Autologous platelet concentrates for treatment of periodontal defects
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the use of APCs as an adjunct to the periodontal surgical techniques of open flap debridement (OFD), GTR, EMD and bone grafting (BG) in the treatment of intrabony defects, as compared with the use of these surgerical techniques alone.
Background
Description of the condition
Periodontitis is a disease of the periodontium characterised by the irreversible loss of connective tissue attachment and supporting alveolar bone (Pihlstrom 2005). Periodontitis begins with the development of pocket formation induced by bacterial plaque, and progresses to the initiation of alveolar bone destruction, resulting in various bone destructive patterns and the alteration of available alveolar bone (Kinane 2001). Intrabony defects associated with periodontal pockets represent the anatomical sequelae of the apical spread of the dental plaque in the course of periodontitis (Waerhaug 1979). Such defects, if left untreated, are risk factors for periodontitis progression and further loss of attachment (Papapanou 1991). Because intrabony defects are common in periodontitis (Vrotsos 1999), there is a considerable interest in approaches that will convert such defects to easily maintainable shallow probing sites (Crea 2014).
Description of the intervention
Several surgical techniques have been developed to regenerate periodontal tissues, such as guided tissue regeneration (GTR) (Needleman 2006) and the use of enamel matrix derivative (EMD) (Esposito 2009). In recent years, the use of autologous platelet concentrates (APCs), which are rich in growth factors, combined with these surgical techniques has emerged as a possible tool to enhance the predictability of the treatment of periodontal defects.
APCs include different types of preparations among which the best known are platelet‐rich plasma (PRP) (Marx 1998), platelet‐rich fibrin (PRF) (Choukroun 2001) and plasma rich in growth factors (PRGF) (Anitua 2001). Several commercial techniques for obtaining APCs are available; however, their applications have been confusing because each method leads to a different product with different biology and potential uses. PRP is considered a first‐generation APC, and releases an array of growth factors for seven days, with release peaking on the first day of application (Dohan Ehrenfest 2009). PRF is considered a second‐generation APC, as the technique for its preparation is simpler than that of PRP. PRF shows a sustained release of growth factor release for a period of 21 days, with a peaking rise at 7 days, thereby inducing the proliferation, differentiation and migration of cells responsible for periodontal regeneration (Carroll 2005). PRGF is also a second‐generation APC; the main difference in respect to PRP is the absence of leukocytes and the requirement for a smaller volume of blood (Anitua 2001). According to a recently proposed article, APCs can be classified into one of four categories, depending on their leukocyte and fibrin content: P‐PRP (pure PRP, without leukocytes, which includes PRGF), L‐PRP (PRP with leukocytes included), P‐PRF and L‐PRF (Dohan Ehrenfest 2009).
The first systematic review that evaluated the effect of PRP on clinical applications in dentistry reported beneficial effects of PRP in the treatment of periodontal defects (Plachokova 2008). Another systematic review that evaluated the effect of a PRP adjunct in the treatment of intra‐osseous defects underlined the limits and the heterogeneity of the available data and cautiously concluded that the specific selection of the graft type and the surgical procedures combined with PRP may be important (Kotsovilis 2010).
A subsequent systematic review also evaluated the effect of PRP in various regenerative procedures of periodontal defects and gingival recession, and concluded that PRP may be advantageously used as an adjunct to grafting procedure treatments for intrabony defects but not for gingival recession (Del Fabbro 2011). This review also suggested that the use of PRP is ineffective when the GTR procedure is used for treating intrabony defects.
How the intervention might work
The contribution of blood‐derived platelets to the bone healing process is thought to be based on the growth factors stored in their granules and released upon activation. Platelet‐derived growth factors are naturally synthesized polypeptides, functioning as potent biologic mediators stimulating various cellular activities during wound healing, like cell proliferation, differentiation, and matrix synthesis and thereby facilitating periodontal regeneration. The main growth factors released from APCs are the following: platelet‐derived growth factor, transforming growth factor‐beta, vascular endothelial growth factor, epithelial growth factor, insulin‐like growth factor 1 and basic fibroblast growth factor, as well as three blood proteins known to act as cell adhesion molecules for osteoconduction (fibrin, fibronectin and vitronectin).
Why it is important to do this review
In the past few years there has been increasing interest in the use of APCs (especially PRF) in the oral field for the surgical treatment of bone defects. In particular, researchers have started to investigate whether the different properties of different APCs (e.g. PRP, PRF) can result in different clinical and radiological outcomes or have variable effects on an individual's postoperative quality of life, or both, which could lead to a preference for the use of specific APCs for specific surgical applications.
Previous systematic reviews on this topic have been published (Plachokova 2008; Kotsovilis 2010; Del Fabbro 2011; Del Fabbro 2013), mainly dealing with the effects of PRP, the most popular of the various APCs available. However, in the past few years a number of randomised controlled trials (RCTs) have been published showing that other APCs, such as PRF, can have positive effects in the treatment of periodontal intrabony defects (e.g. Sharma 2011; Thorat 2011; Pradeep 2012).
The present systematic review will take into account such recent evidence, and will also consider, separately, different surgical protocols.
Objectives
To assess the use of APCs as an adjunct to the periodontal surgical techniques of open flap debridement (OFD), GTR, EMD and bone grafting (BG) in the treatment of intrabony defects, as compared with the use of these surgerical techniques alone.
Methods
Criteria for considering studies for this review
Types of studies
RCTs of both parallel and split‐mouth design.
Types of participants
All individuals with periodontal tissue defects requiring surgical treatment, independent of age or gender.
Types of interventions
The intervention will consist of periodontal surgery with the addition of an APC; periodontal surgery without APC will be used as the comparison. We will include the following surgical interventions for intrabony defects in the review: a) OFD; b) GTR; c) EMD; and d) bone grafting (BG) material.
The main comparisons that we will investigate will be: 1) APCs and OFD versus OFD alone; 2) APCs/BG versus BG alone; 3) APCs/BG/GTR versus BG/GTR alone; 4) EMD/OFD versus APCs/OFD.
Since the review aims at assessing the efficacy of APCs as an adjunct to periodontal surgery, we will not include studies comparing two different APCs, unless they have a further control group in which no APC is used.
Types of outcome measures
Primary outcomes
Tooth survival; pocket closure; oral health‐related quality of life.
Secondary outcomes
Change in pocket depth (PD), clinical attachment level (CAL), radiographic bone defect (RBD) filling, and other participant‐reported outcomes, including preference, pain and cost‐effectiveness.
Search methods for identification of studies
For the identification of studies to be included in, or considered for this review, we will develop detailed search strategies that will aim to identify all published RCTs dealing with the subject of this review.
Electronic searches
The search string we will use is one developed for MEDLINE (OvidSP) (Appendix 1). We will use the Cochrane Highly Sensitive Search Strategy (sensitivity maximising version (2008 revision)), as referenced in Chapter 6.4.11.1 and detailed in Box 6.4.c of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), to identify RCTs in MEDLINE. We will combine this with a specific search for the topic of the present review.
We will search the following electronic databases:
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the Cochrane Oral Health Group Trials Register (to present);
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the Cochrane Central Register of Controlled Trials (CENTRAL, latest);
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MEDLINE via OVID (1946 to present);
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EMBASE via OVID (1980 to present);
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LILACS via BIREME Virtual Health Library (1982 to present).
There will be no restrictions on language or date of publication. We will obtain translations of any languages we are not familiar with.
Searching other resources
We will search the following trial registers: US National Institutes of Health Trials Register (http://www.clinicaltrials.gov) and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) (http://apps.who.int/trialsearch/).
Will will perform an adjunctive search on the reference lists of the included articles and reviews retrieved.
Moreover, we will handsearch the most recent issues (including the 'Early view' or equivalent section) of the following journals: International Journal of Periodontics and Restorative Dentistry; Journal of Clinical Periodontology; Journal of Periodontal Research; Journal of Periodontology; and Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics. Two reviewers will independently perform the searches (SP, CC).
We will also search the grey literature, such as conference abstracts, proceedings and theses, which will help to address the issue of publication bias.
We will contact the authors of the identified trials, known manufacturers of APCs, and will use any personal contacts with research groups known to deal with the topic in attempts to identify unpublished or ongoing trials.
Data collection and analysis
Selection of studies
The titles and abstracts (if available) of identified studies will be independently screened by two reviewers (NDJ, MS) to exclude all articles clearly not meeting the inclusion criteria. We will obtain copies of the full text for all eligible articles and two review authors (NDJ, MS) will assess them independently to determine whether they meet the inclusion criteria. They will resolve any disagreements by discussion or by consulting a third reviewer (MDF). We will record the reason(s) for exclusion for all studies excluded at this stage.
Data extraction and management
Two review authors (SP, VC) will independently extract the data from the articles and record them in ad‐hoc prepared forms. We will resolve any disagreements by discussion or by consulting a third reviewer (MDF).
We will record the following datafor each included report:
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demographic characteristics of the population;
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defect characteristics (PD, CAL, RBD);
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type of APC used (PRP, PRF, PRGF);
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outcome characteristics (outcome variables assessed such as CAL, PD, follow‐up duration);
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the expertise of the clinician, when possible (years of experience with using APCs);
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source of funding.
Assessment of risk of bias in included studies
Two review authors (SP, VC) will independently assess the risk of bias in the included studies. We will resolve any disagreements by discussion or by consulting a third reviewer (MDF).
We will assess risk of bias following the instructions and the approach described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Five items will be considered for each study: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data addressed) and reporting bias (selective reporting). For each domain the risk will be judged as low, unclear or high. If we judge a study as having a low risk in all domains, then we will consider the study to be low risk of bias overall. If we judge a study as having an unclear risk of bias in at least one domain, then we will consider the study to be at unclear risk of bias overall. If we judge a study as having a high risk of bias in at least one domain, we will consider the study to be at high risk of bias overall. We are aware that the blinding of participants, clinicians and examiners might be difficult/impossible to acheive in some studies in which the interventions being tested differ considerably.
Measures of treatment effect
For each trial, we will express the estimate of the effect of an intervention on dichotomous outcomes (e.g. pain, yes/no) as risk ratios together with 95% confidence intervals (CIs). We will use mean differences (change score) along with 95% CIs to summarise data for continuous outcomes (e.g. CAL, PD, RBD) in each treatment group. We will take into account the clinical effect of the OFD control arm in order to establish whether the surgical intervention was properly applied, using data from a previous systematic review as a reference (Heitz‐Mayfield 2002).
Unit of analysis issues
We will use the participant rather than the tooth as the statistical analysis unit, considering one periodontal defect per participant in studies with a parallel design. In the case of split‐mouth studies, we will consider a single defect per participant per group.
Dealing with missing data
When necessary, we will contact the corresponding authors of the articles included by e‐mail to obtain complete data. If authors do not respond, we will send the same e‐mail again (and also to coauthors) up to a maximum of three times. If no answer is obtained, we will exclude the study from the analysis, though we will present the results separately after the meta‐analysis in order to explore consistency of outcomes. When feasible, we will estimate missing standard deviations using the methods described in Section 7.7.3 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of heterogeneity
We will assess heterogeneity among studies using Cochran's test for heterogeneity, considering a P value < 0.1 as significant . We will quantify the heterogeneity using the I2 statistic. We will interpret the I2 statistic using the ranges suggested in Section 9.5.2 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Assessment of reporting biases
We will assess publication bias using the test for funnel plot asymmetry, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will construct a funnel plot if at least 10 studies are included in the meta‐analysis. If asymmetry is found, we will investigate and describe possible causes.
Data synthesis
We will perform meta‐analyses only for studies with similar comparisons reporting the same outcome measures. We will combine risk ratios for dichotomous data, and mean differences for continuous data, using a random‐effects model if at least four studies can be included in the meta‐analysis. If there are fewer than four studies, we will use a fixed‐effect model. We will use Review Manager 5.3 software (RevMan 2014) for meta‐analysis computations. We will combine data from split‐mouth and parallel‐group studies (Elbourne 2002). We will estimate the appropriate standard errors where these are not presented in the original trial reports (Follmann 1992). We will use the generic inverse variance procedure in RevMan 5.3 to combine these two subgroups in the analyses.
Subgroup analysis and investigation of heterogeneity
In addition to the different surgical protocols used for different types of periodontal defects, we will investigate the following factors: type of APC; initial defect severity; and duration of follow up.
Sensitivity analysis
We will perform sensitivity analyses in order to evaluate the effect of risk of bias and source of funding on the overall effects (e.g. omitting studies at unclear or high risk of bias, or those sponsored by the manufacturer of the product under investigation). We will also investigate the effect of excluding specific studies that appear to be outliers.
'Summary of findings' table
We will develop a 'Summary of findings' table for the main outcomes of this review using GRADE methods (GRADE 2004), and GRADEPro software. We will assess the quality of the body of evidence for each comparison and outcome by considering the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, and the risk of publication bias. We will categorise the quality of each body of evidence as high, moderate, low, or very low.
