Abstract
Objectives
To evaluate the effect of local and/or systemic statin use as an adjunct to non-surgical and/or surgical periodontal therapy.
Data
Literature search according to PRISMA guidelines with the following eligibility criteria: (a) English or German language; (b) interventional studies; (c) statins as monotherapy or as an adjunct to non-surgical and/or surgical treatment of periodontitis; (d) clinical and/or radiographic treatment effect size of statin intake reported.
Sources
Medline (PubMed), Embase (Ovid), CENTRAL (Ovid).
Study selection
Thirteen clinical studies regarding local application and 2 with systemic administration of statins as an adjunct to non-surgical treatment (SRP) and 4 studies regarding intrasurgical statin application with a maximum follow-up of 9 months could be included; simvastatin, atorvastatin, and rosuvastatin were used. Local but not systemic statin application as an adjunct to SRP yielded significantly larger probing pocket depth (PD), radiographic defect depth (RDD), and bleeding index reduction, and larger clinical attachment level gain, and less residual PD and RDD (p ≤ 0.016); rosuvastatin appeared as the most efficacious. Three of 4 studies reported a significant positive effect of intrasurgical statin application. No adverse events were reported after statin use. The vast majority of the included studies were from the same research group.
Conclusions
Significant additional clinical and radiographic improvements are obtained after local, but not systemic, statin use as an adjunct to SRP in deep pockets associated with intrabony defects and seemingly with furcation defects; intrasurgical statin application seems similarly beneficial. Confirmation of these results, and especially of the effect size, from other research groups is warranted.
1
Background
The use of local and/or systemic adjunct measures [e.g., chlorhexidine, hyaluronan, probiotics, antibiotics (AB), etc.] to mechanical treatment has been a common therapeutic approach aiming for better infection control, reduced tissue destruction by the immune response, and/or enhanced reparative processes. Due to concerns regarding the increasing bacterial resistance, systemic AB do not meet widespread acceptance ; thus, non-AB alternatives may be a more reasonable approach.
Statins is an example of a non-AB agent evaluated as an adjunct to periodontal therapy. Statins (i.e., 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are primarily indicated as lipid-lowering agents and for prevention of cardiovascular diseases . Nevertheless, statins possess various additional properties relevant to the pathogenesis of periodontal diseases; e.g., statins are anti-inflammatory , promote bone formation , inhibit tissue degrading enzymes [i.e., matrix metalloproteinases (MMPs)] , and have anti-microbial properties . Indeed, in a recent systematic review and meta -analysis of preclinical in vivo trials, a positive effect of statin intake was observed ; in particular, in standard experimentally induced periodontitis models in rodents, statin intake – local application or systemic administration − significantly prevented alveolar bone loss compared to the controls. In this context, there is already a considerable number of clinical trials on this topic, but appropriate systematic evaluation of the available evidence does not exist.
The aim of the present systematic review was to address the following focused question according to the Population, Intervention, Comparison, Outcomes, Study Design (PICOS) criteria : “In periodontally diseased subjects, does local and/or systemic statin intake as monotherapy or as an adjunct to periodontal treatment, compared to no treatment or periodontal treatment alone, result in better histological and/or clinical periodontal parameters in randomized and/or controlled clinical trials?”
2
Materials and methods
2.1
Protocol and eligibility criteria
The present systematic review was reported according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA; Appendix S1 in Supplementary file) . The following inclusion criteria were applied during literature search on 3 sources (Medline – PubMed; Embase − Ovid; CENTRAL − Ovid; last search 31/12/2016—no date restriction used): (a) English or German language; (b) interventional studies [i.e., controlled or randomized controlled trials (RCT)]; (c) statins as monotherapy or as an adjunct to non-surgical and/or surgical treatment of periodontitis; (d) at least 10 patients per group; (e) follow-up ≥ 3 months; (f) treatment effect size of statin intake evaluated [i.e., probing pocket depth (PD), clinical attachment level (CAL), bleeding index, and/or bone level]; and (h) full-text available. The following exclusion criteria were applied: (a) studies not meeting all inclusion criteria; and (b) systemic statin intake since >1 month before study entry. Two authors (KB, AP) independently checked title, abstract, and finally full-text on the pre-defined eligibility criteria, and also assessed the risk of bias (RoB) of the included studies applying the Cochrane Collaboration‘s Tool for assessing RoB. One author (KB) repeated the literature search and RoB assessment. In case of ambiguity, consensus through discussion was achieved together with a third author (AS).
For information on literature search methodology and information sources, data collection and synthesis, RoB, and statistical analysis please see Appendix S2 in Supplementary file.
2.2
Synthesis of results
Two primary outcome parameters (i.e., residual PD, CAL gain) and several secondary outcome parameters [i.e., PD reduction, modified sulcus bleeding index (mSBI) reduction, residual radiographic defect depth (RDD), RDD reduction] were defined and values at 3-, 6-, and 9 months post-treatment were included – if available – for meta-analyses, separately for non-surgical and surgical trials.
Quantitative synthesis was performed using the DerSimonian and Laird random effects methods, in view of the variation in population and settings, and pooled estimates were calculated separately per follow-up period. Monte Carlo permutation test was used for meta-regression with the primary and secondary outcome measures as the response variables and statin type, smoking status, and follow-up period as explanatory variables. Finally, standard funnel plots including an Egger’s test were used to examine publication bias if 10 or more comparisons were available. All statistical analyses were performed using STATA (StataCorp LLC, USA).
2
Materials and methods
2.1
Protocol and eligibility criteria
The present systematic review was reported according to the criteria of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA; Appendix S1 in Supplementary file) . The following inclusion criteria were applied during literature search on 3 sources (Medline – PubMed; Embase − Ovid; CENTRAL − Ovid; last search 31/12/2016—no date restriction used): (a) English or German language; (b) interventional studies [i.e., controlled or randomized controlled trials (RCT)]; (c) statins as monotherapy or as an adjunct to non-surgical and/or surgical treatment of periodontitis; (d) at least 10 patients per group; (e) follow-up ≥ 3 months; (f) treatment effect size of statin intake evaluated [i.e., probing pocket depth (PD), clinical attachment level (CAL), bleeding index, and/or bone level]; and (h) full-text available. The following exclusion criteria were applied: (a) studies not meeting all inclusion criteria; and (b) systemic statin intake since >1 month before study entry. Two authors (KB, AP) independently checked title, abstract, and finally full-text on the pre-defined eligibility criteria, and also assessed the risk of bias (RoB) of the included studies applying the Cochrane Collaboration‘s Tool for assessing RoB. One author (KB) repeated the literature search and RoB assessment. In case of ambiguity, consensus through discussion was achieved together with a third author (AS).
For information on literature search methodology and information sources, data collection and synthesis, RoB, and statistical analysis please see Appendix S2 in Supplementary file.
2.2
Synthesis of results
Two primary outcome parameters (i.e., residual PD, CAL gain) and several secondary outcome parameters [i.e., PD reduction, modified sulcus bleeding index (mSBI) reduction, residual radiographic defect depth (RDD), RDD reduction] were defined and values at 3-, 6-, and 9 months post-treatment were included – if available – for meta-analyses, separately for non-surgical and surgical trials.
Quantitative synthesis was performed using the DerSimonian and Laird random effects methods, in view of the variation in population and settings, and pooled estimates were calculated separately per follow-up period. Monte Carlo permutation test was used for meta-regression with the primary and secondary outcome measures as the response variables and statin type, smoking status, and follow-up period as explanatory variables. Finally, standard funnel plots including an Egger’s test were used to examine publication bias if 10 or more comparisons were available. All statistical analyses were performed using STATA (StataCorp LLC, USA).
3
Results
3.1
Study selection
The flowchart of the literature search is presented in Fig. 1 . Out of 383 identified studies, 26 articles were selected for full-text review; 7 trials were excluded for various reasons (Appendix S3 in Supplementary file). No studies were excluded due to language restriction (i.e. not English or German). Finally, 15 studies on non-surgical and 4 studies on surgical periodontal treatment were included. Additionally, 4 unpublished studies were identified on ClinicalTrials.gov (NCT02372656, NCT02516111, NCT02386033, NCT02612792; all with “status: completed”), but no detail data from those studies could be obtained.
3.2
Study characteristics
An overview of study populations, type of intervention, description of defect and site characteristics, and type and mode of statin application is given in Table 1 . Results on RoB and publication bias assessment, and on funding of the studies are presented in Appendix S4 in Supplementary file.
3.2.1
Study populations ( Table 1 )
The studies on non-surgical periodontal treatment included between 38 and 99 patients and those on surgical periodontal treatment included between 15 and 110 patients, diagnosed with chronic periodontitis. Seventeen studies included only non-smokers and 2 studies only smokers. All studies included systemically healthy patients, except for 3 studies including well-controlled diabetic patients , and hyperlipidemic patients .
3.2.2
Type of intervention ( Table 1 )
All studies on non-surgical periodontal treatment applied the statins as an adjunct to non-surgical treatment (SRP). Two studies tested systemic administration of statins, while the other 13 studies applied a statin formulation locally and subgingivally. Except for 2 studies , all studies used a placebo in the control group. The follow-up period ranged between 6 and 9 months; loss to follow-up was reported in all studies, which was ranging per group from 0 to 8 patients (i.e., 0–21.1%). All studies on surgical periodontal treatment tested combination treatments with or without additional intra-operative statin application. Martande et al. and Pradeep et al. compared open flap debridement (OFD) with OFD with platelet-rich fibrin (PRF) with or without statin application, Kinra et al. compared demineralized freeze-dried bone allograft with or without statin application, and Pradeep et al. compared OFD with OFD with PRF and hydroxyapatite with or without statin application. One study applied a placebo solution in the control group. The follow-up period was 6 to 9 months and loss to follow-up ranged per group from 0 to 2 patients (i.e., 0–6.3%).
3.2.3
Description of defect and site characteristics ( Table 1 )
Among the studies on non-surgical periodontal treatment 10 studies treated specifically intrabony defects with at least 3 mm vertical bone loss, 2 studies furcation defects, and 3 studies did not concentrate on a specific periodontal defect type. All studies clearly specified patient inclusion criteria by PD, CAL, and/or vertical bone loss. Three of the studies on surgical periodontal treatment treated intrabony defects and the fourth furcation defects. Except for one study , clear inclusion criteria have been presented.
3.2.4
Type and mode of statin application ( Table 1 )
Among the studies on non-surgical periodontal treatment 3 different statin types were tested: simvastatin (SMV); atorvastatin (ATV); rosuvastatin (RSV). Five studies tested SMV , 6 studies ATV (including both studies with systemic administration) , one study RSV , one study each compared SMV with ATV , and 2 studies compared ATV with RSV application , respectively. Among the studies on local application, 11 studies used a methylcellulose gel for statin application, one study used a sodium alginate suspension , and one study did not specify the gel composition ; all prepared a 1.2% statin solution. In most studies the statin formulation was applied a single time after SRP; in 2 studies the statin-loaded gel was applied once more after 6 months. Both studies prescribing systemic statin administration used a dose of 10 to 20 mg ATV per day and evaluated the effect 90 days after statin intake. One study did not report on the presence or absence of adverse events, otherwise none were observed.
Three studies on surgical periodontal treatment applied once intra-operatively either ATV or RSV in a statin-loaded methylcellulose gel (i.e., 1.2%), and the fourth study mixed the allograft with an aqueous SMV solution (10 −8 M SMV). No adverse events were observed.
3.3
Reported outcome variables and treatment effect size ( Tables 2 and 3 )
All studies evaluating local application or systemic administration of statins as an adjunct to SRP reported on the relevant clinical and/or radiographic outcome parameters (i.e., PD, CAL, mSBI, RDD). Four studies determined inflammatory and bone-specific parameters in gingival crevicular fluid, periodontal tissue, and/or blood samples. All studies evaluating statin application during surgical periodontal treatment reported on PD, CAL, and RDD, but only one study on site specific mSBI .
Except for one study ( ; unclear risk of bias) all studies (9 studies low risk, 3 studies unclear risk of bias) assessing local statin application as an adjunct to SRP presented a significant added benefit for the test group compared to the control group regarding the clinical parameters (i.e., PD, CAL, and/or mSBI). Among the studies specifically treating intrabony defects (i.e., excluding 2 studies on furcation defects and one study not specifically treating intrabony defects ) the radiographic measurements showed in all studies (8 studies low risk and 2 studies unclear risk of bias), at least in one of the test groups, a significant improvement after statin application. Both studies on non-surgical treatment of furcation defects (low and unclear risk of bias) presented significant improvements regarding clinical and radiographic measurements. Noteworthy, in the 2 studies with systemic statin administration (low risk of bias and no RCT), no significant differences have been detected between test and control group.
Application of statin during surgical periodontal treatment resulted in 3 (high risk, unclear risk, and low risk of bias) out of 4 studies (4th study: unclear risk of bias) in a significant improvement regarding clinical parameters, and in all studies regarding the radiographic measurements.
3.4
Synthesis of results
Eleven studies have been pooled together for the meta-analysis (8 studies low risk and 3 studies unclear risk of bias). The results of the studies on furcation defects were not pooled, as one treated residual defects (i.e., after previous SRP) and the other study untreated defects. Further, due to a different study population (i.e., healthy vs. hyperlipidemic patients) the 2 studies on systemic statin application were not pooled together. Two studies (both unclear risk of bias) out of the 4 studies on surgical treatment have been comparable in terms of study design (i.e., intrabony defect, combination of statin with PRF, observation period 9 months) and were pooled in a meta-analysis.
3.4.1
Statin as an adjunct to non-surgical periodontal treatment ( Fig. 2 , Appendix S5 in Supplementary file)
Statin application as an adjunct to SRP resulted in significantly improved clinical and radiographic parameters compared to SRP alone (p ≤ 0.019) after 3-, 6-, and 9 months. Residual PD and CAL gain in the statin treated groups at the longest follow-up ranged between 2.3–5.0 mm and 1.1.–4.7 mm, respectively, compared with 3.2–6.5 mm and 0.7–2.3 mm, respectively in the control sites. The corresponding RDD values were 1.8–6.6 mm and 2.7–7.2 mm in the statin and control groups, respectively. However, heterogeneity was for most comparisons significant (i.e., 13 out of 16 comparisons).
3.4.2
Statin as an adjunct to surgical periodontal treatment ( Fig. 3 )
Statin application as an adjunct to PRF in surgical treatment of intrabony defects resulted in significantly improved clinical parameters compared to solely PRF application, after 9 months; residual PD and CAL gain in the statin treated groups at the longest follow-up ranged between 3.0–4.0 mm and 3.7–3.9 mm, respectively, compared with 3.8–4.5 mm and 3.3–3.4 mm, respectively in the control sites. Further, the test group was significantly better in terms of residual RDD but not RDD reduction; in particular, RDD ranged from 2.5 to 2.5 mm and 2.7 to 2.8 mm in the statin and control groups, respectively. Heterogeneity was significant for the parameters PD reduction (I 2 = 70.5%; p = 0.065), residual RDD (I 2 = 89.8%; p = 0.002), and RDD reduction (I 2 = 68.0%; p = 0.077).
