This protocol was developed a priori to conducting the study. Any deviations will be reported in all related publications and the PROSPERO record (CRD42020204804) will be adapted accordingly. This systematic review protocol was developed using guidance from the Cochrane handbook for Systematic review of interventions (29) and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) (30).
This review will target patients ≥18 years eligible for de novo implantation of CRT conforming with international guidelines (8). Studies in which the population is undergoing device replacement will not be included however we will consider patients eligible for receiving upgrade from ICD to CRT-D.
The intervention of the included studies will be the CRT device in addition to follow-up from time of implantation of CRT in accordance to guidelines (31, 32). Follow-up methods can be conducted virtually or by in clinic visits.
Studies must report outcomes disaggregated by sex or compare outcomes across sex.
Implantation rate will correspond to the frequency of device implantations for each sex as a proportion of the total number of implantations.
The definitions for the effectiveness outcomes are reported in supplement 1 and were selected based on reporting in international clinical guidelines. Clinical efficacy outcomes include: All cause death, Hospitalization, Peak oxygen consumption (pVO2), Quality of life (QoL), 6 min walk test, NYHA class reduction, LVEF, Heart failure hospitalization (Defined in Supplementary file 1).
We plan to assess both clinical and mechanical complications as categorized by Krahn et al. (33) where mechanical complications stem from mechanical effects of the surgery, while clinical complications arise from new or worsening comorbidities. All the complications to be assessed will be “major” as they will require intervention to provide therapeutic relief (34). Complications were classified short term if they occurred within 2 months of implantation and long term if they emerged thereafter (35). We will assess the emergence of the following device complications (Defined in supplementary file 2): Contrast-induced nephropathy, Pneumothorax, Pocket-related Hematoma, Pericardial tamponade, Phrenic nerve stimulation, Device Infection, Death, Pulmonary edema, Electrical storm, cardiogenic shock, Hypotension requiring resuscitation.
We will include in our review cohort studies (prospective, retrospective). We will exclude Randomized studies, Case reports, case series, review articles, cross-sectional studies, surveys, qualitative or interview/focus group studies, editorials, letters, and commentaries.
No restrictions will be imposed on the type of setting.
No language restriction will be applied.
The search was conducted from the date January 1, 2000 to June 12, 2020 of the following databases: MEDLINE, EMBASE and Web of Sciences. To ensure a thorough search, we will review the reference list of relevant systematic reviews for eligible studies.
With the assistance of an information specialist, we developed a comprehensive search strategy. The search strategy includes a combination of Medical Subject Headings (MeSH) and indexed terms and database-specific terms. An example of the search strategy is available in supplementary file 3.
Keywords used to develop this search are variations of the following terms: “Cardiac Implantable Electronic Device” or “Cardiac Resynchronization Therapy” or “Defibrillators” or “Implantable cardioverter defibrillator” or “heart failure” or “Cardiac failure” or “Biventricular Pacemaker”. Due to the large number of studies retrieved (> 20,000), we will use the most up-to-date cohort study search filter developed by the Inter InterTASC Information Specialists’ Sub-Group (ISSG) (36) to obtain observational studies. We also added variants of the terms: “Registry”, “Prospective” and “Retrospective” for a more comprehensive search. To further narrow our search we will use a validated heart failure search filter that retrieving studies focused on device therapy in heart failure context (37).
Study selection and screening process
Study selection will be conducted in a blinded fashion, by two independent reviews using Covidence program (38). Screening at title and abstract stage and full text stages will be completed in duplicate. Discrepancies will be resolved by discussion between reviewers followed by consensus, or a third reviewer. We will prepare a PRISMA study flow chart. Studies that assess sex differences in outcomes for patients receiving CRT devices will be selected in duplicate, independently. We plan on capturing all outcomes reported in the studies that relate to the clinical effectiveness of the device, implantation rate across sex and as well as adverse events related to complications post implantation. ICD studies with > 50% CRT-D will be considered eligible and extracted. Studies with >75% primary prevention will be extracted, and other studies will be listed with reason for exclusion (e.g. secondary prevention).
Data extraction will be conducted by two independent reviewers using a pretested extraction form. Conflicts will be resolved by consensus between the two reviewers or by a third reviewer. The extraction form will be developed in collaboration with a content expert based on the Data Extraction Template for Cochrane Reviews (39). The form will be pilot tested with a random sample of 5 studies, and further developed accordingly. The extraction process will be facilitated using Microsoft Excel forms customized with extraction criteria.
The extraction form will be developed in collaboration with a content expert, and pilot tested with a random sample of 5 studies, and further developed accordingly.
Reviewers will extract data on study characteristics (name of author, publication date, journal, funding and conflict of interest), study methodology (objectives, target population, recruitment and sampling procedures, setting) participant information (baseline characteristics, device type, disease severity classification, sample size) and outcomes (definitions, time of measurement and results)
Risk of bias and quality of assessment of individual studies
We will be assessing non-randomized studies; therefore, we will be using the Newcastle-Ottawa Scale (NOS) tool to assess risk of bias (40). Scale Items assess selection of cases and controls, comparability of cases and controls and outcome follow up. Judgments will be made by two independent reviewers and disagreements will be resolved through discussion.
Synthesis of results
We will meta-analyze quantitative data when appropriate. We will use I2 statistic to assess heterogeneity. An I2 value greater than 75% would indicate high heterogeneity. An I2 between 50 and 75 percent indicates moderate heterogeneity and calls for investigation via post hoc subgroup analysis (41). We will conduct meta-analysis using random effects methodology using Revman (42). When meta-analysis is inappropriate due to comparative diversity, results will be narratively reported while providing effect sizes and confidence intervals. Individual and pooled analyses will be presented using tables and forest plots respectively.
Interventions that involve implantation of CRT-P and CRT-D will be treated separatory. All the extracted outcomes will be analyzed separately. Categorical outcomes will be assessed using risk ratios (95% Confidence intervals (C.I)) and continuous outcomes will be analyzed using mean differences (95% C.I) (43).
An Intention to treat analysis method will be adopted. We will record how authors dealt with missing data and sensitivity analysis will be used to investigate the effect of missing data on the overall results. Adjusted results reported in the included studies as effect measures will be used in the analyses accordingly.
Where feasible and appropriate, we will conduct exploratory subgroups to investigate the impact of factors on outcomes. We plan on conducting a priori subgroup analysis for the following criteria:
- Age (<65, ≥ 65)
- Type of device (CRT-D, CRT-P)
- Disease severity (NYHA class I-II, NYHA class III-IV)
Sensitivity analysis may be considered with respect to composition of the participants or definitions of outcomes to assess the robustness of the performed meta-analysis. We will inspect publication bias using funnel plots in the case of 10 or more studies are included in our review (44). We will display the meta-analyzed results using forest plots.
Strength of evidence assessment
We will use the GRADE framework to rate the certainty of the evidence of intervention effects (45). GRADE assessment will be conducted in duplicate by two reviewers, independently. Discrepancies will be resolved by discussion or a third reviewer. Summarized results will be presented as summary of findings tables (45).