**Title**
Atrial high-rate episodes in patients with cardiac implantable electronic devices without history of atrial fibrillation: A meta-analysis
**Review question**
The objective of this study is to systematically review the literature and to conduct a meta-analysis to evaluate the incidence of atrial high-rate episodes (AHRE) in patients with cardiac implantable electronic devices but without prior history of atrial fibrillation (AF) , their association with future development of clinical AF and assess their prognostic value as an independent predictor of cardiovascular events.
**Searches**
We will search MEDLINE (via PubMed), EMBASE (via Ovid) and the Cochrane Library. A basic search strategy will be developed for PubMed and modified accordingly for other research engines. We will also search conference proceedings, clinicaltrials.gov site and reference lists from both included studies and relevant reviews. At last, experts will be contacted to identify unpublished studies. We will not apply any language or year of publication limitation.
**Types of study to be included**
All eligible randomized controlled trials (RCTs), case-control or cohort (prospective/retrospective) studies with more than 10 individuals in both arms will be included. Cross-sectional studies, case reports/series, reviews and studies with less than 10 individuals in any arm will be excluded.
**Condition or domain being studied**
Atrial high rate episodes (AHRE); stroke; mortality; major adverse cardiac events
**Participants/population**
*Inclusion criteria:*
(1) Patients with cardiac implantable electronic devices (such as implantable cardiac monitors (ICM), pacemakers, and implantable cardioverter defibrillators (ICD)) and AHRE;
(2) Control group;
(3) Follow-up was at least 3 months.
*Exclusion criteria:*
(1) History of AF;
(2) Permanent AF;
(3) Patients with implantable loop recorder
**Intervention, exposure**
Patients with cardiac implantable electronic devices in whom AHRE were detected
**Comparator/control**
Patients without AHRE
**Main outcome**
Risk of ischemic stroke or transient ischemic attack (TIA) in patients with AHRE
**Additional outcomes**
Incidence of AHRE in patients with cardiac implantable electronic devices and without history of AF
Risk of clinical atrial fibrillation, cardiovascular mortality, and all-cause mortality in patients with AHRE
**Data extraction (selection and coding)**
Our systematic review and restrictive meta-analysis will be performed in accordance with the PRISMA guidelines (Liberati et al. BMJ 2009). All studies will be imported into a reference management software (EndNote X7). After duplicate removal, two reviewers will independently screen all titles and abstracts and peruse full texts for eligible studies. Any discordance regarding study eligibility will be resolved by consultation with a third review author. Authors will be contacted to obtain any missing data relevant to the analysis. Two reviewers will independently extract data from eligible studies using a predetermined excel form. Any conflicts will be resolved by a third reviewer. We will extract data regarding study characteristics, patients’ baseline characteristics, and the aforementioned outcomes. Potential confounders, which may affect the outcomes based on biological plausibility (cardiovascular profile, CHA2DS2VASc score) were also extracted. We will also extract the definition of AHRE in different studies or cutoff for recognizing AHRE, the definition of cardiovascular outcome (stroke/TIAs, clinical AF, all-cause mortality and cardiovascular mortality) examined in each study, and the methods used for describing clinical AF.
**Risk of bias (quality) assessment**
Two independent reviewers (M.G. and I.D.) will assess risk of bias. For RCTs we will use the revised Cochrane Collaboration's Risk of Bias tool. For case-control or cohort studies we will use Newcastle-Ottawa Scale (NOS). We also aim to evaluate the certainty in our estimates applying the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach.
**Strategy for data synthesis**
We will perform meta-analysis for each outcome whenever possible using R Studio (version 1.2.5001) and the R package meta (version 4.9-7). For continuous outcomes we will calculate weighted mean differences and relative risk (RR) or odds ratios (OR) for dichotomous outcomes; both presented with 95% Confidence Intervals (CIs). P-values will be two-tailed and will be considered significant at a 5% significance level.
Heterogeneity will be tested with the Cochran chi-square test and the degree of heterogeneity quantified by the I2 statistics. An I2 > 50% will be described as moderate and more than 75% as considerable heterogeneity and a p-value <0.1 as statistically significant.
**Analysis of subgroups or subsets**
We will conduct a sensitivity analysis based on risk of bias assessment and meta-regression will be performed if heterogeneity is high. Moderators for meta-regression depending on data availability are the definition of AHRE in different studies, different types of thromboembolic events, and CHA2DS2VASc score.
**Funding sources/sponsors**
None
