunteers: mild-moderate plaque-induced gingivitis with few sites with increased PPD of >4mm at partially erupted 8sNo loss of attachment (only due to few facial areas with gingival recession)

TABLE 1. CLINICAL PERIODONTAL CONDITIONS OF THE STUDY POPULATION AT THE ONSET AND ALTERATIONS 6 WEEKS AFTER INTRODUCING EXPERIMENTAL TOOTHPASTES ARE PRESENTED

NO SIGNIFICANT DIFFERENCE BETWEEN GROUPS NEITHER AT BASELINE NOR AT THE END OF THE STUDY

THE DIFFERENCE WERE SMALL WITHIN GROUPS ALTHOUGH BLEEDING TENDENCY ATTENUATED IN BOTH GROUPS

ECOLOGICAL APPROACH

ECOLOGICAL APPROACHTable 2. Correlation between individual mean plaque and BI after week 4

Preparatory PhaseExperimental PhaseControl GroupYesYesTest GroupYesNo

ECOLOGICAL APPROACH

MULTIVARIATE MULTILEVEL MODELSTable 3. Fixed effects estimates during PrepAny increase in the PLI by 1 score inc in the odds of BOP by 34-44%

MULTIVARIATE MULTILEVEL MODELSTable 3. Fixed effects estimates during PrepAny 1 mm increase of PPD inc by 60% BOP odds ratio

MULTIVARIATE MULTILEVEL MODELSTable 4. Random part of multivariate four-level model

TABLE 4. RANDOM PART OF MULTIVARIATE FOUR-LEVEL MODELConstraining the model to fit binomial variation at the lowest level did not substantially alter any of the other parameter estimates (not shown).

Biserial correlation for BOPEstimated extrabinomial parametersLevel 2 (site)Very low: 0.11-0.13Below 1; (+) underdispersionLevel 3 (tooth)Larger: 0.3Below 1Level 4 (subject)Highest: 0.7-0.9Below 1

TABLE 5. FIXED EFFECTS ESTIMATES AFTER PREP AND DURING EXPThere was gradually increasing negative effect of test toothpaste on BOP proportions At the end of the Exp phase, odds of BOP decreased by 30% in the Test Group (OR 0.71%. 95% Confidence Interval 0.56-0.9, p= 0.005)

TABLE 6. SUBJECT VARIATION

Week 4Week 8-10Level 10.60.2

MULTIVARIATE MULTILEVEL MODELS WITH PLI AND CLS AS RESPONSESTest toothpaste had no significant (no reducing) effect on PLITest toothpaste had a small, albeit not significant (negative), effect on LCSOwing to highly localized occurrence of CLS, the model revealed considerable underdispersion at the site level, making the assumption of Binomial distribution questionable.When level 4 (tooth) was removed from the model, extrabinomial variation was essentially reduced.In contrast to the bleeding scores, biserial correlations for CLS were high (about 0.6) at the site level

TABLE 7. ASSOCIATION: BOP AND PLIAt the end of the Exp phase,Association between BOP and Plaque Scores: Test Group < Control Group ( =8.39, p

ADVERSE EFFECTSOne only, but disappeared after termination of the experimentBenign migratory glossitis (painless geographic tongue)

Chart1

1.71.951.491.491.582.111.42

2.032.121.851.831.972.431.86

2.263.922.52.692.542.231.07

Wk 4

Wk 6 - Control

Wk 6 - Test

Wk 8 - Control

Wk 8 - Test

Wk 10 - Control

Wk 10 - Test

Sheet1

Wk 4Wk 6 - ControlWk 6 - TestWk 8 - ControlWk 8 - TestWk 10 - ControlWk 10 - Test

PLI11.71.951.491.491.582.111.42

PLI22.032.121.851.831.972.431.86

PL32.263.922.52.692.542.231.07

Chart1

1.72.032.26

1.952.123.92

1.491.852.5

1.491.832.69

1.581.972.54

2.112.432.23

1.421.861.07

PLI1

PLI2

PL3

Sheet1

Column1PLI1PLI2PL3

Wk 41.72.032.26

Wk 6 - Control1.952.123.92

Wk 6 - Test1.491.852.5

Wk 8 - Control1.491.832.69

Wk 8 - Test1.581.972.54

Wk 10 - Control2.112.432.23

Wk 10 - Test1.421.861.07

Davies et. al., 2004Meta- analyses for both Quigley- Hein Plaque Index and Plaque severity index:- the triclosan/copolymer toothpaste is effective in reducing plaque.

WMD for the QHPI:-0.48 (95% CI (random effects): -0.64 to -0.32)

WMD for the Plaque Severity Index:-0.15 (95% CI (random effects): -0.20 to -0.09)* refer to fig.1, page 1031

Meta-analyses for the Loe and Silnes and gingivitis severity indices:

- showed a reduction in gingivitis when comparing the triclosan/copolymer dentifrice with a fluoride dentifrice

WMD for Loe and Silnes Gingival Index:-0.26 (95% CI (random effects): -0.34 to -0.18)

WMD for Gingivitis Severity Index:-0.12 (95% CI (randon effects): -0.17 to -0.08)

* Refer to fig.2, page 1032

Plaque and gingivitis severity indices demonstrated that:

- the use of triclosan dentifrice reduced the proportion of surfaces with heavy plaque by 15 % and those with gingival bleeding by 12%.

It appeared that:

- The proportion of sites that had plaque was reduced from 0.31 to 0.16 (49% reduction)- the proportion of sites with bleeding was also reduced from 0.24 to 0.12 (49% reduction as well)

The Weighted Mean Difference (WMD) for the Quigley-Hein Plaque Index corresponds to a 23% reduction in plaque when comparing the triclosan dentifrice with a Fluoride dentifrice.

The Weighted mean Difference (WMD) for Loe and Silness Gingival Index also corresponds to 23% reduction.

To determine publication and other biases, a funnel plot was used.

One of the funnel plots of the trials appeared asymmetrical, which was statistically significant thereby indicating some evidence of bias.

RESULTS

Ragy et. al., 2001Muller et. al.,2006Davies et. al, 2004There were no statistically significant differences in plaque scores between groups at either the 4th or 8th weeks There was no significant statistical difference in gingivitis score between the groups at either 4 or 8 weeksAlthough the difference in plaque scores among the three groups was not found to be statistically significant, there was a decrease in plaque scores for all three groups between the baseline and 4th week. A similar pattern was observed in the gingival index of all three groups. No statistical significance was noted, but a decrease in gingival index was observed for all three groups from baseline to week 4. Difference were small within groups although bleeding tendency attenuated in both groups Significant correlations b/n individuals mean plaque and bleeding indices were noticed in the Prep phase as well as in the Control Group thereafter, but during the Exp phase, correlations were no longer significant. At the end of the Exp phase, the association between BOP and Plaque Scores is lower in the Test Group then the Control Group- triclosan/ copolymer dentifrice is effective in reducing plaque Significant reduction in gingivitisReduction in the proportion of surfaces with heavy plaque and gingival bleedingProportion of sites that had plaque and sites with bleeding were both reduced as well

DISCUSSIONS

All three dentifrices demonstrated a slight reduction in gingival index scores after 4 weeks.The lack of difference between the triclosan groups and the fluoride group could be due to the relatively short duration (8 week).Ragy et. al, 2001

Lower values for plaque as compared to the baseline were also observed for all dentifrices.The values for both triclosan dentifrices were not statistically different from those of the fluoride toothpaste.

Zinc citrate and TriclosanSignificant reductions in plaque accumulationBetter able to maintain gingival healthComplementary and additive effects in vivoZinc=existing plaqueTriclosan= inhibit plaque formation

Normal home use toothpaste studies are influenced by a number of factors which may mask the superiority of a particular product over the controls.

FactorsTrue placebo toothpaste productsProduct or benchmark controlFluorideAntiplaque activity and antimicrobial effectsImprovement in toothbrushingReduces ability to detect actual product differencesBaseline prophylaxis

Antimicrobial or antiplaque agentsPotential to disrupt homeostasis if it has:Marked selective activity against organisms associated with healthToo broad a spectrum of activityTriclosanFabl gene= enyol reductase in fatty acid synthesis

Muller et. al., 2006In the clinical trials done (6 months duration; 54-329 subjects with plaque induced gingivitis), mean plaque and gingivitis scores are consistently lower in subjects using triclosan/copolymer-containing toothpaste.The relationship between plaque and bleeding became weaker after introducing triclosan-containing toothpaste. A further serious disadvantage of analyzing summary measures is immediate loss of most of the information usually acquired during examination of numerous periodontal sites.

One advantage of the approach used is that it gives a direct way of looking the influence of the subjects unobserved characteristics on the response variable and hence a direct measure of the effects which are being assessed.The study was intentionally confined to young adult female non-smokers, which demand a more in-depth discussion.In longitudinal studies, heavy tobacco consumption may lead, at site level, to gingival bleeding unrelated to the amount of supragingival plaque pointing to smoking as an independent risk factor for gingival inflammation. Gender differences have been reported in a recent gingivitis experiment.

In some studies, triclosan-related reductions of plaque and/ or gingivitis have been reported only after extended periods of usage. It is most likely that respective effects may be more consistent after longer usage only. A potential effect of higher content of fluoride in control toothpaste on gingival bleeding tendency and the association between plaque and BOP could not be ascertained.After introducing experimental toothpastes, estimate probabilities for BOP gradually decreased in the test group. In addition, the site-specific causal association between BOP and PLI scores became weaker in the test group. Prevention of the potential Hawthorne effect

Significantly improved the removal of supragingival plaque & gingival health: dentifrice containing triclosan/copolymer fluoride dentifrice

Evidence for Publication bias was found on the Gingivitis severity outcome reported

Davies et. al., 2004

Prophylaxis (in 13 studies):Effectiveness of the dentifrices to control the subsequent accumulation of plaque

No prophylaxis (in 3 studies):Effectiveness of the dentifrices in removing existing plaque and reducing further accumulation

Greater clinical significance:Improvement in gingival health & reduction in gingival bleeding in 3 randomized-control trials of at least 3 years duration:Ellwood et al. 1998Rosling et al. 1997Culliman et al. 2003

Studies involved 7 countries:Findings may be generalizable around the world.

CONCLUSIONS

OVERALL CONCLUSIONTriclosan-containing dentifrice has a significant effect in the control of dental plaque and gingivitis. Because of its antimicrobial property, triclosan when incorporated in dentifrices contributes in the removal of existing plaque and prevention of further plaque accumulation.

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