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1 Dr. Bader is a research professor, Department of Operative Dentistry, School of Dentistry, University of North Carolina at Chapel Hill. He also is the associate editor for evidence-based dentistry for The Journal of the American Dental Association.
James D. Bader
Correspondence
Address reprint requests to Dr. Bader at School of Dentistry, University of North Carolina at Chapel Hill, CB#7450, Chapel Hill, N.C. 27599-7450
1 Dr. Bader is a research professor, Department of Operative Dentistry, School of Dentistry, University of North Carolina at Chapel Hill. He also is the associate editor for evidence-based dentistry for The Journal of the American Dental Association.
5 Dr. Amaechi is an associate professor and the director of cariology, Department of Comprehensive Dentistry, Dental School, University of Texas Health Science Center at San Antonio
Bennett T. Amaechi
Footnotes
5 Dr. Amaechi is an associate professor and the director of cariology, Department of Comprehensive Dentistry, Dental School, University of Texas Health Science Center at San Antonio
1 Dr. Bader is a research professor, Department of Operative Dentistry, School of Dentistry, University of North Carolina at Chapel Hill. He also is the associate editor for evidence-based dentistry for The Journal of the American Dental Association. 2 Dr. Vollmer is a senior investigator, Kaiser Permanente Center for Health Research, Portland, Ore. 3 Dr. Shugars is a professor, Department of Operative Dentistry, School of Dentistry, University of North Carolina at Chapel Hill 4 Dr. Gilbert is a professor and the chair, Department of Clinical and Community Sciences, School of Dentistry, University of Alabama at Birmingham 5 Dr. Amaechi is an associate professor and the director of cariology, Department of Comprehensive Dentistry, Dental School, University of Texas Health Science Center at San Antonio 6 Dr. Brown is a professor emeritus, Department of Comprehensive Dentistry, Dental School, University of Texas Health Science Center at San Antonio 7 Ms. Laws is a coordinating centers manager, Kaiser Permanente Center for Health Research, Portland, Ore. 8 Ms. Funkhouser is a data manager, Kaiser Permanente Center for Health Research, Portland, Ore. 9 Dr. Makhija is an associate professor, Department of Clinical and Community Sciences, School of Dentistry, University of Alabama at Birmingham 10 Dr. Ritter is a professor and the graduate program director, School of Dentistry, University of North Carolina at Chapel Hill 11 Dr. Leo is an investigator, Kaiser Permanente Center for Health Research, Portland, Ore.
Although caries is prevalent in adults, investigators have tested few preventive therapies in adult populations. In a randomized controlled trial, the authors evaluated the effectiveness of xylitol lozenges in preventing caries in adults at elevated risk of developing caries.
Methods
The Xylitol for Adult Caries Trial (X-ACT) was a three-site placebo-controlled randomized trial. Participants (n = 691) aged 21 through 80 years consumed five 1.0-gram xylitol or placebo lozenges daily for 33 months. They underwent clinical examinations at baseline and at 12, 24 and 33 months.
Results
Xylitol lozenges reduced the caries increment 10 percent. This reduction, which represented less than one-third of a surface per year, was not statistically significant. There was no indication of a dose-response effect.
Conclusions
Daily use of xylitol lozenges did not result in a statistically or clinically significant reduction in 33-month caries increment among adults at an elevated risk of developing caries.
Clinical Implications
These results suggest that xylitol used as a supplement in adults does not reduce their caries experience significantly.
Many adults continue to develop dental caries throughout their life spans, and caries activity in this population is at least as extensive as it is in children and adolescents.
However, dental caries prevention efforts historically have focused on children rather than adults. Public oral health programs targeting caries prevention for adults are uncommon, and provision of caries-preventive treatment to adult dental patients at an elevated risk of developing caries is relatively infrequent.
One possible reason for this lack of attention may be that knowledge of the effectiveness of caries-prevention methods for adults is incomplete. The 2001 National Institutes of Health (NIH) Consensus Development Conference Statement on the Diagnosis and Management of Dental Caries Throughout Life expressed concern regarding the paucity of studies in adults, noting that “[a]lmost all of the relevant studies included populations of children between 6 and 15 years of age.”
The authors of both this statemen and another published by the Centers for Disease Control and Prevention, Atlanta, that same year recommended evaluation of several preventive interventions in adult populations, particularly adults at an elevated risk of developing caries.
One potentially effective preventive intervention identified in the systematic review prepared for the NIH Consensus Development Conference was xylitol.
Xylitol acts to reduce levels of mutans streptococci in the plaque and saliva. The effectiveness of xylitol-based interventions has been controversial, primarily because of differences in opinion regarding the quality of the published trials.
Xylitol-based caries prevention: is there enough evidence for the existence of a specific xylitol effect? (Comment on Scheie AA, Fejerskov OB. Xylitol in caries prevention: what is the evidence for clinical efficacy? Oral Dis 1998;4(4):268–278).
American Dental Association Council on Scientific Affairs Expert Panel on Nonfluoride Caries-Preventive Agents. Nonfluoride caries-preventive agents: executive summary of evidence-based clinical recommendations.
The conclusions of these reviews differ, principally owing to their assessments of the quality of the studies. Some conclude that there is evidence for a caries-preventive effect of xylitol, and others indicate that the evidence is inconclusive. However, all of the review investigators indicated that the existing evidence should be supplementedby well-designed randomized controlledtrials. The need for evidence is the motivation for the Xylitol for Adult Caries Trial (X-ACT). In X-ACT, we tested the hypothesis that daily use of xylitol lozenges reduces dental caries incidence in adults at an elevated risk of experiencing caries.
METHODS
Because a detailed description of study methods appeared previously,
we merely summarize them here, together with describing one important change in the analysis plan.
Study design
X-ACT was a 33-month, multicenter, placebo-controlled, double-masked, phase 3 randomized controlled clinical trial to test the effectiveness of daily xylitol lozenge use (up to 5 grams per day) versus placebo lozenge use to prevent caries in adults at elevated risk of experiencing caries. The primary outcome was the increment of cavitated lesions. In the trial, we randomly assigned 691 participants, 92 percent of the goal of 750, with assignments stratified according to site and age and allocated randomly in blocks of varying size within strata.
We conducted the trial at three clinical centers in the dental schools of the University of North Carolina at Chapel Hill (UNC), the University of Alabama-Birmingham (UAB) and the University of Texas Health Science Center at San Antonio (UTHSCSA). The Kaiser Permanente Center for Health Research in Portland, Ore., served as the data coordinating center. The institutional review board at each site approved the study, and all participants providedwritten informed consent. The majority of participants were recruited from among patients receiving treatment in the dental schools' clinics. Participants also were recruited in regional dental clinics and through advertisements.
Study procedures
Figure 1 summarizes the trial events from a participant's perspective. The study required a participant to visit the dental school a minimum of five times. Initial telephone or in-person screening preceded an enrollment visit to confirm eligibility and obtain consent, which was followed by a four-week run-in period (involving the use of placebo lozenges) to allow both potential participants and study coordinators to evaluate willingness to adhere to the study regimen.
We randomly assigned adherent, eligible participants to a study group at a baseline visit and scheduled them to return at 12 months, 24 months and 36 months for caries examinations. Before the 24-month visits began, we shifted the final examination schedule to 33 months to adjust for slower-than-expected completion of enrollment. Quarterly telephone contacts by research coordinators at each site occurred between the annual follow-up visits to arrange for resupply of lozenges, inquire about adherence, assess adverse effects and screen for possible serious adverse events (SAEs).
Inclusion criteria were age of 21 through 80 years; the presence of at least one coronal or root-surface cavitated caries lesion (present at screening or documented in the patient record or by self-report as having been restored in the previous year); the presence of at least 12 teeth; the ability to read and understand English; and the ability to provide informed consent. Exclusion criteria were the presence of extensive caries (more than 10 teeth with lesions); periodontal disease requiring aggressive treatment; residing in the same household with another participant; or anticipated move within three years.
Study treatments
The intervention consisted of one lozenge dissolved in the mouth five times during the day. Each active lozenge contained1.0 g of xylitol as a sweetening agent. The placebo lozenge was identical in size and color to the active lozenge but was sweetened with sucralose, which lacks any plausible biological cariostatic or cariogenic properties other than sugar substitution. Both the active and placebo lozenges were peppermint flavored. A second placebo with different flavoring was used for the run-in period. At baseline, we provided participants with a sufficient number of lozenges for three months (seven containers of 75 lozenges each), and we used the quarterly telephone contacts to determine the number of additional containers needed for the next three months.
Caries examinations
Trained and calibrated examiners identified caries lesions visually by using a standard dental operating light and chair, a nonmagnifying plane mirror and a Community Periodontal Index of Treatment Need-Epidemiologic (CPITN-E) probe. Examinersused loupes at their discretion, but consistently within each examiner. They dried tooth surfaces for five seconds with an air-water syringe. They used a modification of the International Caries Detection and Assessment System II (ICDAS II) criteria,
International Caries Detection and Assessment System Coordinating Committee. Criteria Manual: International Caries Detection and Assessment System (ICDAS II). Report of a workshop held in Baltimore Md., March 12–14, 2005 ICDAS II criteria document September 10.doc.
in which four disease levels were possible for each coronal surface: sound (S), noncavitated enamel lesion (D1) (ICDAS codes 1 and 2), cavitated lesion penetrating the enamel or shadowing (D2) (ICDAS codes 3 and 4) or cavitated lesion penetrating into the dentin (D3) (ICDAS codes 5 and 6). Examiners scored tooth surfaces as sound (S), having a lesion with an estimated depth of less than 0.5 mm (D1), and having a lesion with an estimated depth of 0.5 mm or greater (D2). Other surface conditions noted were the presence of pit-and-fissure sealants (P), the presence of restorations (F), the presence of crowns (C), missing teeth (M) and surfaces unable to be scored (Y). Examiners made one classification per tooth surface, with each tooth deemed to have five coronal surfaces (including the incisal surface) and four root surfaces.
A primary examiner at each clinical center completed almost all examinations (100 percent at UAB, 98 percent at UNC and 96 percent at UTHSCSA), although backup examiners were available as needed. To the extent possible, the same examiner who conducted the baseline examination performed all follow-up examinations. A recorder was present for all caries examinations. Primary and back-up examiners and recorders from all three clinical centers participated in a four-day training and calibration session with a reference-standard examiner,
as well as refresher sessions before the 12-, 24- and 33-month examinations. All primary examiners completed second examinations of approximately 5 percent of participants annually to determine intraexaminer reliability. Secondary examiners also completed examinations of these participants.
Study outcomes and statistical power
The primary study outcome was the cumulative decayed or filled surface (D2FS) increment (root and coronal surfaces combined; D2 and D3 lesions combined for coronal surfaces) from baseline through the three follow-up examinations, which we expressed in terms of an annualized increment. In the event of missed visits, we based the increment on the observable transitions, so that only participants with no follow-up visits (5 percent of all randomly assigned participants) had missing increment scores. We computed the D2FS increment as the weighted sum of changes in surface status associated with 64 predefined transitions in tooth-surface status.
We considered illogical reversals to be invalid transitions and gave them a score of 0—effectively excluding them from the analyses. We also scored null transitions (such as from F to F), transitions from D2 to treated status (F or C) or to or from an unscorable status (that is, Y or M) as 0. We scored transitions from S to C as 0 to minimize the influence of non–caries-related treatment on increment counts. We designed the study to provide 80 percent power to detect a 20 percent reduction in the D2FS increment assuming a two-tailed test with a type I error rate of 5 percent. The target sample size of 750 allowed a 10 percent attrition rate per year.
Covariates
We created several measures to characterize participants' baseline oral health and oral health care practices. These included a binary indicator of a routine dental visit (for prophylaxis or examination) in the past year, a three-level indicator of over-the-counter (OTC) fluoride use (toothpaste, mouthrinse or both), a five-level indicator of oral hygiene practices (from infrequent to frequent brushing and flossing) and the baseline D2FS count. We also assessed participants' adherence by comparing the number of containers of resupplied lozenges with the number that would be used under ideal adherence. (Authors' note: Forms used for all data collection are available on the study's public Web site, www.xactstudy.org.)
Safety monitoring
We asked participants about hospital admissions, gastrointestinal (GI) symptoms and mouth symptoms at three-month intervals throughout the study. We also asked participants to characterize symptoms as severe or not severe.
Statistical methods
We performed multiple imputations of missing data by using data augmentation with Markov Chain Monte Carlo sampling (SAS 9.1 PROC MI, SAS Institute, Cary, N.C.). We used an inclusive approach to imputation, as described by Collins and colleagues,
that included a wide range of baseline and interim variables to minimize bias. We carried out all analyses identically on all eight copies of the imputed data and combined them according to the Rubin
rules to adjust statistical test results for the uncertainty inherent in the imputation process.
We conducted the primary outcome analysis on the intent-to-treat sample using negative binomial regression to model the ln(annual incidence) as a function of the xylitol arm while adjusting for clinical center, age at random assignment, age squared, dental cleaning history, use of OTC fluoride, oral hygiene practices and severity of caries at baseline (D2FS) and study site. The regression coefficients from this model have the interpretation of ln(rate ratios), but we have re-expressed them as rate ratios (RRs) for the tables, which can be interpreted as relative risks. We included the natural log of person-years at risk as an offset to adjust for the varying length of time from random assignment to final oral examination across participants.
During the final study year, the data coordinating center uncovered irregularities in participant data at the UTHSCSA site. After subsequent investigation, the study's data safety and monitoring board (DSMB) deemed that, although the caries examination data appeared sound, the adherence data were unreliable. In addition, 10 participants who were household members of existing participants had been randomly assigned in violation of the protocol. The DSMB also could not discount the possibility that some participants had received incorrect lozenges. The DSMB therefore recommended that the primary analysis be based on data from only the unaffected sites, UNC and UAB, although secondary analyses could include the caries examination data from all three sites. They also agreed that, per protocol, we should exclude from all analyses the 10 participants who had been randomly assigned in error. Because the UTHSCSA site's adherence data were unusable, we did not impute missing data from that site. Thus, secondary analyses that include the UTHSCSA data do not include 12 UTHSCSA participants for whom there were no follow-up data, 10 participants who had been randomly assigned in error and an additional five participants for whom covariate data were missing.
Additional secondary analyses we report here were to assess the effect of xylitol in subgroupsdefined according to baseline D2FS score, baseline D2S (decayed surface) score, adherence to the study protocol (that is, lozenge use), sex, and race or ethnicity. For the D2FS score we used a binary split (0-20 versus 21 or higher, roughly a median split), whereas for D2S we defined groups as none versus any, and for adherence we defined three levels (0-40 percent, 41-80 percent and 81-100 percent, corresponding to roughly 20 percent, 40 percent and 40 percent of the sample) on the basis of the quantity of lozenges supplied as a percentage of the quantity that the participant would have used with perfect adherence. For the primary examiners, we report intraexaminer reliability scores on the basis of a roughly 5 percent convenience sample of participants who returned for repeat examinations during the study. We report simple pairwise κ statistics for each year for the combined examiners' reliability in distinguishing D2D3 lesions from all other surface conditions.
RESULTS
Figure 2 delineates the flow of participants through the study. We screened informally in clinics and did not record these contacts. Of 945 participants who attended the enrollment visit, we ultimately randomly assigned 691, 73 percent (344 in the xylitol arm and 347 in the placebo arm). Of the 254 we did not randomly assign, 81 withdrew during the run-in period, and 173 elected not to continue after completing the run-in period. The mean duration of follow-up was 2.56 years for UNC and UAB participants, and loss to follow-up was balanced between study arms.
Figure 2Participant flowchart. UAB: University of Alabama at Birmingham. UNC: University of North Carolina at Chapel Hill. UTHSCSA: University of Texas Health Science Center at San Antonio.
Table 1 shows participant characteristics. The mean age was 47 years (range, 21-80 years), and 65 percent were female. The majority brushed at least twice per day and were exposed to fluoride through office visits, home use of toothpaste or both (all three sites had fluoridated water). A small minority reported having dry mouth. We noted no marked differences between the xylitol and placebo groups in these observations. We observed similar participant characteristics among the primary analysis sample (the 437 randomly assigned participants from UNC and UAB). (Authors' note: Tables for each site are available at www.xactstudy.org).
Table 1Baseline characteristics of study participants from all study sites.
The target intraexaminer reliability value (unweighted κ value; D2D3 versus all else) for primary examiners during examiner training was 0.70. The mean value achieved for the three primary examiners was 0.72.
The mean values achieved during the participant examinations were 0.58, 0.88, 0.67 and 0.71 for the baseline and 12-, 24- and 33-month examinations, respectively. The baseline value was lower primarily owing to small numbers of observed lesions at one site.
Primary outcome analysis
Among participants from the UNC and UAB sites, the crude annualized D2FS increment in the xylitol group was 2.69 compared with 2.98 in the placebo group, a 10 percent lower increment. This difference did not achieve statistical significance (RR, 0.90; 95 percent confidence interval [CI], 0.78-1.03). Results with the full regression model (not shown) indicated that annualized caries increments increased significantly with increasing baseline D2FS score but did not differ according to site, age, routine dental visit history, use of OTC fluoride or frequency of oral hygiene. (Authors' note: Full regression model tables for all analyses are available at www.xactstudy.org.) We saw similar results when we included the UTHSCSA data (Table 2).
Table 2Summary of principal outcome analysis for D2FS
Based on negative binomial model adjusting for age at random assignment, age squared, dental prophylaxis or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush and floss, severity of caries at baseline and study site. CI: Confidence interval.
Based on negative binomial model adjusting for age at random assignment, age squared, dental prophylaxis or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush and floss, severity of caries at baseline and study site. CI: Confidence interval.
Includes imputed data (from baseline to first annual visit) for 22 participants from the University of Alabama at Birmingham or University of North Carolina at Chapel Hill for whom there were no follow-up data.
Includes imputed data (from baseline to first annual visit) for 22 participants from the University of Alabama at Birmingham or University of North Carolina at Chapel Hill for whom there were no follow-up data.
Based on analysis excluding an additional five participants for whom covariate data were missing.
2.64
2.96
* D2FS: Cumulative decayed or filled surface increment.
† Based on negative binomial model adjusting for age at random assignment, age squared, dental prophylaxis or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush and floss, severity of caries at baseline and study site. CI: Confidence interval.
‡ UTHSCSA: University of Texas Health Science Center at San Antonio.
§ Data are expressed as mean (standard deviation).
¶ Time from baseline to last observed follow-up visit.
# Includes imputed data (from baseline to first annual visit) for 22 participants from the University of Alabama at Birmingham or University of North Carolina at Chapel Hill for whom there were no follow-up data.
** Based on analysis excluding an additional five participants for whom covariate data were missing.
Because baseline D2FS score was such a highly statistically significant covariate in the primary analysis, we conducted a secondary analysis to assess treatment effects separately for those with baseline D2FS scores of 20 or lower and those with scores of 21 or higher. We observed no evidence of a treatment effect in the former group (RR = 1.00) but saw a significant effect in the higher D2FS group (RR = 0.80; P = .03) (Table 3, page 28). However, when we included the UTHSCSA data, the treatment effect was reduced in the high D2FS group and no longer was statistically significant (RR = 0.83; P = .05) (Table 3). In both analyses, the interaction P value exceeded .12.
Table 3Summary of analyses for selected subgroups.
Based on negative binomial model adjusting for age at random assignment, dental prophylaxis or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush and floss, severity of caries at baseline and study site. CI: Confidence interval.
Based on negative binomial model adjusting for age at random assignment, dental prophylaxis or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush and floss, severity of caries at baseline and study site. CI: Confidence interval.
* Based on negative binomial model adjusting for age at random assignment, dental prophylaxis or examination in the preceding 12 months, use of over-the-counter fluoride, usually brush and floss, severity of caries at baseline and study site. CI: Confidence interval.
† UTHSCSA: University of Texas Health Science Center at San Antonio.
† D2S: Cumulative decayed or filled surface increment.
To investigate whether this apparent subgroup effect might be more closely related to lesions at baseline, we conducted a similar analysis for the D2S score (Table 3). Here, neither the group with no D2 surfaces at baseline nor the group with one or more D2 surfaces at baseline displayed a significant treatment effect. We found similar results when we reran the analyses including the UTHSCSA data.
We evaluated treatment effects in subgroups according to adherence to the daily protocol of one lozenge five times per day (Table 3). We found a nonsignificant RR associated with lozenge use in all three adherence groups and no evidence of any treatment-by-dose interaction. We also observed no effect of adherence on D2FS increment in analyses restricted to placebo-group participants.
We observed similar results when we included UTHSCSA data. Finally, when we examined treatment effects according to sex and race or ethnicity, we found no difference between men and women in either the two-site or three-site samples; however, we did find that the treatment effect was significant for non-Hispanic whites, but not for Hispanics or those in the “other” category (mostly unkown) in the two-site sample but not in the three-site sample. (Authors' note: These analyses are available on the public Web site.)
Safety outcomes
Randomly assigned participants (including those from UTHSCSA) reported 46 SAEs (22 in the xylitol arm and 24 in the placebo arm). Of these, we considered one (diagnosis of longstanding gastroparesis) possibly study related, whereas we could not determine whether an additional three were study related because participants declined to provide the necessary information. In addition, participants reported severe oral adverse effects at rates of less than 0.5 percent for all reporting periods, whereas participants reported severe GI adverse effects at a rate of 1 percent or less during the study. Reports of any oral or GI adverse effects ranged from 3.2 to 8.4 percent for the mouth and from 3.3 to 11.4 percent for the GI tract across the duration of the study.
Most oral adverse effects were sores, whereas GI adverse effects were distributed across reports of cramps, bloating, constipation, flatulence, and loose stool or diarrhea. For all adverse effects, these patterns were similar for the two study groups.
DISCUSSION
The results of this clinical trial did not demonstrate a statistically significant reduction in 33-month caries incidence either in the primary analysis or in the secondary analysis that included all three sites. This finding is at odds with those in some reviews of xylitol studies in which investigators concluded definitively that xylitol is effective in reducing caries increments,
American Dental Association Council on Scientific Affairs Expert Panel on Nonfluoride Caries-Preventive Agents. Nonfluoride caries-preventive agents: executive summary of evidence-based clinical recommendations.
but it supports findings inother reviews in which researchers determined that the evidence is inconclusive, or that xylitol has little or no effect on caries increments.
It is important to realize that this, to our knowledge, is the first large-scale, placebo-controlled, multisite, randomized, double-masked study of xylitol as a caries-preventive agent. All previous studies lacked one or more of these essential features intended to minimize the likelihood of bias.
The study also differs from most previous studies in that it involved evaluation of lozenges (mints), rather than chewing gum, thereby rendering inoperative one possible method of action: mechanical plaque removal.
Mints may be less effective than gum for this reason. Also, and perhaps most importantly, in this study we evaluated xylitol in adults, rather than in children and adolescents, who have been the focus of virtually every preceding xylitol study. Finally, most of the participants lived in areas with fluoridated water, used fluoridated toothpaste and, owing to our recruitment strategies, could be characterized as recently having received dental care.
The results of this study help explain the existing controversy regarding xylitol's effectiveness. At best, xylitol's effect appears to be modest in this study group. We observed a reduction in the risk of dental caries on the order of 10 percent, which was not statistically significant. Such a small effect would be easy to miss in some trials, and in other trials perhaps would be open to exaggeration through the unintentional incorporation of bias. We saw essentially the same magnitude of risk reduction at each of the three study sites, which gives us confidence that our methods— especially our caries measurements—were well standardized.
Among this group of adults at elevated risk of experiencing caries, this reduction amounts to 0.29 “surfaces saved” per year. However, our observed crude increments, on the order of three decayed and/or filled surfaces per year, are higher than what would be expected from the literature we reviewed to estimate the power of our study,
Thus, the estimate of surfaces saved would be lower if we had adjusted for reversals. Although not negligible, the magnitude of surfaces saved is not encouraging for the widespread adoption of xylitol as either a public health measure or a dentist-recommended supplemental preventive intervention for adults who are at an elevated risk of developing caries and who already use fluoride toothpaste.
We found a significant reduction in the incidence of caries when we analyzed the treatment effect in subgroups stratified according to baseline D2FS. Those with D2FS scores higher than 20 experienced a reduction of 20 percent, whereas those with D2FS scores of 20 or lower showed essentially no reduction. However, this reduction was not statistically significant when we included the UTHSCSA participants in the analysis. When we explored this relationship further by stratifying participants according to their baseline D2 counts, we observed no similar trend toward increased effectiveness in those with any cavitated lesions at baseline versus those with none. Thus, at two sites, participants who had more filled surfaces seemingly had a greater reduction in caries incidence with the use of xylitol, but those who had active disease did not enjoy any increased effect. We speculate that we observed this contradictory effect because, in this group of participants who had received recent dental care, D2FS may have been a better reflection of recent caries activity than was the presence of cavitated lesions.
We observed no apparent xylitol dose-response effect nor any effect associated with adherence in the placebo group. In the placebo group, the extra salivary stimulation resulting from consumption of more lozenges apparently was insufficient to affect caries incidence. Similarly, exposure to increasing amounts of xylitol also had no additive effect on caries incidence. The trial protocol may have specified a daily dose that is below an as-yet-undetermined threshold of daily consumption for effectiveness.
At the time we designed the study, the typical daily dose in reported studies was between 3 and 5 g per day; the range was 0.7 to 7.0 g per day.
We chose the high side of the typical dose to ensure that the trial would provide an effective dose. Furthermore, we recommended five one-lozenge doses to minimize underdosing if a participant missed one dose. In 2009, investigators suggested a threshold dose of 5 to 6 g daily.
However, because the most adherent participants in our study were consuming xylitol near or at this threshold, some effect might be expected. Another explanation might be that frequency of exposure is more important than is the total dose. Because even moderately adherent participants likely would experience the three daily exposures suggested in 2009,
exposure response would be difficult to detect. In any event, dosage protocols requiring more than 5 g daily, near-perfect adherence or both may well mean that benefits experienced in practice will not approach the optimum benefit possible.
Future trials of caries-prevention interventions in adults can benefit from the experiences in this trial. We included only adults at an elevated risk of developing caries, defined for this study as having or recently having had a cavitated lesion. However, the presence of one lesion may not necessarily indicate a person truly at high risk. Thus, trial investigators seeking to assess effectiveness in high-risk populations may need to establish a longitudinal assessment of caries activity. In addition, recruitment of participants from dental clinic populations may mask subtle treatment effects owing to extensive restorative activity that may not be caries related. Our trial had excellent participant retention, possibly because of our use both of a run-in period and of frequent contacts from study coordinators, who deliberately sought to establish continuing relationships with participants. We observed adherence that was higher than what we had expected given the length of the trial and the need for daily action. Again, we attribute this to preselecting adherent participants and establishing close personal relationships with them.
The results of this trial may not apply to younger populations, in which almost all of the previous research on xylitol as a caries-preventive agent has been conducted. Nevertheless, the lack of a statistically significant effect in this adult population at an elevated risk of experiencing caries should serve to temper overoptimistic expectations that xylitol lozenges used as a supplement in patients or the public at large with access to fluoride will substantially reduce their caries experience.
CONCLUSION
Daily use of xylitol lozenges did not result in a statistically or clinically significant reduction in 33-month caries increment among adults at an elevated risk of developing caries.
References
Thomson WM
Dental caries experience in older people over time: what can the large cohort studies tell us?.
Xylitol-based caries prevention: is there enough evidence for the existence of a specific xylitol effect? (Comment on Scheie AA, Fejerskov OB. Xylitol in caries prevention: what is the evidence for clinical efficacy? Oral Dis 1998;4(4):268–278).
American Dental Association Council on Scientific Affairs Expert Panel on Nonfluoride Caries-Preventive Agents. Nonfluoride caries-preventive agents: executive summary of evidence-based clinical recommendations.
International Caries Detection and Assessment System Coordinating Committee. Criteria Manual: International Caries Detection and Assessment System (ICDAS II). Report of a workshop held in Baltimore Md., March 12–14, 2005
Disclosure. None of the authors reported any disclosures.
The authors thank the Xylitol Adult Caries Trial (X-ACT) Data Safety and Monitoring Board. They extend special thanks to the X-ACT participants and to Dr. Christina Gullion.
In addition to the authors of this article, the Xylitol Adult Caries Trial collaborative research group consists of the following people: Jan Carlton Holland, RDH, MS, and Debbie S. Robinson, CDA, MS, from the University of North Carolina, Chapel Hill; Mona Z. Anabtawi, DDS, MS, from the University of Alabama, Birmingham; Anna Theresa Vega, RDA, Bithiah Radcliffe and Belinda Vitolas, RDA, from the University of Texas Health Science Center at San Antonio; Donna J. Eubanks, BSCS, Kelly Kirk, Chuhe Chen, PhD, Deborah Reck, Jeanette Bardsley, BA, Arthur R. Dixon, MSTM, and Elizabeth J. Esterberg, MS, from the Coordinating Center, Kaiser Permanente Center for Health Research, Portland, Ore.; and Jane C. Atkinson, DDS, from the Project Office, National Institute for Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md.
The research described in this article was supported by the following grants from the National Institute of Dental and Craniofacial Research: U01DE018038 (Xylitol Adult Caries Trial [X-ACT] Study Chair), U01DE018047 (Xylitol Adult Caries Trial [X-ACT] Data Coordinating Center), U01DE018048 (Xylitol Adult Caries Trial [X-ACT] UNC Clinical Center), U01DE018049 (Xylitol Adult Caries Trial [X-ACT] UAB Clinical Center) and U01DE018050 (Xylitol Adult Caries Trial [X-ACT] UTHSC San Antonio Clinical Center). The authors receiving grants were Drs. Bader, Vollmer, Shugars, Gilbert and Amaechi.
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