*2.6. Meta-Analysis*

The general methodology of this review followed the directions of the Cochrane Handbook for Systematic Reviews of Interventions [10]. If possible, the odds ratio (OR)/risk ratio (RR) or standardized mean differences (SMD) and their 95% confidence intervals (CI) were calculated for the quantitative data extracted from each RCT. Results from comparable groups of studies were pooled into a meta-analysis using Review Manager (RevMan) Software (version 5.4.1, The Cochrane Collaboration, 2020). The findings are presented in a narrative form, if statistical pooling was not possible. The subgroup analysis was conducted on parameters reported by at least two studies. The significance of any variation and degree of heterogeneity was determined by *I*2 and chi-square statistics, respectively. Publication bias tests were not conducted due to the low number of studies included.

In some cases, the included studies will present with peculiar features (for example, different inclusion criteria with respect to other studies, presence of patients with systemic conditions or asymptomatic patients). Moreover, the sensitivity analysis will be performed to assess if the exclusion of the study will affect the outcome of the analysis.

## **3. Results**

## *3.1. Study Selection*

The search strategy identified 695 records, including 13 duplicates. The remaining 682 records were screened by the title and abstract (Figure 1). In total, 656 records were considered irrelevant and removed, leaving 26 studies that were assessed for eligibility by full-text reviewing. At this stage, 17 studies were excluded [11–27], most commonly since they did not include a BCS (Supplementary Materials Table S1). Finally, nine studies were included for systematic review. Although each of the selected studies evaluated the POP level following different filling techniques, the variability within the study designs and the materials and methods employed required specific consideration during the analysis.

#### *3.2. Study Characteristics*

The characteristics of the selected RCTs are presented in Table 1. All the studies were published single-center RCTs that reported the characteristics of teeth, pre-operative status, diagnosis, instrumentation details and irrigation protocols, endodontic sealers and filling

techniques used, analgesic intake, incidence of flare-ups, number of visits, and pulp and periapical status.

**Figure 1.** The preferred reporting items for systematic reviews and meta-analysis flow diagram of the search results.

**Table 1.** Cochrane PICO formula.


All the selected studies included teeth with pulp or periapical pathologies, without signs of radiolucency, requiring a primary endodontic treatment. However, only three studies included teeth that needed retreatment [28–30]. Four studies included teeth that were asymptomatic pre-operatively [30–33], two studies only included symptomatic teeth [28,34], and three studies examined asymptomatic and symptomatic teeth [29,35,36]. Only one

study managed an endodontic treatment without local anesthesia [31]. Furthermore, three studies assessed POP in anterior single-rooted teeth only [31–33].

The instrumentation and irrigation protocols were similar across the studies, but the filling techniques varied: Warm vertical condensation (WVC) was utilized in five studies, single-cone technique (SCT) in three studies, carrier-based obturation in one study, and lateral condensation in one study. The resin-based sealer (RBS) was utilized as a control group in all the included studies. One study deliberately carried out the filling procedure during a second visit to exclude the influence of instrumentation stage on POP. The other eight studies evaluated POP in the context of a single visit treatment.

A variety of pain rating scales were used, including variations of the Visual Analog Scale and Verbal Rating Scale, as well as the Heft and Parker Pain Rating Scales of 0–10, 0–100, 0–170 or verbal (no pain/mild pain/moderate pain/severe pain). The data were reported as either means or percentages. Four studies reported an analgesic intake and three studies reported an incidence of flare-ups.

Remarkably, none of the included studies identified significant differences in the POP level, analgesic intake or incidence of flare-ups between different endodontic sealers.

#### *3.3. Risk of Bias*

The risk of bias in the nine RCTs is summarized in Table 2. One study was scored as having an overall "low" risk of bias, six studies as having an overall "moderate" risk, and two studies as having an overall "high" risk of bias, since the treatment was managed by undergraduate students.


**Table 2.** Summary of the risk of bias of the included studies.

"+": low risk of bias, "?": unclear risk of bias,"-": high risk of bias. ( **A**) Random sequence generation (selection bias). (**B**) Allocation concealment (selection bias). (**C**) Blinding of participants and personnel (performance bias).(**D**) Blinding of outcome assessment (detection bias). (**E**) Incomplete outcome data (attrition bias). (**F**) Selective reporting (reporting bias). ( **G**) Other bias.
