Disease severity, debridement approach and timing of drug modify outcomes of adjunctive azithromycin in non-surgical management of chronic periodontitis: a multivariate meta-analysis

Abstract

Background: Past meta-analyses have shown adjunctive systemic Azithromycin (AZI) to provide minor clinical benefits in scaling and root surface debridement (S/RSD). However, these have not considered the covariance of key outcome parameters; probing pocket depth (PPD) and Clinical Attachment Level (CAL) or systematically examined some potential sources of heterogeneity.

Aim: To jointly synthesize 6-month outcomes of systemic AZI as adjunctive to S/RSD in chronic periodontitis and investigate 3 potential sources of heterogeneity.

Methods: Four databases were searched for suitable randomized controlled clinical trials (RCTs). Standardized mean differences (SMD) in PPD and CAL between AZI + S/RSD and S/RSD alone, at 6-month follow-up were computed. Within-study covariances of PPD and CAL were derived from reported multiple time-point data. A multivariate meta-analysis with random effects jointly modelled PPD and CAL, factoring in their covariance. This model included 3 moderators with interaction effects; timing of AZI initiation (pre-therapy/post-therapy), type of S/RSD [full-mouth debridement (FMD)/partial-mouth debridement (PMD)], and baseline study-level mean values of PPD/CAL.

Results: Among 276 abstracts, 11 observations from 9 RCTs qualified for meta-analysis. Within-study correlation-coefficients of PPD with CAL significantly increased with increasing study-level baseline mean values (Spearman's r = 0.79, p < 0.01). The full multivariate meta-analysis model showed significant effects for the 3 moderators (Q statistic = 150.03, p < 0.01), retained significant residual heterogeneity (Q statistic = 88.50, p < 0.01) but outperformed (Likelihood- ratio statistic = 102.95, p < 0.01,) a null-model with no moderators (Q statistic = 201.5, p < 0.01). A significant effect was seen only on the SMD for PPD (estimate = 1.16 mm, 95% CI: 0.27 mm-2.07 mm mm, p = 0.01) but not CAL (estimate = 0.17 mm, 95% CI: -0.92 mm-1.26 mm, p = 0.76). SMD in PPD positively interacted with study baseline value (estimate = 0.11, 95% CI: 0.08-0.15, p < 0.01). Significant negative interactions of SMD in PPD with PMD (estimate = - 1.25 mm, 95% CI: -1.73 mm- -0.78 mm, p < 0.01) and pre-therapy drug initiation (estimate = - 1.18 mm, 95% CI: -1.48 mm--0.87 mm, p < 0.01) were evident.

Conclusion: Joint synthesis of PPD and CAL showed, at 6-months, AZI + S/RSD provided a benefit over S/RSD alone for PPD alone when correlation with CAL was accounted for. Deeper study-level baseline PPD, FMD type of S/RSD, and post-therapy drug initiation associated with greater PPD reduction.

Keywords: Azithromycin; Meta-analysis; Non-surgical periodontal therapy; Periodontitis.

Fig. 1

PRISMA flowchart showing the selection of studies

Fig. 2

Summary of quality assessment of included studies

Fig. 3

Within-study correlation of primary outcomes (Spearman’s r-value; PPD and CAL, y-axis) plotted against study-level Baseline Mean Values (blue: CAL, red: PPD, x-axis). The size of the circle corresponds to the number of subjects in the study

Fig. 4

Model performance: 4a: The profile likelihood plot showing study-level random variance component (Sigma squared) for the full-model and 4b: the actual versus the predicted SMD values (blue: CAL, red: PPD, The size of the circle corresponds to the number of subjects in the study)

Fig. 5

Funnel plots for outcomes for the full-model (left) showed lower asymmetry than the reduced model (right)

Fig. 6

Forest plot depicting the full-model and moderators. The observations are ordered according to Outcome (PPD, CAL) and decreasing Baseline Study Mean Values

Fig. 7

a) Bar plots depicting the Standardized mean difference (SMD) in Outcomes within categories of ‘type of S/RSD’ (vertical panels) and ‘timing of drug’ (horizontal panels -top) and b) Line plot showing Standardized mean difference (SMD) variation (y-axis) with Baseline mean value of PPD and CAL (x-axis) (bottom)