nhs r&d hta programme...healozone in addition to current management of dental caries. results:...

Health Technology Assessm

ent 2006;Vol. 10: No. 16

HealO

zone®

for the treatment of occlusal pit/fissure caries and root caries

Systematic review of the effectivenessand cost-effectiveness of HealOzone®

for the treatment of occlusal pit/fissurecaries and root caries

M Brazzelli, L McKenzie, S Fielding, C Fraser, J Clarkson, M Kilonzo and N Waugh

Health Technology Assessment 2006; Vol. 10: No. 16

HTAHealth Technology AssessmentNHS R&D HTA Programme

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M Brazzelli,1* L McKenzie,2 S Fielding,3 C Fraser,1

J Clarkson,4 M Kilonzo2 and N Waugh3

1 Health Services Research Unit, Institute of Applied Health Sciences,University of Aberdeen, UK

2 Health Economics Research Unit, Institute of Applied Health Sciences,University of Aberdeen, UK

3 Department of Public Health, Institute of Applied Health Sciences,University of Aberdeen, UK

4 Dental Health Services Research Unit, MacKenzie Building, Dundee, UK

* Corresponding author. Current affiliation: Department of Clinical Neurosciences,University of Edinburgh, Western General Hospital, UK

Declared competing interests of authors: none

Published May 2006

This report should be referenced as follows:

Brazzelli M, McKenzie L, Fielding S, Fraser C, Clarkson J, Kilonzo M, et al. Systematicreview of the effectiveness and cost-effectiveness of HealOzone® for the treatment ofocclusal pit/fissure caries and root caries. Health Technol Assess 2006;10(16).

Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE,Excerpta Medica/EMBASE and Science Citation Index Expanded (SciSearch®) and Current Contents®/Clinical Medicine.

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ISSN 1366-5278

© Queen’s Printer and Controller of HMSO 2006

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Published by Gray Publishing, Tunbridge Wells, Kent, on behalf of NCCHTA.Printed on acid-free paper in the UK by St Edmundsbury Press Ltd, Bury St Edmunds, Suffolk. T

Objectives: To assess the effectiveness and cost-effectiveness of HealOzone® (CurOzone USA Inc.,Ontario, Canada) for the management of pit and fissurecaries, and root caries. The complete HealOzoneprocedure involves the direct application of ozone gasto the caries lesion on the tooth surface, the use of aremineralising solution immediately after application ofozone and the supply of a ‘patient kit’, which consistsof toothpaste, oral rinse and oral spray all containingfluoride. Data sources: Electronic databases up to May 2004(except Conference Papers Index, which weresearched up to May 2002). Review methods: A systematic review of theeffectiveness of HealOzone for the management oftooth decay was carried out. A systematic review ofexisting economic evaluations of ozone for dental carieswas also planned but no suitable studies wereidentified. The economic evaluation included in theindustry submission was critically appraised andsummarised. A Markov model was constructed toexplore possible cost-effectiveness aspects ofHealOzone in addition to current management ofdental caries.Results: Five full-text reports and five studiespublished as abstracts met the inclusion criteria. Thefive full-text reports consisted of two randomisedcontrolled trials (RCTs) assessing the use of HealOzonefor the management of primary root caries and twodoctoral theses of three unpublished randomised trialsassessing the use of HealOzone for the management ofocclusal caries. Of the abstracts, four assessed theeffects of HealOzone for the management of occlusal

caries and one the effects of HealOzone for themanagement of root caries. Overall, the quality of thestudies was modest, with many importantmethodological aspects not reported (e.g. concealmentof allocation, blinding procedures, compliance ofpatients with home treatment). In particular, therewere some concerns about the choice of statisticalanalyses. In most of the full-text studies analyses wereundertaken at lesion level, ignoring the clustering oflesions within patients. The nature of themethodological concerns was sufficient to raise doubtsabout the validity of the included studies’ findings. A quantitative synthesis of results was deemedinappropriate. On the whole, there is not enoughevidence from published RCTs on which to judge theeffectiveness of ozone for the management of bothocclusal and root caries. The perspective adopted forthe study was that of the NHS and Personal SocialServices. The analysis, carried out over a 5-year period, indicated that treatment using currentmanagement plus HealOzone cost more than currentmanagement alone for non-cavitated pit and fissurecaries (£40.49 versus £24.78), but cost less for non-cavitated root caries (£14.63 versus £21.45). Given the limitations of the calculations these figures shouldbe regarded as illustrative, not definitive. It was notpossible to measure health benefits in terms of quality-adjusted life-years, due to uncertainties aroundthe evidence of clinical effectiveness, and to the factthat the adverse events avoided are transient (e.g. painfrom injection of local anaesthetic, fear of the drill).One-way sensitivity analysis was applied to the model.However, owing to the limitations of the economic


iii

© Queen’s Printer and Controller of HMSO 2006. All rights reserved.

Abstract

Systematic review of the effectiveness and cost-effectiveness ofHealOzone® for the treatment of occlusal pit/fissure caries androot caries

M Brazzelli,1* L McKenzie,2 S Fielding,3 C Fraser,1 J Clarkson,4 M Kilonzo2

and N Waugh3

1 Health Services Research Unit, Institute of Applied Health Sciences, University of Aberdeen, UK2 Health Economics Research Unit, Institute of Applied Health Sciences, University of Aberdeen, UK3 Department of Public Health, Institute of Applied Health Sciences, University of Aberdeen, UK4 Dental Health Services Research Unit, MacKenzie Building, Dundee, UK* Corresponding author. Current affiliation: Department of Clinical Neurosciences, University of Edinburgh,

Western General Hospital, UK

analysis, this should be regarded as merely speculative.For non-cavitated pit and fissure caries, the HealOzoneoption was always more expensive than currentmanagement when the probability of cure using theHealOzone option was 70% or lower. For non-cavitated root caries the costs of the HealOzonecomparator were lower than those of currentmanagement only when cure rates from HealOzonewere at least 80%. The costs of current managementwere higher than those of the HealOzone option when the cure rate for current management was 40%or lower. One-way sensitivity analysis was alsoperformed using similar NHS Statement of DentalRemuneration codes to those that are used in theindustry submission. This did not alter the results fornon-cavitated pit fissure caries as the discounted net

present value of current management remained lowerthan that of the HealOzone comparator (£22.65 versus £33.39).Conclusions: Any treatment that preserves teeth andavoids fillings is welcome. However, the currentevidence base for HealOzone is insufficient to concludethat it is a cost-effective addition to the managementand treatment of occlusal and root caries. To make adecision on whether HealOzone is a cost-effectivealternative to current preventive methods for themanagement of dental caries, further research into itsclinical effectiveness is required. Independent RCTs ofthe effectiveness and cost-effectiveness of HealOzonefor the management of occlusal caries and root cariesneed to be properly conducted with adequate design,outcome measures and methods for statistical analyses.

Abstract

iv


v

List of abbreviations .................................. vii

Executive summary .................................... ix

1 Aim of the review ...................................... 1

2 Background ................................................ 3Dental caries ............................................... 3Current service provision ........................... 7Description of new intervention ................ 11Key questions .............................................. 12

3 Effectiveness ............................................... 13Methods for reviewing effectiveness .......... 13Results ........................................................ 14Discussion of results and conclusions on the evidence for and against the intervention ................................................ 21

4 Systematic review of economic evaluations ................................................. 23Methods ...................................................... 23Results ........................................................ 23Review of industry submission ................... 24

5 Economic analysis ...................................... 29Methods for economic analysis .................. 29Results ........................................................ 33Discussion ................................................... 36

6 Implications for the NHS .......................... 37National Service Framework ...................... 37Health targets ............................................. 37Fair access ................................................... 37Equity issues ............................................... 37

Budget implications to the NHS ............... 37

7 Discussion ................................................... 41Main results ................................................ 41Need for further research .......................... 41

8 Conclusion .................................................. 43

Acknowledgements .................................... 45

References .................................................. 47

Appendix 1 Literature search strategies ..................................................... 51

Appendix 2 Data extraction form ............. 55

Appendix 3 Checklist for the qualityassessment of randomised controlled trials ............................................................ 59

Appendix 4 Characteristics of included studies: full-text reports ............................. 61

Appendix 5 Characteristics of included studies: abstracts ......................................... 71

Appendix 6 Structure of the economic model ......................................................... 75

Health Technology Assessment reportspublished to date ....................................... 81

Health Technology Assessment Programme ................................................ 93

Contents

ANOVA analysis of variance

CDC Centers for Disease Control andPrevention

CI confidence interval

DFS decayed and filled surfaces

DMFS decayed, missing and filledsurfaces

DMFT decayed, missing and filledteeth

ECM electrical conductancemeasurement

FDA Food and Drug Administration

GDS General Dental Services

IADR International Association forDental Research

ITT intention-to-treat

NCHS National Centre for HealthStatistics

NHANES III USA National Health andNutrition Examination Survey

NHS EED NHS Economic EvaluationDatabase

NICE National Institute for Healthand Clinical Excellence

NPV net present value

ns not significant

NS not stated

ORCA European Organisation forCaries Research

PRCL primary root carious lesion

QALY quality-adjusted life-years

QLF quantitative light-inducedfluorescence

QOTI/FOTI quantitative fibre-optictransillumination

RCT randomised controlled trial

SD standard deviation

SDR NHS Statement of DentalRemuneration

TACT tuned aperture computedtomography

UCD ultrasound caries detector

USPHS US Public Health Servicecriteria


vii


List of abbreviations

All abbreviations that have been used in this report are listed here unless the abbreviation is well known (e.g. NHS), or it has been used only once, or it is a non-standard abbreviation used only in figures/tables/appendices in which case the abbreviation is defined in the figure legend or at the end of the table.


ix


BackgroundDental caries is a chronic disease caused by thelocalised and progressive demineralisation of thehard tissues of the coronal and root surfaces of theteeth. Caries location, development andprogression depend on a range of environmental,social and genetic factors, and vary greatly amongindividuals.

Despite the decline in the prevalence of dentalcaries observed in the high-income countriesduring the past few decades as a consequence ofthe increased availability of fluoride products andimproved oral hygiene, dental caries is still acommon disease experienced by almost 80% ofchildren by the age of 18 years and by almost 90%of adults.

The current management of early non-cavitatedocclusal and root caries, and cavitated root caries,which are still accessible to cleaning, is based onnon-operative preventive strategies that includeinformation on oral hygiene, dietary advice, use oftopically applied fluorides and application ofsealants. For cavitated occlusal caries and cavitatedroot caries that are not easily accessible tocleaning, restorative interventions are adopted(drilling and filling).

HealOzone® (CurOzone USA Inc., Ontario,Canada) has recently been proposed as a novelmethod for the treatment of dental caries. It issuggested that HealOzone may reverse, arrest orslow the progression of dental caries. Thecomplete HealOzone procedure involves the directapplication of ozone gas to the caries lesion on thetooth surface, the use of a remineralising solutionimmediately after application of ozone and thesupply of a ‘patient kit’, which consists oftoothpaste, oral rinse and oral spray all containingfluoride.

ObjectiveThe review aims to assess the effectiveness and cost-effectiveness of HealOzone for the management ofpit and fissure caries, and root caries.

MethodsElectronic searches were conducted to identifypublished and unpublished studies. The followingdatabases were searched: MEDLINE (1966 to May 2004), EMBASE (1980 to May 2004),MEDLINE Extra (17 May 2004), Science CitationIndex (1981 to May 2004), BIOSIS (1985 to May 2004), AMED (1985 to May 2004), CochraneLibrary (Issue 2, 2004) National Research Register(Issue 2, 2004), Current Controlled Trials (18 May2004), Clinical Trials (18 May 2004), SCIProceedings (1991 to May 2004), ConferencePapers Index (1982 to May 2002), ZETOCconferences (1993 to May 2004) and IADRmeeting abstracts (2002 to 2004). Two reviewersindependently assessed the methodological qualityof included studies and extracted data. Criteria forassessment of study quality included method andunit of randomisation, concealment of allocation,comparability of groups at baseline, blindingprocedures, number of withdrawals/dropouts andcompleteness of assessment at follow-up.

A systematic review of the effectiveness ofHealOzone for the management of tooth decaywas carried out. A systematic review of existingeconomic evaluations of ozone for dental carieswas also planned but no suitable studies wereidentified. The economic evaluation included inthe industry submission was critically appraisedand summarised.

A Markov model was constructed to explorepossible cost-effectiveness aspects of HealOzone inaddition to current management of dental caries.

ResultsNumber and quality of studies, anddirection of evidenceFive full-text reports and five studies published asabstracts met the inclusion criteria. Of these, onlyone was published in a refereed journal, but itlacked some study details. The remaining studieswere PhD theses, unpublished reports orconference proceedings. The five full-text reportsconsisted of two randomised controlled trials

Executive summary

x

(RCTs) assessing the use of HealOzone for themanagement of primary root caries and two PhDtheses of three unpublished randomised trialsassessing the use of HealOzone for themanagement of occlusal caries. Of the five studiespublished as abstracts, four assessed the effects ofHealOzone for the management of occlusal cariesand one the effects of HealOzone for themanagement of root caries.

Overall, the quality of the studies was modest, withmany important methodological aspects notreported (e.g. concealment of allocation, blindingprocedures, compliance of patients with hometreatment). In particular, there were someconcerns about the choice of statistical analyses. Inmost of the full-text studies analyses wereundertaken at lesion level, ignoring the clusteringof lesions within patients. The nature of themethodological concerns was sufficient to raisedoubts about the validity of the included studies’findings. A quantitative synthesis of results wasdeemed inappropriate.

Summary of benefitsRoot cariesTwo studies (one published and one unpublished)assessing the use of HealOzone for themanagement of primary non-cavitated root cariesreported high success rates for ozone-treatedlesions and no significant changes in the controllesions, despite application of topical fluoride.This is puzzling, since topical fluoride is known tobe effective. Results of cavitated root lesions werepoorly defined and reported in one of these twostudies. Cavitated lesions did not seem to benefitfrom ozone application.

One unpublished study showed that fissuresealants preceded by the application of ozone forthe preventive treatment of non-cavitated rootlesions were more likely to remain intact (61%versus 42%, p < 0.05).

Pit and fissure cariesOne unpublished study did not show anysignificant benefits of HealOzone for themanagement of non-cavitated pit and fissurelesions in the permanent dentition. Similarly, asmall unpublished pilot study did not show anysignificant differences between cavitated occlusallesions treated with or without ozone, apart froman improvement in the hardness and visual clinicalindices. In contrast, findings from conferenceproceedings (which provide little detail for theassessment of their methodological quality andtherefore are of little use in systematic reviews)

reported very high success rates (from 86.6% to99% of reversal of caries).

Adding ozone to a fissure sealant did not seem toproduce better sealant retention in occlusal lesionsextending 2–4 mm into dentine.

Data on the use of HealOzone for the treatment ofocclusal lesion in the deciduous dentition wereavailable from only one unpublished study. Anoverall reduction in clinical severity scores wasreported for non-cavitated occlusal lesions inprimary molars treated with ozone.

On the whole, there is not enough evidence frompublished RCTs on which to judge theeffectiveness of ozone for the management of bothocclusal and root caries.

CostsThe perspective adopted for the study was that ofthe NHS and Personal Social Services. Theanalysis, carried out over a 5-year period, indicatedthat treatment using current management plusHealOzone cost more than current managementalone for non-cavitated pit and fissure caries(£40.49 versus £24.78), but cost less for non-cavitated root caries (£14.63 versus £21.45). Giventhe limitations of the calculations these figuresshould be regarded as illustrative, not definitive.

Cost per quality-adjusted life-yearIt was not possible to measure health benefits interms of quality-adjusted life-years. This wasmainly due to uncertainties around the evidenceof clinical effectiveness, and to the fact that theadverse events avoided are transient (e.g. painfrom injection of local anaesthetic, fear the drill).

Sensitivity analysesOne-way sensitivity analysis was applied to themodel. However, owing to the limitations of theeconomic analysis, this should be regarded asmerely speculative. For non-cavitated pit andfissure caries, the HealOzone option was alwaysmore expensive than current management whenthe probability of cure using the HealOzone optionwas 70% or lower. For non-cavitated root caries thecosts of the HealOzone comparator were lowerthan those of current management only when curerates from HealOzone were at least 80%. The costsof current management were higher than those ofthe HealOzone option when the cure rate forcurrent management was 40% or lower.

One-way sensitivity analysis was also performedusing similar NHS Statement of Dental

Executive summary

Remuneration codes to those that are used in theindustry submission. This did not alter the resultsfor non-cavitated pit fissure caries as thediscounted net present value of currentmanagement remained lower than that of theHealOzone comparator (£22.65 versus £33.39).

ConclusionsAny treatment that preserves teeth and avoidsfillings is welcome. However, the current evidencebase for HealOzone is insufficient to conclude thatit is a cost-effective addition to the managementand treatment of occlusal and root caries.

Limitations of the calculationsThe economic analysis was severely constrained bythe uncertainty over clinical effectiveness, and itcould be argued that such analysis was

inappropriate. It was done merely to illustrate thekey factors involved in economic modelling. Thelong-term effects of HealOzone are unknown andthe assumption that reversed caries remainsinactive may not be reliable.

Recommendations for researchTo make a decision on whether HealOzone is acost-effective alternative to current preventivemethods for the management of dental caries,further research into its clinical effectiveness isrequired. Independent RCTs of the effectivenessand cost-effectiveness of HealOzone for themanagement of occlusal caries and root cariesneed to be properly conducted with adequatedesign, outcome measures and methods forstatistical analyses.


xi


The review aims to assess the effectiveness andcost-effectiveness of HealOzone® (CurOzone

USA Inc., Ontario, Canada) for the managementof both pit and fissure caries, and root caries.


1


Chapter 1

Aim of the review

Dental cariesAetiology, pathology and prognosisDental caries (tooth decay) is a chronic diseasecaused by the localised and progressivedemineralisation of the hard tissues of the coronaland root surfaces of the teeth. Thedemineralisation is caused by the interaction ofacid-producing oral microorganisms (in particularStreptococcus mutans, Lactobacillus and Actinomycesspecies) with dietary carbohydrates (sugar).

Caries occurs when the natural dynamic balancebetween mineralisation and demineralisation ofdental tissues is disrupted. The process begins onthe surface of the enamel (outer surface of thetooth; see Figure 1). In enamel caries, the lesionmay reverse or arrest by remineralisation. Ifremineralisation does not occur, the lesion maypenetrate the enamel and consequently result inthe formation of a cavity, which may progressthrough the dentine and the pulp of the tooth. Inthe absence of treatment, dental caries mayultimately destroy the tooth. Caries location,development and progression are influenced by arange of environmental, social and genetic factors,and vary greatly among individuals. In mostindividuals dental caries tend to progress slowlyover time, with lesions often taking more than2 years to cavitate, although in some it can take ashorter time. Conversely, some lesions nevercavitate.

According to the anatomical location of cariouslesions, it is possible to differentiate betweencoronal lesions, which may affect the pits andfissures or the smooth surfaces of a tooth, and rootlesions, which affect the exposed root cementumand dentine. Root caries occurs in the samemanner as coronal caries, but demineralisationbegins at a higher pH and it is more common inolder people. The term primary caries is used toindicate lesions on the unrestored surfaces ofteeth, while caries that develops adjacent to afilling is referred to as recurrent or secondarycaries. Hidden caries is a term used to identifycarious lesions in the dentine that are not detectedby visual examination but are large enough to beidentified radiographically. According to theiractivity, carious lesions may be classified as active

or inactive/arrested. A lesion that is considered tobe progressive is described as active, whereas alesion that has stopped further progression isdescribed as arrested. This distinction is clinicallyimportant as arrested lesions do not require anyfurther preventive interventions.

The occlusal surfaces (pits and fissures) of teethare particularly susceptible to dental caries owingto their morphological structure (minutedimensions of pits and fissures) and becausemicrobial plaque is more likely to grow in theseareas (plaque stagnation). The teeth are moreprone to plaque stagnation during eruption.Occlusal caries is seen more often in molar teeththan in premolar or anterior teeth.

The incidence of root caries begins at about30–40 years of age and tends to increasethereafter. Root caries is most prevalent in theelderly because when people get older and retaintheir natural teeth, their gums tend to recede andexpose the root surfaces. According to thepublished NHS Plan for Modernising NHS


3


Chapter 2

Background

Cro

wn

Nec

kRo

ot

Enamel

Gum (gingiva)

Bone

Periodontalmembrane

Cementum

Root canal

Opening at tip of root

Dentine

Pulp containingblood vesselsand nerves

FIGURE 1 Structure of a sound tooth. Reproduced withpermission from www.mydr.com.au. Copyright CMPMedicaAustralia 2005.

Dentistry, “nearly 90% of people aged over65 years show some signs of gum diseasecompared with 14% of 16–24 year olds”.1

Significance in terms of ill-healthImpact on patient’s quality of lifeDental caries may have a significant impact on anindividual’s life. The most common consequencesof untreated lesions are discomfort and pain.Restorative dental treatments can now be providedpain free, apart from the pain of the localanaesthetic injection. However, for some peoplerestorative treatments are associated with fear andanxiety, which, may become barriers to dentalattendance. Treatment avoidance can subsequentlylead to further progression of caries which, inturn, may cause more distress and long-termcomplications. Gross decay may lead todisturbances in eating and sleeping patternsbecause of pain. Psychological distress can arisefrom the embarrassment and self-consciousness ofhaving missing or decayed teeth, especially in theanterior dentition. Communication problems mayultimately occur as a possible result of tooth loss.

In addition to human cost, dental caries can becostly for the patients receiving treatment. Formany patients NHS charges can be expensive,especially for those who earn just enough todisqualify them from exemption or remission ofcharges. Moreover, where provision of NHSdentistry is patchy, patients may have to dependon private dental care.

Impact on the NHSTreatments for dental care carry considerable costsfor both the NHS and society. NHS GeneralDental Services (GDS) data reveal that the totalnumber of claims in England and Wales for dentalinterventions in the financial year 2002/03 was 34million. Almost half (48%) of claims were fortreatments requiring no dental intervention (i.e.examination, simple scaling, X-ray, fissure sealant,topical fluoride). The total number of teeth filledwas about 19 million, while the number of teethwith roots filled was just over one million. Overall,the total gross fees authorised was £1634 million.The care and treatment for children accounted for27% (£461 million) of all gross fees authorised.

EpidemiologyThere has been a significant reduction in dentalcaries since the 1970s in industrialised countries,due to environmental and educational factors suchas the increased use of fluoride in public watersupplies, dentifrices and dental products;improved oral hygiene and prophylaxis; dietary

counselling; and increased access to dental care.Nevertheless, dental caries is still a commondisease, experienced by almost 80% of children bythe age of 18 and by almost 90% of adults.2

Prevalence in childrenSince the significant decline in the 1970s and1980s, it seems that over the past 20 years cariesprevalence rates have become relatively stable.2

The 2003 Children’s Dental Health Surveycommissioned by the UK Health Departmentsprovides the most recent estimate of theprevalence of dentine decay in children inEngland and Wales.3 The 2003 survey is the fourthin a series of dental health surveys carried outevery 10 years since 1973. The criteria used in thesurvey to assess dental caries were the following:

� filled decay, otherwise sound: teeth withamalgam, or other fillings that had no cavitateddentine caries present

� obvious decay experience: all teeth withcavitated dentine caries, restorations withcavitated dentine caries, teeth with filled decay(otherwise sound) and teeth extracted due tocaries. The term relates to the DMFT (decayed,missing, and filled teeth) dental decay index.

The preliminary findings of this survey indicatethat:

� there has not been a substantial change in theproportion of 5- and 8-year-olds who presentedwith obvious decay in the primary (milk) teethbetween the 1993 and 2003 dental survey(Table 1)

� the proportion of filled primary teeth as well asthe proportion of the total obvious decayexperience represented by filled primary teethin 5- and 8-year-olds has declined since 1983,indicating a decline in restorative interventions(Table 1)

� the mean number of primary teeth with obviousdecay has decreased since 1983 in 5- and 8-year-olds (Table 2), but the mean number ofprimary teeth with obvious decay amongchildren with decay has not changedconsiderably since 1993, apart from the declinein the number of filled teeth in the 8-year-olds(Table 3)

� the proportion of 8-, 12- and 15-year-olds withobvious tooth decay and cavities into dentine inpermanent teeth has decreased considerablysince 1983 (Figures 2 and 3)

� the proportion of filled permanent teeth hasdeclined considerably since 1983 in 12- and 15-year-olds, but not in 8-year-olds (Figure 4)

Background

4

� the proportion of the total obvious decayexperience represented by the number of filledpermanent teeth in 8-, 12- and 15-year-olds hasincreased since 1993, indicating an increase inrestorative interventions (Table 4).

These findings are consistent with those found bythe USA Third National Health and NutritionExamination Survey (NHANES III), Centers forDisease Control and Prevention (CDC), NationalCentre for Health Statistics (NCHS)4 and theNational Survey of Dental Caries in US SchoolChildren 1986–1987, where 52% of children aged6–8 years and 61% of children aged 15 years

presented with tooth decay in permanent orprimary teeth. The proportion of children withuntreated caries in permanent or primary teethwas 29% for the 6–8-year-olds and 20% for the 15-year-olds (Figure 5).

Dental caries is not evenly distributed across thechild population, with about 26% of children (worstcases) presenting with 75% of all carious lesions.6

This can be interpreted in the light of the fact thatdental caries is a disease of lifestyle with strongsocio-economic and geographical differences. Theuse of deprivation categories in the assessment ofScottish schoolchildren aged 5 years is a goodexample of how measures of socio-economic statusmay correlate with dental caries experience(Figure 6).5 The link between social status andprevalence of caries is also supported by the datafrom the National Children’s Dental Health Surveycarried out in the UK in 1993 (Figure 7).7

Prevalence in adultsFewer prevalence data are available for adults.


5


TABLE 1 Percentage of children with obvious tooth decay inprimary teeth by age (Children’s Dental Health in the UnitedKingdom, 2003)3

Year

Tooth condition 1983 1993 2003

Percentage of children:Obvious decay experience

5-year-olds 50 45 438-year-olds 70 61 57

Teeth with cavities into dentine5-year-olds 41 40 408-year-olds 49 50 50

Filled decay (otherwise sound)5-year-olds 23 15 128-year-olds 47 33 26

Filled teeth as a proportion of total obvious decayexperience

5-year-olds 28 17 158-year-olds 50 35 28

TABLE 2 Mean number of primary teeth with obvious toothdecay by age (Children’s Dental Health in the United Kingdom,2003)3

Year


Mean number of teethTeeth with cavities into dentine

5-year-olds 1.3 1.4 1.48-year-olds 1.2 1.3 1.3

Filled decay (otherwise sound)5-year-olds 0.5 0.3 0.28-year-olds 1.2 0.7 0.5

Obvious decay experience5-year-olds 1.8 1.7 1.68-year-olds 2.3 2.0 1.8

TABLE 3 Mean number of primary teeth with obvious toothdecay in children with obvious decay experience by age(Children’s Dental Health in the United Kingdom, 2003)3

Year

Tooth condition 1993 2003

Mean number of teethTeeth with cavities into dentine

5-year-olds 3.1 3.28-year-olds 2.1 2.3

Filled decay (otherwise sound)5-year-olds 0.6 0.68-year-olds 1.1 0.9

Obvious decay experience5-year-olds 3.7 3.88-year-olds 3.2 3.2

TABLE 4 Proportion of children with obvious tooth decay inpermanent teeth by age (Children’s Dental Health in the UnitedKingdom, 2003)3

Year


Percentage of children:Filled teeth as a proportion of total obvious decayexperience

8-year-olds 58 37 5212-year-olds 70 58 7015-year-olds 74 68 77

Background

6

0

1020

3040

50

6070

8090

100

%

Age (years)

1983

1993

2003

8 12 15

FIGURE 2 Proportion of children with obvious decay experience in permanent teeth by age (Children’s Dental Health in the UnitedKingdom, 2003)3

0

5

10

15

20

25

30

35

40

45

%

Age (years)

1983

1993

2003

8 12 15

FIGURE 3 Proportion of children with cavities into dentine in permanent teeth by age (Children’s Dental Health in the UnitedKingdom, 2003)3

0

10

20

30

40

50

60

70

80

90

%

Age (years)

1983

1993

2003

8 12 15

FIGURE 4 Proportion of children with filled permanent teeth by age (Children’s Dental Health in the United Kingdom, 2003)3

According to the UK 1998 Adult Dental HealthSurvey,8 adults had an average of 1.5 decayed orunsound teeth (teeth with visual or cavitated cariesor those with an unsound restoration) and 55%had at least one decayed or unsound tooth. Thenumbers of adults with decayed or unsound teethvaried according to the regions surveyed. Theproportion of dentate adults with tooth decay inEngland, Wales, Scotland and Northern Ireland isshown in Figure 8.

The mean proportion of filled permanent teethranged from 9% for people aged 16–24 years to39% for people aged 45–54 years (Figure 9).

Overall, 66% of the adult population showed atleast one tooth with a root surface that wasexposed, worn, decayed or filled. Overall, root

surface fillings were found in 43% of people aged65 and older.

Similarly, in the USA, NHANES III – Phase 1found evidence of coronal carious lesions in 94%of the studied population. The mean score fordecayed and filled surfaces (DFS) on permanentteeth in adults was 22.2. Carious lesions werefound in 23% of all dentate adults and in 47% ofpeople aged 65 years and over (NHANES III1998–1991).4

Current service provisionCurrent management of dental cariesIncreasing emphasis has been recently dedicatedto the provision of caries prevention and


7


0

10

20

30

40

50

60

70

%

Age (years)6–8 15

Tooth decayUntreated caries

FIGURE 5 Proportion of children with tooth decay and untreated caries by age (NHANES III)4

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

1 2 3 4 5 6 7

Deprivation categories

Num

ber

of D

MFT

FIGURE 6 Caries distribution by socio-economic ‘deprivation categories’ (DEPCAT) in Scottish schoolchildren aged 5 years.5 DEPCAT 1= most affluent postcode sections. DECAT 7 = most deprived postcode sectors.

Background

8

0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

12Age (years)

15

I, II, III non-manualIII manualIV, V

Num

ber

of D

MFT

FIGURE 7 Average number of decayed, missing or filled teeth in adolescents in the UK by social class (National Children’s DentalHealth Survey, 1993)7

0

10

20

30

40

50

60

%

England Wales Scotland NorthernIreland

FIGURE 8 Proportion of adults with decaying or unsound teeth by country (United Kingdom Adult Dental Health Survey, 1998)8

05

1015

2025

3035

40

%

16–24 25–34 35–44 45–54 55–64 �65 All

Age (years)

FIGURE 9 Mean proportion of filled teeth by age (United Kingdom Adult Dental Health Survey, 1998)8

management strategies. In particular, attention torisk assessment and to preventive non-operativemethods for assisting remineralisation of earlycaries has been advocated. Despite theacknowledged importance for the prevention ofcaries, non-operative, preventive treatments arenot fully funded by the NHS at present. Changesare likely to be introduced with theimplementation of the new contract in 2006.

Efficient management of dental caries depends onthe knowledge of patients’ dental and medicalhistory and risk assessment, correct identificationof carious lesions and identification of the besttreatment options for dental caries. A thoroughdental and medical history provides informationabout patients’ previous experience of dentalcaries, number of active lesions and factors thatmay affect caries activity (e.g. general oralhygiene, diet and sugar intake, exposure tofluoride, salivary flow rate, certain medicalconditions and medications). Caries riskassessment aims at identifying high-riskindividuals who may benefit more from preventivetreatments, and low-risk individuals for whomrestorative treatments could be delayed. Cariouslesions are first identified on the basis of thefindings of the clinical examination (visualcriteria). For visual detection of occlusal caries andfor predicting their activity and severity, theranked scoring system described by Ekstrand andcolleagues9 is recognised as a valid and reliabletool, although mainly used in clinical research. Forassessing the extent and severity of root caries thetactile criteria of ‘soft, leathery and hard’ onprobing are commonly used in dental practice anddental research. Radiographic investigations (X-rays) have been widely used for decades as anadjunct to clinical examination to estimate thedepth of occlusal lesions into dentine or toidentify lesions that are hidden from clinicalexamination. More recently, other quantitative,more advanced methods have been proposed forthe diagnosis of dental caries. These includemethods based on:

� digital radiology [e.g. digital imageenhancement, digital subtraction radiography,tuned aperture computed tomography (TACT)]

� visible light [e.g. quantitative fibre-optictransillumination (QOTI/FOTI), quantitativelight-induced fluorescence (QLF)]

� laser fluorescence (e.g. DIAGNOdent)� electrical current [e.g. electrical conductance

measurement (ECM)]� ultrasound [e.g. ultrasound caries detector

(UCD)].

However, with the exception of digital radiology,these diagnostic procedures are not widely used indental practice. Some procedures need furtherinvestigation (e.g. QOTI/FOTI, QLF) or furtherdevelopment (e.g. UCD) before their use could berecommended in dental practice. Others areprone to false-positive measurements (e.g. smallamount of plaque identified as a carious lesion byDIAGNOdent) or unreliable findings (e.g. becauseof inadequate tooth isolation during ECM),10

which require a careful interpretation andsometimes correction by the dentist. In particular,to the authors’ knowledge the validity ofDIAGNOdent as an instrument for detectingocclusal caries has yet to be demonstrated in invivo studies.

Treatment of early caries (non-cavitated pit andfissure caries and root caries)Treatment options for early caries include thefollowing:

� provision of information about oral hygiene� dietary assessment and advice� fluoride-delivery methods� application of chlorhexidine� pit and fissure sealants� recall at regular intervals.

Oral hygieneInstructions on oral hygiene aim at improvingpersonal removal of plaque by toothbrushing.Regular toothbrushing in children may help toreduce the incidence of caries,11 and childrenwhose level of oral hygiene is good experience lessdecay.12 Despite the lack of evidence on theeffectiveness of oral hygiene instructions,13

toothbrushing, together with the use of fluoridetoothpaste and the advice of reducing sugar intake,is usually recommended in the dental practice formaintaining a good level of oral hygiene.

Dietary assessment and adviceEvidence from epidemiological and experimentalstudies indicates that frequent consumption offermentable carbohydrates is associated withprevalence of dental caries. For some patients thefrequency of intake of a certain type of food mayprimarily contribute to their caries risk andmodification of this factor may be sufficient tochange their risk. The diet–caries association is,however, complex and needs to be evaluated notonly on the basis of the quantity and type offermentable carbohydrates consumed, but alsoconsidering several other background factors suchas age, total food intake, dietary habits, salivaryflow rate, use and type of medications, and use of


9


fluoride products. Dietary assessment is usuallyrecommended in patients with multiple activelesions. In contrast, no diet modifications aresuggested for patients with inactive caries. Thedentist, however, may still provide information onhow unhealthy dietary habits may become aproblem, especially when associated with a poorlevel of oral hygiene.14

Fluoride-delivery methodsUse of fluoride-delivery products and waterfluoridation are among the factors that havecontributed to the observed progressiveimprovement in oral health since the 1970s.Evidence indicates that fluoridation of the watersupply is associated with an increased proportionof children without caries and a reduction in thenumber of teeth affected by caries.1,15,16 Topicalfluoride-delivery methods in the form oftoothpastes, mouth rinses, gels or varnishes areeffective measures to prevent dental caries. Theireffectiveness has been established on evidencefrom randomised trials and more recently from aseries of Cochrane systematic reviews ofrandomised trials.17–22 Overall, fluoride toothpasteis the cheapest and the most widespread methodto control dental caries.23–25 A recent randomised,double-blind, clinical trial examined the anticarieseffectiveness of fluoride dentifrices containing1700, 2200 and 2800 ppm fluoride ion comparedwith a 1100 ppm fluoride control toothpaste, inschoolchildren aged 6–15 years.24 The 1-yearresults demonstrated significant caries reductionsfor higher fluoride dentifrices for all toothsurfaces, but in particular for occlusal surfaces.24

The use of fluoride mouth rinses and gels, as anadjunct to fluoride toothpaste, is usually advisedfor individuals at high risk of developing caries.Fluoride varnish is used to provide fluoridedelivery to specific tooth sites and surfaces and isusually applied at intervals of 3 or 6 months. Arecent systematic review by Marinho andcolleagues17 looked at the effectiveness of fluoridevarnish in preventing dental caries in children andadults and commented on the ability of fluoridevarnish to promote remineralisation of earlycaries. The included studies also considered “non-cavitated incipient enamel lesions”, clinicallyvisible as white spots or discoloured fissures, whichwould be included among those lesions eligible forozone application. The treatment effect wasmeasured in terms of ‘prevented fraction’ (meanincrement in caries in controls minus meanincrement in fluoride group divided by the meanincrement in the controls). For the seven studiesthat contributed to the main meta-analysis, thedecayed, missing and filled surfaces (DMFS)

prevented fraction pooled estimate was 0.46 [95%confidence interval (CI) 0.30 to 0.63, p < 0.0001],indicating a substantial benefit and demonstratingthat fluoride varnish alone can result in reversal ofearly caries. Similarly, the meta-analysis of thethree studies assessing the effect of fluoridevarnish on deciduous teeth suggested a 0.33%(95% CI 0.19% to 0.48%, p < 0.0001) reduction inDMFS. Another recent systematic review26 ofselected caries prevention methods reachedsimilar conclusions, demonstrating that there is afair body of evidence on the effectiveness offluoride varnish to arrest or reverse non-cavitatedcarious lesions in permanent teeth. Other fluorideproducts such as fluoride supplements (e.g.fluoride tablets or drops) are regarded as lesseffective methods of delivering fluoride becausethey rely entirely upon patient compliance. Theiruse is usually limited to high-risk categories ofchildren, adults and, particularly, elderly people.27

Application of chlorhexidineThe effectiveness of chlorhexidine as anantimicrobial for preventing progression of non-cavitated caries has yet to be established. Currentevidence is derived mainly from small studiesevaluating the effects of different forms ofchlorhexidine (varnish, gel or rinse) incombination with other concomitant preventivemeasures.26,28

Pit and fissure sealantsPits and fissures are sealed to prevent cariesdevelopment.28 Evidence indicates that caries doesnot progress as long as the sealant remains inplace.29,30 Sealant applications may be suitable forboth young children and older patients.31

Materials that are currently used to seal a lesioninclude different types of composite resin andglass ionomer cement. The resin-based sealantsare divided into generations according to theirmechanism for polymerisation and their content.The first generation sealants which were activatedby ultraviolet light are no longer available and themost recently developed fourth generationsealants contain fluoride. The effectiveness ofresin sealants for the prevention of caries in thepermanent teeth of children and adolescents wasdemonstrated by Ahovuo-Saloranta andcolleagues32 in a recent Cochrane systematicreview. The review compared second, third andfourth generation resin-based sealants or glassionomer sealants with a control (no sealant) andcompared one type of fissure sealant with anothertype. The focus of the review was on prevention,and the children and adolescents included did notseem to present with obvious caries. The review

Background

10

concluded that resin-based sealants are effective inpreventing caries of the occlusal surfaces ofpermanent molars. Reduction of caries rangedfrom 86% at 12 months to 57% at 48–54 months.Resin sealant retention was good across studiesand sealants were retained completely in 79% and92% of cases at 12 months. Sealant retentiondecreased with time and at 36 months rangedfrom 61 to 80%. Evidence on the effects of glassionomer-based sealants was less convincing.

Treatment of cavitated pit and fissure caries androot cariesFor lesions that have progressed to the stage ofcavity, restorative interventions are often used toremove the decayed tissue and fill the cavity to aidplaque control. However, cavitated root lesionsthat are still accessible to cleaning need not alwaysbe filled because cleaning alone can arrest caries.A number of different materials can be used torestore a tooth. These include composite resin,glass ionomer cement and amalgam. Amalgam isstill the material of choice for large restoration ofmolar teeth. Root caries are usually restored withcomposite resin or glass ionomer cement.According to the NHS Dental Review2002–2003,33 in the quarter ending December2002 the number of teeth filled was 4,896,951 andon average one tooth was filled for every twoclaims (55%). Overall, restorations showed amedian survival interval to next restorativeintervention of just over 8 years. The main factorsassociated with different likelihoods of re-intervention were the age of the patient at thedate of restoration, the position of the tooth andthe type/material of restoration.33

Description of new interventionRationaleThe antimicrobial effects of ozone gas (O3) havebeen known for many years. Direct application ofozone gas to the coronal or root tooth surface isclaimed to have a sterilising effect. In particular,ozone is claimed to stop the action of theacidogenic and aciduric micro-organismsresponsible for the tooth decay. It is consequentlyalleged to be able to reverse, arrest or slow downthe progression of dental caries. It is alsomaintained that ozone is useful for reducing themicrobial flora in cavitated lesions, before fillingsare inserted.

Development of HealOzoneThe ozone unit for dental use was initiallydeveloped by CurOzone Inc. (Canada) and

subsequently manufactured under licence anddistributed by KaVo-Dental GmbH & Co.(Germany) under the name ‘HealOzone’. Its usehas been pioneered by Professor Edward Lynchand his team at Queen’s University in Belfast,Northern Ireland, and Barts and the LondonQueen Mary’s School of Medicine and Dentistry in London, UK. HealOzone is a certified Medical Device [Conformité Europèene (CE)marked] for the management of occlusal pit andfissure caries, and root caries. According to themanufacturer, 294 HealOzone units (as at June2004) are currently in use in dental practices inthe UK and more than one million people havealready received HealOzone treatment. TheHealOzone technology has not yet received Foodand Drug Administration (FDA) approval in theUSA.

The new version of HealOzone (Mark3) waslaunched in July 2004. According to themanufacturer previous models can be upgraded tothe most recent technical functions.

HealOzone procedureThe HealOzone procedure consists of a package,which includes the application of ozone gas, theuse of remineralising agents, a patient kit andinformation on oral hygiene. The HealOzonedevice comprises an air filter, a vacuum pump, anozone generator, a handpiece fitted with a sealingsilicone cup and a flexible hose. The silicone cupsare available in a range of five sizes from 3 to8 mm in diameter. The HealOzone unit requireshigh-voltage power to generate ozone from the airand to convert ozone back to oxygen when theprocess is completed. The air is exposed to high-voltage current to generate ozone at aconcentration of 2100 ppm ± 10% and passesthrough the instrument hose and handpiece. Theflow of air into the system, the delivery of ozone tothe tooth and the removal of ozone from thesystem after completion of treatment are achievedby a vacuum pump, which works at an adjustableflow rate of 615 cm3 per minute to maintain theozone concentration at 2100 ppm.

The procedure usually takes between 20 and 120seconds per tooth. Immediately after ozoneapplication the tooth surface is treated with aremineralising solution (reductant) containingfluoride, calcium, zinc, phosphate and xylitoldispensed from a 2-ml ampoule. The reductant issupplied in packs of 100 ampoules. Patients arealso supplied with a patient kit, which consists oftoothpaste, oral rinse and oral spray, allcontaining fluoride, calcium, zinc, phosphate and


11


xylitol, and aims to enhance the remineralisationprocess. HealOzone application for the treatmentof non-cavitated lesions is usually repeated at 3and 6 months. There is no clear information onhow delivery of ozone at the correct concentrationcan be ensured by the device.

Key questionsThis review aims to answer the followingquestions:

� For the management of pit and fissure caries, isthe HealOzone procedure more effective thanthe combination of oral hygiene, dietary

advice, chlorhexidine/fluoride varnish andfissure sealant? If so, is it a cost-effectivealternative?

� For the management of non-cavitated rootcaries, is the HealOzone procedure moreclinically effective than the combination of oralhygiene, dietary advice and varnish? If so, is itcost-effective?

� For the management of cavitated caries, howoften, if at all, is HealOzone procedure analternative to fillings?

� For the management of cavitated caries, doesthe application of ozone gas and of a re-mineralising solution to the cavity beforerestoration prolong the life of a filling? If so, isit cost-effective?

Background

12

Methods for reviewingeffectivenessSearch strategyInitial database searches were undertaken toidentify relevant systematic reviews and otherevidence-based reports. Several websites were alsoconsulted to obtain background information. Fulldetails of the main sources consulted are listed inAppendix 1.

Electronic searches were conducted to identifypublished and unpublished studies on the clinicaland cost-effectiveness of ozone therapy for dentalcaries. The electronic databases searched aredetailed in Table 5. Full details of the searchstrategies are documented in Appendix 1. It wasanticipated that there was a small body of researchavailable, therefore a sensitive search strategy forclinical effectiveness studies was undertaken toretrieve all useful information on ozone therapyfor dental caries. Additional searches were carriedout for economic data and these are detailed inChapter 4. In addition, selected conferencesproceedings that were not available electronicallywere handsearched. These were InternationalAssociation for Dental Research (IADR) conferenceproceedings for 1999–2001 and the annualEuropean Organisation for Caries Research (ORCA)Congresses 2000–2003. Research abstracts,published on industry and users’ websites (KaVoDental, CurOzone USA, HealOzone and

DentalOzone; see Appendix 1 for full details),were also identified. Reference lists of includedstudies were also checked for additional studyreports.

Inclusion and exclusion criteriaAll citations identified by the search strategy wereassessed for relevance by two reviewers. Copies ofthe full-text, published papers of those consideredto be relevant were then obtained. It was decidedthat studies reported in languages other thanEnglish would be identified but not included inthe review.

For clinical effectiveness assessment, includedstudies were randomised controlled trials (RCTs)of ozone treatment (HealOzone) versus at leastone comparator (nil, placebo or active treatment).Data from studies other than randomised trialswere collected but not included in the review. Theoutcome measures were required to be measures ofclinical effectiveness (e.g. reversal/progression ofcaries). Only in vivo studies involving humansubjects were deemed to be suitable for inclusion,while studies reporting in vitro results wereexcluded. Studies were also excluded if theirfollow-up was less than 6 months or did not reportclinically relevant outcome measures.

Data extraction strategyA data abstraction form was designed (Appendix2) to collect details from each individual study.


13


Chapter 3

Effectiveness

TABLE 5 Electronic databases searched

Database Coverage

MEDLINE/EMBASE/MEDLINE Extra multifile search MEDLINE: 1966 to May Week 1 2004EMBASE: 1980 to Week 20 2004MEDLINE: Extra: 17 May 2004

Science Citation Index (SCI) 1981 to 16 May 2004BIOSIS 1985 to 12 May 2004AMED 1985 to May 2004Cochrane Controlled Trials Register (CCTR) Cochrane Library, Issue 2, 2004National Research Register (NRR) Issue 2, 2004Current Controlled Trials (CCT) 18 May 2004Clinical Trials 18 May 2004SCI Proceedings 1991 to 15 May 2004Conference Papers Index 1982 to May 2002ZETOC Conferences 1993 to May 2004IADR Meetings Abstracts 2002 to 2004

These included the type of study design, numberof participants and their characteristics,intervention characteristics, caries informationincluding location and severity of lesion, patientoutcomes such as reversal/progression of caries,and any reported adverse events.

In particular, the outcomes sought for theincluded studies were as follows:

(a) Non-cavitated caries

� reversal of caries� progression of caries� utilisation of dental services (e.g. visits to dental

care units; duration of dental treatment)� adverse events� patient-centred measures (e.g. patient

satisfaction and preference, relief ofpain/discomfort)

� quality of life.

(b) Cavitated caries

� time to restorative interventions� need for further restorative interventions and

length of time between restorations� symptoms of pulpal pathology.

Inclusion criteria were assessed independently bytwo reviewers. Any disagreements were resolved byconsensus or referred to a third reviewer.Reviewers were not blinded to the names of studyauthors, institutions or publications.

Quality assessment strategyTwo reviewers assessed the methodological qualityof all included studies and any disagreements wereresolved by discussion. The quality assessment ofRCTs was formally assessed using a publishedchecklist modified by the reviewers for thepurpose of this review.34 The checklist consisted of

12 questions, which focus on the followingmethodological aspects: method of randomisation,unit of randomisation, concealment of allocation,comparability of groups at baseline, blindingprocedures, number of withdrawals/dropouts andcompleteness of assessment at follow-up.

For each question a ‘Yes’, ‘No’ or ‘Unclear’ answerwas required. The quality assessment checklist ispresented in Appendix 3.

ResultsQuantity and quality of researchavailableAfter removing duplicates a total of 331 reportswas identified (Table 6): 78% (257) were abstractsand 22% (74) were full-text reports. Eighty-fivereports (seven full-text papers and 78 abstracts)were selected for full assessment, of which 21(three full-text papers and 18 abstracts) met thepredefined criteria for inclusion in the review. Inaddition, two reports, both PhD theses, wereidentified from reference lists. All 23 identifiedreports were written in English.

Number of studies identifiedIn total, five studies reported in five full-textpapers and 13 abstracts, and five studies reportedonly as abstracts, met the inclusion criteria forstudies of clinical effectiveness. In case of multiplepublications the report with the longest follow-uptime and/or largest sample size was chosen as themain source of information.

Number and type of studies excludedAfter identifying duplicates, several studies wereexcluded as they did not meet the inclusioncriteria. The main reasons for exclusion, togetherwith the corresponding number of studiesexcluded are listed in Table 7.

Effectiveness

14

TABLE 6 Number of screened and selected reports according to database searched

Database searched Number screened Number selected Included studies

MEDLINE/EMBASE/MEDLINE Extra 46 4 1SCI 38 7 1BIOSIS 38 1 0CENTRAL 8 1 0IADR abstracts 175 43 12Handsearch 14 2Websites 15 5Other databases 26 0 0

Total 331 85 21

Number and type of studies includedThe five full-text studies consisted of two RCTsassessing the use of HealOzone for themanagement of primary root caries – onepublished trial by Holmes35 and one unpublishedtrial by Baysan and Lynch,36 and two PhD thesesassessing the use of HealOzone for themanagement of pit and fissure caries, one by Abu-Naba’a37 reporting two unpublished trials and one by Abu-Salem38 reporting oneunpublished trial.

Root caries studiesHolmes (2003): this published randomisedtrial35,39,40 of management of primary non-cavitated root caries had two treatment groups:ozone plus reductant plus patient care kit versusair treatment plus reductant plus patient care kit.This study was set in a general dental practice.

Baysan and Lynch (2004): this unpublishedrandomised trial on cavitated and non-cavitatedroot caries36,41–44 had four treatment groups:ozone plus reductant versus reductant only, andozone plus sealant versus sealant only. It recruitedpatients who attended the School of Dentistry inBelfast.

Pit and fissure caries studiesAbu-Naba’a PhD thesis37 included two randomisedstudies: a main study (Abu-Naba’a, 2003) and apilot study (Abu-Naba’a pilot study, 2003), whichare considered separately as they do not includethe same patient population. The main studyassessed exclusively non-cavitated occlusal lesions,whereas the pilot study included cavitated occlusallesions. Patients were recruited from the School ofDentistry in Belfast for both the main and pilotstudies.

The Abu-Naba’a main study37,45–50 had fourtreatment groups: ozone plus reductant versus airtreatment plus reductant, and ozone plusreductant plus sealant versus reductant plussealant only. It involved 90 patients with 254lesions.

The Abu-Naba’a pilot study37,51,52 had twotreatment groups: ozone plus reductant versusreductant only. It involved eight patients with 34lesions.

The Abu-Salem study38 had two treatment groups:HealOzone plus reductant versus reductant only. Itrecruited 21 patients with 74 lesions, from Belfastprimary schools.

Of the five studies published only as abstracts,four assessed the effects of HealOzone for themanagement of occlusal pit and fissure cariouslesions,53–56 and one assessed the effects ofHealOzone on primary root carious lesions.57

Tabulation of quality of studies, characteristics ofstudies and evidence ratingThe characteristics of the five full-text studies(type and number of participants and cariouslesions, details of study design, inclusion criteria,characteristics of intervention and main results)are shown in Appendix 4.

Method of randomisation was reported in threestudies.35,37,38 Concealment of allocation was notspecified in any of the included studies. One studywas described as double blind35 and another studystated that outcome assessment was undertaken bya blinded examiner.38 In particular, the double-blind study by Holmes was reported to involvethree dentists: the first dentist performed the


15


TABLE 7 Number of studies and reasons for exclusion

Reason for exclusion Number of studies/abstracts

Follow-up less than 6 months 17No HealOzone treatment; other experiments involving ozone 14No measures of clinical effectiveness 6HealOzone used on extracted teeth (in vitro studies) 4Evaluation of diagnostic tests for detection of dental caries; no clinical effectiveness 5

measures Time studies, no clinical effectiveness measures 3Discussion paper, no comparative information on clinical effectiveness 1Costs, no clinical effectiveness measures 1No random allocation 2Patients’ attitudes, no effectiveness measures 7Studies not involving ozone 4

initial assessment of primary root carious lesions;the second randomised the lesions to treatmentgroups; the first then treated and assessed theresult without knowing which were given ozoneand which air, using a modified HealOzonemachine; the third dentist independently assessedlesions in 15 patients. The practicality of theentire process is, however, doubtful. Holmes is theonly author of the study and the other assessorsare neither listed as authors nor acknowledged inthe paper.

It was unclear whether blinding procedures weresecured in the remaining three included studies.The total number of people in the studies was287, with a total of 768 carious lesions. Across thestudies, the ages of the participant groups rangedfrom 7 to 82 years. Only three studies providedinformation on the gender of the participants.36–38

The length of follow-up ranged from 6 to21 months.

Each study involved either two or fourintervention groups. Ozone was always used incombination with other active interventions (i.e.ozone plus reductant, ozone plus reductant pluspatient care kit, ozone plus sealant, ozone plusreductant plus sealant) and compared to the sameintervention without ozone or to a shamprocedure (air treatment). The dosage of ozonetreatment varied between studies. In the Baysanand Lynch study,36 the Abu-Salem study38 and theAbu-Naba’a main study,37 ozone was administeredfor 10 seconds, whereas in the Holmes study35 andthe Abu-Naba’a pilot study37 ozone wasadministered for 40 seconds. In all studies ozoneapplications were repeated at some point beforethe final follow-up. None of the included studiesprovided information on the model/version of theHealOzone device.

The main outcome measure was reversal of caries. This included the proportion of cariouslesions becoming hard and, for some of theincluded studies, the proportion of lesionsreversing from ‘leathery’ to ‘leathery approachinghard texture’, but not necessarily hardening. Theproportion of lesions that deteriorated fromleathery to soft was also recorded, although notconsistently. Where appropriate the proportion ofintact sealants was documented. Changes in theECM and DIAGNOdent readings were alsoreported in the identified studies, but notconsidered in this review, owing to theunreliability of their measurements (i.e. high-falsepositive rates) and poor correlation with clinicaloutcomes.58

In the majority of the included studies, dataanalysis was conducted at the level of the lesion.Holmes used �2 statistics, but did not specifywhether they were for related samples (i.e.McNemar �2 test). In the Baysan and Lynch study no information was provided on the choice of statistical test used. In both Abu-Naba’astudies the unit of analysis was tooth-pair, but it was unclear whether the occurrence of multiple pairs of lesions per mouth was taken into account. Abu-Salem used a mixed-effectsanalysis of variance (ANOVA) with random effects for patient and teeth within patient, and fixed effects for group and time of treatment.

The characteristics of the five studies published asabstracts are shown in Appendix 5.

Tabulation of results and assessment ofeffectivenessThe clinical effectiveness results are presentedaccording to type of carious lesions (root cariesresults are presented separately from occlusalcaries results). Within this categorisation studiesresults are presented according to:

� type of outcome measures� type of publication (results of full-text studies

are presented separately from results of studiespublished as conference proceedings)

� type of dentition (treatment results of primaryteeth are presented separately from treatmentresults of permanent teeth).

It was planned to undertake further statisticalanalyses of the data reported in the full-textstudies and when appropriate to combine themquantitatively. However, owing to the limited rawdata provided, this proved unfeasible. The p-values of statistical analyses in the results sectionare those originally quoted by the studies’ authors.However, as the data were not analysed as ‘paireddata’ on a patient basis, their validity andreliability are open to question.

Primary root carious lesionsTwo full-text studies by Holmes35 and Baysan andLynch36 and one abstract by Lynch andcolleagues57 assessed the use of ozone for themanagement of primary non-cavitated rootcarious lesions. The Baysan and Lynch study alsoincluded the assessment of a non-specifiednumber of cavitated root lesions. In the Holmesstudies the clinical criteria of ‘soft, leathery andhard’ were adopted for the assessment of cariouslesions, whereas in the Baysan and Lynch study

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lesions were classified according to a five-pointseverity index as follows:

0 all ‘hard’ lesions 1 ‘leathery’ lesions considered to be small, easily

cleanable and approaching a ‘hard’ texture2 ‘leathery’ lesions judged to be shallow and

where the surface of the exposed sound dentinecould be easily maintained plaque free

3 ‘leathery’ lesions judged to be in surfaces thatwere difficult to maintain plaque free, and large,cavitated ‘leathery’ lesions where pulpalintegrity was judged to be at risk

4 all ‘soft’ lesions.

No information was provided on the validity andreproducibility of the above severity index, or onhow lesions were clinically identified as ‘leathery’‘soft’ or ‘hard’. In particular, the distinction

between three degrees of ‘leathery’ seemed ratherartificial.

Change in clinical severity Table 8 shows for each ofthe included studies the proportions of cariouslesions that according to the studies’ authorsreversed (became hard), improved (became lesssevere) or deteriorated in the ozone-treated groupand the control group. The Holmes study35

reported that 100% of ozone-treated primary rootcarious lesions (PRCLs) had reversed by18 months, while 37% of PRCLs in the controlgroup had worsened from leathery to soft and 1%had reversed. However, comparisons of results atdifferent follow-up points show someinconsistencies in the way data were reported(Table 9). In particular, the results at 21 months(published as an abstract) showed an increase inthe number of control lesions that stabilised


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TABLE 8 Results of root carious lesions

Ozone final follow-up Control final follow-upNo. (%) No. (%)

PRCLs becoming hardBaysan and Lynch, 200436 (12 months)a NR (47) NR (0)Holmes, 200335 (18 months)b 87/87 (100) 1/87 (1)

PRCLs becoming less severe (from index 2 to 1)Baysan and Lynch, 200436 (12 months)a NR (52) NR (12)

PRCLs becoming softHolmes, 200335 (18 months)b 0/87 (0) 32/87 (37)

NR, not reported (the denominator was not clearly reported in the study, so the number of caries cannot be calculated,hence only percentages are given).a Baysan and Lynch: non-cavitated and cavitated primary root carious lesions.b Holmes: non-cavitated primary root carious lesions.

TABLE 9 Results of the Holmes study at each recall visit35

Ozone at follow-up Control at follow-upNo. (%) No. (%)

PRCLs becoming hard12 months 85/87 (98) 1/87 (1)18 months 87/87 (100) 1/87 (1)21 months 81/81 (100) 6/81 (8)

PRCLs remaining leathery12 months 2/87 (2) 65/87 (75)18 months 0/87 (0) 54/87 (62)21 months 0/81 (0) 65/81 (80)

PRCLs becoming soft12 months 0/87 (0) 21/87 (24)18 months 0/87 (0) 32/87 (37)21 months 0/81 (0) 10/81 (12)

(from 54/87 at 18 months to 65/81 at 21 months)and a subsequent decrease in the number ofcontrol lesions that had become soft (from 32/87at 18 months to 10/81 at 21 months), indicatingan improvement over time in lesions receivingtreatment other than ozone. No comments onthese changes were provided by the authors.

In the Baysan and Lynch study,36 47% of theozone-treated lesions had arrested by 12 months,whereas none had become hard in the controlgroup (p < 0.001), and 52% had reversed fromindex 2 (leathery) to index 1 (leatheryapproaching hard texture) in the ozone groupcompared with 12% of lesions in the control group(p < 0.001). So, if one combines the ‘approachinghard’ (from index 2 to 1) and ‘hard’ lesions (fromindex 2 to 0), 99% of lesions improved, as in theHolmes study. This study included both cavitatedand non-cavitated root lesions, but results were notclearly presented according to the type of lesionsand it is unclear how many cavitated and non-cavitated lesions were assessed in eachintervention group. Only one figure in the paperpresented results for both types of lesions in theozone group: the percentage of cavitated lesionsthat had reversed (become hard) decreased from9.1% at 1 month to 1.4% at 9 months, indicatingan increase/progression in the severity of cavitatedroot lesions treated with ozone. No statisticalanalysis was undertaken by the authors, nocorresponding data were given for the controlgroup, and no comments on reversal/progressionof cavitated lesions were provided in the text ofthe paper.

In addition, the abstract by Lynch andcolleagues57 indicated that 80% (48/60) of non-cavitated PRCLs treated with ozone reversed fromseverity index 4 to 3, whereas none of the softlesions in the control group significantly changed,and that 94% (189/200) of leathery lesions becamehard and arrested in the ozone group, whereasthose in the control group did not significantlychange.

Marginal adaptation of the root sealant The Baysanand Lynch study36 also assessed the effects ofozone with or without a fissure sealant using themodified US Public Health Service (USPHS)criteria. In the ozone plus sealant group 61% ofsealants were retained compared with 42% in thesealant only group (p < 0.05) at 12 months.

It is worth noticing that both groups had the same other active interventions such as reductant,patient care kits and sealants. The very low

improvement rates in the control groups aretherefore surprising.

Summary: root carious lesions The two full-textstudies assessing the use of ozone for root cariouslesions both report very high success rates withozone and very low improvement rates in thecontrols.

Fissure sealants after application of ozone for thepreventive treatment of non-cavitated root lesionsare more likely to remain intact (61% versus 42%,p < 0.05).

Pit and fissure carious lesionsThe three remaining studies – the Abu-Naba’amain study (2003),37 Abu-Naba’a pilot study(2003)37 and Abu-Salem (2004) study38 – assessedthe effects of ozone on pit and fissure cariouslesions. Both Abu-Naba’a studies involved patientsaged over 12 years with primary lesions in thepermanent posterior teeth, while the Abu-Salemstudy involved children 7–9 years old with cariouslesions in the posterior primary teeth. The Abu-Naba’a main study and the Abu-Salem studyassessed non-cavitated lesions, while the Abu-Naba’a pilot study included lesions withcavitation.

Change in clinical severity: permanent dentitionResults of full-text studies Tables 10 and 11 illustratethe results of the Abu-Naba’a main study.37

Clinical severity of non-cavitated pit and fissurelesions was assessed using the criteria described byEkstrand and colleagues (0 = least severe, 1, 2, 3,4 = most severe).9 The change in severity score iscalculated as the score at follow-up minus thescore at baseline. Thus, a negative changeindicates an improvement, while a positive changeimplies a worsening of lesion severity. The meanchange from baseline in clinical severity score at12 months was not significantly different(p = 0.112) between the two intervention groups:ozone (10 seconds) plus reductant group versusreductant only group (Table 10).

It was also reported that a greater proportion ofozone-treated lesions improved or stabilisedcompared with control lesions at all recalls(Table 11). However, statistical analyses of thesedata were not provided. The relationship betweenclinical severity score and the need for futurefillings was not explained.

No significant difference in the clinical severityscore was found between the ozone and controlgroups in the Abu-Naba’a main study. The

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18

reported proportions of lesions improved,stabilised and deteriorated appeared similarbetween groups, but no statistical analyses wereundertaken and the clinical relevance of thesefindings was not explained in terms of fillingsavoided.

Abu-Naba’a pilot study In the Abu-Naba’a pilotstudy,37 17 lesions (with cavitation) were treatedwith ozone plus reductant and 17 reserved ascontrols (reductant only) in eight patients.Outcomes were measured using Ekstrand andcolleagues’ clinical index9 as well as the followingclinical indices: hardness index (hard, leathery,soft), visual index (sound, arrested, active),cavitation score (1 = no cavitation, 2 = microcavitation, 3 = frank cavitation), colourindex (normal, yellow, light brown, grey, darkbrown, black), frosted enamel measure (mm),stained enamel measure (mm) and perceivedtreatment need index (e.g. requiring nointervention, requiring preventive resinrestoration, requiring drilling and filling).Thirteen lesions in the treatment group and 12lesions in the control group were assessed at6 months. Lesions treated with ozone showed asignificant reduction in the hardness and visualindices (Table 12). No significant differencesbetween groups were found for any other indicesor for the Ekstrand clinical index (p > 0.05).

This study was only a pilot study, which did notadd much to the results of the Abu-Naba’a mainstudy.37

Results of abstracts The abstracts gave little detail ofstudies, their methodology could not be easilyassessed and therefore their findings must beinterpreted with caution. They are included herefor completeness and as a guide to emergingresearch.

Three abstracts compared pit and fissure lesionsreceiving ozone (at different concentrations) withpit and fissure lesions receiving no-ozonetreatment.54–56 Their results are presented inTable 13. The proportion of lesions reported asclinically reversed, the extent of which was notspecified, ranged from 86.6 to 99% in the ozone-treated groups. All studies reported that nosignificant clinical changes were observed in thecontrol group, but no numerical information wasgiven.

Another abstract53 compared the use of ozoneversus conventional treatment in 35 patients, eachwith two occlusal lesions extendingradiographically 2–4 mm into dentine. Theauthors defined the occlusal lesions as non-cavitated, but lesions 2–4 mm into dentine onradiographs are likely to have small cavities that


19


TABLE 10 Mean change in clinical severity score of pit/fissure lesions from baseline (Abu-Naba’a main study)37

Ozone group Control group p-ValueChange in clinical severity score (n = 106) (n = 106)

Mean change from baseline 0.283 0.443 0.112Standard deviation 0.64 0.74Standard error 0.06 0.07

TABLE 11 Percentage of pit/fissure lesions that improved, remained stable, or increased in clinical severity at each recall visit (Abu-Naba’a main study)37

Month(s) of Treatment Decreased severity Stable Increased severity follow-up group (improvement) (worsening)

1 Ozone 11.4% 74.6% 14.0%Control 5.3% 81.6% 13.2%

3 Ozone 17.7% 63.9% 18.5%Control 8.4% 73.1% 17.6%

6 Ozone 10.8% 55.9% 33.3%Control 5.9% 59.8% 34.3%

9 Ozone 7.8% 57.8% 34.5%Control 6.9% 56.0% 37.1%

12 Ozone 7.4% 56.5% 36.1%Control 5.6% 48.6% 45.8%

trap plaque and are likely to progress unlesscleaned thoroughly. The ozone-treated lesionsreceived ozone for 40 seconds and application of aglass ionomer preventive sealing, which wassubsequently replaced with a posterior compositeat 3 months. The control lesions receivedconventional drilling and filling (posteriorcomposite). All the ozone-treated lesions werereported to have reversed at 3 months. Sixcomplaints (17.1%) of postoperative sensitivity werereported after conventional drilling and filling at6 months compared with none after ozonetreatment (p < 0.05). Postoperative sensitivity is,however, a measure commonly used to assess largecarious lesions and it is questionable whether itshould be used for early carious lesions. Moreover,complaints of postoperative sensitivity afterocclusal restorations are rare.

Clinical reversal of caries: primary dentition Onefull-text study assessed the use of ozone for thetreatment of non-cavitated primary posterior teethin children aged 7–9 years.38 Occlusal lesions wereassigned to receive ozone for 10 seconds followedby a reductant or a reductant only. The proportionof lesions that improved, remained stable ordeteriorated in each intervention group was notprovided and the clinical severity findings were

only presented graphically. The graph showed asteady increase in the mean change from baselineclinical severity scores for the control group,compared with an initial slight decrease and asubsequent levelling in the ozone group at 12 months. The overall changes in the clinicalseverity scores9 were analysed using a mixed-effects ANOVA. This analysis assumed thatpatients and teeth within patients had a randomeffect, while group and time of treatment had afixed effect. There was overall little reduction inclinical severity scores in the ozone-treated group,while an overall increase was observed in thecontrol group. There was a statistically significanteffect of treatment upon clinical severity scoreswith time (p < 0.01).

Sealant retention The Abu-Naba’a main study37

also assessed the use of ozone for 10 seconds withand without a fissure sealant. No sealants werereported to be lost in either the ozone plus sealantgroup or the sealant-only group. The percentageof partial loss in the ozone plus sealant group at12 months was 32.7%, and in the sealant-onlygroup was 29.8%, with no significant differencesbetween groups (this indicates similar rates ofreinterventions between groups for repairingpartial sealant loss).

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TABLE 13 Reversal of pit/fissure caries: findings from abstracts

Ozone at follow-up Control at follow-upNo. (%) No. (%)

Holmes 200354 (12 months) 1918/1937 (99) 0/427 (0)Hamid, 200355 (6 months) 80/92 (86.9) 0/92 (0)Megighian and Bertolini, 200456 (6 months) p < 0.05 0/80 (0)

(220 lesions treated)

TABLE 12 Number of pit/fissure lesions showing a reduction in the clinical indices at 6 months (Abu-Naba’a pilot study)37

Colour index

Hardness indexa Visual indexb Cavitation scorec Darkerd Lightere Perceived treatment needf

Treatment 11/13 (84.6%) 8/13 (61.5%) 6/13 (46.2%) 3/13 (23.1%) 2/13 (15.4%) 12/13 (92%)Control 4/12 (33.3%) 1/12 (8.3%) 5/12 (41.7%) 2/12 (16.7%) 6/12 (50%) 9/12 (75%)p-Value <0.05 <0.05 ns 0.084 (ns) 0.16 (ns)

a The proportion of lesions becoming hardb The proportion of lesions with increasing scorec The proportion of lesions with reduction in cavity scored The proportion of darker lesionse The proportion of lighter lesionsf The proportion of lesions with a reduced treatment need

Discussion of results andconclusions on the evidence forand against the interventionOnly a limited number of RCTs (five full-textreports and five studies reported as abstracts) wereavailable for assessing the effects of ozone for themanagement of root carious lesions and pit andfissure carious lesions. Of these only one waspublished in a refereed journal, but lacked somestudy details, while the remaining studies werederived from PhD theses, unpublished reports orconference proceedings. All full-text studies withthe exception of the Holmes study were conductedby the same research team that developed theprocedure, led by Professor Lynch of Queen’sUniversity, but Holmes was at one time part of thesame group, having done his PhD in Belfast. Themethodological quality varied across studies andinformation on method of randomisation,concealment of allocation, blinding proceduresand statistical methods was lacking in many ofthem. Therefore, interpretation of studies resultswas not straightforward. A quantitative synthesis ofresults was not feasible owing to the differencesamong studies regarding intervention, dosage ofozone and outcome measures.

There were some concerns over theappropriateness of the methods of analysisadopted by study investigators. All studies in thisreview were of a hierarchical structure, althoughnot necessarily treated as such for analysis.Specific types of analysis are required when datahave a hierarchical structure. The hierarchy occursas smaller units, such as lesions or teeth, areclustered together within a larger unit, the patient.In most studies included in this review, thestatistical analysis was carried out at the lesionlevel. However, two lesions within one patient arenot strictly independent, so analysis at the lesionlevel is inappropriate. A more suitable statisticalanalysis takes into account the hierarchicalclustering of lesions within a subject.59

In the simple case of two lesions per person, onereceiving control and one receiving the ozonetreatment, paired data are produced. In this case,the appropriate paired analysis would be aMcNemar �2 test for dichotomous data, a Wilcoxon signed rank test for ordinal data and a paired t-test for continuous data. The choice ofstatistical tests that ignore the pairing of the datais more conservative and may fail to detectimportant differences found by paired analysis.59

In the case of more than two lesions per subject,

multilevel modelling procedures would need to be used.

Baysan and Lynch36 stated that statistical testswere used, but they did not specify whichparticular tests. Holmes used �2 tests, but did notspecify whether they were McNemar �2 tests. Abu-Naba’a37 (main and pilot studies) recognisedthe fact that there were pairs of teeth. However, insome cases there were multiple pairs of teeth perperson and it is not clear whether this was takeninto account. Abu-Salem38 used analysis ofvariance for a mixed effects model. This type ofanalysis is hierarchical in nature, with onecomponent for the patients and one for the toothwithin the patient. However, as not enoughinformation was provided by the author it was notpossible to determine whether the statisticalanalysis was conducted appropriately.

For primary non-cavitated root caries both theHolmes study35 and the Baysan and Lynch study36

reported high success rates for ozone-treatedlesions compared with control lesions. However,the lack of reversal of caries among controlsreceiving conventional treatment (reductant)known to be efficacious is puzzling.

Cavitated root lesions did not seem to benefitfrom ozone application, showing indeed anegative effect over time, but no formal statisticalanalysis was presented.

Treatment results of pit and fissure caries ofpermanent teeth were not consistent acrossstudies. The Abu-Naba’a main study did not showany significant differences between non-cavitatedlesions treated with or without ozone. Similarly,the Abu-Naba’a pilot study,37 which includedlesions with cavitation, did not demonstrate anysignificant effect of ozone apart from animprovement in the hardness and visual clinicalindices. In contrast, results from conferenceproceedings (methodologically less reliable)provided very high success rates (from 86.6% to100% of reversal of caries).

Data on the use of ozone for the treatment of primary teeth were available from only onestudy, which suggested an overall reduction inclinical severity scores for non-cavitated occlusallesions in primary molars treated with ozone(p < 0.01).38

The adjunct of ozone to a fissure sealant produceda better sealant retention in root carious lesions(61% of sealant retention versus 42%, p < 0.05),36


21


but not in pit and fissure carious lesions (32.7%versus 29.8%).37

On the whole, and despite the differencesreported in some studies (e.g. Holmes), there areas yet insufficient published full-text studies (onlyone refereed journal article) to provide convincingevidence on the effectiveness of ozone for themanagement of caries.

This review was done independently of theCochrane systematic review on ozone therapy forthe treatment of dental caries,60 which concludedthat at present there is no reliable evidence on theeffectiveness of ozone applications to arrest orreverse the decay process. The present version ofthe Cochrane review does not include the Holmes(2003) and Abu-Salem (2004) studies.

Important subgroup differencesThere are not enough data on which to assess theeffects of ozone on cavitated caries in thepermanent dentition (both occlusal caries and rootcaries) or on non-cavitated occlusal caries in thedeciduous dentition (only one study involvedchildren with primary teeth38). No data areavailable on cavitated occlusal caries in deciduousteeth, secondary caries or high-risk patientcategories.

Adverse effects of interventionNone of the studies reported any adverse events inthe intervention group.

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MethodsSearch strategiesIn addition to the electronic searches andhandsearches detailed in Chapter 3, a search ofthe NHS Economic Evaluation Database (NHSEED) and the Health Management InformationConsortium was undertaken for economicevaluations of ozone for dental caries. Details ofthe searches are provided in Appendix 1.

Studies that reported both costs and outcomes ofHealOzone compared with any of the comparatorswere sought. The manufacturer’s submission to theNational Institute for Health and ClinicalExcellence (NICE) was also scanned for relevanteconomic evidence.

Inclusion and exclusion criteriaTo be included, studies needed to compareHealOzone with any of the existing comparatorsin terms of their costs and effectiveness. Studiesreported in languages other than English wereidentified from the literature searches, but wouldnot be included in the review unless a structuredabstract was available from NHS EED. A singleeconomist assessed all abstracts for relevance. Full-text papers were then obtained for all studies thatappeared potentially relevant and were formallyassessed for relevance.

Data abstractionThe following data were extracted for eachincluded study:

� study characteristics:– research question– study design– comparison– setting– basis of costing

� characteristics of the study population or of thepopulations that formed the basis of data usedin a modelling exercise:– numbers receiving or randomised to each

intervention– dates to which data of effectiveness and costs

relate� duration of follow-up for both effectiveness and

costs

� results– summary of effectiveness and costs (point

estimate and, if reported, range or standarddeviation)

– summary of cost-effectiveness/utility (pointestimate and, if reported, range or standarddeviation)

– sensitivity analysis� conclusions as reported by the authors of the

study.

Quality assessmentA single economist assessed the quality of includedstudies using a published checklist.61 Thequestions were set out on a standard formgenerated before the review.

Data synthesisData from included studies were assessed andsummarised by a single economist, andinterpreted alongside the results of the systematicreview of effectiveness so that conclusions could bedrawn on the relative efficiency of HealOzonecompared with alternative treatments.

ResultsThe search revealed no published economicevaluations of HealOzone. One published trial wasfound which discussed the costs and effectivenessof the management of primary root caries withHealOzone.35 However, since the cost informationis limited to estimates of the total cost of dentistry,with no detail of costs and consequences of thealternatives, the study did not meet all of themethodological criteria listed in Table 14 to beclassified as an economic evaluation and thereforewas not further reviewed. Two abstractsconcerning studies on the costs and benefits ofHealOzone for dental caries were found, but didnot provide sufficient details of study design ordata for the purpose of this review.62,63 However,the industry submission from KaVo Dental (August2004) provided an economic evaluation. Theremainder of this section provides a summary andcritique of that submission.

The unpublished industry submission from KaVoDental Ltd, UK (KaVo: Clinical and cost


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Chapter 4

Systematic review of economic evaluations

effectiveness of HealOzone for the treatment andmanagement of dental caries, 2004) included aneconomic model of HealOzone compared withcurrent treatment for non-cavitated pit and fissurecaries, cavitated pit and fissure caries, and rootcaries. Both a base-case and a probabilistic analysiswere included. The submission comprised both atext document and supporting Excel spreadsheets.

Table 14 provides a summarised assessment of theKaVo industry submission based on the ten criticalappraisal components.61

Review of industry submissionThe first part of this section provides a summaryof the methods and results from the economicevaluation of HealOzone reported in the industrysubmission. This is followed by a critical review ofthe evaluation.

Summary of the industry submissionThe submission by KaVo included a cost-effectiveness analysis over a 5-year time horizon ofHealOzone treatment versus current managementfor non-cavitated pit and fissure caries, cavitatedpit and fissure caries, and cavitated root caries.The current management treatments were definedas follows:

� non-cavitated pit and fissure caries: sealants� cavitated pit and fissure caries: glass ionomer,

composite resin and amalgam fillings� root caries glass ionomer and composite resin

restorations.

These comparators were identified from theexpert opinion of four dentists. The submissiondoes not consider preventive treatments such asoral hygiene or advice on diet along with surfaceapplications of fluoride and sealants as acomparator. The intervention with HealOzone is


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TABLE 14 Quality assessment of the economic evaluation presented in the industry submission by KaVo

Quality component Assessment and comments

1. Was a well-defined question posed in an answerable form? Yes

2. Was a comprehensive description of the competing Yes: current treatments were defined as:alternatives given (i.e. can you tell who did what, to NC-PFC: sealantswhom, where and how often)? C-PFC: glass ionomer, composite resin and amalgam

restorationRC: glass ionomer and composite resin restoration

3. Was there evidence that the programme’s effectiveness Limited owing to short follow-up of included studies and had been established? inability to compare/combine results from more than one

study owing to differences in study characteristics. Noneof the studies used specifically considered C-PFC,although the model does include such effectiveness databased on assumptions outlined in the following critique

4. Were all the important and relevant costs and Yes: the base-case analysis assumes that the capital consequences for each alternative identified? cost of HealOzone is borne by dental practices. This

assumption is varied for sensitivity analysis

5. Were costs and consequences measured accurately in Yesappropriate physical units?

6. Were costs and consequences valued credibly? Not always: see critique of QALY estimation

7. Were costs and consequences adjusted for differential Yes: a discount rate of 3.5% was usedtiming?

8. Was an incremental analysis of costs and consequences Yes: see critiqueof alternatives performed?

9. Was allowance made for uncertainty in the estimates of Yescosts and consequences?

10. Did the presentation and discussion of study results Yesinclude all issues of concern to users?

C-PCF, cavitated pit and fissure caries; NC-PCF, non-cavitated pit and fissure caries; QALY, quality-adjusted life-year; RC, root caries.

defined as an initial treatment with HealOzonefollowed by 12 weeks of treatment withmineralising toothpaste, oral rinse and spray, withthe possible addition of restorative treatments. Anopinion survey of 243 dentists practisingHealOzone treatment was used to estimate theproportion of teeth that would require additionalrestorative treatment at the same time as theHealOzone application or at any timesubsequently, but only 48 provided usableresponses.

Effectiveness data were obtained from a review ofpublished evidence for HealOzone and thecurrent management of dental caries. Clinicaloutcomes included caries progression and reversal.

Costs included those of comparators plus costs ofrerestorations avoided. The costs of each currenttreatment comparator were estimated frompublished data for the treatments defined above.All cost data were estimated from the perspectiveof the NHS and were presented in UK poundssterling (£) at 2003 prices. Their method was totranslate the treatments into relevant treatmentcodes listed in the Statement of DentalRemuneration (SDR codes)64 and then to useGDS65 data to identify the total annual numbers ofsuch treatments. These data are presentedseparately for patients aged less than 18 years andthose aged 18 years and over. The same source(GDS) gives annual total treatment costs which,when combined with annual treatment numbers,gave a unit cost per treatment item. These figureswere adjusted to take account of SDR codesrelating to more than one tooth and more thanone type of caries. The unit cost estimates do notappear to differentiate between primaryrestorations on virgin tooth surfaces andsecondary restorations, the latter being outside thescope of the study since these would be unsuitablefor treatment with HealOzone. Finally, these unitcost estimates were adjusted to reflect the fact thatpatients under 18 years receive free NHS dentalcare and those aged 18 years and over pay 80% oftheir NHS dental fees, unless they are eligible forfree treatment. It was assumed that the dentalpractice and not the NHS would fund the capitalcost and running cost of the actual HealOzonedevice.

Using these unit cost estimates the industry modelassesses the annual cost to the NHS for eachcomparator. To estimate the annual cost to theNHS of the HealOzone comparator the industrysubmission carried out a survey of dentists toestimate the proportion of teeth currently treated

for either non-cavitated pit and fissure caries,cavitated pit and fissure caries or root caries thatwould be suitable for treatment with HealOzone.This survey also asked dentists to estimate theproportion of HealOzone-treated teeth that wouldrequire some restorative treatment either at thetime of HealOzone treatment or sometimeafterwards. These restorative treatments weredefined similarly to current managementtreatments for each caries type.

The unit cost of HealOzone treatment was basedon the cost of patient consumables and dentists’time (in practice, a dentist is remunerated by a feeper item of service as listed in the SDR and thesefees are intended to reflect the costs incurred bydental practices). Using the results of aquestionnaire survey of dentists who useHealOzone in their own dental practice theestimated unit cost for a course of HealOzone-treatment was then adjusted to reflect theestimated percentages of HealOzone-treated teeththat would require additional restorativetreatment. On the basis of responses to thisquestionnaire an additional cost of restoration(using current management in addition toHealOzone) was applied to 44% of non-cavitatedpit and fissure caries, 84% of cavitated pit andfissure caries and 47% of root caries.

The cost to the NHS of HealOzone also took intoaccount the proportion of treatment fees paid bythe NHS rather than by patients as describedabove for current treatment costs. The unit costfor a course of HealOzone procedure was based onan assumption of more than one HealOzoneapplication per course of treatment. The modelused a mean of 2.5 HealOzone applications percourse of treatment (range 1–4). This was basedon data from KaVo Dental.

An additional cost was added to reflect theweighted average cost per tooth year ofrerestorations avoided. This was based on datafrom a study that reported the average cost pertooth year of restoration in teeth previously filledwith amalgam or composite resin for each type ofcaries over 5 and 10 years. When calculating thecost of rerestorations avoided the costs of theoriginal restoration are removed to avoid doublecounting.66

The model uses rates of caries progression andregression taken from a variety of unpublishedand published clinical studies. The mean valuesfor annual rates of caries progression for thecurrent treatments assumed in the industry


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submission, along with the study reference fromwhich these values were obtained, are: non-cavitated pit and fissure caries 0%,67 cavitated pitand fissure caries 4.9%,68–70 and root caries3.9%.68,69

The progression rates cited for HealOzone wereall 0%, taken from studies with follow-up of3–21 months.35,40,42,44,53,71,72

Caries reversal rates for non-HealOzonetreatments were assumed to be zero. The industrysubmission does cite a 15% reversal rate found ina study reporting the use of varnish(chlorhexidine), but this value was excluded fromthe industry submission on the grounds that suchvarnish is not cited in the SDR codes. Rates ofcaries reversal in teeth treated with HealOzonewere derived from 11 studies with follow-up timesranging from 3 to 21 months. The annualisedmean values used for base-case analysis were: non-cavitated pit and fissure caries 93.3%,53,55 cavitatedpit and fissure caries 79.0%,72–77 and root caries84.5%.35,40,42,44,57,71

Although no evidence was available to estimateunderlying QALY scores, the industry submissionmodel estimated alternative cost per QALYthresholds of between £10,000 and £40,000assuming quality of life benefits from 1 day to1 month. The assumptions for QALY estimateswere utility gains of 0.01, 0.02, 0.05 and 0.1 forrestorations avoided.

The model was run to provide results using base-case data. The deterministic base-case analysisused mean values from the minimum andmaximum values inputted for each parameter.Both one-way analysis and multivariate sensitivityanalysis were also conducted. Stochastic analysiswas conducted using Monte Carlo simulation over10,000 cycles. Random numbers were used toselect data inputs from those provided.

ResultsThe average baseline figure estimated in theindustry model, across all caries types, for theincremental cost to the NHS per tooth treatedwith HealOzone was £6.24. Allowing for the costof rerestorations avoided (see earlier description),the net incremental cost per tooth treated withHealOzone was ‘minus’ £9.70. The industry modelalso resulted in an estimated NHS cost of £61 percase of caries progression avoided (for all cariestypes) using a 5-year model time horizon, andassuming up to 35 cases per 1000 avoided peryear (152 over 5 years). An estimated 846 cases of

caries reversal per 100 cases treated withHealOzone were reported, with an estimated NHScost case of per caries reversal of £7.38, again forall caries types.

The estimated minimum utility gain (at 0.095) toachieve a cost per QALY of £30,000 was found tobe for the use of HealOzone for root cariestreatment. This was estimated using alternativecost-effectiveness acceptability thresholds based onvarying the length of time over which a utility gainwas accrued.

Sensitivity analysis indicated that the main driversof cost and cost-effectiveness were numbers ofteeth treated per treatment session and thenumbers of treatments per course of therapy.Multivariate analysis revealed that despiteuncertainty around the cost of HealOzone,HealOzone would be likely to be cost-effectiveover a 10-year follow-up period.

The report also discusses the wider implications tothe NHS, impact on patient health and equityissues. The results of the economic evaluation areused to estimate the budget impact to the NHSfrom the use of HealOzone technology for allcaries treatment of all eligible teeth. The figuresinclude both initial treatment costs and theestimated costs of rerestorations avoided. On thisbasis, an annual net incremental cost of £48.1million in year 1, reducing to £11.8 million byyear 5, was estimated for HealOzone. Theseresults assume that the capital and running costs of the HealOzone device are funded bydental practices, with no contribution from theNHS apart from the fee for service. If theexchequer provided additional funds for thedevice this would cost the NHS an additional£110.4 million, assuming one device per dentalpractice in England and Wales. Additional annual servicing costs are estimated at £10.8million.

Although the evaluation does not include patienthealth as an outcome in the model, the resultsinclude a brief description of possible effects onpatient health, based on studies of patientattitudes to dental treatment.

Equity issues are also briefly discussed in theresults. The report cites evidence suggesting a linkbetween caries incidence and deprivation, andthat deprived populations would be one group lesslikely to benefit from HealOzone technology aslong as it is only available through private dentaltreatment.


26

Critique of industry submissionOn the whole, the economic evaluation submittedby KaVo Ltd is based on reasonable economicevaluation methodology. Nevertheless, a numberof concerns can be raised relating to the choice ofcomparators and the quality of data used toparameterise the economic model.

The comparators used in the industry submissionfor non-cavitated caries were based on restorativetreatment of caries. The evaluation did notconsider preventive measures for early caries.However, the management of non-cavitated cariesrarely requires fillings, as it is now well establishedthat preventive treatments for early lesions can beeffective in reversing and arresting furtherprogression of caries. Furthermore, HealOzonehas been cited as being “most effective in the roleof prevention and early management of lesions”.78

It would therefore have been appropriate for theindustry model to include conservative treatmentsaimed at ensuring reversal of early caries asadditional comparators for non-cavitated caries.

The HealOzone comparator includes anassumption about the proportions of teeth thatwould require additional treatment to HealOzonetreatment alone. These assumptions are takenfrom a survey of 243 dentists who currently useHealOzone, of whom only 48 provided usableresponses. Given the absence of robust, objectiveclinical data, options to obtain relevant modelparameter values are limited. Nonetheless, suchdata are potentially biased and unreliable and theconsiderable uncertainty would be reduced ifactual clinical evidence were to exist. This was anon-randomised survey of opinion and cannottherefore be interpreted as having a strongevidence source. It does not appear that anyrandom selection process was used to recruitdentists for the survey, and therefore it is unclearwhether any attempt was made to obtain abalanced opinion.

The industry evaluation of implications to theNHS includes an assumption about the numbersof teeth suitable for treatment with HealOzone.These figures were again estimated frominformation taken from a survey of dentists whoare users of HealOzone.

The assumption concerning the funding of thecapital cost of providing a HealOzone device indental surgeries was that this would not affect thefee for service. In reality, however, it would beexpected that any additional contribution by theNHS towards capital costs incurred by dental

practices would be offset by lowering subsequentfees paid to dentists for the associated therapy.

Estimates of caries progression and reversal rateswere extracted from a range of studies of varyingdegrees of quality, including published andunpublished RCTs, conference abstracts and PhDtheses. Some of the limitations of these datasources are discussed in Chapter 3. Cariesprogression rates for current management wereextracted from studies that did not includeHealOzone as a comparator and the patient mixmay be different. Caries progression rates forHealOzone were estimated from studies withfollow-up periods from as little as 3 months, all ofwhich claimed a 0% caries progression rate. Otherstudies show higher caries progression rates.Selecting the most favourable studies biases theresults.

Rates of caries reversal with current managementwere assumed to be zero despite a 15% reversalrate being reported in one study. This rate wasexcluded from the analysis on the grounds that itwas associated with the application ofchlorhexidine varnish and this was assumed by theauthors of the industry report not to be a standardNHS dental treatment. However, dentistscommonly rank application of varnish among‘treatments for sensitive cementum or dentine’(code 3631 in the SDR).

Source data for caries reversal associated with theuse of HealOzone came from 14 studies, three ofwhich had follow-up of less than 3 months. Onlythe latter were included in the sensitivity analysis.The remaining 11 studies differed in design andquality. For non-cavitated pit and fissure carieseffectiveness data were extracted from studies with3–6-month follow-up.53,55 For cavitated pit andfissure caries, despite finding no availableevidence, data from five studies were used in themodel. The assumption used to justify this is thefollowing:

“None of the available studies specifically describesthe treatment of cavitated pit and fissure caries. In theabsence of such detail, the studies presented in thissection refer to carious lesions, which are deemed torequire drilling and filling. While non-cavitated cariesmay be treated in this way, drilling and filling is theconventional treatment for cavitated caries and it istherefore assumed that these studies included aproportion of cavitated caries.” (KaVo Dental, 2004).

A further concern is that, although the industrysubmission report does acknowledge the limitationof combining data from more than one study,


27


given the disparity in inclusion/exclusion criteriaand other study characteristics, the reversal ratesand progression rates used as the mean rates forbase-case analysis were calculated using the resultsfrom more than one study.

Estimates of the cost of rerestorations avoided are based on a number of assumptions and thereport does acknowledge the absence of published data for rates of future rerestorations.Instead, the model uses published data for theaverage cost per tooth year of rerestoration inteeth previously filled with amalgam or composite resin over 5 and 10 years (KaVoindustry submission, 2004). It is unclear in thereport exactly how estimates of the numbers offuture rerestorations would be avoided as a result of HealOzone treatment, although thereport does provide estimates for the cost of suchrerestorations avoided. Given the considerableuncertainty surrounding the rate of rerestorations,

the figures used should be interpreted with care.Realistically, such data could only be obtainedfrom the outcomes of a long-term study of theeffectiveness of the relevant comparators. QALYestimates are included in the economic evaluation,but are not based on quality of life data. Instead,assumptions concerning the amount of utility gainand duration of gain were used to derive QALYthresholds. Given the short duration of anypotential intermittent change in quality of life,along with the high degree of uncertaintysurrounding any estimates of QALY scores, theadditional information value of such QALYthresholds is dubious.

Although the economic evaluation in the industrysubmission is well presented, the choice ofcomparator is questionable and considerableuncertainty surrounds many of the parametervalues used in the model. Therefore, their resultsoverestimate the benefits of HealOzone.


28

Given the current state of the clinicaleffectiveness evidence, with little published in

full in peer-reviewed journals, it could be arguedthat economic analysis is premature. However,NICE always requests some attempt at economicappraisal, if only to clarify the data deficits.Therefore, the following analysis has beenproduced more as illustrative modelling than ashard evidence.

Methods for economic analysisThe economic evaluation aimed to assess the cost-effectiveness of HealOzone relative to thealternative interventions for the treatment of bothocclusal pit and fissure caries and root caries. Asidentified in the previous section, economicevaluations of HealOzone versus conventionaltreatments of dental caries were virtually non-existent at the time of this review. This sectionprovides an economic evaluation using cost-effectiveness analysis and presents economicmodels of the treatment of non-cavitated pit andfissure caries, and root caries. They comparecurrent management versus current managementplus HealOzone. The results over the extendedperiod must be qualified by the fact that follow-updata on HealOzone are limited to 2 years. Theresults reported in this section should beinterpreted on the understanding that theyentirely depend on the model parameters andassumptions made. The authors recommend thatthe model be rerun in the future if evidence onclinical effectiveness is published.

Markov model frameworkThis section presents a description of the Markovmodel developed for the assessment, and of theparameters that were common across all models.Key parameters specific to each model and results are then presented separately for eachcomparator. The section concludes with asummary of the results for all comparators and ofthe factors deemed to be most critical in affectingthe results.

Markov modelling techniques were used to assessthe cost-effectiveness of HealOzone plus currentmanagement, relative to the standard current

management of dental caries. A Markov model iscomposed of a set of defined health states amongwhich a patient can move over successive periodsand is run using a hypothetical cohort of patients.The model incorporates both the logical andtemporal sequences of treatment, including theevents that follow from the initial treatmentprocedure and the outcomes for the patient thatare associated with each possible scenario orclinical pathway. Transition probabilities are usedto allow patients to move within and betweenthese states of health. A patient can only be in onestate of health at any time and can only make onetransition per cycle. A relevant period is chosenfor the length of a cycle and the cycles then linktogether to form a Markov chain. The length ofcycle used in this study was 1 year. When themodel is run over the defined number of cycles, adiscounted net present value (NPV) for the cost ofan intervention is calculated, determined by theoccurrence of different states and the length oftime in various states.

The models were designed to estimate a typicalpatient’s costs and outcomes for the alternativetreatments over a 5-year period. A 5-year timehorizon was chosen to facilitate comparison withthe results from the industry model. Figure 10summarises the basic structure of the model.Similar models were developed to carry out theanalysis for non-cavitated pit and fissure caries,and non-cavitated root caries

Non-cavitated pit and fissure cariesThe model for non-cavitated pit and fissure cariescompares current management strategies (i.e.watchful waiting, oral hygiene/removal of plaque,fluoride applications and sealants) versus the samestrategy plus HealOzone.

Non-cavitated root cariesThe model for non-cavitated root caries comparescurrent management strategies (i.e. removal ofplaque, topical fluorides, chlorhexidine and asealant) versus the same strategy plus HealOzone.

Model pathwaysThe pathways for each model were developed inaccordance with the protocol for the assessmentalong with expert opinion from members of a


29


Chapter 5

Economic analysis

local dental school. All models have simplifiedclinical event pathways, but are designed to reflectthose clinical events of importance to theevaluation (Figures 15–18 in Appendix 6).

Non-cavitated pit and fissure caries and rootcariesFollowing initial treatment carious lesions mayeither reverse or not reverse. Lesions that do notshow reversal of caries progression after the initialintervention require additional treatment. This is afurther application of the initial preventive/non-restorative treatment or a restorative treatment (i.e.drilling and filling). In those receiving furtherpreventive/non-restorative treatments, caries canagain be reversed or treated with filling (Figure 10).The event pathway is split into two mutuallyexclusive events, the reversal (cure) of caries andno reversal of caries. The arrows between thesestates represent the possible transitions betweenthem. Movement between the different states isgoverned by the transition probabilities, such asthe chance of the caries reversing. The absorbingstate in this model is a tooth with a filling. Whilethis is not an absorbing state in reality, given the

5-year timescale of the model, and that a typicalfilling would last longer than 5 years, no statesbeyond filling were included. It was assumed thatonce a tooth was cured it remained in a cured statefor the rest of the 5 years. TREEAGE DATA 4.0software (TREEAGE Software, 2001) was used toconstruct the model.

Estimation of parametersProbabilitiesThe time horizon considered in the Markov modelwas a maximum of 5 years. The outcomeconsidered in the economic evaluation was thenumbers of carious lesions cured. The mainprobabilities used in the model were the rates ofreversal (cure) of caries. These rates were derivedfrom the effectiveness study (Chapter 3) andconsultation with dental practitioners. Theprobability of cure rates (Table 15) obtained fromthe effectiveness studies and used in the first runof the economic model were: HealOzone 0.074(7.4%) for the non-cavitated pit and fissurecaries37 and 0.98 (98%)35 for the non-cavitatedroot caries. The rates used for currentmanagement were 0.056 (5.6%)37 for non-

Economic analysis

30

Early caries initialtreatment

Current management (watchfulwaiting, oral hygiene/plaqueremoval, fluoride, sealants)

Current management plusHealOzone

Reversal of caries

Progression of cariesReversal of caries

Tooth filledInitial treatment

repeated

Progression of caries Reversal of caries

Tooth filled

FIGURE 10 Model for primary non-cavitated pit and fissure caries

cavitated pit and fissure caries and 0.01(1%) fornon-cavitated root caries.35 These values, whichare highly favourable to HealOzone, were differentto those used in the industry model, whichaggregated data from a number of studies, someof which did not meet the inclusion criteriaspecified in this review. In the absence of anyalternative information, it was assumed for thepurposes of the model that, following initialtreatment, there was a 0.50 (50%) chance ofsubsequent treatment being the same treatment asthe initial one received or a filling.

The root caries cure rates are taken from theHolmes study,54 the results of which seempuzzling; they reflect a best possible case forHealOzone.

CostsThe perspective adopted for the study is that ofthe NHS and Personal Social Services. The unitcosts of dental treatments were taken directly fromcost data published by the NHS.65 Table 16provides details of the different treatments withcorresponding codes from the NHS SDR for eachtreatment item. Unit costs are listed for eachtreatment item and represent the fee paid by theNHS to the dentist for each item of service.

Resource-use data were identified from existingliterature, reports from manufacturers and advicefrom experts in this field. Based on existingevidence and clinical opinion, patients wereassumed to visit the dentist every 6 months. Costdata were measured in pounds sterling (£) for the


31


TABLE 15 Probabilities used in the economic model

Intervention Probability Source

HealOzone cure rate (non-cavitated pit fissures) 0.074 Table 11, Chapter 3Current management cure rate (non-cavitated pit fissures) 0.056 Table 11, Chapter 3HealOzone cure rate (non-cavitated root caries) 0.98 Table 9, Chapter 3Current management cure rate (non-cavitated root caries) 0.01 Table 9, Chapter 3Percentage being retreated with initial treatment 0.50 Discussions with expertPercentage being retreated with filling 0.50 Discussions with expert

TABLE 16 Unit cost per itema

Type Current treatment (SDR code) Cost (£)

Non-cavitated pit and fissure cariesHygiene/diet advice (0601) 7.70Chlorhexidine gel/varnish or fluoride varnish (3631) 4.60Fissure sealant (0701) 6.95Total (sum of above) 19.25

Non-cavitated root cariesHygiene/diet advice (0601) 7.70Chlorhexidine gel/varnish or fluoride varnish (3631) 4.60Total (sum of above) 12.30

Cavitated pit and fissure cariesSealant only (1441) 6.95Composite resin (1442) 9.80Glass-ionomer (1443) 10.55Amalgam (1401 or 1421) 7.15

(posterior)14.15(anterior)

Total (average of above) 16.98HealOzone (No SDR code) 20

(estimate)

a Costs are those that would be incurred by the NHS and exclude patient contributions to dental fees. Further details ofcost calculations are presented in Appendix 6.

year 2004. As specified by the guidelines forconducting health technology assessment, cost-effectiveness results should reflect the presentvalue of the stream of costs and benefit accruingover the time horizon of the analysis.79 To makethe analysis consistent with the model used in theindustry submission the analysis was carried outover a period of 5 years. An annual discount rateof 3.5% was applied to both costs and benefitsaccrued, the rate currently specified in the HTAguidelines.79

The per-item fee for service paid by the NHS wasused as a proxy for costs to the NHS of currentmanagement. Under the current NHS dentalsystem patients pay 80% of the dentist’s fee, withthe remaining 20% being paid by the exchequer(except that there is a maximum charge for acourse of dental treatment of £366). Somepatients, including all those less than 18 years old,are entitled to free treatment and the exchequerpays the full cost of treatment. Recent figuresreport that 25% of all claims for patients aged 18years and over were exempt from patientcharges.65 The other 75% of claims for patientsaged 18 and over therefore include a patientcontribution at 80% of the amount of the claimand an NHS contribution of 20%. Taking thesedata into account, the average net NHScontribution equates to 40% [25% + (20% of75%)] of any NHS dental claim for patients aged18 and over. As children (persons under 18 yearsof age) are exempt from paying NHS dentaltreatment fees, the full cost of all claims for thoseless than 18 years old was used as the cost to theNHS. The data used in the industry modelindicated that the NHS contribution to those aged18 and over was 52%.

In the absence of separate effectiveness data foradults and children it was decided to combine allage groups for the base-case analysis. A two-stageprocess was required to weight the unit costs torepresent a mixed population of adults andchildren. Further details of the stages involved inthe cost calculations are reported in Appendix 6.Published statistics65 indicate that adults andchildren do not receive similar proportions of eachtreatment item among the different treatmentitems listed in Table 16. The first stage wastherefore to calculate the percentage mix ofchildren and adults for each identified SDRcomponent of the treatment. These proportionswere then weighted by the amount that the NHScontributed using the figures described earlier, at100% of the amount of a claim per child and 40%per adult. Following this two-stage weightingprocess, the adjusted costs to the NHS used in themodel were £9.02 for the non-cavitated pit andfissure caries and £6.09 for non-cavitated rootcaries, and a filling was estimated at £12.75.Details of the costs are included in Table 17.

The costs of HealOzone were calculated using theexisting NHS methods and information from themanufacturer. Most of the studies indicated thatHealOzone treatment is given at the start, andrepeated at 3 and 6 months. The cost ofHealOzone therefore took into account thatpatients could receive between one and threeapplications. The cost of HealOzone treatmentalso included that of current management asHealOzone was considered as an additionaltreatment and not as a stand-alone treatment. Theweighted average cost of ‘current managementplus HealOzone treatment’ used in the model was£20.03 for non-cavitated pit and fissure caries and

Economic analysis

32

TABLE 17 Weighted average costs used in the modela

Cost (£)

Intervention Under 18 Over 18 Weighted

Current managementNon-cavitated pit and fissure caries 19.25 7.70 9.02Non-cavitated root caries 12.30 4.92 6.09

Current management plus HealOzoneNon-cavitated pit and fissure caries 39.25 15.70 20.03Non-cavitated root caries 32.30 12.92 17.10

Restorative interventionsFilling 19.67 7.87 12.75

a Costs are those that would be incurred by the NHS excluding patient contributions to dental fees.

£17.10 for non-cavitated root caries. These valueswere not similar to those used in the industrymodel as they focused on costs and benefits to theNHS in England and Wales as a whole, ratherthan on costs and benefits faced by the averagepatient.

Quality of lifeIt was not possible to measure health benefits interms of QALYs. This was mainly because theadverse events avoided are transient: a fewseconds’ pain from injection of local anaesthetic;the anxiety/fear of having a drill and numbnessuntil the local anaesthesia wears off.

Sensitivity analysisAs every economic analysis contains some degreeof uncertainty, imprecision or methodologicalcontroversy, and this one more than most, asensitivity analysis was performed. Given thelimited effectiveness data for estimating rates ofcaries reversal, the models were rerun usingdifferent probability values of reversal of caries.Assumptions were also made about what items toinclude in each of the interventions and sensitivityanalysis was performed using different codes todetermine the costs, namely the SDR codes usedin the industry submission.

ResultsThe analysis, carried out over a 5-year periodusing the data reported in the trials, indicated thattreatment using current management plusHealOzone cost more than current managementalone for non-cavitated pit and fissure caries(£40.49 versus £24.78), but cost less for non-cavitated root caries (£14.63 versus £21.45). Fornon-cavitated pit and fissure caries 91.8% of theteeth treated using current management receiveda filling and 8.2% of teeth were cured. For teethtreated with current management plusHealOzone, 89.2% received fillings and 10.8%were cured. This was different from the results ofthe Cochrane review by Ahovuo-Saloranta andcolleagues,32 which reported that the reduction incaries ranged from 86% at 12 months to 57% at48–54 months. This review focused, however, onthe prevention (and not the treatment) of toothdecay in children and adolescents who presentedwith no obvious caries. Based on the Holmesstudy,54 1.5% of teeth were cured at 5 years in thenon-cavitated root caries group treated withcurrent management and 98.5% teeth were filled,while 99.9% of teeth were cured by thecombination of current management and

HealOzone and 0.01% were filled. The presentauthors remain sceptical about these results.

Sensitivity analysisThere was very little suitable evidence on theeffectiveness of the HealOzone comparator. One-way sensitivity analysis was applied to the model toassess the robustness of the results to variations inthe underlying data. The probability of cariesbeing cured was varied for each comparatorseparately, using the baseline cure rate for thealternative comparator. These results indicatedthat when higher probability cure rates were usedthe proportion of teeth filled was lower at12 months. These results were similar to those ofthe Cochrane review by Ahovuo-Saloranta andcolleagues.32 However, as the focus of theCochrane review was on the prevention of dentaldecay in the permanent teeth of children andadolescents, the extrapolation of its results to anadult population with dental caries might bequestionable.

The results of the one-way sensitivity analyses areillustrated in Figures 11–14 and presented intabular form in Appendix 6 (Tables 29–32).

In Figure 11 the costs refer to those of currentmanagement when the baseline cure rates ofHealOzone are used (0.074). The discounted NPVfor the cost of HealOzone was £40.49. The aboveresults indicate that the discounted NPV of thecost of the HealOzone comparator, using baselineparameter values for HealOzone, was higher thanthat of current management at any probability ofcure with current management. This is mainlyattributable to the fact that the baseline cure rateused in the model is less than 10%. The resultsalso indicate that as the probability of cure rateincreases, the cost reduces and the number ofteeth filled also reduces.

In Figure 12 the costs refer to those of HealOzoneplus current management when the baselineannual cure rate of current management is used(0.056). The discounted NPV for the cost ofcurrent management was £24.78. Varying theprobability of the cure rates of HealOzone pluscurrent management, and using the baseline curerate probability for current management,indicated that the HealOzone option was alwaysmore expensive than current management whenthe probability of cure using the HealOzoneoption was 70% or lower.

In Figure 13 the costs of HealOzone reflect thecosts when the baseline probability of cure of


33


current management (0.01) was used and theprobability of cure of HealOzone management wasvaried accordingly. The one-way sensitivity analysisresults show that discounted NPVs for the costs ofcurrent management plus HealOzone were lowerthan those of current management only when curerates from current management plus HealOzonewere at least 80% and above.

In Figure 14 the costs of current management reflectthe costs when the baseline probability of cure ofHealOzone (0.98) was used and the probability ofcure of current management was varied accordingly.The discounted NPVs for the costs of currentmanagement were higher than those of currentmanagement plus HealOzone when the cure ratefor current management was 40% or lower.

Economic analysis

34

0

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0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

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(£)

Current management

HealOzone

FIGURE 11 One-way sensitivity analysis for non-cavitated pit and fissure caries: discounted NPV of each comparator at alternativecure rates for current management, holding the baseline cure rate for HealOzone plus current management constant

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FIGURE 12 One-way sensitivity analysis for non-cavitated pit and fissure caries: discounted NPV of each comparator at alternativecure rates for HealOzone plus current management, holding the baseline cure rate for current management constant


35


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FIGURE 13 One-way sensitivity analysis for non-cavitated root caries: discounted NPV of each comparator at alternative cure ratesfor HealOzone plus current management, holding the baseline cure rate for current management constant

0

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FIGURE 14 One-way sensitivity analysis for non-cavitated root caries: discounted NPV of each comparator at alternative cure ratesfor current management, holding the baseline cure rate for HealOzone plus current management constant

One-way sensitivity analysis was also carried outusing similar SDR codes to those used in theindustry submission. Table 18 shows the SDR codesused by the industry for patients under 18 years ofage. The figures for those over 18 years weresimilar. This did not alter the results for non-cavitated pit fissure caries as the discounted NPVof current management remained lower than thatof the HealOzone comparator (£22.65 versus£33.39). These results could be attributed to thefact that it was assumed that patients received thesame treatment as the initial one and the cost ofcurrent management plus HealOzone is muchhigher than that of current management alone,given that HealOzone is an additional treatmentrather than an alternative treatment. Results usingthe SDR codes used for non-cavitated root cariesin the industry model gave similar results to thosein the base-case analysis. HealOzone cost less thancurrent management (£17.66 versus £30.41).

DiscussionThe economic analysis was greatly constrained bythe uncertainty over clinical effectiveness;

therefore, the results should be regarded mainly asillustrations of the key variables and henceinterpreted cautiously as they reflect theparameter values and assumptions used in themodel. A further constraint was the lack of long-term data on the effectiveness of HealOzone (it isnot known whether caries that is reversed willalways stay in the inactive/arrested state orwhether future treatments will be required). Toattempt to model longer term effects the available12-month data were extrapolated to 5 years. It isnot known at this stage whether this assumption isvalid. Another possible area of uncertainty wasrelated to whether the response to HealOzonetreatment would increase with increasing doselevels.

It was not possible to model the treatment ofcavitated caries since no effectiveness data ondirect comparisons were available. The analysiswas carried out on a hypothetical cohort of teethwith carious lesions and did into take into accountthe proportion of teeth that are unsuitable forHealOzone treatment. Further research istherefore necessary to support a completeeconomic evaluation.

Economic analysis

36

TABLE 18 Industry submission model inputs for annual treatment items and cost for patients under 18 years of agea

Procedure SDR code Unit cost (£)

Non-cavitated pit and fissure cariesFissure sealant: sealant only 1441 6.50Fissure sealant: composite resin 1442 9.15Fissure sealant: composite resin and glass ionomer 1444 13.71

Root cariesComposite/synthetic: one filling 1421 13.22Composite/synthetic: two or more fillings 1421 10.32Glass ionomer: one filling 1426 12.08Glass ionomer: two or more fillings 1426 8.22

a The current costs of treatment were estimated using the GDS treatment items reported for the year ending March 2003(KaVo Dental Ltd, industry submission, 2004, p. 62).

National Service FrameworkThe majority of general dental practitioners in theUK are contracted to the NHS through GDS,although, as independent contractors, dentistswho offer NHS treatment may also offer certaintreatments on a private basis. Dentists receivefixed fees per item of treatment for adults, whilefor children they receive a combination of fixedfees per item and capitation fees. Under this NHSsystem patients can pay up to 80% of the cost oftheir treatment up to a maximum cost of around£366. Some patients are entitled to free NHSdental treatment, including children, youngpeople in full-time education, pregnant womenand those with a child under 1 year old, andpeople on low incomes. The costs of running adental practice, including capital costs ofequipment, are met by the dental practice ratherthan the NHS, and recovered from the fee forservice charges paid by the patients and the NHS.In addition to dentists contracted to provide NHStreatment, some of whom also offer privatetreatment, there are many dentists in the UK whoonly provide treatment on a private basis.Currently, HealOzone treatment is only availableas a private treatment from a limited number ofdentists.

Health targetsThere are no specific health targets, although inEngland the Department of Health set a target toreduce tooth decay in 5-year-olds to low levels by2003, while in Wales the official target was toachieve no more than 48% of 5-year-olds havingtooth decay by 2002.80

The new Base Dental Contract (based on thepersonal dental services model) will be introducedfor all practices in April 2006. The new contractwill be more likely to have a greater preventiveand capitation element.81

Fair accessAt the time of writing HealOzone treatment wasonly available through private dental care and it

was estimated that there were 294 HealOzoneunits in the UK (at June 2004). Were ozonetherapy to be made available, provision ofHealOzone units would have to be increased muchbeyond this to allow all suitable patients fair accessto the treatment.

Equity issuesThe availability of HealOzone treatment iscurrently limited to those people who are able and willing to pay for the treatment privately.However, in the present state of knowledge, itcannot be said that people suffer by being unableto afford it.

Budget implications to the NHSAt present, HealOzone is only available to patientsthrough private dental care. The aim of thissection is to estimate what the implications wouldbe to the NHS if HealOzone were made availableas an NHS dental service.

The models used in the economic evaluationdescribed in Chapter 5 considered the costs andeffectiveness of current treatment with and withoutthe addition of HealOzone for arresting theprogression of dental caries (further details ofthese cost calculations are presented in Appendix6). The evaluation does not consider those teethwith carious lesions, which would be unsuitable forHealOzone therapy. These could be considered inthe estimated implications to the NHS for thetotal population of teeth with carious lesions ifestimated numbers of such teeth were available. Toachieve this it is necessary to make assumptionsabout the proportion of teeth currently treated forcaries that would be suitable for alternativeHealOzone treatment. This proportion would beused to calculate the total annual number oftreated teeth.

Data from GDS provide statistics for the numbersof teeth treated by SDR code in a year for adultsand children in England and Wales. At the time ofwriting the latest available GDS data were thosepertaining to the year ending March 2003.


37


Chapter 6

Implications for the NHS

The following results were calculated bycombining the GDS data with assumptions aboutthe SDR codes relevant to each caries type toestimate annual numbers of teeth treated for non-cavitated pit and fissure caries and non-cavitatedroot caries. Again, teeth with cavitated caries werenot considered given the absence of evidence onthe effectiveness of HealOzone as a comparatortreatment for cavitated caries.

Non-cavitated pit and fissure cariesThe discounted NPV for the cost over 5 years ofteeth treated initially with current management orHealOzone plus current management wasreported in Chapter 5. These figures werecombined with the numbers of teeth treatedinitially using annual GDS data for the SDR codesin the present treatment definitions. The resultsshould, however, be interpreted with extremecaution given that they are based on the limitedeffectiveness data available for the economicanalysis, as reported in Chapters 3 and 5 of thisreport.

The total discounted NPV over 5 years for treatingnon-cavitated primary fissure caries was estimatedat £8,565,765 for current management and£13,996,280 for HealOzone therapy (Table 19).The base-case results showed that by 5 yearsfillings were present in 91.8% of teeth treated withcurrent management compared with 89.2% ofteeth treated with HealOzone plus currentmanagement. Using these figures the incrementalcost per tooth treated would be £15.71, at aninitial total cost to the NHS of £5,430,515. Theincremental cost over 5 years for the HealOzonecomparator compared with current management(£13,996,280–£8,565,765 ) was divided by the

difference in numbers of teeth filled at 5 years forthe HealOzone comparator and currentmanagement (308,340–317,327). The incrementalcost per filling avoided, using these assumptions,would be estimated at £604.23.

The industry submission estimates for thepercentage of teeth currently treated that wouldbe suitable for HealOzone, obtained from theopinion of current users of HealOzone, were 92%for non-cavitated pit and fissure caries, 76% forcavitated pit and fissure caries, and 76% for rootcaries. These figures were derived from Table 15 inthe industry submission.

Non-cavitated root cariesThe total discounted NPV over 5 years for treatingnon-cavitated root caries, using the best case forHealOzone again, would be estimated at£7,371,882 for current management and£5,876,885 for HealOzone therapy. The netdifference in these two costs shows thatHealOzone therapy would save the NHS £4.35 pertooth treated initially with HealOzone in additionto current management for root caries, a total costsaving over 5 years of £1,494,997 (Table 20).

These figures are estimated using base-case valuesfor caries reversal rates. Limited suitableeffectiveness data were available for reversal ratesof root caries, apart from a single study reportingreversal rates of 1% for current management and98% for HealOzone treatment. Given the extremevalues of reversal rates for the comparators, basedon the limited effectiveness data available at thetime of analysis, these results need to beinterpreted with caution. It was only possible tocarry out limited one-way sensitivity analyses,

Implications for the NHS

38

TABLE 19 NHS annual cost for treatment of non-cavitated pit and fissure caries

NPV of treatment cost over 5 years (£)

Current management 8,565,765HealOzone plus current management 13,996,280Net difference in cost 5,430,515Net difference in cost per tooth treated initially 15.71

TABLE 20 NHS annual cost for treatment of non-cavitated root caries

NPV of treatment cost over 5 years (£)

Current management 7,371,882HealOzone plus current management 5,876,885Net difference in cost –1,494,997Net difference in cost per tooth treated initially –4.35

varying cure rates separately for the HealOzoneand current management comparators (seeChapter 5). From the results of the sensitivityanalyses it can be seen that the net difference incost per tooth treated initially was higher forcurrent management unless the probability of curefor the HealOzone comparator was lower thanapproximately 80%.

It is advisable that the reader interprets all suchresults merely as an illustration of possiblescenarios. In the light of limited evidence oneffectiveness, a more detailed analysis of budgetimplications was not considered likely to add anyuseful information to the evaluation.

The cost implications over time are difficult toascertain since there are many uncertain factors totake into account. Further research is required tomodel the cost implications over time, taking intoaccount the cost of rerestorations beyond thelifetime of first fillings and their effects over time

on the tooth population. For example, it isunknown how long an arrested carious lesionremains inactive. Any prospective trial should havesufficient follow-up to allow for this.

Importantly, the above results are based on theauthors’ assumptions for the management of thedifferent types of caries.

In addition, it is difficult to estimate the actualcost of HealOzone to the NHS. Assuming thatpatients who pay some of their dental treatmentfees are willing to pay no more than currenttreatment for the same condition initially, whatwould the cost-effectiveness ratio be? Wouldpatients opt for this treatment if it was moreexpensive?

Finally, would patients be given a choice for cariesmanagement or would dentists have to followsome guidelines about the best treatment? Thishas implications on the numbers of teeth treated.


39


Main resultsClinical effectivenessThe literature on ozone treatment is still at arelatively early stage, in the sense that only onepaper has been published in full in a refereedjournal. Most of the reports are available only inabstract form, as conference proceedings, andinevitably give few details. Many trials are still veryshort term and none of the studies has followedup the patients after they have stopped ozonetreatment for a reasonable length of time. It is alsoworthwhile remembering that caries is a dynamicprocess: a lesion can remineralise without theneed for any intervention, and the rate of cariesprogression can be very slow.

HealOzone is supposed to kill the microorganisms(bacteria) responsible for dental plaque formation.However, unless patients have improved theirplaque control and eliminated the causes of theincreased numbers of microorganisms, the plaquewill re-form and the lesion will progress again.This raises the question of whether HealOzone isa reasonable preventive technology. Furthermore,treatments based on HealOzone would need to berepeated for an indeterminate numbers of years tobe beneficial, with obvious cost implications.

The available evidence is conflicting, with the rootcaries treatment showing much better results thantreatment for pit and fissure caries. However, theresults are surprising, partly because the ozonegroup did so well, with 99% cure or improvement,but mainly because the control group performedvery badly, despite receiving the same carepackage (oral hygiene, topical fluoride, etc.) butwithout the application of ozone. Compliance ofpatients with treatment, however, was not assessedin the included studies.

In particular, it proved difficult to identify theadditional role of ozone gas from the patient kitor the synergistic effect between ozone and thepatient kit, which contained, among otherelements, fluoride and xyliton. It would have beenuseful, for example, to know the effects of ozonealone, namely ozone gas, together with thepatient’s normal brushing or how HealOzonecompares to professional plaque control (the

removal of plaque by a dentist or hygienist), whichhas been used effectively in the management ofdental caries in adults. A recent study assessing theoutcomes of a 30-year preventive programmebased on professional and self-performed plaquecontrol has shown how high standards of oralhygiene are associated with a very low incidence ofdental caries and periodontal disease in adults.82

Cost-effectivenessIf HealOzone led to a reduction in future fillings,then the extra cost might be justified. The authorsdo not believe that the evidence base yet supportsthat.

Need for further researchNearly all the research to date comes from thesame group who developed and pioneered theprocedure, and have the greatest experience in itsuse. There is a need for large, well-conductedRCTs to assess the effectiveness and cost-effectiveness of HealOzone for the management ofboth occlusal and root caries. In particular, futuretrials:

� should be conducted by independent researchteams

� should be properly randomised so that an equalnumber of lesions, or paired lesions, per mouthare allocated to intervention groups

� should apply appropriate statistical methods forthe analysis of paired-data on a patient basis;

� should use validated and reproducible criteriafor the assessment of caries

� should measure relevant outcomes such asreduction in caries incidence over a reasonableperiod (at least 2 years, but realistically muchlonger)

� should mask participants and outcome assessors� should provide both a statistical and a clinical

interpretation of their findings� should conform to the CONSORT guidelines

for the reporting of RCTs.83

Owing to the natural history of the caries process,any future trial would need to include a very longfollow-up, which would have a significant impacton trial costs.


41


Chapter 7

Discussion

There also appears to be a need for evaluation ofthe different methods of assessing caries severity.The base case could be clinical examination, withthe marginal benefits and costs of moresophisticated techniques assessed. Although theeconomic evaluation was not able to provideresults that could be used by decision-makers, itwas a valuable exercise in highlighting the paucityof good quality data on key parameters. Inparticular, the paucity of suitable data frompublished clinical trials comparing theeffectiveness of HealOzone with appropriatecomparators restricted the scope of the economicmodel. No comparable quality of life data wereavailable for the comparators, thus limiting therange of outcomes available for an evaluation.These gaps in the data needed to undertake aninformative economic evaluation of HealOzonecan only be filled through further research in theform of prospective RCTs.

To provide adequate information to assess thecost-effectiveness of HealOzone, any futureeconomic evaluation of HealOzone should featurethe following characteristics:

� It should be based on data from properlyconducted RCTs of HealOzone versusappropriate comparators (e.g. no treatment orcurrent management).

� Follow-up of patients should be long enough toallow identification of both short-term andlong-term resource use and effectiveness.

� Outcome data must include both short-termand long-term rates of caries reversal, cariesprogression, retreatment and/or rerestoration.

� Separate consideration is needed for cavitatedand non-cavitated caries.

� Sufficient power is needed to allow for robustsubgroup analyses for deciduous andpermanent teeth, and for variation in cariesseverity.

� An estimate of the unit cost of HealOzone tothe NHS should be based on calculationssimilar to those underlying the SDR figures forcurrent dental treatments provided by the NHS.

� Factors affecting patients’ quality of life shouldbe considered, both at the point of treatmentand during follow-up (e.g. the effect on qualityof life due to pain from toothache).

Discussion

42

Any treatment that preserves teeth and avoidsfillings is welcome. However, the current

evidence base for HealOzone is insufficient to

conclude that it is a cost-effective addition to themanagement and treatment of occlusal and rootcaries.


43


Chapter 8

Conclusion

Grateful thanks to Heather Mackintosh for hersecretarial support.

The views and opinions expressed are those of theauthors and do not necessarily reflect those of thefunding bodies.

Publication informationThe Aberdeen Health Technology AssessmentGroup is part of the Institute of Applied HealthSciences (IAHS). The Institute of Applied HealthSciences within the College of Medicine and LifeSciences of the University of Aberdeen is made upof discrete but methodologically related researchgroups. The HTA Group is drawn mainly from theHealth Services Research Unit, the Department ofPublic Health and the Health Economics Research Unit.

The HTA Group carries out independent healthtechnology assessment reports (TARs) for the UKHTA Programme, which commissions TARs forthe National Institute for Health and ClinicalExcellence (NICE) and other bodies, such as theNational Screening Committee. In addition, a

joint venture between the Health ServicesResearch Unit at Aberdeen and the Medical CareResearch Unit at Sheffield University forms theReview Body for Interventional Procedures(ReBIP) Programme within NICE. ReBIPundertakes systematic reviews and, whereappropriate, establishes UK registries to collectand analyse data on the efficacy and safety ofselected procedures.

Contribution of authorsMiriam Brazzelli (Research Fellow) and ShonaFielding (Medical Statistician) completed thereview of effectiveness. Lynda McKenzie (ResearchFellow) conducted the review of economicevaluations. Lynda McKenzie and Mary Kilonzo(Research Fellow) conducted the economicevaluation. Cynthia Fraser (Information Scientist)developed and ran the search strategies. NormanWaugh (Professor of Public Health) providedoversight and contributed to drafting the review.Jan Clarkson (Honary Consultant in PaediatricDentistry) provided clinical advice andcommented on the draft review.


45


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72. Morrison R, Lynch E. Remineralization of occlusalpit and fissure caries after using ozone. 32ndAnnual Meeting of AADR, San Antonio, Texas,March 2003 [conference proceedings on theInternet]. URL: from:http://iadr.confex.com/iadr/2003SanAnton/techprogram/abstract_27482.htm.

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74. Cronshaw MA. Treatment of primary occlusal pitand fissure caries with ozone: six-month results.81st Annual Conference of the InternationalAssociation for Dental Research, Goteberg, Sweden,June 2003 [conference proceedings on theInternet]. URL: http://iadr.confex.com/iadr/2003Goteborg/techprogram/abstract_34889.htm.

75. Domingo H, Abu-Naba’a LA, Al Shorman HM,Holmes J, Marashdeh M, Abu-Salem O, et al.Reducing barriers to care in patients managed withozone. 32nd Annual Meeting of AADR, SanAntonio, Texas, March 2003 [conferenceproceedings on the Internet]. URL: http://iadr.confex.com/iadr/2003SanAnton/techprogram/abstract_27392.htm.

76. Holmes J, Lynch E. Clinical reversal of occlusalfissure caries using ozone. 81st Annual Conferenceof the International Association for DentalResearch, Goteberg, Sweden, June 2003[conference proceedings on the Internet]. URL: http://iadr.confex.com/iadr/2003Goteborg/techprogram/abstract_36308.htm.

77. Megighian GD, Bertolini L, De Pieri A, Lynch E.In-vivo treatment of occlusal caries with ozone: one and two months effect with light inducedfluorescence (QLF) as diagnostic methods. 81stAnnual Conference of the International Associationfor Dental Research, Goteberg, Sweden, June 2003[conference proceedings on the Internet]. URL:http://iadr.confex.com/iadr/2003Goteborg/techprogram/abstract_36918.htm.

78. Healozone Users Congresses. July 2003 [documenton the Internet]. HealOzone website. URL: http://www.the-o-zone.cc/O3cong.doc.Accessed April 2004.

79. National Institute for Clinical Excellence. Guide tothe methods of technology appraisal (reference N0515).London: NICE, 2004.

80. Primary dental care services in England & Wales[document on the Internet]. London: AuditCommission; 2002. URL: http://www.audit-commission.gov.uk/. Assessed August 2004.

81. NHS Dentistry: next steps in local commissioning[document on the Internet]. London: UKDepartment of Health; 2004. URL: http://www.dh.gov.uk/assetRoot/04/08/68/59/04086859.pdf. Accessed August 2004.

82. Axelsson P, Nystrom B, Lindhe J. The long-termeffect of a plaque control program on toothmortality, caries and periodontal disease in adults.Results after 30 years of maintenance. J ClinPeriodontol 2004;31:749–57.

83. Moher D, Schulz KF, Altman D, for the CONSORTGroup. The CONSORT statement: revisedrecommendations for improving the quality ofreports of parallel-group randomized trials. JAMA2001;285:1987–91.

References

50

Sources searched for systematicreviews, other evidence-basedreports and backgroundinformationDatabasesCochrane Database of Systematic Reviews (CDSR).The Cochrane Library (Issue 2, 2004).Database of Abstracts of Reviews of Effectiveness(NHS Centre for Reviews and Dissemination),April 2004.HTA Database (NHS Centre for Reviews andDissemination), April 2004.Trip database. URL: http://www.tripdatabase.com/.Accessed May 2004.

WebsitesThe Dental, Oral and Craniofacial Data Resource

Center (DRC). URL: http://drc.nidcr.nih.gov/default.htm. Accessed July 2004.

National Center for Health Statistics. URL: http://www.cdc.gov/nchs/nhanes.htm.Accessed July 2004.

British Association for the Study of CommunityDentistry. URL: http://www.bascd.org/ AccessedJuly 2004.

KaVo Dental Ltd. URL: http://www.kavo.com/En/default.asp. Accessed April 2004.

CurOzone USA Inc. URL: http://www.curozone.com/. Accessed April2004.

DentalOzone. London: Dental Clinique. URL: http://www.dentalozone.co.uk/. AccessedApril 2004.

HealOzone. Dr Julian Holmes. URL:http://www.the-o-zone.cc/. Accessed April 2004.

NHS Dental Practice Board. URL: http://www.dpb.nhs.uk/gds/index.shtml.Accessed July 2004.

Department of Health. URL: http://www.dh.gov.uk/Home/fs/en.Accessed April 2004.

Search strategies used to identifyreports assessing ozone therapyfor dental cariesMEDLINE (1966 to week 1 2004),EMBASE (1980 to week 20 2004),(MEDLINE Extra 17 May 2004) Ovid Multifile Search. URL: http://gateway.ovid.com/athens

1 (healozone or curazone).tw. 2 ozone/ (14334)3 (ozone or o3).tw. 4 (oxidat$ or oxidis$).tw. 5 or/2-46 exp tooth demineralization/ use mesz 7 dental caries/ use emez 8 demineralization/ use emez 9 Dental Caries Susceptibility/ use mesz

10 Dental Enamel Solubility/ 11 (caries or carious).tw. 12 ((tooth or teeth or dental or dentine or enamel

or root? or occlusal) adj5 decay$).tw. 13 ((tooth or teeth or dental or dentine or enamel

or root? or occlusal) adj5 cavit$).tw. 14 ((tooth or teeth or dental or root? or dentine or

occlusal or enamel or cavitated) adj5lesion?).tw.

15 ((tooth or teeth or dental or dentine orenamel) adj5 (minerali$ or deminerali$ orreminerali$)).tw.

16 or/6-15 17 1 or (5 and 16) 18 human/ 19 animal/ use mesz 20 nonhuman/ use emez 21 (19 or 20) not 18 22 17 not 21 23 remove duplicates from 22


51


Appendix 1

Literature search strategies

Science Citation Index 1981 to 16 May2004)Web of Science Proceedings 1990 to 15 May 2004)Web of Knowledge. URL: http://wok.mimas.ac.uk/

#1 TS= (Healozone or curazone)#2 TS= (ozone or o3)#3 TS=(oxidat* or oxidis*)#4 #2 or #3#5 TS=(caries or carious)#6 TS=((tooth or teeth or dental or dentine or

enamel or root* or occlusal) SAME decay*)#7 TS=((tooth or teeth or dental or root* or

dentine or occlusal or enamel or cavitated)SAME lesion*)

#8 TS=((tooth or teeth or dental or dentine orenamel or root* or occlusal) SAME cavit*)

#9 TS=(( tooth or teeth or dental or dentine orenamel) SAME (minerali* OR deminerali*OR reminerali*))

#10 #5 OR #6 OR #7 OR #8 OR #9#11 #4 AND #10#12 #1 OR #11

BIOSIS (1985 to 12 May 2004)Edina. URL: http://edina.ac.uk/biosis/(tn: (humans)) and (((al: (healozone)) or al:(curazone)) or ((((al: (oxidat*)) or al: (oxidis*)) or((al: (ozone)) or al: (o3))) and ((((((al: (caries)) oral: (carious)) or ((((al: (root n5 decay*)) or al:(roots n5 decay*)) or (((al: (dentine n5 decay*)) oral: (enamel n5 decay*)) or al: (occlusal n5decay*))) or (((al: (tooth n5 decay*)) or al: (teethn5 decay*)) or al: (dental n5 decay*)))) or ((((al:(root n5 cavit*)) or al: (roots n5 cavit*)) or (((al:(dentine n5 cavit*)) or al: (occlusal n5 cavit*)) oral: (enamel n5 cavit*))) or (((al: (tooth n5 cavi*))or al: (teeth n5 cavit*)) or al: (dental n5 cavit*))))or (((((al: (root n5 lesion*)) or al: (roots n5lesion*)) or (((al: (dentine n5 lesion*)) or al:(enamel n5 lesion*)) or al: (occlusal n5 lesion*)))or (((al: (tooth n5 lesion*)) or al: (teeth n5lesion*)) or al: (dental n5 lesion*))) or (al:(cavitated n5 lesion*)))) or ((((((al: (tooth n5minerali*)) or al: (tooth n5 reminerali*)) or al:(tooth n5 deminerali*)) or (((al: (teeth n5mineral*)) or al: (teeth n5 reminerali*)) or al:(teeth n5 deminerali*))) or (((al: (dent* n5minerali*)) or al: (dent* n5 reminerali*)) or al:(dent* n5 deminerali*))) or (((al: (enamel n5minerali*)) or al: (enamel n5 reminerali*)) or al:(enamel n5 deminerali*))))))

AMED (1985 to May 2004)Ovid. URL: http://gateway.ovid.com/athens

1 (healozone or curazone).tw2 (ozone or o3).tw.3 (oxidat$ or oxidis$).tw. 4 or/2-35 (caries or carious).tw6 ((tooth or teeth or dental or dentine or enamel

or root? or occlusal) adj5 decay$).tw7 ((tooth or teeth or dental or dentine or enamel

or root? or occlusal) adj5 cavit$).tw8 ((tooth or teeth or dental or root? or dentine or

occlusal or enamel or cavitated) adj5 lesion?).tw9 ((tooth or teeth or dental or dentine or

enamel) adj5 (minerali$ or deminerali$ orreminerali$)).tw

10 or/5-911 1 or (4 and 10)12

Cochrane Library Issue 2, 2004URL: http://www.update-software.com/clibng/cliblogon.htmNational Research Register (Issue 2, 2004)URL: http://www.update-software.com/National/

#1. (healozone or curazone) #2. OZONE single term (MeSH)#3. (ozone or o3) #4. (oxidat* or oxidis*) #5. (#2 or #3 or #4) #6. TOOTH DEMINERALIZATION explode

tree 1 (MeSH) #7. DENTAL CARIES SUSCEPTIBILITY single

term (MeSH) #8. DENTAL ENAMEL SOLUBILITY single

term (MeSH) #9. (caries or carious)

#10. ((tooth or teeth or dental or dentine orenamel or root* or occlusal) and decay*)

#11. ((tooth or teeth or dental or dentine orenamel or root* or occlusal) and cavit*)

#12. ((tooth or teeth or dental or dentine orenamel or root* or occlusal or cavitated) andlesion*)

#13. ((tooth or teeth or dental or dentine orenamel) and (mineralis* or demineralis* orremineralis*))

#14. ((tooth or teeth or dental or dentine orenamel) and (mineraliz* or demineraliz* orremineraliz*))

#15. (#6 or #7 or #8 or #9 or #10 or #11 or#12 or #13 or #14) #16. (#5 and #15) #17. (#1 or #16)

Appendix 1

52

DARE, NHS Economic EvaluationDatabase and HTA Databases (April 2004)NHS Centre for Reviews andDisseminationURL: http://nhscrd.york.ac.uk/welcome.htmOzone or healozone or oxid* - all fieldsDental or caries or carious – all fields

Clinical Trials (18 May 2004)URL: http://clinicaltrials.gov/ct/gui/c/r

Current Controlled Trials (18 May2004)URL: http://www.controlled-trials.com/Ozone or healozone or oxid* – all fields

Health Management InformationConsortium (May 2004)

1 (healozone or curazone).tw. 2 dental caries/ 3 (caries or carious).tw. 4 ((tooth or teeth or dental or dentine or enamel

or root? or occlusal) adj1 decay$).tw. 5 ((tooth or teeth or dental or dentine or enamel

or root? or occlusal) adj1 cavit$).tw.6 ((tooth or teeth or dental or dentine or enamel

or cavitated) adj1 lesion?).tw. 7 ((tooth or teeth or dental or dentine or

enamel) adj1 (minerali$ or deminerali$ orreminerali$)).tw.

8 or/1-7 9 limit 8 to yr=1995 – 2004

Conference Papers Index (1982 to May 2002)Cambridge Scientific Abstracts URL: http://www.csa1.co.uk/KW=(healozone or curazone) or (KW=(ozone oroxidat* or oxidis*) and KW=(caries or carious ordental)) or (KW=(ozone or oxidat* or oxidis*)and KW=(teeth or tooth or cavit*)) or(KW=(ozone or oxidat* or oxidis*) andKW=(occlusal or decay* or lesion*))

Zetoc Conference Search (1993 to May 2004)MIMAS URL: http://zetoc.mimas.ac.uk/Ozone or healoaone or oxid* and (conference:dental or dentist or caries)

IADR Meeting abstractsURL: http://www.iadr.com/Meetings/index.htmlIARD/AADR/CADR 80th General Session, SanDiego, March 2002

IARD/AADR/CADR 82nd General Session,Honolulu, March2004AADR 32nd Annual Meeting and Exhibition, SanAntonio, March 2003IADR 81st General Session, Goteberg 2003IADR, Irish Division Annual Meeting, Belfast,2004BSDR Ann Scientific Meeting, Birmingham, April2004

ozone or healozone or oxid*

HandsearchingJournal of Dental ResearchVol. 79 (Special Issue 2000): 78th General Sessionof IADR, Washington, USA, April 2000.Vol. 79(5) 2000: British Section: Annual ScientificSession, Lancaster, UK, April 2000; Irish Section:Annual Scientific Meeting, Newcastle, Ireland,January 1999.Vol. 80 (Special Issue, AADR Abstracts, January2001): 30th Annual Meeting AADR/25th AnnualMeeting CADR, Chicago, USA, March 2001.Vol. 80(4) (April 2001): British Society for DentalResearch and Irish Division, ContinentalEuropean (1999 and 2000).

Caries ResearchVol. 37(4): 50th Annual ORCA Congress, KonstanzGermany, July 2003.Vol. 36(3): 49th Annual ORCA Congress, NaantaliFinland, July 2002.Vol. 35(4): 48th Annual ORCA Congress, Graz,Austria, July 2001.Vol 34(4): 47th Annual ORCA Congress, Alghero,Sardinia, July 2000.

WebsitesKaVo Dental Ltd. URL: http://www.kavo.com/En/

default.asp. Accessed April 2004.CurOzone USA Inc.

URL: http://www.curozone.com/. Accessed April2004.

DentalOzone. London: Dental Clinique. URL: http://www.dentalozone.co.uk/. AccessedApril 2004.

HealOzone. Dr Julian Holmes. URL: http://www.the-o-zone.cc. Accessed April2004.


53


‘HEALOZONE’ TECHNOLOGY ASSESSMENT REVIEW

DATA EXTRACTION FORM

Reviewer ID: Date information extracted:

Study Details

Study ID: _____________________________________________

Study identifier: _______________________________________

(Surname of first author + year of publication)

Study origin: _________________________________________

Language: ____________________________________________

Published Unpublished

Full text Abstract only

Study Design

RCT Other __________________________________________

Quasi – RCT

Observational Study

For RCTs only: What is the unit of randomisation?

Patient

Tooth/lesion

Tooth/lesion pair


55


Appendix 2

Data extraction form

Participants

Number of eligible patients: Number of patients randomised:

Inclusion criteria: Exclusion criteria:

Interventions

Type of intervention Number of participants

Group 1:

Group 2:

Group 3:

Patient Characteristics

Intervention 1 Intervention 2 Intervention 3 Total

Age (mean, range)

Sex (M/F)

Permanent/Deciduous teeth

Primary or Secondary caries

Comparability at baseline

Characteristics of the intervention

Location of trial centre(s):

Source of participants:

Method of recruitment:

Appendix 2

56

Method of randomisation:

Dosage of HealOzone application:

Repeated applications:

Was a reductant applied? If yes, what was its formulation?

Did patient receive the aftercare kit (e.g. toothpaste, mouth rinse and spray)?

Length of follow-up:

Compliance with the treatment:

Number lost to follow-up:

Caries Information

Method of caries examination:

Tooth location, lesion location, and type of lesion:

Severity of caries:

Outcomes

Intervention 1 Intervention 2 Intervention 3

Non-cavitated caries

Reversal of caries

Progression of caries

Utilisation of dental resources


57


Adverse reactions

Patient–centred measures (e.g. patient satisfaction and preference, relief of pain/discomfort)

Quality of life

Cavitated caries

Time to restorative interventions

Need for further restorative interventions

Symptoms of pulpal pathology

Other comments

Appendix 2

58


59


Appendix 3

Checklist for the quality assessment of randomised controlled trials

(adapted from Verhagen, 199834)

Criteria Yes No Unclear Comments

1. Was the assignment to the treatment groups really random?Adequate approaches to sequence generation � computer-generated random tables � random number tablesInadequate approaches to sequence generation� use of alternation, case record numbers, birth dates or week days

2. Was the unit of randomisation clear?

3. Was the treatment allocation concealed?Adequate approaches to concealment of randomisation� centralised or pharmacy-controlled randomisation� serially-numbered identical containers� on-site computer based system with a randomisation sequence that is

not readable until allocation� other approaches with robust methods to prevent foreknowledge of

the allocation sequence to clinicians and patients Inadequate approaches to concealment of randomisation� use of alternation, case record numbers, birth dates or week days� open random numbers lists� serially numbered envelopes (even sealed opaque envelopes can be

subject to manipulation)

4. Were the groups similar at baseline in terms of prognostic factors?

5. Were the eligibility criteria specified?

6. Were the groups treated in the same way apart from the intervention received?

7. Was the outcome assessor blinded to the treatment allocation?

8. Was the care provider blinded?

9. Were the patients blinded?

10. Were the point estimates and measures of variability presented for the primary outcome measures?

11. Was the withdrawal/dropout rate likely to cause bias?

12. Did the analyses include an intention-to-treat analysis?


61


Appendix 4

Characteristics of included studies:

full-text reports

Appendix 4

62 TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

cont

inue

d

Roo

t ca

ries

: per

man

ent

dent

itio

n

Bays

an a

nd L

ynch

,20

0436

,41–

44

(Bel

fast

, UK

)

n=

79 (2

20 p

rimar

yca

vita

ted

and

non-

cavi

tate

d ro

ot c

ario

usle

sions

)

Age

, mea

n ±

SD (r

ange

):65

±14

.76

(30–

72) y

ears

Gen

der

(M/F

):49

/30

Toot

h an

d le

sion

loca

tion:

root

sur

face

lesio

ns.

Car

ies

risk

asse

ssm

ent:

NS

Des

ign:

RC

T(u

npub

lishe

d)

Uni

t of

rand

omisa

tion:

lesio

n

Met

hod

ofra

ndom

isatio

n:N

S

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: unc

lear

ITT:

no

Leng

th o

f fol

low

-up

: 12

mon

ths

Lost

at

follo

w-u

p:fiv

e su

bjec

ts

Com

para

bilit

y of

grou

ps a

tba

selin

e: u

ncle

ar

Sett

ing:

gen

eral

dent

al p

ract

ices

Two

or fo

urpr

imar

y no

n-ca

vita

ted

and

cavi

tate

d ro

otca

rious

lesio

nsw

ith s

ever

ityin

dex

II(le

athe

ryle

sions

)

Gro

up 1

:cle

anin

g of

the

toot

h su

rfac

e, a

pplic

atio

n of

O3

+ r

educ

tant

The

pro

cedu

re w

asre

peat

ed a

fter

1 m

onth

with

out

ozon

e an

d at

3m

onth

s w

ith o

zone

Gro

up 2

:red

ucta

nt o

nly.

The

pro

cedu

re w

asre

peat

ed a

fter

1 m

onth

and

at t

he 3

-mon

th fo

llow

-up

Gro

up 3

:O3

+ s

eala

nt (S

eal

& P

rote

ct, D

ents

ply,

Ger

man

y)

The

pro

cedu

re w

asre

peat

ed a

t 3

mon

ths.

Seal

ants

wer

e re

appl

ied

only

if a

part

ial o

r co

mpl

ete

loss

of t

he s

eala

nt w

as s

uspe

cted

Gro

up 4

:sea

lant

onl

y (S

eal

& P

rote

ct, D

ents

ply,

Ger

man

y)

Seal

ants

wer

e re

appl

ied

afte

r 1

and

3 m

onth

s on

ly if

a pa

rtia

l or

com

plet

e lo

ss o

fth

e se

alan

t w

as s

uspe

cted

Redu

ctan

t fo

rmul

atio

n:So

dium

fluo

ride

(110

0pp

mF)

, xyl

itol,

sodi

um b

enzo

ate,

amon

g ot

her

activ

ein

gred

ient

s

Ozo

ne d

osag

e:10

sec

onds

Reve

rsal

of c

arie

s, g

roup

s 1

and

2:at

12

mon

ths

47%

of P

RCLs

reve

rsed

from

sev

erity

inde

x 1

to0

(har

d) in

the

ozo

ne g

roup

,w

hile

non

e be

cam

e ha

rd in

the

cont

rol g

roup

(p<

0.00

1). 5

2%of

lesio

ns r

ever

sed

from

2 t

o 1

inth

e oz

one

grou

p co

mpa

red

with

11.6

% in

the

con

trol

gro

up(p

<0.

001)

Cav

itate

d le

sions

in t

he o

zone

grou

p di

d no

t sh

ow t

he s

ame

tren

d of

impr

ovem

ent

of n

on-

cavi

tate

d le

sions

. Per

cent

age

ofle

sions

tha

t be

cam

e ha

rdde

crea

sed

from

9.1

at

1 m

onth

to

1.4

at 9

mon

ths,

sug

gest

ing

wor

seni

ng o

f cav

itate

d ca

rious

lesio

ns. D

ata

for

the

cont

rol

grou

p w

ere

not

give

n

Mar

gina

l ada

ptat

ion

of t

he r

oot

seal

ant

(mod

ified

USP

HS

crite

ria):

61%

inta

ct s

eala

nts

in t

he

O3

+ s

eala

nt g

roup

com

pare

dw

ith 2

6.1%

in t

he s

eala

nt-o

nly

grou

p (p

<0.

001)

Sign

ifica

nt d

iffer

ence

s in

the

chan

ges

in b

oth

the

ECM

read

ings

and

DIA

GN

Ode

ntre

adin

gs in

the

ozon

e an

d co

ntro

l gro

ups

(p<

0.0

01)

Adv

erse

eve

nts:

none

obs

erve

d

The

num

ber

of le

sions

inea

ch in

terv

entio

n gr

oup

was

not

clea

rly r

epor

ted

All

subj

ects

enr

olle

d in

the

stud

y re

ceiv

ed p

reve

ntiv

ead

vice

, inc

ludi

ng o

ral

hygi

ene

and

diet

ary

advi

ce,

and

wer

e gi

ven

a to

othb

rush

and

toot

hpas

te (N

atur

alW

hite

, Nat

ural

Whi

te In

c.,

USA

, 110

0 pp

m F

)

Unc

lear

whe

ther

cle

anin

g of

the

root

sur

face

was

perf

orm

ed b

efor

e tr

eatm

ent

in g

roup

s 2,

3 a

nd 4

It w

as r

epor

ted

that

sub

ject

sw

ho “

pres

ente

d w

ith a

nyfo

rm o

f disc

omfo

rt w

ere

imm

edia

tely

tre

ated

with

conv

entio

nal d

rillin

g an

dfil

ling

proc

edur

es”,

but

no

furt

her

info

rmat

ion

was

prov

ided

Met

hods

for

stat

istic

alan

alys

es n

ot c

lear

lyre

port

ed. U

ncle

ar w

heth

erth

e re

sults

wer

e ad

just

edfo

r co

varia

tes/

risk

fact

ors

Emph

asis

on n

on-c

avita

ted

lesio

ns


63


TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

(con

t’d)

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

Car

ies

asse

ssm

ent:

ECM

III

(Lod

e D

iagn

ostic

s BV

, The

Net

herla

nds)

, DIA

GN

oden

t(K

aVo,

Ger

man

y) a

ndcl

inic

al c

riter

ia. T

he s

ever

ityof

lesio

ns w

as a

sses

sed

on a

four

-poi

nt s

cale

(0 =

har

dle

sions

; 4 =

sof

t le

sions

). In

addi

tion,

mod

ified

USP

HS

crite

ria w

ere

used

for

asse

ssin

g gr

oups

3 a

nd 4

Ass

esso

rs/o

pera

tors

: sin

gle

oper

ator

(A. B

aysa

n)

Ozo

ne d

evic

e ou

tput

: NS

cont

inue

d

Appendix 4

64 TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

(con

t’d)

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

Hol

mes

, 200

335,3

9,40

(Ber

kshi

re, U

K)

n=

89

(178

prim

ary

non-

cavi

tate

d ro

ot c

ario

usle

sions

, 89

lesio

ns in

eac

hgr

oup)

Age

, mea

n ±

SD (r

ange

):70

.8 ±

6 (6

0–82

)

Toot

h an

d le

sion

loca

tion

:lea

ther

y ro

ofsu

rfac

e le

sions

(sev

erity

inde

x II)

Car

ies

risk

asse

ssm

ent:

NS

Des

ign:

RCT

Uni

t of

rand

omisa

tion:

lesio

n

Met

hod

ofra

ndom

isatio

n:co

mpu

ter-

gene

rate

dra

ndom

tab

les

Con

ceal

men

t of

allo

catio

n:N

S

Blin

ding

:dou

ble

blin

d

ITT:

no

Leng

th o

f fol

low

-up

:3, 6

, 12,

18

and

21m

onth

s

Lost

at

follo

w-u

p:tw

o at

18

mon

ths

Com

para

bilit

y of

grou

ps a

tba

selin

e:un

clea

r

Sett

ing:

gene

ral

dent

al p

ract

ice

Adu

lts w

ithtw

o le

athe

ryno

n-ca

vita

ted

PRC

Ls

Gro

up 1

:app

licat

ion

of O

3+

red

ucta

nt +

pat

ient

car

eki

t

Gro

up 2

:air

trea

tmen

t +

redu

ctan

t on

ly +

pat

ient

care

kit

Repe

ated

app

licat

ions

of O

3+

red

ucta

nt a

t 3,

6, 1

2 an

d18

mon

ths

Redu

ctan

t fo

rmul

atio

n:xy

litol

, flu

orid

e, c

alci

um,

phos

phat

e an

d zi

nc (n

oco

ncen

trat

ions

pro

vide

d)

Ozo

ne d

osag

e:40

sec

onds

Car

ies

asse

ssm

ent:

ECM

(Lod

e D

iagn

ostic

s BV

, The

Net

herla

nds)

, DIA

GN

oden

t(K

aVo,

Ger

man

y) a

ndvi

sual

/tac

tile

exam

inat

ion

met

hod

Ass

esso

rs/o

pera

tors

:the

ozon

e tr

eatm

ent

was

appl

ied

by a

diff

eren

top

erat

or t

o th

e on

ere

cord

ing

the

seve

rity

ofle

sions

. Unc

lear

whe

ther

the

oper

ator

who

ass

esse

dou

tcom

es w

as t

he s

ame

one

who

did

allo

cate

d su

bjec

tsto

inte

rven

tion

grou

ps. A

sam

ple

of 1

5 su

bjec

ts (3

0le

sions

) was

exa

min

ed b

y a

third

den

tist

to t

est

repr

oduc

ibili

ty o

f res

ults

18 m

onth

s fo

llow

-up.

Reve

rsal

of c

arie

s: 8

7/87

lesio

ns in

the

ozon

e gr

oup

reve

rsed

(bec

ame

hard

) com

pare

d w

ith1/

87 in

the

con

trol

gro

up

(p<

0.0

1)

Prog

ress

ion

of c

arie

s: 3

2/87

lesio

ns in

the

con

trol

gro

upw

orse

ned

from

leat

hery

to

soft

and

54/8

7 di

d no

t ch

ange

Adv

erse

eve

nts:

non

e ob

serv

ed

All

subj

ects

enr

olle

d in

the

stud

y re

ceiv

ed in

form

atio

non

ora

l hyg

iene

, bru

shin

gte

chni

ques

and

die

t. In

part

icul

ar, a

ll su

bjec

tsre

ceiv

ed in

stru

ctio

ns o

nho

w t

o us

e th

ere

min

eral

ising

too

thpa

ste

twic

e a

day,

the

min

eral

mou

thw

ash

twic

e a

day

and

the

rem

iner

alisi

ng s

pray

four

times

a d

ay

All

subj

ects

wer

e of

fere

d a

phar

mac

olog

ical

tre

atm

ent,

whi

ch t

hey

all a

ccep

ted

asan

alte

rnat

ive

to t

hetr

aditi

onal

dril

ling

and

fillin

g.N

o de

tails

of t

heph

arm

acol

ogic

al t

reat

men

tw

ere

prov

ided

The

tw

o de

ntist

s w

hoal

loca

ted

subj

ects

to

inte

rven

tion

grou

ps a

ndas

sess

ed s

ever

ity o

f les

ions

,an

d th

e th

ird d

entis

t w

hoas

sess

ed r

epro

duci

bilit

y of

data

, wer

e no

tac

know

ledg

ed in

the

pap

er

The

21-

mon

th fi

ndin

gspu

blish

ed in

abs

trac

t fo

rmat

(Hol

mes

, 200

440se

em t

oco

ntra

dict

tho

se r

epor

ted

inth

e fu

ll te

xt

cont

inue

d


65


TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

(con

t’d)

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

Ozo

ne d

evic

e ou

tput

: it

was

repo

rted

tha

t th

eH

ealO

zone

uni

t w

as fi

tted

with

a m

odifi

ed c

ontr

olin

tegr

ated

ele

ctro

nic

chip

.U

ncle

ar w

heth

er t

his

mod

ified

chi

p co

uld

allo

wbe

tter

cal

ibra

tion

and

mon

itorin

g of

ozo

ne d

oses

cont

inue

d

Appendix 4

66 TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

(con

t’d)

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

cont

inue

d

Pit

and

fiss

ure

cari

es: p

erm

anen

t de

ntit

ion

Abu

-Nab

a’a,

200

3,m

ain

stud

y37,4

5–50

(Bel

fast

, UK

)

n=

90

(258

prim

ary

occl

usal

pit

and

fissu

re c

ario

usle

sions

)

Age

: 79

subj

ects

bet

wee

n12

and

31

year

s, 8

subj

ects

bet

wee

n 32

and

41 y

ears

, and

3 s

ubje

cts

>41

yea

rs

Gen

der

(M/F

): 35

/55

Toot

h an

d le

sion

loca

tion:

al

l pos

terio

r te

eth

in t

heup

per

and

low

er ja

ws.

Cen

tral

gro

oves

and

pits

wer

e th

e m

ost

com

mon

lyob

serv

ed le

sions

Car

ies

risk

asse

ssm

ent:

NS

Des

ign:

RC

T(u

npub

lishe

d)

Uni

t of

rand

omisa

tion:

lesio

n

Met

hod

ofra

ndom

isatio

n:ra

ndom

sam

plin

gdi

git

tabl

es

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: unc

lear

ITT:

no

Leng

th o

f fol

low

-up

: 1, 3

, 6, 9

and

12 m

onth

s

Lost

at

follo

w-u

p:32

sub

ject

s

Com

para

bilit

y of

grou

ps a

t ba

selin

e:m

ore

seve

rele

sions

(ind

exsc

ores

of 2

and

3)

in t

he t

reat

men

tgr

oup

(p =

0.0

55).

Mor

e m

olar

s in

the

trea

tmen

t gr

oup

than

in t

he c

ontr

olgr

oup.

Sett

ing:

gen

eral

dent

al p

ract

ice

Mal

es a

ndfe

mal

es>

12ye

ars

old

with

prim

ary

occl

usal

pit

and

fissu

reca

rious

lesio

nsin

at

leas

t tw

ote

eth

of t

hepe

rman

ent

post

erio

rde

ntiti

on,

whi

ch w

ere

acce

ssib

le fo

rth

e di

agno

stic

proc

edur

es

Befo

re t

reat

men

t al

l les

ions

wer

e di

sclo

sed

and

clea

ned

with

an

air-

abra

sive

syst

em(P

ROPH

Yfle

x 2,

KaV

o,G

erm

any)

Gro

up 1

: app

licat

ion

of O

3+

red

ucta

nt

Gro

up 2

: red

ucta

nton

ly/c

ontr

ol

Gro

up 3

: O3

+ r

educ

tant

+fis

sure

sea

lant

(Gua

rdia

n,Ke

rr)

Gro

up 4

: red

ucta

nt +

seal

ant

Redu

ctan

t fo

rmul

atio

n:So

dium

fluo

ride

(110

0pp

mF)

, xyl

itol a

nd z

inc

chlo

ride

amon

g ot

her

activ

ein

gred

ient

s

Ozo

ne d

osag

e: 1

0 se

cond

s

Car

ies

asse

ssm

ent:

ECM

(Lod

e D

iagn

ostic

s BV

, The

Net

herla

nds)

, DIA

GN

oden

t(K

aVo,

Ger

man

y) a

ndcl

inic

al s

ever

ity (E

kstr

and,

1998

).9In

add

ition

, mod

ified

USP

HS

crite

ria +

radi

ogra

phic

ass

essm

ents

wer

e us

ed fo

r as

sess

ing

grou

ps 3

and

4

Gro

ups

1 an

d 2

Reve

rsal

of c

arie

s: n

o sig

nific

ant

diffe

renc

es b

etw

een

grou

ps in

the

mea

n ch

ange

from

bas

elin

e:G

roup

1: 0

.283

(0.6

4)

Gro

up 2

: 0.4

43 (0

.74)

; (p

= 0

.112

)

ECM

val

ues:

no

signi

fican

tdi

ffere

nces

in t

he m

ean

chan

gefr

om b

asel

ine

valu

es b

etw

een

grou

ps:

Gro

up 1

(109

lesio

ns):

mea

n lo

g ech

ange

0.0

20 (1

.4)

Gro

up 2

(109

lesio

ns):

0.07

3(1

.61)

(p=

0.7

5)

Excl

udin

g te

eth

with

bas

elin

eEC

M s

core

0:

Gro

up 1

(77

lesio

ns):

0.32

7 (1

.32)

Gro

up 2

(69

lesio

ns):

0.07

3(1

.37)

; p =

0.5

4

DIA

GN

Ode

nt v

alue

s: n

osig

nific

ant

diffe

renc

es b

etw

een

grou

ps (p

> 0

.05)

at

any

follo

w-

up v

isits

Gro

ups

3 an

d 4

Seco

ndar

y ca

ries:

no

signi

fican

tdi

ffere

nces

bet

wee

n gr

oups

(tw

ose

cond

ary

carie

s in

the

ozo

negr

oup

and

two

seco

ndar

y ca

ries

in t

he c

ontr

ol g

roup

)

All

subj

ects

enr

olle

d in

the

stud

y re

ceiv

ed p

reve

ntiv

ead

vice

and

wer

e gi

ven

ato

othb

rush

and

toot

hpas

te(N

atur

al W

hite

; Nat

ural

Whi

te In

c., U

K, 1

100

ppm

F)

Seal

ant

was

rea

pplie

d if

nece

ssar

y an

d O

3ap

plic

atio

nre

peat

ed

Subj

ects

’ att

enda

nce

tofo

llow

-up

visit

s va

ried.

The

num

ber

of s

ubje

cts

asse

ssed

by E

CM

diff

ered

from

the

num

ber

of s

ubje

cts

asse

ssed

by D

IAG

NO

dent

at

follo

w-

up v

isits


67


TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

(con

t’d)

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

cont

inue

d

Ass

esso

rs/o

pera

tors

: thr

eeop

erat

ors

wer

e re

port

ed t

oas

sess

rad

iogr

aphs

. A s

ingl

eop

erat

or a

sses

sed

the

lesio

ns a

nd in

terp

rete

d EC

Man

d D

IAG

NO

dent

find

ings

(L. A

bu-N

aba’

a)

Ozo

ne d

evic

e ou

tput

: NS

Seal

ant

rete

ntio

n: p

artia

l los

s in

the

mar

gins

of t

he s

eala

nts

in32

.7%

in t

he O

3+

sea

lant

gro

upco

mpa

red

with

29.

8% in

the

seal

ant-

only

gro

up (p

> 0

.05)

No

signi

fican

t di

ffere

nces

in t

erm

sof

fiss

ure

seal

ant

colo

ur a

ndra

diog

raph

ic d

epth

of

radi

oluc

ency

bet

wee

n gr

oups

Appendix 4

68 TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

(con

t’d)

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

cont

inue

d

Abu

-Nab

a’a,

200

3,pi

lot

stud

y37,5

1,52

(Bel

fast

, UK

)

n=

8(3

8 oc

clus

al p

it an

d fis

sure

lesio

ns, 1

9 in

eac

h gr

oup)

Des

ign:

RC

T(u

npub

lishe

d)

Uni

t of

rand

omisa

tion:

lesio

n

Met

hod

ofra

ndom

isatio

n:ra

ndom

sam

plin

gdi

git

tabl

es

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: unc

lear

ITT:

no

Leng

th o

f fol

low

-up

: 1, 3

and

6m

onth

s

Lost

at

follo

w-u

p:un

clea

r

Com

para

bilit

y of

grou

ps a

t ba

selin

e:m

ore

seve

rele

sions

(ind

exsc

ore

of 3

) in

the

cont

rol g

roup

Sett

ing:

gen

eral

dent

al p

ract

ice

Mal

es a

ndfe

mal

es>

12ye

ars

old

with

prim

ary

occl

usal

pit

and

fissu

reca

rious

lesio

nsin

at

leas

t tw

ote

eth

of t

hepe

rman

ent

post

erio

rde

ntiti

on,

whi

ch w

ere

acce

ssib

le fo

rth

e di

agno

stic

proc

edur

es

Befo

re t

reat

men

t al

l les

ions

wer

e di

sclo

sed

and

clea

ned

with

an

air-

abra

sive

syst

em(P

ROPH

Yfle

x 2,

KaV

o,G

erm

any)

Gro

up 1

: app

licat

ion

of O

3+

red

ucta

nt

Gro

up 2

: red

ucta

nt o

nly

At

3 m

onth

s gr

oup

1re

ceiv

ed a

noth

er a

pplic

atio

nof

O3

Redu

ctan

t fo

rmul

atio

n:so

dium

fluo

ride

(110

0 pp

m F

), xy

litol

and

zinc

chl

orid

e am

ong

othe

rac

tive

ingr

edie

nts

Ozo

ne d

osag

e: 4

0 se

cond

s

Car

ies

asse

ssm

ent:

ECM

(Lod

e D

iagn

ostic

s BV

, The

Net

herla

nds)

, DIA

GN

Ode

nt(K

aVo,

Ger

man

y), a

ndcl

inic

al c

riter

ia (E

kstr

and,

1998

)9

Ass

esso

rs/o

pera

tors

:U

ncle

ar. I

t w

ould

see

m t

hat

a sin

gle

oper

ator

ass

esse

dth

e le

sions

and

inte

rpre

ted

ECM

and

DIA

GN

Ode

ntfin

ding

s (L

. Abu

-Nab

a’a)

Ozo

ne d

evic

e ou

tput

: 33%

of t

he o

utco

me

expe

cted

Clin

ical

sev

erity

sco

res:

not

signi

fican

t di

ffere

nces

bet

wee

ngr

oups

at

any

follo

w-u

p vi

sits

(p>

0.0

5)

ECM

and

DIA

GN

Ode

nt r

eadi

ngs:

no s

igni

fican

t di

ffere

nces

bet

wee

ngr

oups

(p>

0.0

5)

Clin

ical

indi

ces

Har

dnes

s in

dex

scor

e: 1

1 le

sions

in t

he o

zone

gro

up b

ecam

eha

rder

com

pare

d w

ith fo

ur in

the

cont

rol g

roup

(p <

0.0

5)Tw

o le

sions

in t

he c

ontr

ol g

roup

beca

me

softe

r

Cha

nge

in t

he v

isual

inde

x sc

ore:

eigh

t te

eth

in t

he t

reat

men

tgr

oup

chan

ged

posit

ivel

y at

the

6-

mon

th fo

llow

-up

com

pare

dw

ith o

ne t

ooth

in t

he c

ontr

olgr

oup

(p<

0.05

)

Cha

nge

in t

he c

avita

tion

scor

e:

six t

eeth

had

a d

ecre

ased

cav

itysc

ore

in t

he o

zone

gro

upco

mpa

red

with

five

tee

th in

the

cont

rol g

roup

. The

diff

eren

cebe

twee

n in

terv

entio

n gr

oups

was

not

signi

fican

t (p

> 0

.05)

Cha

nge

in c

olou

r: n

o sig

nific

ant

diffe

renc

es b

etw

een

grou

ps(p

>0.

05)

Cha

nge

in fr

oste

d en

amel

and

unde

rmin

ed e

nam

el: n

o sig

nific

ant

diffe

renc

es b

etw

een

grou

ps(p

>0.

05)

All

subj

ects

enr

olle

d in

the

stud

y re

ceiv

ed p

reve

ntiv

ead

vice

and

wer

e gi

ven

ato

othb

rush

and

too

thpa

ste

(110

0 pp

m F

)


69


TA

BLE

21

Char

acte

ristic

s of

full-

text

repo

rts

(con

t’d)

Aut

hor(

s)N

o. a

nd c

hara

cter

isti

csD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

and

cav

eats

of p

arti

cipa

nts

and

crit

eria

cari

ous

lesi

ons

NS,

not

sta

ted;

ITT,

inte

ntio

n-to

-tre

at, O

3, o

zone

gas

.

Pit

and

fiss

ure

cari

es: p

rim

ary

dent

itio

n

Abu

-Sal

em, 2

00438

(Bel

fast

, UK

)n

= 2

1(7

4 no

n-ca

vita

ted

occl

usal

cario

us le

sions

in p

rimar

ym

olar

s)

Age

ran

ge: 7

–9 y

ears

(7 y

ears

28%

, 8 y

ears

48%

, 9 y

ears

24%

)

Gen

der

(M/F

): 9/

21

Car

ies

risk

asse

ssm

ent:

NS

Des

ign:

RC

T (u

npub

lishe

d)

Uni

t of

ran

dom

isatio

n:le

sion

Met

hod

of r

ando

misa

tion:

com

pute

r-ge

nera

ted

rand

om t

able

s

Con

ceal

men

t of

allo

catio

n:N

S

Blin

ding

: exa

min

er b

linde

dto

res

ults

of p

revi

ous

test

san

d ou

tcom

es o

f pre

viou

sre

cord

s

ITT:

no

Leng

th o

f fol

low

-up:

3, 6

, 9an

d 12

mon

ths

Lost

at

follo

w-u

p: fo

ursu

bjec

ts (1

6le

sions

)

Com

para

bilit

y of

gro

ups

atba

selin

e: t

here

was

asig

nific

ant

diffe

renc

e in

mea

n D

IAG

NO

dent

sco

res

at b

asel

ine

(p<

0.0

1).

Lesio

ns in

ozo

ne g

roup

appe

ared

to

be m

ore

seve

re t

han

thos

e in

the

cont

rol g

roup

.

Sett

ing:

gen

eral

den

tal

prac

tice

Chi

ldre

n7–

9ye

ars

old

with

at

leas

ttw

o ca

rious

lesio

ns in

the

post

erio

rpr

imar

y te

eth

and

abse

nce

of o

cclu

sal

rest

orat

ion,

fissu

rese

alan

ts,

hypo

plas

ticpi

ts a

ndfr

actu

res

exte

ndin

g in

tode

ntin

e or

cavi

tatio

nsre

sulti

ng fr

omca

rious

att

ack

on t

heoc

clus

alsu

rfac

e

Befo

re t

reat

men

t, te

eth

wer

e cl

eane

d us

ing

the

PRO

PHYf

lex-

2 sy

stem

for

5se

cond

s

Gro

up 1

: O3

+ r

educ

tant

Gro

up 2

: red

ucta

nt o

nly

Redu

ctan

t fo

rmul

atio

n:so

dium

ben

zoat

e (1

100

ppm

F),

xylit

ol, z

inc

chlo

ride

and

sodi

um c

itrat

eam

ong

othe

r ac

tive

ingr

edie

nts

Ozo

ne d

osag

e: 1

0 se

cond

s

Car

ies

asse

ssm

ent:

ECM

(Lod

e D

iagn

ostic

s BV

, The

Net

herla

nds)

, DIA

GN

Ode

nt(K

aVo,

Ger

man

y) a

ndcl

inic

al c

riter

ia (E

kstr

and,

1998

)9

12-m

onth

follo

w-u

p

Clin

ical

sev

erity

sco

res:

over

all t

here

was

a li

ttle

redu

ctio

n in

clin

ical

seve

rity

scor

es in

the

ozon

e gr

oup

and

anin

crea

se in

sco

res

in t

heco

ntro

l gro

up. T

here

was

a sig

nific

ant

effe

ct o

ftr

eatm

ent

on c

linic

alse

verit

y sc

ores

ove

r tim

e(m

ixed

mod

els

AN

OVA

p<

0.0

1)

Log

ECM

and

DIA

GN

Ode

nt r

eadi

ngs:

ther

e w

as a

sig

nific

ant

effe

ct o

f tim

e an

dtr

eatm

ent

on t

he m

ean

log e

ECM

rea

ding

s(p

<0.

001)

and

the

mea

nD

IAG

NO

dent

rea

ding

s(p

<0.

001)

. The

re w

asal

so a

n ov

eral

l sig

nific

ant

effe

ct o

f tim

e an

dtr

eatm

ent

on E

CM

sco

res

(p<

0.00

1) a

nd a

n ov

eral

lin

crea

se in

the

DIA

GN

Ode

nt s

core

s in

the

cont

rol g

roup

com

pare

d w

ith t

he o

zone

grou

p (p

<0.

05)

All

subj

ects

rec

eive

dpr

even

tive

advi

ce a

ndw

ere

give

n a

toot

hbru

sh (B

rillia

nt,

soft

toot

hbru

sh;

Brill

iant

Pro

duct

s, U

K)

and

toot

hpas

te(N

atur

al W

hite

, Nat

ural

Whi

te In

c., U

K11

00pp

m F

) at

each

reca

ll to

be

used

thro

ugho

ut t

he s

tudy

The

mea

n lo

g eEC

Mre

adin

gs, m

ean

DIA

GN

Ode

nt r

eadi

ngs,

ECM

sco

res,

DIA

GN

Ode

nt s

core

san

d cl

inic

al s

ever

ityin

dex

wer

e an

alys

edus

ing

AN

OVA

(mix

edef

fect

mod

el)

Resu

lts r

epor

ted

in a

form

at t

hat

did

not

allo

w a

ny fu

rthe

ran

alys

is


71


Appendix 5

Characteristics of included studies:

abstracts

Appendix 5

72 TA

BLE

22

Char

acte

ristic

s of

abs

trac

ts

Aut

hor(

s)N

o. o

f par

tici

pant

sD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

(no.

and

typ

e of

cr

iter

iale

sion

s)

cont

inue

d

Lync

h et

al.,

2004

57(B

elfa

st,

UK

)

260

(tw

o PR

CLs

: 60

subj

ects

with

tw

o so

ftPR

CLs

and

200

with

two

leat

hery

non

-ca

vita

ted

PRC

Ls, l

east

seve

re c

ateg

ory)

Des

ign:

RC

T

Uni

t of

rand

omisa

tion:

lesio

n

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: blin

ded

outc

ome

asse

ssor

ITT:

no

Leng

th o

f fol

low

-up:

6m

onth

s

Lost

at

follo

w-u

p: N

S

Sett

ing:

NS

Two

prim

ary

root

car

ious

lesio

ns

Gro

up 1

: O3

(260

lesio

ns)

Gro

up 2

: no

trea

tmen

t(2

60 le

sions

)

Ozo

ne d

osag

e: N

S

Car

ies

asse

ssm

ent:

clin

ical

asse

ssm

ent

Reve

rsal

of c

arie

s:

Soft

lesio

ns: a

t 6

mon

ths,

48/

60 o

foz

one-

trea

ted

soft

PRC

Ls h

adre

vers

ed (f

rom

inde

x 4

to 3

), no

signi

fican

t ch

ange

s in

con

trol

sof

tle

sions

(p <

0.0

1)

Leat

hery

lesio

ns: 1

89/2

00 o

foz

one-

trea

ted

PRC

Ls h

adre

vers

ed fr

om in

dex

1 to

0 (h

ard

to a

rres

ted)

, no

signi

fican

tch

ange

s fo

r co

ntro

l les

ions

(p<

0.01

)

Adv

erse

eve

nts:

non

e ob

serv

ed

Roo

t ca

ries

Hol

mes

and

Lyn

ch,

2004

53(B

elfa

st,

UK

)

38 (7

6 no

n-ca

vita

ted

occl

usal

car

ies

lesio

ns)

Des

ign:

RC

T

Uni

t of

rand

omisa

tion:

lesio

n

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: NS

ITT:

no

Leng

th o

f fol

low

-up:

6m

onth

s

Lost

at

follo

w-u

p:th

ree

subj

ects

Sett

ing:

gen

eral

den

tal

prac

tice

Two

non-

cavi

tate

d ea

rlyoc

clus

alca

rious

lesio

nsw

ithra

diog

raph

icra

diol

ucen

cies

exte

ndin

g2–

4m

m in

tode

ntin

e

Gro

up 1

: air

abra

sion

+ O

3+

min

eral

was

h +

gla

ssio

nom

er s

eala

nt. A

fter

3m

onth

s th

e gl

ass

iono

mer

seal

ant

was

diss

ecte

d an

dre

plac

ed w

ith a

pos

terio

rco

mpo

site

Gro

up 2

: con

vent

iona

ldr

illin

g an

d fil

ling

usin

gpo

ster

ior

com

posit

e

Ozo

ne d

osag

e: 4

0 se

cond

s

Car

ies

asse

ssm

ent:

radi

ogra

phic

and

clin

ical

asse

ssm

ent

No

post

-ope

rativ

e se

nsiti

vity

was

asso

ciat

ed w

ith o

zone

tre

atm

ent,

whi

le 6

/35

subj

ects

in t

heco

nven

tiona

l tre

atm

ent

grou

pco

mpl

aine

d of

som

e po

st-

oper

ativ

e se

nsiti

vity

Reve

rsal

of c

arie

s: a

t 3

mon

ths

all

ozon

e de

ntin

e ca

ries

was

har

dan

d re

quire

d no

add

ition

alre

mov

al

Adv

erse

eve

nts:

non

e ob

serv

ed

Prog

ress

ion

of c

arie

s in

the

conv

entio

nal t

reat

men

tgr

oup

not

repo

rted

‘Sen

sitiv

ity’ i

s a

mea

sure

used

to

asse

ss la

rge

necr

otic

lesio

ns a

nd it

is c

onsid

ered

inap

prop

riate

for

asse

ssin

gea

rly c

ario

us le

sions

Pit

and

fiss

ure

cari

es


73


TA

BLE

22

Char

acte

ristic

s of

abs

trac

ts (

cont

’d)

Aut

hor(

s)N

o. o

f par

tici

pant

sD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

(no.

and

typ

e of

cr

iter

iale

sion

s)

cont

inue

d

Hol

mes

, 200

354

(Ber

kshi

re, U

K)

376

(236

4 pr

imar

y no

n-ca

vita

ted

occl

usal

fiss

ure

lesio

ns)

Des

ign:

RC

T

Uni

t of

rand

omisa

tion:

lesio

n

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: NS

ITT:

no

Leng

th o

f fol

low

-up:

12 m

onth

s

Lost

at

follo

w-u

p: 6

1

Sett

ing:

gen

eral

den

tal

prac

tice

Prim

ary

occl

usal

fissu

re le

sions

with

car

ies

judg

ed t

oex

tend

2 m

min

to d

entin

e(1

170

teet

h)

Gro

up 1

: O3

trea

tmen

t

Gro

up 2

: no

trea

tmen

t

Ozo

ne d

osag

e: 1

0, 2

0, 3

0 or

40 s

econ

ds d

epen

ding

on

the

clin

ical

sev

erity

.A

pplic

atio

ns w

ere

repe

ated

ever

y 3

mon

ths

if re

vers

alha

d no

t oc

curr

ed

Car

ies

asse

ssm

ent:

DIA

GN

Ode

nt (K

aVo,

Ger

man

y) a

nd c

linic

alas

sess

men

t

Reve

rsal

of c

arie

s: 9

9% in

the

ozon

e gr

oup

(191

8 le

sions

); th

eco

ntro

l les

ions

did

not

cha

nge

signi

fican

tly

The

DIA

GN

Ode

nt v

alue

sco

rrel

ated

with

the

clin

ical

findi

ngs

(p <

0.0

1)

Adv

erse

eve

nts:

non

e ob

serv

ed

A t

otal

of 1

937/

2364

rece

ived

ozo

ne a

pplic

atio

n.U

ncle

ar h

ow m

any

lesio

nsw

ere

rand

omly

allo

cate

d to

each

gro

up (u

nbal

ance

dra

ndom

isatio

n?)

Ham

id, 2

00355

(Lon

don,

UK

)18

4 (1

84 n

on-c

avita

ted

pit

and

fissu

re c

ario

usle

sions

)

Des

ign:

RC

T

Uni

t of

rand

omisa

tion:

pat

ient

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: NS

ITT:

unc

lear

Leng

th o

f fol

low

-up:

6m

onth

s

Lost

at

follo

w-u

p:un

clea

r

Sett

ing:

NS

Prim

ary

early

occl

usal

pit/

fissu

rele

sions

with

carie

sex

tend

ing

upto

1 m

m in

tode

ntin

e

Gro

up 1

: O3

trea

tmen

t(9

2le

sions

)

Gro

up 2

: no

trea

tmen

t(9

2le

sions

)

Ozo

ne d

osag

e: 4

0 se

cond

sat

bas

elin

e an

d at

3 m

onth

s

Car

ies

asse

ssm

ent:

clin

ical

asse

ssm

ent

and

DIA

GN

Ode

nt (K

aVo,

Ger

man

y)

Reve

rsal

of c

arie

s: 8

6.6%

in t

heoz

one

grou

p; t

he c

ontr

ol le

sions

did

not

chan

ge s

igni

fican

tly(p

<0.

05)

The

DIA

GN

Ode

nt v

alue

sco

rrel

ated

with

the

clin

ical

findi

ngs

Adv

erse

eve

nts:

non

e ob

serv

ed

Appendix 5

74 TA

BLE

22

Char

acte

ristic

s of

abs

trac

ts (

cont

’d)

Aut

hor(

s)N

o. o

f par

tici

pant

sD

esig

nIn

clus

ion

Inte

rven

tion

sR

esul

tsN

otes

(no.

and

typ

e of

cr

iter

iale

sion

s)

Meg

ighi

an a

ndBe

rtol

ini,

2004

56

(Ver

ona,

Ital

y)

80 (3

00 p

it an

d fis

sure

cario

us le

sions

)D

esig

n: r

ando

mise

dcl

inic

al t

rial

Uni

t of

rand

omisa

tion:

lesio

n

Con

ceal

men

t of

allo

catio

n: N

S

Blin

ding

: dou

ble

blin

d

ITT:

no

Leng

th o

f fol

low

-up:

6m

onth

s

Lost

at

follo

w-u

p: N

S

Sett

ing:

priv

ate

prac

tice,

Ital

y

Pit

and

fissu

reca

rious

lesio

nsG

roup

1: O

3(2

20 le

sions

)

Gro

up 2

: no

trea

tmen

t (8

0le

sions

)

Ozo

ne d

osag

e: 2

0, 3

0 or

40

seco

nds

acco

rdin

g to

clin

ical

seve

rity

Car

ies

asse

ssm

ent:

clin

ical

asse

ssm

ent

and

DIA

GN

Ode

nt (K

aVo,

Ger

man

y)

Reve

rsal

of c

arie

s: o

zone

-tre

ated

lesio

ns c

linic

ally

rev

erse

d (p

< 0

.05)

, whi

le c

ontr

ol le

sions

did

not

DIA

GN

Ode

nt: s

igni

fican

t ov

eral

lre

duct

ion

in r

eadi

ngs

for

ozon

e-tr

eate

d le

sions

, whi

le c

ontr

olle

sions

sho

wed

an

incr

ease

inD

IAG

NO

dent

rea

ding

s

85%

of t

eeth

clin

ical

ly r

ever

sed

and

show

ed a

DIA

GN

Ode

ntre

duct

ion

Unc

lear

whe

ther

the

prop

ortio

n of

lesio

ns t

hat

clin

ical

ly r

ever

sed

orsh

owed

a r

educ

tion

inD

IAG

NO

dent

rea

ding

sw

ere

all o

zone

-tre

ated

lesio

ns o

r in

clud

ed s

ome

cont

rol l

esio

ns

Decision models to assess costsand benefits of HealOzoneThe four models depicted in Figures 15–18 have asimilar structure; therefore, only currentmanagement plus HealOzone is described here.Markov models can be used to estimate costs and

consequences that occur over a series of years (inthis study up to 5 years). At the beginning of thefirst year each patient receives currentmanagement plus HealOzone and hence aprobability of 1 is attached. At the end of the firstyear there is a chance that the patients are cured(caries are reversed) or they have progressed. If


75


Appendix 6

Structure of the economic model

Current managementplus HealOzone


Cured post currentmanagement plus HealOzone

Retreatment

Cured post retreatment

Filled tooth

1

0

0

0

0

Cure

Progress

probcurel

Curedprobcure

probretreat#

Progress

1-probcurel

#

Cured post current management plus HealOzone


Filled tooth

Retreatment

New treatment

Retreatment

Filled tooth

M

FIGURE 15 Decision model to assess the cost and benefits of current management plus HealOzone of non-cavitated root caries(Markov model)

Current management

Current management

Cure

Progress

Cured post current management


Filled tooth

Retreatment

1

0

0

0

0

probcure

probretreat

1-probcure

Cured

Progressprobcure

##



Filled tooth

Retreatment

Filled tooth

Retreatment

New treatment

M

FIGURE 16 Decision model to assess the costs and benefits of current management of non-cavitated root caries

they have progressed there is a chance that theyreceive the same treatment or a new treatment(filling). The chance of a patient being cured is‘pbcure1’ and not being cured is ‘1-pbcure1’. Thechance that a patient will receive the sametreatment is ‘probretreat’. In the model it isassumed that the patient has a 50% chance ofreceiving the same treatment or having a filling. Ifthe first treatment fails the patient moves to thethird branch or the fifth branch. The probability

of cure does not change in the third branch andthose who go into the third branch are eithercured or filled. The filled tooth state is a terminalstate and patients do not leave it. The model alsoassumes that when a patient is cured they remaincured for as long as the model runs.

Details of cost calculations are shown in Tables 23–30.

Appendix 6

76

Current management

Current management

Cure

Progress



Filled tooth

Retreatment

1

0

0

0

0

probcure

probretreat

1-probcure

Cured

Progressprobcure

##



Filled tooth

Retreatment

Filled tooth

Retreatment

New treatment

M

FIGURE 17 Decision model to assess the costs and benefits of current management of non-cavitated pit and fissure caries



Cured post currentmanagement plus HealOzone

Retreatment


Filled tooth

1

0

0

0

0

Cure

Progress

probcurel

Curedprobcurel

probretreat

#

Progress

1-probcurel

#

Cured post current management plus HealOzone


Filled tooth

Retreatment

New treatment

Retreatment

Filled tooth

M

FIGURE 18 Decision model to assess the costs and benefits of current management plus HealOzone of non-cavitated pit and fissurecaries


77


TABLE 23 Annual treatment numbers for non-cavitated caries based on each relevant SDR code by age group for year ending March200365

Treatment No. of Total teeth SDR code numbers caries types No. of teeth treated

Age <18 yearsNon-cavitated pit and fissure caries 601 3,930 2 1 1,965

3631 2,393 2 1 1,196.5701 73 1 1 73

Total 3,234.5

Non-cavitated root caries 601 3,930 2 1 1,9653631 2,393 2 1 1,196.5

Total 3,161.5

Age ≥18 yearsNon-cavitated pit and fissure caries 601 11,728 2 1 5,864

3631 669,304 2 1 334,652701 1,922 1 1 1,922

Total 342,438

Non-cavitated root caries 601 11,728 2 1 5,8643631 669,304 2 1 334,652

Total 340,516

Where one SDR code was relevant to more than one type of caries the published treatment numbers were divided by thenumber of relevant types of caries. Similar adjustments were provided for the numbers of teeth to which any one SDR codeapplied.

TABLE 24 Percentage teeth treated by age group of patient, based on numbers in Table 23

SDR code <18 years (%) ≥18 years (%)

Non-cavitated pit and fissure caries 601 25.1 74.93631 0.4 99.6

701 3.7 96.3

Non-cavitated root caries 601 25.1 74.93631 0.4 99.6

TABLE 25 Calculation for cost to NHS based on 100% treatment items paid for those <18 years and 40% all treatment items paidfor those ≥ 18 years

NHS cost (£)

SDR code <18 years ≥18 years Unit cost <18 years ≥18 years Weighted(£) average NHS

fee across allage (£)

Non-cavitated pit and 601 25.1% 74.9% 7.70 7.70 3.08 4.24fissure caries 3631 0.4% 99.6% 4.60 4.60 1.84 1.85

701 3.7% 96.3% 6.95 6.95 2.78 2.93Total 19.25 7.70 9.02

Non-cavitated root caries 601 25.1% 74.9% 7.70 7.70 3.08 4.243631 0.4% 99.6% 4.60 4.60 1.84 1.85Total 12.30 4.92 6.09

Appendix 6

78

TABLE 26 Cost calculations for treatment of cavitated caries

SDR code Total annual Annual No. of No. of Total teeth treatment treatment caries teeth treated numbers numbers types

Age <18 yearsCavitated pit and fissure caries 1441 1,025,404 1 1

1442 201,308 1 1 201,3081443 163,379 1 1 163,379

Anterior teeth 1401a 557,753 278,876.5 1 1 278,876.5Posterior teeth 1421a 386,061 193,030.5 1 1 193,030.5

1421a 35,681 17,840.5 1 2 35,681

Age ≥18 yearsCavitated pit and fissure caries 1441 147,980 1 1 147,980

1442 86,667 1 1 86,6671443 68,353 1 1 68,3531401a 1,671,224 835,612 1 1 835,6121421a 4,141,954 2,070,977 1 1 2,070,9771421a 346,816 173,408 1 2 346,816

Figures assume a treatment mix of SDR codes 1441, 1442 and 1443 plus either 1401 or 1421. All patients also receive SDRcode 0101 (initial dental assessment).It is also assumed that 50% of treatments are for anterior and 50% for posterior teeth.a 50% mix assumed.

TABLE 27 Steps used to calculate the mean cost of a filling when different proportions of children and adults receive differenttreatment mixes by SDR code

% treatment for NHS cost (£)cavitated caries (fillings)

SDR <18 years �18 years Unit cost <18 years �18 years Weightedcode (£) average NHS

fee across allage (£)

1441 87.4 12.6 6.95 6.95 2.78 6.421442 69.9 30.1 9.80 9.80 3.92 8.031443 70.5 29.5 10.55 10.55 4.22 8.681401a 25.0 75.0 7.50 7.50 3.00 4.131421a 8.5 91.5 14.15 14.15 5.66 6.381421a 9.3 90.6 14.15 14.15 5.66 6.45

63.10 63.10 25.24 40.10

Overall % mix children/adults for fillings and mean cost per filling 45.1 54.9 12.62 12.62 5.05 8.02

Initial dental assessment 101 100 100 7.05 7.05 2.82 4.73

Total average cost per filling visit 19.67 7.87 12.75

a 50% mix assumed.


79


TABLE 28 HealOzone cost calculations

% who have caries

Cost to NHS (£)treatmenta

1st year initial treatment Unit cost <18 years �18 years <18 years �18 years Weighted option (£) average cost

to NHS (£)

Non-cavitated pit and fissure cariesCurrentb 19.25 19.25 7.70 9.02HealOzone 20.00 20.00 8.00 25.1 74.9 11.01Current + HealOzone 39.25 15.70 20.03

Non-cavitated root cariesCurrentb 12.30 12.30 4.92 6.09HealOzone 20.00 20.00 8.00 25.1 74.9 11.01Current + HealOzone 32.30 12.92 17.10

a Non-cavitated pit and fissure caries treatment or non-cavitated root caries treatment (see Table 25).b See Tables 24 and 25.

TABLE 29 Results of one-way sensitivity analysis for non-cavitated pit fissure caries (current management versus current managementand HealOzone) holding ‘current management plus HealOzone’ cost constant

Current Additional cost of Probability Proportion cured Proportion filled management HealOzone HealOzone

0 0 1 £26.06 £40.49 £14.430.1 0.015 0.985 £23.81 £40.49 £16.680.2 0.145 0.855 £21.67 £40.49 £18.820.3 0.28 0.72 £19.66 £40.49 £20.830.4 0.405 0.595 £17.77 £40.49 £22.720.5 0.52 0.48 £16.00 £40.49 £24.490.6 0.625 0.375 £14.36 £40.49 £26.130.7 0.72 0.28 £12.84 £40.49 £27.650.8 0.805 0.195 £11.44 £40.49 £29.050.9 0.88 0.12 £10.17 £40.49 £30.321 1 0 £9.02 £40.49 £31.47

TABLE 30 Results of one-way sensitivity analysis for non-cavitated pit fissure caries (current management versus current managementand HealOzone) holding current management cost constant


0 0 1 £24.78 £42.58 £17.800.1 0.015 0.985 £24.78 £39.77 £14.990.2 0.145 0.855 £24.78 £37.08 £12.300.3 0.28 0.72 £24.78 £34.52 £9.740.4 0.405 0.595 £24.78 £32.08 £7.300.5 0.52 0.48 £24.78 £29.76 £4.980.6 0.625 0.375 £24.78 £27.57 £2.790.7 0.72 0.28 £24.78 £25.50 £0.720.8 0.805 0.195 £24.78 £23.55 –£1.230.9 0.88 0.12 £24.78 £21.73 –£3.051 1 0 £24.78 £20.03 –£4.75

Non-cavitated pit and fissure cariesThe combined cost of HealOzone and current management is £40.49 and the cost of currentmanagement alone is £24.78.

Appendix 6

80

Non-cavitated root cariesThe combined cost of HealOzone and current management is £14.63 and the cost of currentmanagement alone is £21.45 (Tables 31 and 32).

TABLE 31 Results of one-way sensitivity analysis for non-cavitated root caries (current management versus current management andHealOzone) holding current management cost constant


0 0 1 £21.45 £38.18 £16.730.1 0.145 0.855 £21.45 £35.52 £14.070.2 0.28 0.72 £21.45 £32.98 £11.530.3 0.405 0.595 £21.45 £30.57 £9.120.4 0.52 0.48 £21.45 £28.27 £6.820.5 0.625 0.375 £21.45 £26.10 £4.650.6 0.72 0.28 £21.45 £24.06 £2.610.7 0.805 0.195 £21.45 £22.13 £0.680.8 0.88 0.12 £21.45 £20.33 –£1.120.9 0.945 0.055 £21.45 £18.65 –£2.801 1 0 £21.45 £17.10 –£4.35

TABLE 32 Results of one-way sensitivity analysis for non-cavitated root caries (current management versus current management andHealOzone) holding ‘current management plus HealOzone’ cost constant


0 0 1 £21.67 £14.63 –£7.040.1 0.145 0.855 £19.56 £14.63 –£4.930.2 0.28 0.72 £17.57 £14.63 –£2.940.3 0.405 0.595 £15.70 £14.63 –£1.070.4 0.52 0.48 £13.96 £14.63 £0.670.5 0.625 0.375 £12.34 £14.63 £2.290.6 0.72 0.28 £10.84 £14.63 £3.790.7 0.805 0.195 £9.47 £14.63 £5.160.8 0.88 0.12 £8.22 £14.63 £6.410.9 0.945 0.055 £7.09 £14.63 £7.541 1 0 £6.09 £14.63 £8.54


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Volume 1, 1997

No. 1Home parenteral nutrition: a systematicreview.

By Richards DM, Deeks JJ, SheldonTA, Shaffer JL.

No. 2Diagnosis, management and screeningof early localised prostate cancer.

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No. 5A review of near patient testing inprimary care.

By Hobbs FDR, Delaney BC,Fitzmaurice DA, Wilson S, Hyde CJ,Thorpe GH, et al.

No. 6Systematic review of outpatient servicesfor chronic pain control.

By McQuay HJ, Moore RA, EcclestonC, Morley S, de C Williams AC.

No. 7Neonatal screening for inborn errors ofmetabolism: cost, yield and outcome.

A review by Pollitt RJ, Green A,McCabe CJ, Booth A, Cooper NJ,Leonard JV, et al.

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A review by Snowdon SK, Stewart-Brown SL.

No. 9Implications of socio-cultural contextsfor the ethics of clinical trials.

A review by Ashcroft RE, ChadwickDW, Clark SRL, Edwards RHT, Frith L,Hutton JL.

No. 10A critical review of the role of neonatalhearing screening in the detection ofcongenital hearing impairment.

By Davis A, Bamford J, Wilson I,Ramkalawan T, Forshaw M, Wright S.

No. 11Newborn screening for inborn errors ofmetabolism: a systematic review.

By Seymour CA, Thomason MJ,Chalmers RA, Addison GM, Bain MD,Cockburn F, et al.

No. 12Routine preoperative testing: a systematic review of the evidence.

By Munro J, Booth A, Nicholl J.

No. 13Systematic review of the effectiveness of laxatives in the elderly.

By Petticrew M, Watt I, Sheldon T.

No. 14When and how to assess fast-changingtechnologies: a comparative study ofmedical applications of four generictechnologies.

A review by Mowatt G, Bower DJ,Brebner JA, Cairns JA, Grant AM,McKee L.

Volume 2, 1998

No. 1Antenatal screening for Down’ssyndrome.

A review by Wald NJ, Kennard A,Hackshaw A, McGuire A.

No. 2Screening for ovarian cancer: a systematic review.

By Bell R, Petticrew M, Luengo S,Sheldon TA.

No. 3Consensus development methods, andtheir use in clinical guidelinedevelopment.

A review by Murphy MK, Black NA,Lamping DL, McKee CM, SandersonCFB, Askham J, et al.

No. 4A cost–utility analysis of interferon beta for multiple sclerosis.

By Parkin D, McNamee P, Jacoby A,Miller P, Thomas S, Bates D.

No. 5Effectiveness and efficiency of methodsof dialysis therapy for end-stage renaldisease: systematic reviews.

By MacLeod A, Grant A, Donaldson C, Khan I, Campbell M,Daly C, et al.

No. 6Effectiveness of hip prostheses inprimary total hip replacement: a criticalreview of evidence and an economicmodel.

By Faulkner A, Kennedy LG, Baxter K, Donovan J, Wilkinson M,Bevan G.

No. 7Antimicrobial prophylaxis in colorectalsurgery: a systematic review ofrandomised controlled trials.

By Song F, Glenny AM.

No. 8Bone marrow and peripheral bloodstem cell transplantation for malignancy.

A review by Johnson PWM, Simnett SJ,Sweetenham JW, Morgan GJ, Stewart LA.

No. 9Screening for speech and languagedelay: a systematic review of theliterature.

By Law J, Boyle J, Harris F, HarknessA, Nye C.

No. 10Resource allocation for chronic stableangina: a systematic review ofeffectiveness, costs and cost-effectiveness of alternativeinterventions.

By Sculpher MJ, Petticrew M, Kelland JL, Elliott RA, Holdright DR,Buxton MJ.

No. 11Detection, adherence and control ofhypertension for the prevention ofstroke: a systematic review.

By Ebrahim S.

No. 12Postoperative analgesia and vomiting,with special reference to day-casesurgery: a systematic review.

By McQuay HJ, Moore RA.

No. 13Choosing between randomised andnonrandomised studies: a systematicreview.

By Britton A, McKee M, Black N,McPherson K, Sanderson C, Bain C.

No. 14Evaluating patient-based outcomemeasures for use in clinical trials.

A review by Fitzpatrick R, Davey C,Buxton MJ, Jones DR.

Health Technology Assessment reports published to date

No. 15Ethical issues in the design and conductof randomised controlled trials.

A review by Edwards SJL, Lilford RJ,Braunholtz DA, Jackson JC, Hewison J,Thornton J.

No. 16Qualitative research methods in healthtechnology assessment: a review of theliterature.

By Murphy E, Dingwall R, GreatbatchD, Parker S, Watson P.

No. 17The costs and benefits of paramedicskills in pre-hospital trauma care.

By Nicholl J, Hughes S, Dixon S,Turner J, Yates D.

No. 18Systematic review of endoscopicultrasound in gastro-oesophagealcancer.

By Harris KM, Kelly S, Berry E,Hutton J, Roderick P, Cullingworth J, et al.

No. 19Systematic reviews of trials and otherstudies.

By Sutton AJ, Abrams KR, Jones DR,Sheldon TA, Song F.

No. 20Primary total hip replacement surgery: a systematic review of outcomes andmodelling of cost-effectivenessassociated with different prostheses.

A review by Fitzpatrick R, Shortall E,Sculpher M, Murray D, Morris R, LodgeM, et al.

Volume 3, 1999

No. 1Informed decision making: an annotatedbibliography and systematic review.

By Bekker H, Thornton JG, Airey CM, Connelly JB, Hewison J,Robinson MB, et al.

No. 2Handling uncertainty when performingeconomic evaluation of healthcareinterventions.

A review by Briggs AH, Gray AM.

No. 3The role of expectancies in the placeboeffect and their use in the delivery ofhealth care: a systematic review.

By Crow R, Gage H, Hampson S,Hart J, Kimber A, Thomas H.

No. 4A randomised controlled trial ofdifferent approaches to universalantenatal HIV testing: uptake andacceptability. Annex: Antenatal HIVtesting – assessment of a routinevoluntary approach.

By Simpson WM, Johnstone FD, BoydFM, Goldberg DJ, Hart GJ, GormleySM, et al.

No. 5Methods for evaluating area-wide andorganisation-based interventions inhealth and health care: a systematicreview.

By Ukoumunne OC, Gulliford MC,Chinn S, Sterne JAC, Burney PGJ.

No. 6Assessing the costs of healthcaretechnologies in clinical trials.

A review by Johnston K, Buxton MJ,Jones DR, Fitzpatrick R.

No. 7Cooperatives and their primary careemergency centres: organisation andimpact.

By Hallam L, Henthorne K.

No. 8Screening for cystic fibrosis.

A review by Murray J, Cuckle H,Taylor G, Littlewood J, Hewison J.

No. 9A review of the use of health statusmeasures in economic evaluation.

By Brazier J, Deverill M, Green C,Harper R, Booth A.

No. 10Methods for the analysis of quality-of-life and survival data in healthtechnology assessment.

A review by Billingham LJ, AbramsKR, Jones DR.

No. 11Antenatal and neonatalhaemoglobinopathy screening in theUK: review and economic analysis.

By Zeuner D, Ades AE, Karnon J,Brown J, Dezateux C, Anionwu EN.

No. 12Assessing the quality of reports ofrandomised trials: implications for theconduct of meta-analyses.

A review by Moher D, Cook DJ, JadadAR, Tugwell P, Moher M, Jones A, et al.

No. 13‘Early warning systems’ for identifyingnew healthcare technologies.

By Robert G, Stevens A, Gabbay J.

No. 14A systematic review of the role of human

papillomavirus testing within a cervicalscreening programme.

By Cuzick J, Sasieni P, Davies P,Adams J, Normand C, Frater A, et al.

No. 15Near patient testing in diabetes clinics:appraising the costs and outcomes.

By Grieve R, Beech R, Vincent J,Mazurkiewicz J.

No. 16Positron emission tomography:establishing priorities for healthtechnology assessment.

A review by Robert G, Milne R.

No. 17 (Pt 1)The debridement of chronic wounds: a systematic review.

By Bradley M, Cullum N, Sheldon T.

No. 17 (Pt 2)Systematic reviews of wound caremanagement: (2) Dressings and topicalagents used in the healing of chronicwounds.

By Bradley M, Cullum N, Nelson EA,Petticrew M, Sheldon T, Torgerson D.

No. 18A systematic literature review of spiraland electron beam computedtomography: with particular reference toclinical applications in hepatic lesions,pulmonary embolus and coronary arterydisease.

By Berry E, Kelly S, Hutton J, Harris KM, Roderick P, Boyce JC, et al.

No. 19What role for statins? A review andeconomic model.

By Ebrahim S, Davey Smith G,McCabe C, Payne N, Pickin M, SheldonTA, et al.

No. 20Factors that limit the quality, numberand progress of randomised controlledtrials.

A review by Prescott RJ, Counsell CE,Gillespie WJ, Grant AM, Russell IT,Kiauka S, et al.

No. 21Antimicrobial prophylaxis in total hipreplacement: a systematic review.

By Glenny AM, Song F.

No. 22Health promoting schools and healthpromotion in schools: two systematicreviews.

By Lister-Sharp D, Chapman S,Stewart-Brown S, Sowden A.

No. 23Economic evaluation of a primary care-based education programme for patientswith osteoarthritis of the knee.

A review by Lord J, Victor C,Littlejohns P, Ross FM, Axford JS.

Volume 4, 2000

No. 1The estimation of marginal timepreference in a UK-wide sample(TEMPUS) project.

A review by Cairns JA, van der PolMM.

No. 2Geriatric rehabilitation followingfractures in older people: a systematicreview.

By Cameron I, Crotty M, Currie C,Finnegan T, Gillespie L, Gillespie W, et al.


82


83


No. 3Screening for sickle cell disease andthalassaemia: a systematic review withsupplementary research.

By Davies SC, Cronin E, Gill M,Greengross P, Hickman M, Normand C.

No. 4Community provision of hearing aidsand related audiology services.

A review by Reeves DJ, Alborz A,Hickson FS, Bamford JM.

No. 5False-negative results in screeningprogrammes: systematic review ofimpact and implications.

By Petticrew MP, Sowden AJ, Lister-Sharp D, Wright K.

No. 6Costs and benefits of communitypostnatal support workers: arandomised controlled trial.

By Morrell CJ, Spiby H, Stewart P,Walters S, Morgan A.

No. 7Implantable contraceptives (subdermalimplants and hormonally impregnatedintrauterine systems) versus other formsof reversible contraceptives: twosystematic reviews to assess relativeeffectiveness, acceptability, tolerabilityand cost-effectiveness.

By French RS, Cowan FM, MansourDJA, Morris S, Procter T, Hughes D, et al.

No. 8An introduction to statistical methodsfor health technology assessment.

A review by White SJ, Ashby D, Brown PJ.

No. 9Disease-modifying drugs for multiplesclerosis: a rapid and systematic review.

By Clegg A, Bryant J, Milne R.

No. 10Publication and related biases.

A review by Song F, Eastwood AJ,Gilbody S, Duley L, Sutton AJ.

No. 11Cost and outcome implications of theorganisation of vascular services.

By Michaels J, Brazier J, PalfreymanS, Shackley P, Slack R.

No. 12Monitoring blood glucose control indiabetes mellitus: a systematic review.

By Coster S, Gulliford MC, Seed PT,Powrie JK, Swaminathan R.

No. 13The effectiveness of domiciliary healthvisiting: a systematic review ofinternational studies and a selective review of the Britishliterature.

By Elkan R, Kendrick D, Hewitt M,Robinson JJA, Tolley K, Blair M, et al.

No. 14The determinants of screening uptakeand interventions for increasing uptake:a systematic review.

By Jepson R, Clegg A, Forbes C,Lewis R, Sowden A, Kleijnen J.

No. 15The effectiveness and cost-effectivenessof prophylactic removal of wisdomteeth.

A rapid review by Song F, O’Meara S,Wilson P, Golder S, Kleijnen J.

No. 16Ultrasound screening in pregnancy: asystematic review of the clinicaleffectiveness, cost-effectiveness andwomen’s views.

By Bricker L, Garcia J, Henderson J,Mugford M, Neilson J, Roberts T, et al.

No. 17A rapid and systematic review of theeffectiveness and cost-effectiveness ofthe taxanes used in the treatment ofadvanced breast and ovarian cancer.

By Lister-Sharp D, McDonagh MS,Khan KS, Kleijnen J.

No. 18Liquid-based cytology in cervicalscreening: a rapid and systematic review.

By Payne N, Chilcott J, McGoogan E.

No. 19Randomised controlled trial of non-directive counselling,cognitive–behaviour therapy and usualgeneral practitioner care in themanagement of depression as well asmixed anxiety and depression inprimary care.

By King M, Sibbald B, Ward E, BowerP, Lloyd M, Gabbay M, et al.

No. 20Routine referral for radiography ofpatients presenting with low back pain:is patients’ outcome influenced by GPs’referral for plain radiography?

By Kerry S, Hilton S, Patel S, DundasD, Rink E, Lord J.

No. 21Systematic reviews of wound caremanagement: (3) antimicrobial agentsfor chronic wounds; (4) diabetic footulceration.

By O’Meara S, Cullum N, Majid M,Sheldon T.

No. 22Using routine data to complement andenhance the results of randomisedcontrolled trials.

By Lewsey JD, Leyland AH, Murray GD, Boddy FA.

No. 23Coronary artery stents in the treatmentof ischaemic heart disease: a rapid andsystematic review.

By Meads C, Cummins C, Jolly K,Stevens A, Burls A, Hyde C.

No. 24Outcome measures for adult criticalcare: a systematic review.

By Hayes JA, Black NA, Jenkinson C, Young JD, Rowan KM,Daly K, et al.

No. 25A systematic review to evaluate theeffectiveness of interventions to promote the initiation of breastfeeding.

By Fairbank L, O’Meara S, RenfrewMJ, Woolridge M, Sowden AJ, Lister-Sharp D.

No. 26Implantable cardioverter defibrillators:arrhythmias. A rapid and systematicreview.

By Parkes J, Bryant J, Milne R.

No. 27Treatments for fatigue in multiplesclerosis: a rapid and systematic review.

By Brañas P, Jordan R, Fry-Smith A,Burls A, Hyde C.

No. 28Early asthma prophylaxis, naturalhistory, skeletal development andeconomy (EASE): a pilot randomisedcontrolled trial.

By Baxter-Jones ADG, Helms PJ,Russell G, Grant A, Ross S, Cairns JA, et al.

No. 29Screening for hypercholesterolaemiaversus case finding for familialhypercholesterolaemia: a systematicreview and cost-effectiveness analysis.

By Marks D, Wonderling D,Thorogood M, Lambert H, HumphriesSE, Neil HAW.

No. 30A rapid and systematic review of theclinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIaantagonists in the medical managementof unstable angina.

By McDonagh MS, Bachmann LM,Golder S, Kleijnen J, ter Riet G.

No. 31A randomised controlled trial ofprehospital intravenous fluidreplacement therapy in serious trauma.

By Turner J, Nicholl J, Webber L,Cox H, Dixon S, Yates D.

No. 32Intrathecal pumps for giving opioids inchronic pain: a systematic review.

By Williams JE, Louw G, Towlerton G.

No. 33Combination therapy (interferon alfaand ribavirin) in the treatment ofchronic hepatitis C: a rapid andsystematic review.

By Shepherd J, Waugh N, Hewitson P.

No. 34A systematic review of comparisons ofeffect sizes derived from randomisedand non-randomised studies.

By MacLehose RR, Reeves BC,Harvey IM, Sheldon TA, Russell IT,Black AMS.

No. 35Intravascular ultrasound-guidedinterventions in coronary artery disease:a systematic literature review, withdecision-analytic modelling, of outcomesand cost-effectiveness.

By Berry E, Kelly S, Hutton J,Lindsay HSJ, Blaxill JM, Evans JA, et al.

No. 36A randomised controlled trial toevaluate the effectiveness and cost-effectiveness of counselling patients withchronic depression.

By Simpson S, Corney R, Fitzgerald P,Beecham J.

No. 37Systematic review of treatments foratopic eczema.

By Hoare C, Li Wan Po A, Williams H.

No. 38Bayesian methods in health technologyassessment: a review.

By Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR.

No. 39The management of dyspepsia: asystematic review.

By Delaney B, Moayyedi P, Deeks J,Innes M, Soo S, Barton P, et al.

No. 40A systematic review of treatments forsevere psoriasis.

By Griffiths CEM, Clark CM, ChalmersRJG, Li Wan Po A, Williams HC.

Volume 5, 2001

No. 1Clinical and cost-effectiveness ofdonepezil, rivastigmine andgalantamine for Alzheimer’s disease: arapid and systematic review.

By Clegg A, Bryant J, Nicholson T,McIntyre L, De Broe S, Gerard K, et al.

No. 2The clinical effectiveness and cost-effectiveness of riluzole for motorneurone disease: a rapid and systematicreview.

By Stewart A, Sandercock J, Bryan S,Hyde C, Barton PM, Fry-Smith A, et al.

No. 3Equity and the economic evaluation ofhealthcare.

By Sassi F, Archard L, Le Grand J.

No. 4Quality-of-life measures in chronicdiseases of childhood.

By Eiser C, Morse R.

No. 5Eliciting public preferences forhealthcare: a systematic review oftechniques.

By Ryan M, Scott DA, Reeves C, BateA, van Teijlingen ER, Russell EM, et al.

No. 6General health status measures forpeople with cognitive impairment:learning disability and acquired braininjury.

By Riemsma RP, Forbes CA, Glanville JM, Eastwood AJ, Kleijnen J.

No. 7An assessment of screening strategies forfragile X syndrome in the UK.

By Pembrey ME, Barnicoat AJ,Carmichael B, Bobrow M, Turner G.

No. 8Issues in methodological research:perspectives from researchers andcommissioners.

By Lilford RJ, Richardson A, StevensA, Fitzpatrick R, Edwards S, Rock F, et al.

No. 9Systematic reviews of wound caremanagement: (5) beds; (6) compression;(7) laser therapy, therapeuticultrasound, electrotherapy andelectromagnetic therapy.

By Cullum N, Nelson EA, FlemmingK, Sheldon T.

No. 10Effects of educational and psychosocialinterventions for adolescents withdiabetes mellitus: a systematic review.

By Hampson SE, Skinner TC, Hart J,Storey L, Gage H, Foxcroft D, et al.

No. 11Effectiveness of autologous chondrocytetransplantation for hyaline cartilagedefects in knees: a rapid and systematicreview.

By Jobanputra P, Parry D, Fry-SmithA, Burls A.

No. 12Statistical assessment of the learningcurves of health technologies.

By Ramsay CR, Grant AM, Wallace SA, Garthwaite PH, Monk AF,Russell IT.

No. 13The effectiveness and cost-effectivenessof temozolomide for the treatment ofrecurrent malignant glioma: a rapid andsystematic review.

By Dinnes J, Cave C, Huang S, Major K, Milne R.

No. 14A rapid and systematic review of theclinical effectiveness and cost-effectiveness of debriding agents intreating surgical wounds healing bysecondary intention.

By Lewis R, Whiting P, ter Riet G,O’Meara S, Glanville J.

No. 15Home treatment for mental healthproblems: a systematic review.

By Burns T, Knapp M, Catty J, Healey A, Henderson J, Watt H, et al.

No. 16How to develop cost-consciousguidelines.

By Eccles M, Mason J.

No. 17The role of specialist nurses in multiplesclerosis: a rapid and systematic review.

By De Broe S, Christopher F, Waugh N.

No. 18A rapid and systematic review of theclinical effectiveness and cost-effectiveness of orlistat in themanagement of obesity.

By O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G.

No. 19The clinical effectiveness and cost-effectiveness of pioglitazone for type 2diabetes mellitus: a rapid and systematicreview.

By Chilcott J, Wight J, Lloyd JonesM, Tappenden P.

No. 20Extended scope of nursing practice: amulticentre randomised controlled trialof appropriately trained nurses andpreregistration house officers in pre-operative assessment in elective generalsurgery.

By Kinley H, Czoski-Murray C,George S, McCabe C, Primrose J, Reilly C, et al.

No. 21Systematic reviews of the effectiveness ofday care for people with severe mentaldisorders: (1) Acute day hospital versusadmission; (2) Vocational rehabilitation;(3) Day hospital versus outpatient care.

By Marshall M, Crowther R, Almaraz-Serrano A, Creed F, Sledge W, Kluiter H, et al.

No. 22The measurement and monitoring ofsurgical adverse events.

By Bruce J, Russell EM, Mollison J,Krukowski ZH.

No. 23Action research: a systematic review andguidance for assessment.

By Waterman H, Tillen D, Dickson R,de Koning K.

No. 24A rapid and systematic review of theclinical effectiveness and cost-effectiveness of gemcitabine for thetreatment of pancreatic cancer.

By Ward S, Morris E, Bansback N,Calvert N, Crellin A, Forman D, et al.


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No. 25A rapid and systematic review of theevidence for the clinical effectivenessand cost-effectiveness of irinotecan,oxaliplatin and raltitrexed for thetreatment of advanced colorectal cancer.

By Lloyd Jones M, Hummel S,Bansback N, Orr B, Seymour M.

No. 26Comparison of the effectiveness ofinhaler devices in asthma and chronicobstructive airways disease: a systematicreview of the literature.

By Brocklebank D, Ram F, Wright J,Barry P, Cates C, Davies L, et al.

No. 27The cost-effectiveness of magneticresonance imaging for investigation ofthe knee joint.

By Bryan S, Weatherburn G, BungayH, Hatrick C, Salas C, Parry D, et al.

No. 28A rapid and systematic review of theclinical effectiveness and cost-effectiveness of topotecan for ovariancancer.

By Forbes C, Shirran L, Bagnall A-M,Duffy S, ter Riet G.

No. 29Superseded by a report published in alater volume.

No. 30The role of radiography in primary carepatients with low back pain of at least 6weeks duration: a randomised(unblinded) controlled trial.

By Kendrick D, Fielding K, Bentley E,Miller P, Kerslake R, Pringle M.

No. 31Design and use of questionnaires: areview of best practice applicable tosurveys of health service staff andpatients.

By McColl E, Jacoby A, Thomas L,Soutter J, Bamford C, Steen N, et al.

No. 32A rapid and systematic review of theclinical effectiveness and cost-effectiveness of paclitaxel, docetaxel,gemcitabine and vinorelbine in non-small-cell lung cancer.

By Clegg A, Scott DA, Sidhu M,Hewitson P, Waugh N.

No. 33Subgroup analyses in randomisedcontrolled trials: quantifying the risks offalse-positives and false-negatives.

By Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M,Davey Smith G.

No. 34Depot antipsychotic medication in thetreatment of patients with schizophrenia:(1) Meta-review; (2) Patient and nurseattitudes.

By David AS, Adams C.

No. 35A systematic review of controlled trialsof the effectiveness and cost-effectiveness of brief psychologicaltreatments for depression.

By Churchill R, Hunot V, Corney R,Knapp M, McGuire H, Tylee A, et al.

No. 36Cost analysis of child healthsurveillance.

By Sanderson D, Wright D, Acton C,Duree D.

Volume 6, 2002

No. 1A study of the methods used to selectreview criteria for clinical audit.

By Hearnshaw H, Harker R, CheaterF, Baker R, Grimshaw G.

No. 2Fludarabine as second-line therapy forB cell chronic lymphocytic leukaemia: a technology assessment.

By Hyde C, Wake B, Bryan S, BartonP, Fry-Smith A, Davenport C, et al.

No. 3Rituximab as third-line treatment forrefractory or recurrent Stage III or IVfollicular non-Hodgkin’s lymphoma: asystematic review and economicevaluation.

By Wake B, Hyde C, Bryan S, BartonP, Song F, Fry-Smith A, et al.

No. 4A systematic review of dischargearrangements for older people.

By Parker SG, Peet SM, McPherson A,Cannaby AM, Baker R, Wilson A, et al.

No. 5The clinical effectiveness and cost-effectiveness of inhaler devices used inthe routine management of chronicasthma in older children: a systematicreview and economic evaluation.

By Peters J, Stevenson M, Beverley C,Lim J, Smith S.

No. 6The clinical effectiveness and cost-effectiveness of sibutramine in themanagement of obesity: a technologyassessment.

By O’Meara S, Riemsma R, ShirranL, Mather L, ter Riet G.

No. 7The cost-effectiveness of magneticresonance angiography for carotidartery stenosis and peripheral vasculardisease: a systematic review.

By Berry E, Kelly S, Westwood ME,Davies LM, Gough MJ, Bamford JM,et al.

No. 8Promoting physical activity in SouthAsian Muslim women through ‘exerciseon prescription’.

By Carroll B, Ali N, Azam N.

No. 9Zanamivir for the treatment of influenzain adults: a systematic review andeconomic evaluation.

By Burls A, Clark W, Stewart T,Preston C, Bryan S, Jefferson T, et al.

No. 10A review of the natural history andepidemiology of multiple sclerosis:implications for resource allocation andhealth economic models.

By Richards RG, Sampson FC, Beard SM, Tappenden P.

No. 11Screening for gestational diabetes: asystematic review and economicevaluation.

By Scott DA, Loveman E, McIntyre L,Waugh N.

No. 12The clinical effectiveness and cost-effectiveness of surgery for people withmorbid obesity: a systematic review andeconomic evaluation.

By Clegg AJ, Colquitt J, Sidhu MK,Royle P, Loveman E, Walker A.

No. 13The clinical effectiveness of trastuzumabfor breast cancer: a systematic review.

By Lewis R, Bagnall A-M, Forbes C,Shirran E, Duffy S, Kleijnen J, et al.

No. 14The clinical effectiveness and cost-effectiveness of vinorelbine for breastcancer: a systematic review andeconomic evaluation.

By Lewis R, Bagnall A-M, King S,Woolacott N, Forbes C, Shirran L, et al.

No. 15A systematic review of the effectivenessand cost-effectiveness of metal-on-metalhip resurfacing arthroplasty fortreatment of hip disease.

By Vale L, Wyness L, McCormack K,McKenzie L, Brazzelli M, Stearns SC.

No. 16The clinical effectiveness and cost-effectiveness of bupropion and nicotinereplacement therapy for smokingcessation: a systematic review andeconomic evaluation.

By Woolacott NF, Jones L, Forbes CA,Mather LC, Sowden AJ, Song FJ, et al.

No. 17A systematic review of effectiveness andeconomic evaluation of new drugtreatments for juvenile idiopathicarthritis: etanercept.

By Cummins C, Connock M, Fry-Smith A, Burls A.

No. 18Clinical effectiveness and cost-effectiveness of growth hormone inchildren: a systematic review andeconomic evaluation.

By Bryant J, Cave C, Mihaylova B,Chase D, McIntyre L, Gerard K, et al.


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No. 19Clinical effectiveness and cost-effectiveness of growth hormone inadults in relation to impact on quality oflife: a systematic review and economicevaluation.

By Bryant J, Loveman E, Chase D,Mihaylova B, Cave C, Gerard K, et al.

No. 20Clinical medication review by apharmacist of patients on repeatprescriptions in general practice: arandomised controlled trial.

By Zermansky AG, Petty DR, RaynorDK, Lowe CJ, Freementle N, Vail A.

No. 21The effectiveness of infliximab andetanercept for the treatment ofrheumatoid arthritis: a systematic reviewand economic evaluation.

By Jobanputra P, Barton P, Bryan S,Burls A.

No. 22A systematic review and economicevaluation of computerised cognitivebehaviour therapy for depression andanxiety.

By Kaltenthaler E, Shackley P, StevensK, Beverley C, Parry G, Chilcott J.

No. 23A systematic review and economicevaluation of pegylated liposomaldoxorubicin hydrochloride for ovariancancer.

By Forbes C, Wilby J, Richardson G,Sculpher M, Mather L, Reimsma R.

No. 24A systematic review of the effectivenessof interventions based on a stages-of-change approach to promote individualbehaviour change.

By Riemsma RP, Pattenden J, Bridle C,Sowden AJ, Mather L, Watt IS, et al.

No. 25A systematic review update of theclinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIaantagonists.

By Robinson M, Ginnelly L, SculpherM, Jones L, Riemsma R, Palmer S, et al.

No. 26A systematic review of the effectiveness,cost-effectiveness and barriers toimplementation of thrombolytic andneuroprotective therapy for acuteischaemic stroke in the NHS.

By Sandercock P, Berge E, Dennis M,Forbes J, Hand P, Kwan J, et al.

No. 27A randomised controlled crossover trial of nurse practitioner versus doctor-led outpatient care in abronchiectasis clinic.

By Caine N, Sharples LD,Hollingworth W, French J, Keogan M,Exley A, et al.

No. 28Clinical effectiveness and cost –consequences of selective serotoninreuptake inhibitors in the treatment ofsex offenders.

By Adi Y, Ashcroft D, Browne K,Beech A, Fry-Smith A, Hyde C.

No. 29Treatment of established osteoporosis: a systematic review and cost–utilityanalysis.

By Kanis JA, Brazier JE, Stevenson M,Calvert NW, Lloyd Jones M.

No. 30Which anaesthetic agents are cost-effective in day surgery? Literaturereview, national survey of practice andrandomised controlled trial.

By Elliott RA Payne K, Moore JK,Davies LM, Harper NJN, St Leger AS,et al.

No. 31Screening for hepatitis C amonginjecting drug users and ingenitourinary medicine clinics:systematic reviews of effectiveness,modelling study and national survey ofcurrent practice.

By Stein K, Dalziel K, Walker A,McIntyre L, Jenkins B, Horne J, et al.

No. 32The measurement of satisfaction withhealthcare: implications for practicefrom a systematic review of theliterature.

By Crow R, Gage H, Hampson S,Hart J, Kimber A, Storey L, et al.

No. 33The effectiveness and cost-effectivenessof imatinib in chronic myeloidleukaemia: a systematic review.

By Garside R, Round A, Dalziel K,Stein K, Royle R.

No. 34A comparative study of hypertonicsaline, daily and alternate-day rhDNase in children with cystic fibrosis.

By Suri R, Wallis C, Bush A,Thompson S, Normand C, Flather M, et al.

No. 35A systematic review of the costs andeffectiveness of different models ofpaediatric home care.

By Parker G, Bhakta P, Lovett CA,Paisley S, Olsen R, Turner D, et al.

Volume 7, 2003

No. 1How important are comprehensiveliterature searches and the assessment oftrial quality in systematic reviews?Empirical study.

By Egger M, Jüni P, Bartlett C,Holenstein F, Sterne J.

No. 2Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of home versus hospital orsatellite unit haemodialysis for peoplewith end-stage renal failure.

By Mowatt G, Vale L, Perez J, WynessL, Fraser C, MacLeod A, et al.

No. 3Systematic review and economicevaluation of the effectiveness ofinfliximab for the treatment of Crohn’sdisease.

By Clark W, Raftery J, Barton P, Song F, Fry-Smith A, Burls A.

No. 4A review of the clinical effectiveness andcost-effectiveness of routine anti-Dprophylaxis for pregnant women whoare rhesus negative.

By Chilcott J, Lloyd Jones M, WightJ, Forman K, Wray J, Beverley C, et al.

No. 5Systematic review and evaluation of theuse of tumour markers in paediatriconcology: Ewing’s sarcoma andneuroblastoma.

By Riley RD, Burchill SA, Abrams KR,Heney D, Lambert PC, Jones DR, et al.

No. 6The cost-effectiveness of screening forHelicobacter pylori to reduce mortalityand morbidity from gastric cancer andpeptic ulcer disease: a discrete-eventsimulation model.

By Roderick P, Davies R, Raftery J,Crabbe D, Pearce R, Bhandari P, et al.

No. 7The clinical effectiveness and cost-effectiveness of routine dental checks: asystematic review and economicevaluation.

By Davenport C, Elley K, Salas C,Taylor-Weetman CL, Fry-Smith A, Bryan S, et al.

No. 8A multicentre randomised controlledtrial assessing the costs and benefits ofusing structured information andanalysis of women’s preferences in themanagement of menorrhagia.

By Kennedy ADM, Sculpher MJ,Coulter A, Dwyer N, Rees M, Horsley S, et al.

No. 9Clinical effectiveness and cost–utility ofphotodynamic therapy for wet age-relatedmacular degeneration: a systematic reviewand economic evaluation.

By Meads C, Salas C, Roberts T,Moore D, Fry-Smith A, Hyde C.

No. 10Evaluation of molecular tests forprenatal diagnosis of chromosomeabnormalities.

By Grimshaw GM, Szczepura A,Hultén M, MacDonald F, Nevin NC,Sutton F, et al.


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No. 11First and second trimester antenatalscreening for Down’s syndrome: theresults of the Serum, Urine andUltrasound Screening Study (SURUSS).

By Wald NJ, Rodeck C, Hackshaw AK, Walters J, Chitty L,Mackinson AM.

No. 12The effectiveness and cost-effectivenessof ultrasound locating devices forcentral venous access: a systematicreview and economic evaluation.

By Calvert N, Hind D, McWilliamsRG, Thomas SM, Beverley C, Davidson A.

No. 13A systematic review of atypicalantipsychotics in schizophrenia.

By Bagnall A-M, Jones L, Lewis R,Ginnelly L, Glanville J, Torgerson D, et al.

No. 14Prostate Testing for Cancer andTreatment (ProtecT) feasibility study.

By Donovan J, Hamdy F, Neal D,Peters T, Oliver S, Brindle L, et al.

No. 15Early thrombolysis for the treatment of acute myocardial infarction: asystematic review and economicevaluation.

By Boland A, Dundar Y, Bagust A,Haycox A, Hill R, Mujica Mota R,et al.

No. 16Screening for fragile X syndrome: a literature review and modelling.

By Song FJ, Barton P, Sleightholme V,Yao GL, Fry-Smith A.

No. 17Systematic review of endoscopic sinussurgery for nasal polyps.

By Dalziel K, Stein K, Round A,Garside R, Royle P.

No. 18Towards efficient guidelines: how tomonitor guideline use in primary care.

By Hutchinson A, McIntosh A, Cox S,Gilbert C.

No. 19Effectiveness and cost-effectiveness ofacute hospital-based spinal cord injuriesservices: systematic review.

By Bagnall A-M, Jones L, Richardson G, Duffy S, Riemsma R.

No. 20Prioritisation of health technologyassessment. The PATHS model:methods and case studies.

By Townsend J, Buxton M, Harper G.

No. 21Systematic review of the clinicaleffectiveness and cost-effectiveness of tension-free vaginal tape fortreatment of urinary stress incontinence.

By Cody J, Wyness L, Wallace S,Glazener C, Kilonzo M, Stearns S,et al.

No. 22The clinical and cost-effectiveness ofpatient education models for diabetes: a systematic review and economicevaluation.

By Loveman E, Cave C, Green C,Royle P, Dunn N, Waugh N.

No. 23The role of modelling in prioritisingand planning clinical trials.

By Chilcott J, Brennan A, Booth A,Karnon J, Tappenden P.

No. 24Cost–benefit evaluation of routineinfluenza immunisation in people 65–74years of age.

By Allsup S, Gosney M, Haycox A,Regan M.

No. 25The clinical and cost-effectiveness ofpulsatile machine perfusion versus coldstorage of kidneys for transplantationretrieved from heart-beating and non-heart-beating donors.

By Wight J, Chilcott J, Holmes M,Brewer N.

No. 26Can randomised trials rely on existingelectronic data? A feasibility study toexplore the value of routine data inhealth technology assessment.

By Williams JG, Cheung WY, Cohen DR, Hutchings HA, Longo MF, Russell IT.

No. 27Evaluating non-randomised interventionstudies.

By Deeks JJ, Dinnes J, D’Amico R,Sowden AJ, Sakarovitch C, Song F, et al.

No. 28A randomised controlled trial to assessthe impact of a package comprising apatient-orientated, evidence-based self-help guidebook and patient-centredconsultations on disease managementand satisfaction in inflammatory boweldisease.

By Kennedy A, Nelson E, Reeves D,Richardson G, Roberts C, Robinson A,et al.

No. 29The effectiveness of diagnostic tests forthe assessment of shoulder pain due tosoft tissue disorders: a systematic review.

By Dinnes J, Loveman E, McIntyre L,Waugh N.

No. 30The value of digital imaging in diabeticretinopathy.

By Sharp PF, Olson J, Strachan F,Hipwell J, Ludbrook A, O’Donnell M, et al.

No. 31Lowering blood pressure to preventmyocardial infarction and stroke: a new preventive strategy.

By Law M, Wald N, Morris J.

No. 32Clinical and cost-effectiveness ofcapecitabine and tegafur with uracil forthe treatment of metastatic colorectalcancer: systematic review and economicevaluation.

By Ward S, Kaltenthaler E, Cowan J,Brewer N.

No. 33Clinical and cost-effectiveness of new and emerging technologies for earlylocalised prostate cancer: a systematicreview.

By Hummel S, Paisley S, Morgan A,Currie E, Brewer N.

No. 34Literature searching for clinical andcost-effectiveness studies used in healthtechnology assessment reports carriedout for the National Institute forClinical Excellence appraisal system.

By Royle P, Waugh N.

No. 35Systematic review and economicdecision modelling for the preventionand treatment of influenza A and B.

By Turner D, Wailoo A, Nicholson K,Cooper N, Sutton A, Abrams K.

No. 36A randomised controlled trial toevaluate the clinical and cost-effectiveness of Hickman line insertions in adult cancer patients bynurses.

By Boland A, Haycox A, Bagust A,Fitzsimmons L.

No. 37Redesigning postnatal care: arandomised controlled trial of protocol-based midwifery-led carefocused on individual women’s physical and psychological health needs.

By MacArthur C, Winter HR, Bick DE, Lilford RJ, Lancashire RJ,Knowles H, et al.

No. 38Estimating implied rates of discount inhealthcare decision-making.

By West RR, McNabb R, Thompson AGH, Sheldon TA, Grimley Evans J.

No. 39Systematic review of isolation policies inthe hospital management of methicillin-resistant Staphylococcus aureus: a review ofthe literature with epidemiological andeconomic modelling.

By Cooper BS, Stone SP, Kibbler CC,Cookson BD, Roberts JA, Medley GF, et al.

No. 40Treatments for spasticity and pain inmultiple sclerosis: a systematic review.

By Beard S, Hunn A, Wight J.

No. 41The inclusion of reports of randomisedtrials published in languages other thanEnglish in systematic reviews.

By Moher D, Pham B, Lawson ML,Klassen TP.

No. 42The impact of screening on futurehealth-promoting behaviours and healthbeliefs: a systematic review.

By Bankhead CR, Brett J, Bukach C,Webster P, Stewart-Brown S, Munafo M,et al.

Volume 8, 2004

No. 1What is the best imaging strategy foracute stroke?

By Wardlaw JM, Keir SL, Seymour J,Lewis S, Sandercock PAG, Dennis MS, et al.

No. 2Systematic review and modelling of theinvestigation of acute and chronic chestpain presenting in primary care.

By Mant J, McManus RJ, Oakes RAL,Delaney BC, Barton PM, Deeks JJ, et al.

No. 3The effectiveness and cost-effectivenessof microwave and thermal balloonendometrial ablation for heavymenstrual bleeding: a systematic reviewand economic modelling.

By Garside R, Stein K, Wyatt K,Round A, Price A.

No. 4A systematic review of the role ofbisphosphonates in metastatic disease.

By Ross JR, Saunders Y, Edmonds PM,Patel S, Wonderling D, Normand C, et al.

No. 5Systematic review of the clinicaleffectiveness and cost-effectiveness ofcapecitabine (Xeloda®) for locallyadvanced and/or metastatic breast cancer.

By Jones L, Hawkins N, Westwood M,Wright K, Richardson G, Riemsma R.

No. 6Effectiveness and efficiency of guidelinedissemination and implementationstrategies.

By Grimshaw JM, Thomas RE,MacLennan G, Fraser C, Ramsay CR,Vale L, et al.

No. 7Clinical effectiveness and costs of theSugarbaker procedure for the treatmentof pseudomyxoma peritonei.

By Bryant J, Clegg AJ, Sidhu MK,Brodin H, Royle P, Davidson P.

No. 8Psychological treatment for insomnia inthe regulation of long-term hypnoticdrug use.

By Morgan K, Dixon S, Mathers N,Thompson J, Tomeny M.

No. 9Improving the evaluation of therapeuticinterventions in multiple sclerosis:development of a patient-based measureof outcome.

By Hobart JC, Riazi A, Lamping DL,Fitzpatrick R, Thompson AJ.

No. 10A systematic review and economicevaluation of magnetic resonancecholangiopancreatography comparedwith diagnostic endoscopic retrogradecholangiopancreatography.

By Kaltenthaler E, Bravo Vergel Y,Chilcott J, Thomas S, Blakeborough T,Walters SJ, et al.

No. 11The use of modelling to evaluate newdrugs for patients with a chroniccondition: the case of antibodies againsttumour necrosis factor in rheumatoidarthritis.

By Barton P, Jobanputra P, Wilson J,Bryan S, Burls A.

No. 12Clinical effectiveness and cost-effectiveness of neonatal screening forinborn errors of metabolism usingtandem mass spectrometry: a systematicreview.

By Pandor A, Eastham J, Beverley C,Chilcott J, Paisley S.

No. 13Clinical effectiveness and cost-effectiveness of pioglitazone androsiglitazone in the treatment of type 2 diabetes: a systematic review and economic evaluation.

By Czoski-Murray C, Warren E,Chilcott J, Beverley C, Psyllaki MA,Cowan J.

No. 14Routine examination of the newborn:the EMREN study. Evaluation of anextension of the midwife role including a randomised controlled trial of appropriately trained midwivesand paediatric senior house officers.

By Townsend J, Wolke D, Hayes J,Davé S, Rogers C, Bloomfield L, et al.

No. 15Involving consumers in research anddevelopment agenda setting for theNHS: developing an evidence-basedapproach.

By Oliver S, Clarke-Jones L, Rees R, Milne R, Buchanan P, Gabbay J, et al.

No. 16A multi-centre randomised controlledtrial of minimally invasive directcoronary bypass grafting versuspercutaneous transluminal coronaryangioplasty with stenting for proximalstenosis of the left anterior descendingcoronary artery.

By Reeves BC, Angelini GD, BryanAJ, Taylor FC, Cripps T, Spyt TJ, et al.

No. 17Does early magnetic resonance imaginginfluence management or improveoutcome in patients referred tosecondary care with low back pain? A pragmatic randomised controlledtrial.

By Gilbert FJ, Grant AM, GillanMGC, Vale L, Scott NW, Campbell MK,et al.

No. 18The clinical and cost-effectiveness ofanakinra for the treatment ofrheumatoid arthritis in adults: asystematic review and economic analysis.

By Clark W, Jobanputra P, Barton P,Burls A.

No. 19A rapid and systematic review andeconomic evaluation of the clinical andcost-effectiveness of newer drugs fortreatment of mania associated withbipolar affective disorder.

By Bridle C, Palmer S, Bagnall A-M,Darba J, Duffy S, Sculpher M, et al.

No. 20Liquid-based cytology in cervicalscreening: an updated rapid andsystematic review and economic analysis.

By Karnon J, Peters J, Platt J, Chilcott J, McGoogan E, Brewer N.

No. 21Systematic review of the long-termeffects and economic consequences oftreatments for obesity and implicationsfor health improvement.

By Avenell A, Broom J, Brown TJ,Poobalan A, Aucott L, Stearns SC, et al.

No. 22Autoantibody testing in children withnewly diagnosed type 1 diabetesmellitus.

By Dretzke J, Cummins C,Sandercock J, Fry-Smith A, Barrett T,Burls A.


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No. 23Clinical effectiveness and cost-effectiveness of prehospital intravenousfluids in trauma patients.

By Dretzke J, Sandercock J, Bayliss S,Burls A.

No. 24Newer hypnotic drugs for the short-term management of insomnia: asystematic review and economicevaluation.

By Dündar Y, Boland A, Strobl J,Dodd S, Haycox A, Bagust A, et al.

No. 25Development and validation of methodsfor assessing the quality of diagnosticaccuracy studies.

By Whiting P, Rutjes AWS, Dinnes J,Reitsma JB, Bossuyt PMM, Kleijnen J.

No. 26EVALUATE hysterectomy trial: amulticentre randomised trial comparingabdominal, vaginal and laparoscopicmethods of hysterectomy.

By Garry R, Fountain J, Brown J,Manca A, Mason S, Sculpher M, et al.

No. 27Methods for expected value ofinformation analysis in complex healtheconomic models: developments on thehealth economics of interferon-� andglatiramer acetate for multiple sclerosis.

By Tappenden P, Chilcott JB,Eggington S, Oakley J, McCabe C.

No. 28Effectiveness and cost-effectiveness ofimatinib for first-line treatment ofchronic myeloid leukaemia in chronicphase: a systematic review and economicanalysis.

By Dalziel K, Round A, Stein K,Garside R, Price A.

No. 29VenUS I: a randomised controlled trialof two types of bandage for treatingvenous leg ulcers.

By Iglesias C, Nelson EA, Cullum NA,Torgerson DJ on behalf of the VenUSTeam.

No. 30Systematic review of the effectivenessand cost-effectiveness, and economicevaluation, of myocardial perfusionscintigraphy for the diagnosis andmanagement of angina and myocardialinfarction.

By Mowatt G, Vale L, Brazzelli M,Hernandez R, Murray A, Scott N, et al.

No. 31A pilot study on the use of decisiontheory and value of information analysisas part of the NHS Health TechnologyAssessment programme.

By Claxton Kon K, Ginnelly L, SculpherM, Philips Z, Palmer S.

No. 32The Social Support and Family HealthStudy: a randomised controlled trial andeconomic evaluation of two alternativeforms of postnatal support for mothersliving in disadvantaged inner-city areas.

By Wiggins M, Oakley A, Roberts I,Turner H, Rajan L, Austerberry H, et al.

No. 33Psychosocial aspects of genetic screeningof pregnant women and newborns: a systematic review.

By Green JM, Hewison J, Bekker HL,Bryant, Cuckle HS.

No. 34Evaluation of abnormal uterinebleeding: comparison of threeoutpatient procedures within cohortsdefined by age and menopausal status.

By Critchley HOD, Warner P, Lee AJ, Brechin S, Guise J, Graham B.

No. 35Coronary artery stents: a rapid systematicreview and economic evaluation.

By Hill R, Bagust A, Bakhai A,Dickson R, Dündar Y, Haycox A, et al.

No. 36Review of guidelines for good practicein decision-analytic modelling in healthtechnology assessment.

By Philips Z, Ginnelly L, Sculpher M,Claxton K, Golder S, Riemsma R, et al.

No. 37Rituximab (MabThera®) for aggressivenon-Hodgkin’s lymphoma: systematicreview and economic evaluation.

By Knight C, Hind D, Brewer N,Abbott V.

No. 38Clinical effectiveness and cost-effectiveness of clopidogrel andmodified-release dipyridamole in thesecondary prevention of occlusivevascular events: a systematic review andeconomic evaluation.

By Jones L, Griffin S, Palmer S, MainC, Orton V, Sculpher M, et al.

No. 39Pegylated interferon �-2a and -2b incombination with ribavirin in thetreatment of chronic hepatitis C: asystematic review and economicevaluation.

By Shepherd J, Brodin H, Cave C,Waugh N, Price A, Gabbay J.

No. 40Clopidogrel used in combination withaspirin compared with aspirin alone inthe treatment of non-ST-segment-elevation acute coronary syndromes: asystematic review and economicevaluation.

By Main C, Palmer S, Griffin S, Jones L, Orton V, Sculpher M, et al.

No. 41Provision, uptake and cost of cardiacrehabilitation programmes: improvingservices to under-represented groups.

By Beswick AD, Rees K, Griebsch I,Taylor FC, Burke M, West RR, et al.

No. 42Involving South Asian patients inclinical trials.

By Hussain-Gambles M, Leese B,Atkin K, Brown J, Mason S, Tovey P.

No. 43Clinical and cost-effectiveness ofcontinuous subcutaneous insulininfusion for diabetes.

By Colquitt JL, Green C, Sidhu MK,Hartwell D, Waugh N.

No. 44Identification and assessment ofongoing trials in health technologyassessment reviews.

By Song FJ, Fry-Smith A, DavenportC, Bayliss S, Adi Y, Wilson JS, et al.

No. 45Systematic review and economicevaluation of a long-acting insulinanalogue, insulin glargine

By Warren E, Weatherley-Jones E,Chilcott J, Beverley C.

No. 46Supplementation of a home-basedexercise programme with a class-basedprogramme for people with osteoarthritisof the knees: a randomised controlledtrial and health economic analysis.

By McCarthy CJ, Mills PM, Pullen R, Richardson G, Hawkins N,Roberts CR, et al.

No. 47Clinical and cost-effectiveness of once-daily versus more frequent use of samepotency topical corticosteroids for atopiceczema: a systematic review andeconomic evaluation.

By Green C, Colquitt JL, Kirby J,Davidson P, Payne E.

No. 48Acupuncture of chronic headachedisorders in primary care: randomisedcontrolled trial and economic analysis.

By Vickers AJ, Rees RW, Zollman CE,McCarney R, Smith CM, Ellis N, et al.

No. 49Generalisability in economic evaluationstudies in healthcare: a review and casestudies.

By Sculpher MJ, Pang FS, Manca A,Drummond MF, Golder S, Urdahl H, et al.

No. 50Virtual outreach: a randomisedcontrolled trial and economic evaluationof joint teleconferenced medicalconsultations.

By Wallace P, Barber J, Clayton W,Currell R, Fleming K, Garner P, et al.

Volume 9, 2005

No. 1Randomised controlled multipletreatment comparison to provide a cost-effectiveness rationale for theselection of antimicrobial therapy inacne.

By Ozolins M, Eady EA, Avery A,Cunliffe WJ, O’Neill C, Simpson NB, et al.

No. 2Do the findings of case series studiesvary significantly according tomethodological characteristics?

By Dalziel K, Round A, Stein K,Garside R, Castelnuovo E, Payne L.

No. 3Improving the referral process forfamilial breast cancer geneticcounselling: findings of threerandomised controlled trials of twointerventions.

By Wilson BJ, Torrance N, Mollison J,Wordsworth S, Gray JR, Haites NE, et al.

No. 4Randomised evaluation of alternativeelectrosurgical modalities to treatbladder outflow obstruction in men withbenign prostatic hyperplasia.

By Fowler C, McAllister W, Plail R,Karim O, Yang Q.

No. 5A pragmatic randomised controlled trialof the cost-effectiveness of palliativetherapies for patients with inoperableoesophageal cancer.

By Shenfine J, McNamee P, Steen N,Bond J, Griffin SM.

No. 6Impact of computer-aided detectionprompts on the sensitivity and specificityof screening mammography.

By Taylor P, Champness J, Given-Wilson R, Johnston K, Potts H.

No. 7Issues in data monitoring and interimanalysis of trials.

By Grant AM, Altman DG, BabikerAB, Campbell MK, Clemens FJ,Darbyshire JH, et al.

No. 8Lay public’s understanding of equipoiseand randomisation in randomisedcontrolled trials.

By Robinson EJ, Kerr CEP, StevensAJ, Lilford RJ, Braunholtz DA, EdwardsSJ, et al.

No. 9Clinical and cost-effectiveness ofelectroconvulsive therapy for depressiveillness, schizophrenia, catatonia andmania: systematic reviews and economicmodelling studies.

By Greenhalgh J, Knight C, Hind D,Beverley C, Walters S.

No. 10Measurement of health-related qualityof life for people with dementia:development of a new instrument(DEMQOL) and an evaluation ofcurrent methodology.

By Smith SC, Lamping DL, Banerjee S, Harwood R, Foley B, Smith P, et al.

No. 11Clinical effectiveness and cost-effectiveness of drotrecogin alfa(activated) (Xigris®) for the treatment ofsevere sepsis in adults: a systematicreview and economic evaluation.

By Green C, Dinnes J, Takeda A,Shepherd J, Hartwell D, Cave C, et al.

No. 12A methodological review of howheterogeneity has been examined insystematic reviews of diagnostic testaccuracy.

By Dinnes J, Deeks J, Kirby J,Roderick P.

No. 13Cervical screening programmes: canautomation help? Evidence fromsystematic reviews, an economic analysisand a simulation modelling exerciseapplied to the UK.

By Willis BH, Barton P, Pearmain P,Bryan S, Hyde C.

No. 14Laparoscopic surgery for inguinalhernia repair: systematic review ofeffectiveness and economic evaluation.

By McCormack K, Wake B, Perez J,Fraser C, Cook J, McIntosh E, et al.

No. 15Clinical effectiveness, tolerability andcost-effectiveness of newer drugs forepilepsy in adults: a systematic reviewand economic evaluation.

By Wilby J, Kainth A, Hawkins N,Epstein D, McIntosh H, McDaid C, et al.

No. 16A randomised controlled trial tocompare the cost-effectiveness oftricyclic antidepressants, selectiveserotonin reuptake inhibitors andlofepramine.

By Peveler R, Kendrick T, Buxton M,Longworth L, Baldwin D, Moore M, et al.

No. 17Clinical effectiveness and cost-effectiveness of immediate angioplastyfor acute myocardial infarction:systematic review and economicevaluation.

By Hartwell D, Colquitt J, LovemanE, Clegg AJ, Brodin H, Waugh N, et al.

No. 18A randomised controlled comparison ofalternative strategies in stroke care.

By Kalra L, Evans A, Perez I, Knapp M, Swift C, Donaldson N.

No. 19The investigation and analysis of criticalincidents and adverse events inhealthcare.

By Woloshynowych M, Rogers S,Taylor-Adams S, Vincent C.

No. 20Potential use of routine databases inhealth technology assessment.

By Raftery J, Roderick P, Stevens A.

No. 21Clinical and cost-effectiveness of newerimmunosuppressive regimens in renaltransplantation: a systematic review andmodelling study.

By Woodroffe R, Yao GL, Meads C,Bayliss S, Ready A, Raftery J, et al.

No. 22A systematic review and economicevaluation of alendronate, etidronate,risedronate, raloxifene and teriparatidefor the prevention and treatment ofpostmenopausal osteoporosis.

By Stevenson M, Lloyd Jones M, De Nigris E, Brewer N, Davis S, Oakley J.

No. 23A systematic review to examine theimpact of psycho-educationalinterventions on health outcomes andcosts in adults and children with difficultasthma.

By Smith JR, Mugford M, Holland R,Candy B, Noble MJ, Harrison BDW, et al.

No. 24An evaluation of the costs, effectivenessand quality of renal replacementtherapy provision in renal satellite unitsin England and Wales.

By Roderick P, Nicholson T, ArmitageA, Mehta R, Mullee M, Gerard K, et al.

No. 25Imatinib for the treatment of patientswith unresectable and/or metastaticgastrointestinal stromal tumours:systematic review and economicevaluation.

By Wilson J, Connock M, Song F, YaoG, Fry-Smith A, Raftery J, et al.

No. 26Indirect comparisons of competinginterventions.

By Glenny AM, Altman DG, Song F,Sakarovitch C, Deeks JJ, D’Amico R, et al.

No. 27Cost-effectiveness of alternativestrategies for the initial medicalmanagement of non-ST elevation acutecoronary syndrome: systematic reviewand decision-analytical modelling.

By Robinson M, Palmer S, SculpherM, Philips Z, Ginnelly L, Bowens A, et al.


90

No. 28Outcomes of electrically stimulatedgracilis neosphincter surgery.

By Tillin T, Chambers M, Feldman R.

No. 29The effectiveness and cost-effectivenessof pimecrolimus and tacrolimus foratopic eczema: a systematic review andeconomic evaluation.

By Garside R, Stein K, Castelnuovo E,Pitt M, Ashcroft D, Dimmock P, et al.

No. 30Systematic review on urine albumintesting for early detection of diabeticcomplications.

By Newman DJ, Mattock MB, DawnayABS, Kerry S, McGuire A, Yaqoob M, et al.

No. 31Randomised controlled trial of the cost-effectiveness of water-based therapy forlower limb osteoarthritis.

By Cochrane T, Davey RC, Matthes Edwards SM.

No. 32Longer term clinical and economicbenefits of offering acupuncture care topatients with chronic low back pain.

By Thomas KJ, MacPherson H,Ratcliffe J, Thorpe L, Brazier J,Campbell M, et al.

No. 33Cost-effectiveness and safety of epiduralsteroids in the management of sciatica.

By Price C, Arden N, Coglan L,Rogers P.

No. 34The British Rheumatoid Outcome StudyGroup (BROSG) randomised controlledtrial to compare the effectiveness andcost-effectiveness of aggressive versussymptomatic therapy in establishedrheumatoid arthritis.

By Symmons D, Tricker K, Roberts C,Davies L, Dawes P, Scott DL.

No. 35Conceptual framework and systematicreview of the effects of participants’ andprofessionals’ preferences in randomisedcontrolled trials.

By King M, Nazareth I, Lampe F,Bower P, Chandler M, Morou M, et al.

No. 36The clinical and cost-effectiveness ofimplantable cardioverter defibrillators: a systematic review.

By Bryant J, Brodin H, Loveman E,Payne E, Clegg A.

No. 37A trial of problem-solving by communitymental health nurses for anxiety,depression and life difficulties amonggeneral practice patients. The CPN-GPstudy.

By Kendrick T, Simons L, Mynors-Wallis L, Gray A, Lathlean J,Pickering R, et al.

No. 38The causes and effects of socio-demographic exclusions from clinicaltrials.

By Bartlett C, Doyal L, Ebrahim S,Davey P, Bachmann M, Egger M, et al.

No. 39Is hydrotherapy cost-effective? Arandomised controlled trial of combinedhydrotherapy programmes comparedwith physiotherapy land techniques inchildren with juvenile idiopathicarthritis.

By Epps H, Ginnelly L, Utley M,Southwood T, Gallivan S, Sculpher M, et al.

No. 40A randomised controlled trial and cost-effectiveness study of systematicscreening (targeted and total populationscreening) versus routine practice forthe detection of atrial fibrillation inpeople aged 65 and over. The SAFEstudy.

By Hobbs FDR, Fitzmaurice DA,Mant J, Murray E, Jowett S, Bryan S, et al.

No. 41Displaced intracapsular hip fractures in fit, older people: a randomisedcomparison of reduction and fixation,bipolar hemiarthroplasty and total hiparthroplasty.

By Keating JF, Grant A, Masson M,Scott NW, Forbes JF.

No. 42Long-term outcome of cognitivebehaviour therapy clinical trials incentral Scotland.

By Durham RC, Chambers JA, Power KG, Sharp DM, Macdonald RR,Major KA, et al.

No. 43The effectiveness and cost-effectivenessof dual-chamber pacemakers comparedwith single-chamber pacemakers forbradycardia due to atrioventricularblock or sick sinus syndrome: systematic review and economicevaluation.

By Castelnuovo E, Stein K, Pitt M,Garside R, Payne E.

No. 44Newborn screening for congenital heartdefects: a systematic review and cost-effectiveness analysis.

By Knowles R, Griebsch I, DezateuxC, Brown J, Bull C, Wren C.

No. 45The clinical and cost-effectiveness of leftventricular assist devices for end-stageheart failure: a systematic review andeconomic evaluation.

By Clegg AJ, Scott DA, Loveman E,Colquitt J, Hutchinson J, Royle P, et al.

No. 46The effectiveness of the HeidelbergRetina Tomograph and laser diagnosticglaucoma scanning system (GDx) indetecting and monitoring glaucoma.

By Kwartz AJ, Henson DB, Harper RA, Spencer AF, McLeod D.

No. 47Clinical and cost-effectiveness ofautologous chondrocyte implantationfor cartilage defects in knee joints:systematic review and economicevaluation.

By Clar C, Cummins E, McIntyre L,Thomas S, Lamb J, Bain L, et al.

No. 48Systematic review of effectiveness ofdifferent treatments for childhoodretinoblastoma.

By McDaid C, Hartley S, Bagnall A-M, Ritchie G, Light K,Riemsma R.

No. 49Towards evidence-based guidelines for the prevention of venousthromboembolism: systematic reviews of mechanical methods, oralanticoagulation, dextran and regionalanaesthesia as thromboprophylaxis.

By Roderick P, Ferris G, Wilson K,Halls H, Jackson D, Collins R,et al.

No. 50The effectiveness and cost-effectivenessof parent training/educationprogrammes for the treatment ofconduct disorder, including oppositionaldefiant disorder, in children.

By Dretzke J, Frew E, Davenport C,Barlow J, Stewart-Brown S, Sandercock J, et al.

Volume 10, 2006

No. 1The clinical and cost-effectiveness ofdonepezil, rivastigmine, galantamineand memantine for Alzheimer’s disease.

By Loveman E, Green C, Kirby J,Takeda A, Picot J, Payne E, et al.

No. 2FOOD: a multicentre randomised trialevaluating feeding policies in patientsadmitted to hospital with a recentstroke.

By Dennis M, Lewis S, Cranswick G,Forbes J.

No. 3The clinical effectiveness and cost-effectiveness of computed tomographyscreening for lung cancer: systematicreviews.

By Black C, Bagust A, Boland A,Walker S, McLeod C, De Verteuil R, et al.


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No. 4A systematic review of the effectivenessand cost-effectiveness of neuroimagingassessments used to visualise the seizure focus in people with refractoryepilepsy being considered for surgery.

By Whiting P, Gupta R, Burch J,Mujica Mota RE, Wright K, Marson A, et al.

No. 5Comparison of conference abstracts and presentations with full-text articles in the health technologyassessments of rapidly evolvingtechnologies.

By Dundar Y, Dodd S, Dickson R,Walley T, Haycox A, Williamson PR.

No. 6Systematic review and evaluation ofmethods of assessing urinaryincontinence.

By Martin JL, Williams KS, AbramsKR, Turner DA, Sutton AJ, Chapple C,et al.

No. 7The clinical effectiveness and cost-effectiveness of newer drugs forchildren with epilepsy. A systematicreview.

By Connock M, Frew E, Evans B-W, Bryan S, Cummins C, Fry-Smith A, et al.

No. 8Surveillance of Barrett’s oesophagus:exploring the uncertainty throughsystematic review, expert workshop andeconomic modelling.

By Garside R, Pitt M, Somerville M,Stein K, Price A, Gilbert N.

No. 9Topotecan, pegylated liposomaldoxorubicin hydrochloride andpaclitaxel for second-line or subsequenttreatment of advanced ovarian cancer: asystematic review and economicevaluation.

By Main C, Bojke L, Griffin S,Norman G, Barbieri M, Mather L, et al.

No. 10Evaluation of molecular techniques inprediction and diagnosis ofcytomegalovirus disease inimmunocompromised patients.

By Szczepura A, Westmoreland D,Vinogradova Y, Fox J, Clark M.

No. 11Screening for thrombophilia in high-risksituations: systematic review and cost-effectiveness analysis. The Thrombosis:Risk and Economic Assessment ofThrombophilia Screening (TREATS)study.

By Wu O, Robertson L, Twaddle S,Lowe GDO, Clark P, Greaves M, et al.

No. 12A series of systematic reviews to informa decision analysis for sampling andtreating infected diabetic foot ulcers.

By Nelson EA, O’Meara S, Craig D,Iglesias C, Golder S, Dalton J, et al.

No. 13Randomised clinical trial, observationalstudy and assessment of cost-effectivenessof the treatment of varicose veins(REACTIV trial).

By Michaels JA, Campbell WB,Brazier JE, MacIntyre JB, Palfreyman SJ,Ratcliffe J, et al.

No. 14The cost-effectiveness of screening fororal cancer in primary care.

By Speight PM, Palmer S, Moles DR,Downer MC, Smith DH, Henriksson M et al.

No. 15Measurement of the clinical and cost-effectiveness of non-invasive diagnostictesting strategies for deep veinthrombosis.

By Goodacre S, Sampson F, StevensonM, Wailoo A, Sutton A, Thomas S, et al.

No. 16Systematic review of the effectivenessand cost-effectiveness of HealOzone®

for the treatment of occlusal pit/fissurecaries and root caries.

By Brazzelli M, McKenzie L, FieldingS, Fraser C, Clarkson J, Kilonzo M, et al.


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93

Health Technology AssessmentProgramme

Prioritisation Strategy GroupMembers

Chair,Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Professor Bruce Campbell,Consultant Vascular & GeneralSurgeon, Royal Devon & ExeterHospital

Dr Edmund Jessop, MedicalAdvisor, National Specialist,Commissioning Advisory Group(NSCAG), Department ofHealth, London

Professor Jon Nicholl, Director,Medical Care Research Unit,University of Sheffield, Schoolof Health and Related Research

Dr John Reynolds, ClinicalDirector, Acute GeneralMedicine SDU, RadcliffeHospital, Oxford

Dr Ron Zimmern, Director,Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Deputy Director, Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

HTA Commissioning BoardMembers

Programme Director, Professor Tom Walley, Director, NHS HTA Programme,Department of Pharmacology &Therapeutics,University of Liverpool

Chair,Professor Jon Nicholl,Director, Medical Care ResearchUnit, University of Sheffield,School of Health and RelatedResearch

Deputy Chair, Professor Jenny Hewison,Professor of Health CarePsychology, Academic Unit ofPsychiatry and BehaviouralSciences, University of LeedsSchool of Medicine

Dr Jeffrey AronsonReader in ClinicalPharmacology, Department ofClinical Pharmacology,Radcliffe Infirmary, Oxford

Professor Deborah Ashby,Professor of Medical Statistics,Department of Environmentaland Preventative Medicine,Queen Mary University ofLondon

Professor Ann Bowling,Professor of Health ServicesResearch, Primary Care andPopulation Studies,University College London

Dr Andrew Briggs, PublicHealth Career Scientist, HealthEconomics Research Centre,University of Oxford

Professor John Cairns, Professorof Health Economics, PublicHealth Policy, London School ofHygiene and Tropical Medicine,London

Professor Nicky Cullum,Director of Centre for EvidenceBased Nursing, Department ofHealth Sciences, University ofYork

Mr Jonathan Deeks, Senior Medical Statistician,Centre for Statistics inMedicine, University of Oxford

Dr Andrew Farmer, SeniorLecturer in General Practice,Department of Primary Health Care, University of Oxford

Professor Fiona J Gilbert,Professor of Radiology,Department of Radiology,University of Aberdeen

Professor Adrian Grant,Director, Health ServicesResearch Unit, University ofAberdeen

Professor F D Richard Hobbs,Professor of Primary Care &General Practice, Department ofPrimary Care & GeneralPractice, University ofBirmingham

Professor Peter Jones, Head ofDepartment, UniversityDepartment of Psychiatry,University of Cambridge

Professor Sallie Lamb, Professor of Rehabilitation,Centre for Primary Health Care, University of Warwick

Professor Stuart Logan,Director of Health & SocialCare Research, The Peninsula Medical School, Universities of Exeter &Plymouth

Dr Linda Patterson, Consultant Physician,Department of Medicine,Burnley General Hospital

Professor Ian Roberts, Professorof Epidemiology & PublicHealth, Intervention ResearchUnit, London School ofHygiene and Tropical Medicine

Professor Mark Sculpher,Professor of Health Economics,Centre for Health Economics,Institute for Research in theSocial Services, University of York

Dr Jonathan Shapiro, SeniorFellow, Health ServicesManagement Centre,Birmingham

Ms Kate Thomas,Deputy Director,Medical Care Research Unit,University of Sheffield

Ms Sue Ziebland,Research Director, DIPEx,Department of Primary HealthCare, University of Oxford,Institute of Health Sciences

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)


Health Technology Assessment Programme

94Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Diagnostic Technologies & Screening PanelMembers

Chair,Dr Ron Zimmern, Director ofthe Public Health Genetics Unit,Strangeways ResearchLaboratories, Cambridge

Ms Norma Armston,Lay Member, Bolton

Professor Max BachmannProfessor of Health Care Interfaces, Department of Health Policy and Practice,University of East Anglia

Professor Rudy BilousProfessor of Clinical Medicine &Consultant Physician,The Academic Centre,South Tees Hospitals NHS Trust

Dr Paul Cockcroft, Consultant MedicalMicrobiologist and ClinicalDirector of Pathology,Department of ClinicalMicrobiology, St Mary'sHospital, Portsmouth

Professor Adrian K Dixon,Professor of Radiology,University Department ofRadiology, University ofCambridge Clinical School

Dr David Elliman, Consultant Paediatrician/Hon. Senior Lecturer,Population Health Unit, Great Ormond St. Hospital,London

Professor Glyn Elwyn,Primary Medical Care Research Group,Swansea Clinical School,University of Wales Swansea

Mr Tam Fry, HonoraryChairman, Child GrowthFoundation, London

Dr Jennifer J Kurinczuk,Consultant ClinicalEpidemiologist,National PerinatalEpidemiology Unit, Oxford

Dr Susanne M Ludgate, MedicalDirector, Medicines &Healthcare Products RegulatoryAgency, London

Professor William Rosenberg,Professor of Hepatology, LiverResearch Group, University ofSouthampton

Dr Susan Schonfield, Consultantin Public Health, SpecialisedServices Commissioning NorthWest London, HillingdonPrimary Care Trust

Dr Phil Shackley, SeniorLecturer in Health Economics,School of Population andHealth Sciences, University ofNewcastle upon Tyne

Dr Margaret Somerville, PMSPublic Health Lead, PeninsulaMedical School, University ofPlymouth

Dr Graham Taylor, ScientificDirector & Senior Lecturer,Regional DNA Laboratory, TheLeeds Teaching Hospitals

Professor Lindsay WilsonTurnbull, Scientific Director,Centre for MR Investigations &YCR Professor of Radiology,University of Hull

Professor Martin J Whittle,Associate Dean for Education,Head of Department ofObstetrics and Gynaecology,University of Birmingham

Dr Dennis Wright, Consultant Biochemist &Clinical Director, Pathology & The KennedyGalton Centre, Northwick Park & St Mark’sHospitals, Harrow

Pharmaceuticals PanelMembers

Chair,Dr John Reynolds, ChairDivision A, The John RadcliffeHospital, Oxford RadcliffeHospitals NHS Trust

Professor Tony Avery, Head of Division of PrimaryCare, School of CommunityHealth Services, Division ofGeneral Practice, University ofNottingham

Ms Anne Baileff, ConsultantNurse in First Contact Care,Southampton City Primary CareTrust, University ofSouthampton

Professor Stirling Bryan,Professor of Health Economics,Health Services Management Centre,University of Birmingham

Mr Peter Cardy, ChiefExecutive, Macmillan CancerRelief, London

Professor Imti Choonara,Professor in Child Health,Academic Division of ChildHealth, University ofNottingham

Dr Robin Ferner, ConsultantPhysician and Director, WestMidlands Centre for AdverseDrug Reactions, City HospitalNHS Trust, Birmingham

Dr Karen A Fitzgerald,Consultant in PharmaceuticalPublic Health, National PublicHealth Service for Wales,Cardiff

Mrs Sharon Hart, Head of DTB Publications, Drug &Therapeutics Bulletin, London

Dr Christine Hine, Consultant inPublic Health Medicine, SouthGloucestershire Primary CareTrust

Professor Stan Kaye,Cancer Research UK Professor of Medical Oncology,Section of Medicine, The Royal Marsden Hospital,Sutton

Ms Barbara Meredith,Lay Member, Epsom

Dr Andrew Prentice, SeniorLecturer and ConsultantObstetrician & Gynaecologist,Department of Obstetrics &Gynaecology, University ofCambridge

Dr Frances Rotblat, CPMPDelegate, Medicines &Healthcare Products RegulatoryAgency, London

Professor Jan Scott, Professor of Psychological Treatments,Institute of Psychiatry,University of London

Mrs Katrina Simister, AssistantDirector New Medicines,National Prescribing Centre,Liverpool

Dr Richard Tiner, MedicalDirector, Medical Department,Association of the BritishPharmaceutical Industry,London

Dr Helen Williams,Consultant Microbiologist,Norfolk & Norwich UniversityHospital NHS Trust


95

Therapeutic Procedures PanelMembers

Chair, Professor Bruce Campbell,Consultant Vascular andGeneral Surgeon, Departmentof Surgery, Royal Devon &Exeter Hospital

Dr Aileen Clarke,Reader in Health ServicesResearch, Public Health &Policy Research Unit, Barts &the London School of Medicine& Dentistry, London

Dr Matthew Cooke, Reader inA&E/Department of HealthAdvisor in A&E, WarwickEmergency Care andRehabilitation, University ofWarwick

Dr Carl E Counsell, ClinicalSenior Lecturer in Neurology,Department of Medicine andTherapeutics, University ofAberdeen

Ms Amelia Curwen, ExecutiveDirector of Policy, Services andResearch, Asthma UK, London

Professor Gene Feder, Professorof Primary Care R&D,Department of General Practiceand Primary Care, Barts & theLondon, Queen Mary’s Schoolof Medicine and Dentistry,London

Professor Paul Gregg,Professor of OrthopaedicSurgical Science, Department ofGeneral Practice and PrimaryCare, South Tees Hospital NHSTrust, Middlesbrough

Ms Bec Hanley, Co-Director,TwoCan Associates,Hurstpierpoint

Ms Maryann L Hardy, Lecturer, Division ofRadiography, University ofBradford

Professor Alan Horwich,Director of Clinical R&D,Academic Department ofRadiology, The Institute ofCancer Research, London

Dr Simon de Lusignan,Senior Lecturer, Primary Care Informatics,Department of CommunityHealth Sciences,St George’s Hospital MedicalSchool, London

Professor Neil McIntosh,Edward Clark Professor of Child Life & Health,Department of Child Life &Health, University of Edinburgh

Professor James Neilson,Professor of Obstetrics andGynaecology, Department ofObstetrics and Gynaecology,University of Liverpool

Dr John C Pounsford,Consultant Physician,Directorate of Medical Services,North Bristol NHS Trust

Karen Roberts, NurseConsultant, Queen ElizabethHospital, Gateshead

Dr Vimal Sharma, ConsultantPsychiatrist/Hon. Senior Lecturer,Mental Health Resource Centre,Cheshire and Wirral PartnershipNHS Trust, Wallasey

Dr L David Smith, ConsultantCardiologist, Royal Devon &Exeter Hospital

Professor Norman Waugh,Professor of Public Health,Department of Public Health,University of Aberdeen

Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Health Technology Assessment Programme

96Current and past membership details of all HTA ‘committees’ are available from the HTA website (www.hta.ac.uk)

Expert Advisory NetworkMembers

Professor Douglas Altman,Director of CSM & CancerResearch UK Med Stat Gp,Centre for Statistics inMedicine, University of Oxford,Institute of Health Sciences,Headington, Oxford

Professor John Bond,Director, Centre for HealthServices Research, University ofNewcastle upon Tyne, School ofPopulation & Health Sciences,Newcastle upon Tyne

Mr Shaun Brogan, Chief Executive, RidgewayPrimary Care Group, Aylesbury

Mrs Stella Burnside OBE,Chief Executive, Office of theChief Executive. TrustHeadquarters, AltnagelvinHospitals Health & SocialServices Trust, Altnagelvin AreaHospital, Londonderry

Ms Tracy Bury, Project Manager, WorldConfederation for PhysicalTherapy, London

Professor Iain T Cameron,Professor of Obstetrics andGynaecology and Head of theSchool of Medicine,University of Southampton

Dr Christine Clark,Medical Writer & ConsultantPharmacist, Rossendale

Professor Collette Clifford,Professor of Nursing & Head ofResearch, School of HealthSciences, University ofBirmingham, Edgbaston,Birmingham

Professor Barry Cookson,Director, Laboratory ofHealthcare Associated Infection,Health Protection Agency,London

Professor Howard Cuckle,Professor of ReproductiveEpidemiology, Department ofPaediatrics, Obstetrics &Gynaecology, University ofLeeds

Dr Katherine Darton, Information Unit, MIND – The Mental Health Charity,London

Professor Carol Dezateux, Professor of PaediatricEpidemiology, London

Mr John Dunning,Consultant CardiothoracicSurgeon, CardiothoracicSurgical Unit, PapworthHospital NHS Trust, Cambridge

Mr Jonothan Earnshaw,Consultant Vascular Surgeon,Gloucestershire Royal Hospital,Gloucester

Professor Martin Eccles, Professor of ClinicalEffectiveness, Centre for HealthServices Research, University ofNewcastle upon Tyne

Professor Pam Enderby,Professor of CommunityRehabilitation, Institute ofGeneral Practice and PrimaryCare, University of Sheffield

Mr Leonard R Fenwick, Chief Executive, Newcastleupon Tyne Hospitals NHS Trust

Professor David Field, Professor of Neonatal Medicine,Child Health, The LeicesterRoyal Infirmary NHS Trust

Mrs Gillian Fletcher, Antenatal Teacher & Tutor andPresident, National ChildbirthTrust, Henfield

Professor Jayne Franklyn,Professor of Medicine,Department of Medicine,University of Birmingham,Queen Elizabeth Hospital,Edgbaston, Birmingham

Ms Grace Gibbs, Deputy Chief Executive,Director for Nursing, Midwifery& Clinical Support Services, West Middlesex UniversityHospital, Isleworth

Dr Neville Goodman, Consultant Anaesthetist,Southmead Hospital, Bristol

Professor Alastair Gray,Professor of Health Economics,Department of Public Health,University of Oxford

Professor Robert E Hawkins, CRC Professor and Director ofMedical Oncology, Christie CRCResearch Centre, ChristieHospital NHS Trust, Manchester

Professor Allen Hutchinson, Director of Public Health &Deputy Dean of ScHARR,Department of Public Health,University of Sheffield

Dr Duncan Keeley,General Practitioner (Dr Burch& Ptnrs), The Health Centre,Thame

Dr Donna Lamping,Research Degrees ProgrammeDirector & Reader in Psychology,Health Services Research Unit,London School of Hygiene andTropical Medicine, London

Mr George Levvy,Chief Executive, MotorNeurone Disease Association,Northampton

Professor James Lindesay,Professor of Psychiatry for theElderly, University of Leicester,Leicester General Hospital

Professor Julian Little,Professor of Human GenomeEpidemiology, Department ofEpidemiology & CommunityMedicine, University of Ottawa

Professor Rajan Madhok, Medical Director & Director ofPublic Health, Directorate ofClinical Strategy & PublicHealth, North & East Yorkshire& Northern Lincolnshire HealthAuthority, York

Professor David Mant, Professor of General Practice,Department of Primary Care,University of Oxford

Professor Alexander Markham, Director, Molecular MedicineUnit, St James’s UniversityHospital, Leeds

Dr Chris McCall, General Practitioner, TheHadleigh Practice, Castle Mullen

Professor Alistair McGuire,Professor of Health Economics,London School of Economics

Dr Peter Moore, Freelance Science Writer, Ashtead

Dr Sue Moss, Associate Director,Cancer Screening EvaluationUnit, Institute of CancerResearch, Sutton

Mrs Julietta Patnick, Director, NHS Cancer ScreeningProgrammes, Sheffield

Professor Tim Peters,Professor of Primary CareHealth Services Research,Academic Unit of PrimaryHealth Care, University ofBristol

Professor Chris Price, Visiting Chair – Oxford, ClinicalResearch, Bayer DiagnosticsEurope, Cirencester

Professor Peter Sandercock,Professor of Medical Neurology,Department of ClinicalNeurosciences, University ofEdinburgh

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Dr Ross Taylor, Senior Lecturer, Department ofGeneral Practice and PrimaryCare, University of Aberdeen

Mrs Joan Webster, Consumer member, HTA –Expert Advisory Network

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HTA

Health Technology Assessm

ent 2006;Vol. 10: No. 16

HealO

zone®

for the treatment of occlusal pit/fissure caries and root caries



M Brazzelli, L McKenzie, S Fielding, C Fraser, J Clarkson, M Kilonzo and N Waugh


HTAHealth Technology AssessmentNHS R&D HTA Programme

The National Coordinating Centre for Health Technology Assessment,Mailpoint 728, Boldrewood,University of Southampton,Southampton, SO16 7PX, UK.Fax: +44 (0) 23 8059 5639 Email: [email protected]://www.hta.ac.uk ISSN 1366-5278

FeedbackThe HTA Programme and the authors would like to know

your views about this report.

The Correspondence Page on the HTA website(http://www.hta.ac.uk) is a convenient way to publish

your comments. If you prefer, you can send your comments to the address below, telling us whether you would like

us to transfer them to the website.

We look forward to hearing from you.

May 2006

nhs r&d hta programme...healozone in addition to current management of dental caries. results:...

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