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Abstract
Objective To assess the effectiveness of lasers (at sub-ablative parameters) in reducing caries incidence compared with traditional prophylactic interventions (TPIs) when used alone or together with other TPIs such as pits and fissures sealant or fluoride gels or varnishes.
Design A systematic review. Data sources include Medline (via PubMed), Embase, Web of Science and the Cochrane Library (December 2019).
Eligibility criteria Only randomised trials (RCTs) and controlled clinical trials (CCTs) dealing with prophylactic lasers use (vs TPI or untreated teeth) were considered as eligible. We excluded in vitro and ex vivo studies.
Data extraction Eligible studies were selected and data extracted independently by two reviewers. Risk of bias was assessed adopting the Cochrane Risk of Bias tool. Data on caries incidence, sealant retention, fluoride uptake, adverse events, treatment duration, patients’ discomfort and cost-effectiveness ratio was extracted.
Data analysis Extracted data were presented narratively due to the heterogeneity of included studies.
Results Seven RCTs and two CCTs, all with an evident risk of bias, met inclusion criteria, pooling together 269 individuals and 1628 teeth. CO2, neodymium-doped yttrium aluminium garnet, erbium-doped yttrium aluminum garnet (Er:YAG), erbium, chromium: yttrium scandium gallium garnet (Er,Cr:YSGG) and Argon lasers were used. In the permanent dentition, lasers only when used in combination with TPIs were effective in reducing caries when compared with untreated teeth (risk ratio (RR)=0.44 (0.20–0.97); Er:YAG laser) or with TPIs used alone (RR=0.39 (0.22–0.71); CO2 laser). Moreover, Argon laser significantly improved the fluoride uptake into the enamel surfaces (ANalysis Of VAriance (ANOVA) tests: 95%, p<0.0001). Likewise, sealant retention improved when acid etching was performed on previously irradiated enamel fissures by CO2 laser (RR=0.63 (0.38–1.04)) or Er:YAG laser (RR=0.54 (95% CI: 0.34 to 0.87)). In addition, laser resulted safe and well tolerated by patients.
Conclusion Despite some positive indications, an inadequate level of evidence was found in the included studies concerning the lasers’ effectiveness in preventing caries. Further studies with a higher methodological quality level are required.
- dental caries
- lasers
- prevention
- prophylaxis
- sub-ablative energy
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Strengths and limitations of this study
This review systematically and with rigorous methodological procedures addressed the topic of laser use to prevent caries.
Cochrane Risk of Bias (RoB) tool was adopted to evaluate the RoB of the included studies.
The original Cochrane RoB was adopted rather than the recent Cochrane RoB2.
The study protocol was not registered in the International prospective register of systematic reviews (PROSPERO).
Few studies were found with a wide number of described types of laser (high heterogeneity), which hindered any meta-analysis of data.
Introduction
Dental caries represent a relevant public health problem due to its universally high prevalence among both children and adults. In a worldwide epidemiological evaluation performed in 2010, untreated caries in permanent teeth was the most prevalent disease compared with all other illnesses.1 Prophylactic interventions against caries are strongly recommended by the WHO.2 The most universally used of traditional prophylactic interventions (TPIs) against caries are the application of sealant on enamel pits and fissures of molars3 and the topical administration of high fluoride gel or varnish.4 5 Laser might represent an alternative or complementary prophylactic treatment to TPIs to improve the prevention of caries.
Laser in dentistry was used in different fields such as conservative,6 endodontics,7 periodontology,8 implantology,9 oral surgery,10 etc. Laser, in recent years, has also been used for prophylactic purposes against caries at sub-ablative levels, energy enough to modify enamel structure but without any tissue ablative capacity. Since the 1980s, laser light has been shown to be able to modify the structure of superficial dental enamel tissues.11 When the laser light at sub-ablative energy interacts with the enamel, it produces a superficial and instantaneous increase in temperature from 100°C to 1600°C inducing structural tissue modification.11 In particular, the laser light interacts with water and hydroxyapatite, two chromophores of the enamel. The water inside the irradiated enamel decreases its concentration,12 particularly of its molecules around the hydroxyapatite crystals with a consequent decrease of tissue permeability,13 including the penetration of acids produced by caries bacteria.14 Moreover, when hydroxyapatite is irradiated, the content of its chemical components is modified: the calcium and phosphate ions increase14 while the carbonate ions decrease.12 These changes increase the chemical stability of the irradiated hydroxyapatite.14 15 In particular, the loss of calcium carbonates increases the degree of enamel crystallinity with an improvement in its structural proprieties.16
The use of the laser has demonstrated further validity in vitro: increasing the absorption of fluoride in the enamel and improving sealant retention when used in combination with acid gel for etching enamel pits and fissures.17
The above-mentioned laser properties noted above have motivated our further interest in evaluating the prophylactic capacity of this tool in preventing caries, even in vivo studies.
Objectives
The first objective of this review was to verify whether the use of laser at sub-ablative energy induces enamel modification sufficient to improve it in the following ways: resistance against caries and fluoride uptake and retention of sealant materials by improving traditional etching procedures. The second objective was to determine whether laser use was safe for the dental pulp vitality, and moreover whether participants assessed as acceptable this intervention.
Methods
Study design
It is a systematic review of scientific literature. The reporting of this study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Inclusion criteria
Type of studies
Only clinical trials were included, excluding any in vitro study. Likewise, ex vivo studies (where teeth were examined after their extraction or exfoliation) were excluded. Both randomised controlled trials (RCTs) and controlled clinical trials (CCTs) carried out in humans were included. Among RCTs, both parallel-group and split-mouth clinical trials were considered eligible. The minimum or maximum follow-up times of studies were not considered as an exclusion criterion.
Type of participants
Participants, irrespective of age and gender, with sound primary and/or permanent teeth (without caries or other treatments such as fillings, prosthetic manufactures or orthodontic brackets and/or bands), who had undergone laser prophylaxis (primary prevention) interventions on enamel coronal surfaces, were considered.
Type of interventions
Intervention group was any laser application (specific to increasing the resistance against demineralisation of enamel) alone or in combination with any TPI.
Control group was no treatment, placebo alone or in combination with any TPI, or any TPI alone.
Type of outcomes
Primary outcomes
Incidence of caries, enamel fluoride uptake, sealant retention and adverse effects (ie, irreversible dental pulpitis or necrosis, and dental abscess) were primary outcomes.
Secondary outcomes
Operator preference, participant discomfort, treatment duration and cost effectiveness were secondary outcomes.
Studies selection
A comprehensive search to identify all relevant studies, regardless of language, was carried out in the following database (December 2019): Medline (via PubMed), Embase, Web of Science and Cochrane Library. The PubMed search strategy (adapted to each database) is reported in online supplemental appendix 1. All the references were collected in the EndNote V.X7 software and duplicates were removed.
Supplemental material
Two reviewers (SP and BC) independently screened titles and abstracts in the above-mentioned databases, which met the inclusion criteria. Disagreements were resolved through discussion between the two researchers, and when a resolution was not obtained a third reviewer was consulted (SC). Once the full texts of the chosen records were obtained, two additional reviewers (GL and MO), working independently, deleted those deemed not useful for the review. In case of disagreement, a third reviewer was consulted (SC).
Data extraction
The same two reviewers (GL and MO) who assessed the eligible studies for this review independently performed data extraction and in case of disagreement a third researcher was consulted (SC). From included studies, data concerning authors, year of publication, country and setting, as well as the number of participants, age and gender were extracted. Moreover, data describing the adopted interventions in both experimental and control groups (with the different devices or materials used) were extracted.
In outcomes such as incidence of caries, sealant retention and adverse events, data of incidence was extracted, that is, the number of cases of new caries, sealant filling detachments and pulpitis episodes in either teeth or sealants of each sample group tested during the duration of the studies. In addition, fluoride intake data was measured in terms of the ratio or difference between the mean values of enamel fluoride content (parts per million) before and after each surgery. Treatment duration data were recorded in terms of the average time (s) elapsed during each treatment from start to finish. Patients’ discomfort average (measured with specific graded rating scales) or incidence (individuals experiencing distress) as data was also extracted.
Assessment of risk of bias in included studies
In the included studies a ‘risk of bias’ (RoB) was assessed by two researchers (MO and IA) with independent evaluations. In the case of lack of final agreement, a third researcher was consulted (SC). For this type of assessment, the recommendations formulated in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions18 19 were followed. RoB assessment involved the following domains: selection bias (sequence generation and allocation concealment), performance bias, detection bias, attrition bias and selective outcome reporting bias. The RoB judgement for each outcome was expressed in three degrees: low RoB, unclear RoB and high RoB.
Statistical analysis
The effectiveness and safety of laser prophylactic intervention was calculated for dichotomous outcomes between the treatment and control groups measuring the risk ratio (RR) with a 95% CI, while for continuous data we calculated the mean difference (MD) with 95% CI. In case of studies with similar populations, interventions, comparators and outcomes, we have planned to carry out meta-analyses using the Review Manager V.5.3 software. We would have combined relative risks for dichotomous data and MDs for continuous data, using the random-effects method (DerSimonian and Laird inverse variance).
Data synthesis
Due to the high heterogeneity of type of lasers and outcome measures, we did not perform meta-analyses and presented the results in a narrative way.
Patient and public involvement
No patient involved.
Results
We identified 1224 records through the literature search, which were reduced to 825 records when duplicates were removed. Thirty-three records were assessed to fulfil the selection criteria and, therefore, selected as valid to be obtained in their full text version. The level of consistency found (kappa coefficient of agreement) between two reviewers performing the initial screening of records was high (κ value=0.93). After the full text examination, nine studies (10 publications20–29) meeting the inclusion criteria were included (figure 1 and table 1), while the remaining 23 studies were excluded due to the reasons reported in the online supplemental appendix 2. The study carried out by Nammour et al was described in two publications.25 26 All nine studies20–29 were written in English.
Supplemental material
Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram.
Main characteristics of included studies population
Included studies
The nine included studies were published between 1996 and 2015. Seven studies were RCTs21–28 while the remaining two studies were CCTs.20 29 All the studies had a split-mouth design where both intervention and control groups were represented by teeth located in opposite sides of single dental arcs rather than in different patients. Characteristics of included studies are reported in tables 1 and 2.
Main characteristics of included studies interventions
Participants
Pooling the participants from all the nine included studies, 269 individuals were obtained and 1628 teeth were tested. The number of enrolled participants in each study varied from 12 to 51. Excluding Nammour’s two papers,25 26 where the buccal surface of anterior teeth was treated, in the other eight trials only the occlusal surface of posterior teeth (molars and premolars) was tested for the laser evaluation. In five studies, the treatments were carried out in children20 21 24 27 29 while in the remaining studies young adults were enrolled.
Treatments
In all nine studies, the lasers were employed with sub-ablative parameters, with a low level of fluency ranging from 10 J/cm2 to 85 J/cm2. In three studies, the CO2 laser was adopted20 22 28; in two studies, the neodymium-doped yttrium aluminium garnet (Nd:YAG) laser was used27 29; in another study, the argon (two publications) laser was employed25 26; in one study, the erbium-doped yttrium aluminum garnet (Er:YAG) laser was used21 and in the last two studies,23 24 the erbium, chromium: yttrium scandium gallium garnet (Er,Cr:YSGG) laser was used. To support the use of laser prophylactic interventions, other interventions were adopted in the included studies such as 1.23% acidulated phosphate fluoride gel or foam,27 29 enamel pit and fissure resin sealant,28 and 5% fluoride varnish.20
RoB assessment of the body of evidence
The RoB assessment was carried out through the Cochrane RoB tool18 19 (figure 2). Two studies20 29 were considered to be at high risk of selection bias because they were CCTs without any randomisation procedure for the participants’ allocation in both control and intervention groups. The remaining seven studies (eight publications) were RCTs,21–28 but only one reported adequate concealment of allocation.22
Risk of Bias summary of included studies.
All studies were at high risk of performance bias (blinding of participants and personnel) due to the nature of treatments. Moreover, four out of nine studies20 25 26 29 did not describe the presence of blinded assessors for evaluating outcomes with an unclear risk of detection bias.
In terms of attrition bias, four out of nine included studies which presented a high risk of this type of bias20 21 27 28 due to participants drop-out varying from 18% to 50% in a time period ranging from 12 months to 4 years. When the selective outcome reporting bias was considered, all the trials were considered as having an unclear risk of this bias given that none of them evaluated all the primary outcomes (specifically incidence of caries and adverse events).
Effectiveness of treatments
Caries incidence
Four studies reported this outcome.20 21 27 29 Three studies were carried out on permanent teeth (molar and premolars)20 21 29, while one study considered only primary molars.24 CO2, Nd:YAG and Er:YAG lasers were the type of devices used in these four included studies.
Permanent teeth
The three studies were all carried out on children with ages ranging between 6 and 11 years. The number of enrolled participants varied from 28 to 51 with an overall of 558 teeth examined, and the duration of the studies ranged from 1 year to 4 years.
When laser was used alone (CO2 laser),20 it did not result effective in reducing caries incidence on untreated teeth (RR=0.89 (95% CI: 0.40 to 1.97), p=0.77).
Conversely, when laser was combined with TPIs, it resulted effective as demonstrated in two studies.20 21 In the first of these two studies,20 CO2 laser combined with the sealants (compared with a control group of untreated teeth) contributed to the reduction, with a statistical relevance, of the caries incidence with a preventable fraction of 78% (RR=0.22 (95% CI: 0.05 to 0.94), p=0.02). In the second study,21 Er:YAG laser, combined with sealants (intervention group) and compared with the same sealants used alone (control group), resulted in a caries incidence reduction of 56% (RR=0.44 (95% CI: 0.20 to 0.97), p=0.03).
In a further study,29 laser (Nd:YAG laser) in combination with acidulated phosphate fluoride gel (intervention group) was compared with this fluoride gel used alone (control group). Also in this case, laser combined with fluoride gel resulted more effective than gel alone with a caries incidence reduction of 61% (RR=0.39 (95% CI: 0.22 to 0.71), p=0.001).
Primary teeth
In the only study where primary teeth were treated,27 35 children were enrolled and 280 first and second primary molars were treated. Four interventions were used as follows: Nd:YAG laser; 1.23% phosphate acidulated fluoride gel and 5% fluoride varnish and sealants. Nd:YAG was used alone or in association with each of the other three interventions. The control group comprised untreated teeth. The study duration was 1 year. Only when laser was used alone, it was found able to significantly reduce caries incidence with mean values of 70% (RR=0.30; (95% CI: 0.11 to 0.78), p=0.004).
Sealant retention
Four studies described this outcome.20 21 23 28 Sealant retention was assessed by comparing two different types of enamel etching, laser light irradiation (laser etching) and traditional acid gel apposition (acid etching). Two types of comparisons were performed: (a) laser light used alone was compared with acid gel and (b) laser light in addition to acid gel was compared with acid gel.
Laser etching combined with acid etching versus acid etching alone
The following two studies20 22 compared the combined etching procedure (laser light and acid gel) with traditional acid etching.
In the two studies, the number of patients enrolled ranged from 28 to 42 with a total number of 224 teeth. The duration of the studies ranged from 18 months to 24 months.
In both these studies, laser light combined with acid gel resulted in better etching than acid gel used alone in terms of sealant retention. In fact, when CO2 laser in addition of acid gel was used,20 a reduction from 19 (n=19/28) to 12 (n=12/28) detachments was found, with a 37% of drop-out decrease (RR=0.63 (95% CI: 0.38 to 1.04), p=0.059). Similarly, when Er:YAG laser was combined with acid gel,21 there was a 46% of detachment reduction (RR=0.54 (95% CI: 0.34 to 0.87)), passing from 35 (n=35/84) to 19 (n=19/84) sealant fillings, which fell out during the period of follow-up visits.
Laser etching versus acid etching
Three studies23 24 28 dealt with this topic. In these trials, the number of participants varied from 16 to 50 and their ages from 6 years to 23 years, with only a single study evaluating children.24 A total of 438 permanent molars and premolars were evaluated. The duration of the studies ranged from 1 year to 3 years.
In this topic, similar results were found: in all three studies,23 24 28 there was no statistically significant difference between the laser light etching and the acid etching with regard to sealant filling drop-out. In the first of the three studies, in fact, in which Er,Cr:YSGG laser was used, 9 out of 56 sealant fillings (n=9/56) were detached in the intervention group (laser etching), while 8 out of 56 in the control group (acid etching) showed no significant difference between the two groups (RR=0.87 (95% CI: 0.37 to 2.06)).23 Likewise in the second study,24 where again Er,Cr:YSGG laser was used, in both acid and laser etching groups, the same number of detachments (78/100) were found. In the third study,28 similar to the other two, 2 sealant fillings out of 96 were detached in the laser etching group (n=2/96), while 4 out of 74 were detached in the acid etching group, with no significant difference (RR=0.39 (95% CI: 0.07 to 2.05), p=0.24).
Fluoride uptake into the enamel surfaces
One study (two publications) carried out by Nammour et al reported on this outcome.25 26 Twelve participants were enrolled in this trial and 98 upper permanent anterior teeth were tested. In the intervention group, argon laser irradiation was performed before 1.23% acidulated phosphate fluoride gel administration. In the control group, only fluoride gel was administered. The fluoride uptake was evaluated at 1 week and after 6 months. The intervention group showed a higher degree of fluoride adsorption than the control group, with statistically significant differences both at 1 week and at 6 months (ANalysis Of VAriance (ANOVA) tests=95%, p<0.0001; R2=0.9751—Bartlett’s statistic corrected=134 and p<0.0001).
Adverse events
Two trials investigated dental pulp health after laser irradiation.22 28 A total of 44 participants, aged 15–38 years, were enrolled in the two studies and 174 permanent molars and premolars (including third molars) were examined by clinical evaluation (symptomatology) as well as with electrical and thermal pulp vitality tests. Control radiographs were also taken in one of the two studies.22 In the two studies, there was only one case of reversible pulpitis 3 days after treatment.
Treatment duration
In the studies where this outcome was described, the laser irradiation duration varied as follows: 7 s,28 10 s24 up to 30 s.20 25–27 In the remaining included studies, the time employed for laser irradiation was no reported. In addition, in none of the studies was a comparison between laser and other interventions in terms of treatment duration performed.
Patients’ discomfort
In the only study reporting this outcome, both Er,Cr:YSGG laser and orthophosphoric acid were equally well accepted by patients (p=1). The Visual Analogue Scale mean score measuring the patients’ discomfort, indeed, resulted very low for both laser or acid etching procedures, with the same value of 0.33 (SD=2.22).23
Cost-effectiveness ratio
This outcome was not reported in any of the included studies.
All results related to each outcome were synthesised in table 3.
Results for each outcome in the included studies
Discussion
The aim of this study was to carry out a systematic review of scientific literature to search evidence supporting the use of lasers at sub-ablative irradiation energy levels for preventing dental caries. The sub-ablative energy level can be defined as an amount of energy not able to ablate the dental tissues but sufficient to modify their structure. Although a cut-off value between ablative and sub-ablative energies has not yet been precisely established in the literature, nevertheless on the basis of the data found both in this review and another two similar ones,17 30 the energy density value of the sub-ablative lasers never exceeds 100 mJ/cm2.
In our systematic literature review, nine studies (10 publications), which met the inclusion criteria, were found. A possible limitation was that in all trials many outcomes showed either unclear or high RoB; therefore, also the degree of confidence in their results was low. In addition, due to the limited number of studies found for each tested laser (with a small sample of enrolled participants), there were also doubts on the results’ precision. Moreover, methodological limitations on the review process should also be mentioned due to the absence of a study protocol publication prior to performing the present study’s final version. In addition, the use of the original RoB assessment rather than its last version (RoB2) could be considered a further methodological limitation. However, some interesting conclusion might be drawn out from this review as reported below.
Summary of evidences
Based on the data found in our review, when sub-ablative laser was used on permanent teeth as a prophylactic intervention against caries, it was clinically effective only if used in association with a TPI such as sealant or fluoride gel. Laser combined with a TPI, indeed, reduces the incidence of caries by reinforcing enamel, and moreover it reduces the detachment of sealant fillings from the dental enamel surfaces. Conversely, when the laser was used alone, it did not improve enamel resistance against caries or sealants retention.
Laser, therefore, instead of being an alternative to TPIs, should be considered a prophylactic intervention able to improve the effectiveness of TPIs. TPIs, indeed, although effective in reducing caries, show some clinical limitations according to the literature. Sealants, for example, present 5%–10% of fillings detachment per year31 while a high content of fluoride gels or varnishes present a potential chronic and acute toxicity32 and additionally required repeated applications, which can be difficult among subjects with low education and socioeconomic status, where this disease is particularly prevalent.33 34 Laser might contribute to reduce these limitations, decreasing the number of detachment cases. In addition, laser when combined with fluoride varnishes and gels (favouring the fluoride uptake of four times) might increase their effectiveness against caries, with a theoretical possibility of limiting both the dosage and the number of dental visits required for administrating fluoride. The absorption of fluorine affects its positive clinical action by increasing the enamel content of the fluorapatite, making it more resistant against acid demineralisation.35
In the only study where laser was used on primary teeth, it seemed effective in reducing caries incidence, also when used alone, with better results than in permanent teeth. This difference of effectiveness could be explained by considering the difference in enamel structure shown in permanent and primary dentitions. However, the paucity of information (one single study with few participants) makes this all hypothetical.
There were no studies that described the cost-effectiveness outcome, resulting in a significant lack of relevant information, considering that the laser being a high-tech device could most likely require higher costs than TPIs.
Similar studies in the literature
In the literature, two reviews dealt with the use of lasers as a prophylactic intervention, one in vitro17 and the other in vivo.30 The in vitro review showed that the intervention of some types of lasers (CO2, argon, diodes and Er,Cr:YSGG lasers) used alone or in combination with TPIs was able to reinforce the enamel against acid demineralisation (acids similar or analogous to those of caries). In fact, the enamel treated with laser light, after being subjected to cycles of demineralisation in acid solutions, showed a lower loss of minerals (spectroscopic analysis), a lower loss of surface hardness (microhardness tests) and a lower average depth of cavity lesions (scanning electron microscopy and light polarised microscope evaluations) compared with untreated enamel. The in vitro review, therefore, presented a number of advantages only partially confirmed by our in vivo review.
The second review30 we found, which exclusively analysed clinical trials, evaluated the laser clinical efficacy in etching enamel with results similar to our review: the laser used alone did not increase the retention rate of sealant fillings, conversely when used in addition to TPIs it improved this retention. Moreover, as in our review, the laser at sub-ablative levels was as well accepted by patients as were TPIs.
Finally, the use of laser in prophylaxis is part of a very modern vision of dentistry, based on prevention instead of caries reparative treatments as recommended by the most important scientific societies in this field (eg, American Pediatric Dentistry). More generally, the scientific dental community in recent times has been oriented towards an approach to caries based on minimally invasive interventions,36 aimed at maximum tissue preservation, and in this new approach prophylaxis has assumed a central role never played in the past.
Conclusions
Despite both the limited number of studies (few participants) and the evident RoB found in all outcomes considered in this review, lasers used at sub-ablative energy level in combination with TPIs resulted in an increased caries prevention effectiveness compared with TPIs alone or to untreated teeth. However, until now, there was not sufficient evidence for recommending the use of laser as an alternative clinical solution compared with traditional caries prophylactic interventions. Finally, the safety of lasers was evaluated in a few of the studies reporting the absence of side effects such as irreversible dental pulp phlogosis or necrosis. High-quality methodological studies are required to obtain a more thorough knowledge of all topics considered in this study. Studies also including outcomes such as patients’ discomfort and cost-effectiveness ratio would be required.
Acknowledgments
Sheila K Tabakoff assisted with corrections to the English text in translation from the Italian text.
References
Supplementary materials
Supplementary Data
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Footnotes
Contributors The authors SP, BC and SC conceived the original idea for this study. The remaining three authors (GL, MO and IA) established both the search strategy and the study protocol. Moreover, SP and BC screened titled and abstracts of records obtained from literature databases, independently, in order to obtain their full texts. GL and MO screened independently the full texts. In case of disagreement, SC was consulted. GL and MO performed data extraction from the selected full texts. IA and MO performed the risk of bias assessment. All authors revised critically the manuscript and approved its final version.
Funding This study was funded by the National Centre for Disease Prevention and Control - Ministry of Health (Grant CCM 2019). The sponsor was not involved in the format of the study, the collection, the analysis or interpretation of the data, nor in the writing of the article and the decision to submit it for publication. The authors were independent from the study sponsors.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No additional data are available.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.