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Remote ischaemic preconditioning for transcatheter aortic valve replacement: a protocol for a systematic review with meta-analysis and trial sequential analysis
  1. Weiyi Zhang1,
  2. Li Du2,
  3. Guo Chen1,
  4. Bin Du1,
  5. Lu Zhang1,
  6. Jianqiao Zheng1
  1. 1 Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
  2. 2 Department of Anesthesiology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
  1. Correspondence to Dr Jianqiao Zheng; zhjq1983{at}163.com

Abstract

Introduction Transcatheter aortic valve replacement (TAVR) has become an important treatment in patients with aortic valve disease with the continuous advancement of technology and the improvement of outcomes. However, TAVR-related complications still increase patient morbidity and mortality. Remote ischaemic preconditioning (RIPC) is a simple procedure that provides perioperative protection for many vital organs. However, the efficiency of RIPC on TAVR remains unclear based on inconsistent conclusions from different clinical studies. Therefore, we will perform a protocol for a systematic review and meta-analysis to identify the efficiency of RIPC on TAVR.

Methods and analysis English databases (PubMed, Web of Science, Ovid Medline, Embase and Cochrane Library), Chinese electronic databases (Wanfang Database, VIP Database and China National Knowledge Infrastructure) and trial registry databases will be searched from inception to December 2023 to identify randomised controlled trials of RIPC on TAVR. We will calculate mean differences or standardised mean differences with 95% CIs for continuous data, and the risk ratio (RR) with 95% CIs for dichotomous data by Review Manager version 5.4. Fixed-effects model or random-effects model will be used according to the degree of statistical heterogeneity assessed by the I-square test. We will evaluate the risk of bias using the Cochrane risk-of-bias tool 2 and assess the evidence quality of each outcome by the Grading of Recommendations Assessment, Development and Evaluation. The robustness of outcomes will be evaluated by trial sequential analysis. In addition, we will evaluate the publication bias of outcomes by Funnel plots and Egger’s regression test.

Ethics and dissemination Ethical approval was not required for this systematic review protocol. The results will be disseminated through peer-reviewed publications.

PROSPERO registration number CRD42023462926

  • transcatheter aortic valve replacement
  • TAVR
  • transcatheter aortic valve implantation
  • TAVI
  • remote ischemic preconditioning
  • RIPC
  • meta-analysis
  • randomized controlled trial

Data availability statement

Not applicable for this protocol.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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STRENGTHS AND LIMITATIONS OF THIS STUDY

  • Trial sequential analysis was performed to assess the robustness of each outcome.

  • Funnel plots and Egger’s regression test were performed to evaluate the publication bias.

  • Cochrane risk-of-bias tool 2 was used to evaluate the risk of bias.

  • The Grading of Recommendations Assessment, Development and Evaluation was used to confirm the evidence quality.

  • The study will be limited to potential heterogeneity.

Introduction

Transcatheter aortic valve replacement (TAVR) or transcatheter aortic valve implantation (TAVI) was first performed via a transseptal approach by Cribier in a critically ill patient with severe aortic stenosis in 2002.1 Since this first-in-man case, TAVR was considered to be an alternative treatment option for patients with severe aortic stenosis at high surgical risk, as surgical aortic valve replacement (SAVR) was considered to have an unacceptably elevated risk of complications or death.2–5 Continuous advances in TAVR technology have created different types of access, such as classical transfemoral, transcaval, trans‐subclavian, transaxillary, transcarotid, transaortic and transapical.6–8 In addition, ongoing improvements in devices and techniques also decreased the composite adverse events and mortality.9

Based on the improving outcomes of TAVR, its indications have expanded from high to intermediate surgical risks, and younger populations with low surgical risks are also included.10–14 In addition, the initiated indications also extend from isolated severe aortic stenosis to mixed aortic valve disease and pure native aortic regurgitation disease.15–19 With the broadening of indications, the collected data from the Society of Thoracic Surgeons (STS)/American College of Cardiology (ACC)/Transcatheter Valve Therapy (TVT) Registry indicate that TAVR volumes first exceeded isolated SAVR volumes between 2015 and 2016 and then exceeded all forms of SAVR volumes between 2018 and 2019.20 21

However, the TAVR procedure (such as incentive rapid ventricular pacing, balloon valvuloplasty and prosthesis deployment) and abnormal conditions (such as releasing microemboli from aortic scraping during catheter manipulation; releasing debris from calcified native valves during AV dilations; thrombi formed on the catheter or introducer sheath surface; air emboli even with meticulous catheter preparation and flushing; and displaced endovascular atheroma) could cause composite adverse events (such as ventricular fibrillation, cardiac arrest, stroke, acute kidney injury and other complications of myocardial ischaemia).22–27 Owing to significant technological advancements and increased operator experience, rates of TAVR-associated AKI and stroke have slightly declined over time.9 28 However, the incidence of TAVR-associated AKI remains at 10.5% to 11.5% in the USA and 6.8% in Asia.9 29 On the other side, the incidence of stroke is approximately 3–5%.30 In addition, systemic inflammatory response syndrome occurs in approximately 50% of patients after the TAVR procedure.31 These complications are associated with a significant increase in morbidity and mortality.32–37 The most recently published STS/ACC/TVT Registry reported that the incidence of 30-day composite adverse events was 10.5%, and the 1-year mortality was 10.1%.9 Therefore, effective techniques to reduce these adverse events could benefit patients undergoing TAVR.

Remote ischaemic preconditioning (RIPC) is as simple as performing TAVR, as no procedure protects an organ against subsequent ischaemic damage through the application of repeated ischaemia-reperfusion in the peripheral sites, such as the upper or lower extremities.38 RIPC was first described by Przyklenk,39 and then the first randomised controlled study of RIPC was designed by Cheung to confirm its myocardial protective effect on congenital cardiac surgery.40 Subsequent studies have reported that RIPC protects many vital organs, including the heart, liver, kidney, brain and lungs.41–49 As a non-invasive, easily feasible, safe and inexpensive method, RIPC was also used in the TAVR procedure to induce multiorgan protection.50–53 However, the efficiency of RIPC on TAVR remains controversial based on inconsistent conclusions from different clinical studies.

Therefore, it is necessary to conduct a systematic review and meta-analysis to analyse the clinical efficacy of RIPC for TAVR. The outcomes of this systematic review will provide evidence for better clinical decision-making and possible future directions for further clinical trials.

Objectives

This systematic review with meta-analysis and trial sequential analysis (TSA) of randomised controlled trials (RCTs) aims to evaluate the clinical efficiency of RIPC for TAVR.

Methods and analysis

Design and registration of the review

This protocol has been prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines and was registered on PROSPERO 2023 (registration number: CRD42023462926).54 Then, this systematic review and meta-analysis will be performed based on the Cochrane Handbook and report the results following the PRISMA statement.55 56 This study is anticipated to begin a literature search in December 2023, and the final manuscript of this systematic review is anticipated to be completed in December 2025.

Inclusion criteria for study selection

Types of studies

Only RCTs related to the clinical efficacy of RIPC for TAVR will be included. No language restrictions will be applied. Duplicate publications, protocols, conference abstracts, conference articles, editorial materials, letters and any type of reviews will be excluded. After contacting the corresponding authors, study data that remained unavailable after data transformation, remained incomplete or still could not be obtained will also be excluded.

Types of participants

Participants indicated for TAVR through any vascular access. There were no limitations on participant characteristics, including participants' age, sex, ethnicity, body mass index (BMI), aortic valvular disease, comorbidities, American Society of Anesthesiologists (ASA) classification, Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM), Society of Thoracic Surgeons score (STS score), New York Heart Association classification, and European System for Cardiac Operative Risk (EuroSCORE).

Types of interventions/controls

The intervention group will be participants receiving TAVR and accepting any form of RIPC. The control group will be participants accepting TAVR without RIPC. There were no limitations on vascular access for TAVR, and no restrictions on the RIPC technique.

Types of outcome measures

Primary outcomes

The primary outcome will be early all-cause mortality (in-hospital mortality and 30-day mortality).

Secondary outcomes
  1. Incidence of acute kidney injury (AKI)

  2. Incidence of cerebrovascular events: stroke or transient ischaemic attack (TIA)

  3. Incidence of acute myocardial infarction (AMI)

  4. Incidence of new pacemaker implantation

  5. Incidence of postoperative pulmonary complications: defined as respiratory infection, atelectasis, respiratory failure, bronchospasm, pleural effusion and pneumothorax according to consensus definitions for pulmonary complications and the ARISCAT definition.57

  6. Incidence of major vascular events

  7. Incidence of major or life-threatening bleeding

  8. Incidence of neurological complications: postoperative delirium and cognitive dysfunction

  9. Length of intensive care unit stay

  10. Length of hospital stay

  11. Change in biomarkers: (1) cardiac biomarkers: serum troponin I, serum troponin T and serum creatine kinase isoenzyme-MB (CK-MB); (2) renal biomarkers: serum creatinine level, glomerular filtration rates (GFRs) and the renal stress biomarker neutrophil gelatinase-associated lipocalin (NGAL); (3) cerebral biomarkers: serum level of brain-derived proteins S-100 calcium-binding protein B (S100-b) and neuron-specific enolase (NSE); and (4) inflammatory responses and oxidative stress: serum concentration of IL-6, IL-8, TNF-α, malondialdehyde (MDA) and serum superoxide dismutase (SOD) activity.

  12. Pulmonary gas exchange function: arterial-alveolar oxygen tension ratio (a/A ratio), alveolar-arterial oxygen tension difference (A-aDO2), respiratory index (RI), PaO2/FiO2 and PaCO2.

  13. The interim all-cause mortality (90-day, 6-month and 12-month mortality).

Search strategy

Two reviewers (Z-WY and DL) will independently conduct the systematic search, and the third reviewer (ZL) will attempt to resolve any disagreements between the two reviewers. English electronic databases (including PubMed, Web of Science, Ovid Medline, Embase and Cochrane Library) and Chinese electronic databases [including Wanfang database, VIP Database and China National Knowledge Infrastructure (CNKI)] will be searched from inception to December 2023 to identify RCTs related to the efficacy of RIPC on TAVR. The reference lists of each included study and relevant reviews will also be screened as to avoid missing studies. In addition, the trial registry database (including the WHO International Clinical Trials Registry Platform, Clinical Trials.gov, and Chinese Clinical Trials Registry) will also be scrutinised for potential additional sources and ongoing or unpublished clinical trials.

Keyword search terms will be used in the search strategy, and the keywords will be related to ‘transcatheter aortic valve replacement, transcatheter aortic valve implantation, TAVR, TAVI, remote ischaemic preconditioning, RIPC, and randomized controlled trial’. In addition, related keyword search terms will be translated into Chinese and then used in literature research in Chinese databases for study identification. The search strategies are provided in Supplementary Appendix file 1. The literature search results will be updated before the final publication of systematic reviews to avoid missing published studies during the preparation of systematic reviews.

Data collection and analysis

Selection of studies

In the first step, titles and abstracts of the potentially eligible studies will be screened by two authors (Z-WY and DL) independently. Then, the full text of all identified and relevant publications retrieved from the database will be screened thoroughly. Records that are clearly ineligible will be removed, and specific reasons for study exclusion will be recorded and reported according to the PRISMA flow diagram. A third review coauthor (Z-JQ) will be consulted if any disagreement on the eligibility criteria of studies exists. Before the final confirmation of the data extraction, a fourth reviewer (ZL) will carefully check all procedures again. Suspected companion papers of the same trial or suspected duplicate publications will be resolved by all review authors through discussion. The entire search and selection process is provided in the PRISMA flow diagram (figure 1).

Figure 1

The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) flow diagram. *Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Data extraction

Data in all included studies will be extracted according to a standardised data extraction form (Excel version 2013) by two review authors (Z-WY and DL). Data elements to be extracted will include the following items: the basic publication information (including the first author’s name, publication year, author’s country), participants’ demographic data (including sample size, age, gender, BMI, New York Heart Association Class, European system for cardiac operative risk evaluation, ASA physical status classification levels, society of thoracic surgeons predicted risk of mortality, comorbidities, if available), detailed information on TAVR (including aortic valvular disease: stenosis, regurgitation or mixed aortic valve disease; artificial valve type; valve implantation route: transfemoral, transcaval, trans‐subclavian, transaxillary, transcarotid, transaortic or transapical implantation route); anaesthesia protocols (including anaesthesia techniques: local anaesthesia, monitored anaesthesia care, sedation or general anaesthesia; anaesthesia maintenance: total intravenous anaesthesia, volatile anaesthesia or intravenous anaesthesia combined with volatile anaesthesia; airway management technique: endotracheal intubation, laryngeal mask intubation or spontaneous breath), RIPC protocols (including location of RIPC: upper limb or lower limb; number of RIPC cycles; periods of cuff inflated and cuff deflation; cuff inflation pressure) and outcomes of any kind.

Study design characteristics, including the following domains: randomisation process, allocation concealment method, blinding (including blinding of patients, blinding of personnel and blinding of outcome investigators), information related to incomplete outcome data collection, statistical analysis technique and details in outcome reporting, will be extracted and recorded. Continuous data will be extracted and recorded as the mean±SD, and the unit will also be recorded. Dichotomous data will be extracted and recorded as percentages or proportions. A third review author (CG) will reconfirm the data to ensure accuracy. We will attempt to obtain the missing or incomplete data from the corresponding author by email. If necessary, we will extract the numerical data in the graphs by Adobe Photoshop.58 In addition, we will also transform the data, such as estimating the mean and SD from the median, mid-range and/or mid-quartile range.59 60

Quality assessment

Two review authors (Z-WY and DB) will evaluate the risk of bias in all included studies independently, according to the guidance of the Cochrane risk-of-bias tool 2 (RoB 2.0).61 The methodology will include random sequence generation (selection bias), allocation concealment (selection bias), blinding (including blinding of patients and personnel: performance bias; blinding of outcome assessment: detection bias), incomplete outcome data (attrition bias) and selective outcome reporting (reporting bias). In addition, other risks of bias and the overall risk of bias will also be evaluated. Each included study will be evaluated by the RoB 2.0 and then classified into ‘low risk’, ‘unclear risk’ or ‘high risk’.55 62 Any disagreements will be resolved through arbitration by a third reviewer (CG) or discussions by all reviewers. The assessment of risk of bias is listed in Supplementary Appendix fie 2.

We will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to assess the evidence quality of each outcome.63 The evidence quality will be described as ‘high‘, ‘moderate’, ‘low’ or ‘very low’ according to items as follows: the risk of bias, consistency, directness, precision, publication bias, large effect and plausible confounding.64 After assessment, we will export the table concerning the GRADE evidence profile from GRADE profiler version 3.6.1.

Measures of treatment effect

The meta-analysis of the included studies will be performed using Review Manager version 5.4 (Rev Man, Cochrane Collaboration, London, UK). Mean differences (MDs) with 95% CIs will be used for continuous outcome data with the same unit. Standardised mean differences (SMDs) with 95% CIs will be used for continuous outcome data with different units. We will calculate relative risk (RR) with 95% CIs for dichotomous outcome data. Heterogeneity analyses will be performed by Rev Man V.5.4. Statistical heterogeneity of each outcome will be assessed by the standard χ2 test for heterogeneity (significance level: α=0.1) and the I-square (Ι2) test for the degree of heterogeneity. The degree of heterogeneity will be classified as follows: Ι2=0–25%: no heterogeneity; Ι2=25–49%, low heterogeneity; Ι2=50–74%, moderate heterogeneity; Ι2≥75%: high heterogeneity. If p≥0.1 and if Ι2≤50%, we will use the fixed-effects model. If p<0.1 or Ι2>50%, we will use the random-effects model.55 A p value of less than 0.05 indicates statistical significance. The random effects estimate of the intervention is more beneficial than the fixed effects estimate as medical studies often suffer from small sample bias.65 Therefore, we will compare the fixed effects estimate against the random effects model to assess the possible presence of a small sample bias in the published literature. If there is high heterogeneity among the studies, we will conduct meta-regression or subgroup analysis to identify the sources of heterogeneity.66 Then, sensitivity analysis will be conducted by excluding individual studies one by one to observe the stability level of the synthesis results.

Trial Sequential Analysis

We will use the TSA programme version 0.9.5.10 Beta (Copenhagen Trial Unit, Copenhagen, Denmark) to perform the TSA to test the robustness of each outcome.67 68 The TSA programme version is available at http://www.ctu.dk/tsa.69 We will evaluate the validity of each outcome by calculating the required information size (RIS), the cumulative Z-curve and the TSA monitoring boundaries of each outcome.70 71

To calculate the RIS of continuous and dichotomous outcomes, the risk of type I error will be defined as 5% and the power will be defined as 90%.72 Then, a mean difference of the observed SD/2 will be used for continuous outcomes, and a relative risk reduction (RRR) of±20% will be used for dichotomous outcomes during the calculation of the RIS. If necessary, we will use clinical experience to define the value of SD or RRR for RIS calculation.71–73

Subgroup analysis

The results will be comprehensively interpreted through an analysis of subgroups or subsets as much as possible. If sufficient trials are available, data from different types of TAVR, participant characteristics, different types of RIPC and different types of anaesthesia protocols will be analysed independently.

  1. Different types of TAVR

    • Different valve implantation routes: transfemoral, transcaval, trans‐subclavian, transaxillary, transcarotid, transaortic and transapical.

    • Different types of valves: self-expandable valve and balloon-expandable valve.

  2. Different participant characteristics

    • Different aortic valvular diseases: stenosis, regurgitation or mixed aortic valve disease.

    • Different surgical risks: low surgical risk, intermediate surgical risk or high surgical risk.

  3. Different types of RIPC

    • Different locations of RIPC: upper limb and lower limb.

    • Different total durations of ischaemia: total times ≥20 min and total times 20 min.

  4. Different types of anaesthesia protocols

    • Different anaesthesia techniques: local anaesthesia, monitored anaesthesia care, sedation or general anaesthesia.

    • Different anaesthesia maintenance methods: total intravenous anaesthesia, volatile anaesthesia or intravenous anaesthesia combined with volatile anaesthesia.

    • Different airway management strategies: endotracheal intubation, laryngeal mask intubation or spontaneous breathing.

Subgroup difference will be assessed by the interaction p value, an interaction p value of less than 0.05 indicates significant difference between subgroups, and the result for each subgroup will be reported separately.55

Assessment of publication biases

When more than 10 original studies are included in one outcome measure, we will use the visual judgement of the funnel plot asymmetry and Egger’s regression test to estimate the potential publication bias.74 75 When publication bias occurs, we will use the trim and fill analysis to estimate the number of missing but might exist studies and then amend the influences of publication bias on the outcomes.76 Stata/MP 16.0 (Stata Corp, College Station, TX, USA) will be used for publication bias.74 A p value of less than 0.05 indicates potential publication bias.

Grading the quality of evidence

We will use the GRADE criteria to assess the evidence quality of each outcome.63 We will define the evidence quality from the RCTs as high, moderate, low or very low depending on the GRADE criteria, including the risk of bias, consistency, directness, precision and publication bias.59 However, the evidence quality can be degraded according to each item of the GRADE criteria.

Patient and public involvement statement

Patients or the public were not involved in the design, conduct, reporting or dissemination plans of our research.

Discussion

The TAVR volume has exceeded that of isolated SAVR and then gradually exceeded that of all forms of SAVR, based on the improving outcomes and continuous advances in TAVR technology.20 21 However, complications of TAVR still affect patient outcomes and are associated with significantly increased morbidity and mortality.32–37 Therefore, effective techniques to reduce adverse complications have important clinical significance to patients undergoing TAVR. RIPC originated from laboratory studies and was gradually applied to clinical trials, as RIPC could decrease inflammation and oxidative stress, providing a protective effect on many vital organs.41–49 77–84 RIPC was also performed in TAVR, as a non-invasive, easily feasible technique.51–54 However, controversy remains regarding the efficiency of RIPC based on the different inconsistent clinical conclusions.

To our knowledge, this is the first systematic review and meta-analysis of RCTs to synthesise evidence on the efficiency of RIPC in patients receiving TAVR. This systematic review will provide a comprehensive overview of the current published clinical evidence on the efficacy of RIPC in TAVR. We will examine the all-cause mortality (in-hospital, and 30-day, 90-day, 6-month and 12-month mortality), adverse events (AKI, cardiac complications, cerebrovascular events, pulmonary complications, neurological complications) and biomarkers (cardiac, renal, cerebral, inflammatory responses and oxidative stress biomarkers) of RIPC in TAVR. The results of this systematic review will facilitate the optimum use of RIPC in TAVR patients. If a clinically significant efficiency exists in RIPC, the evidence of our meta-analysis could improve the management of TAVR. If evidence is lacking, more clinical investigations should be performed on this topic in the future.

Strengths and limitations

Our systematic review has several strengths. First, the protocol of this systematic review was rigorously performed according to the PRISMA-P guidelines to achieve the highest scientific quality. Second, a comprehensive search strategy: English and Chinese electronic databases will be searched to broaden the range of data sources during the selection of studies. Third, at least two review authors will conduct the literature retrieval, data extraction and evidence evaluation independently according to the guidelines rigorously, and another review author will be consulted if any disagreement occurs, as to avoid personal biases. Fourth, well-established methodological procedures, including subgroups to analyse the heterogeneity and interpret the clinical efficiency comprehensively, TSA to control the risks of random errors, quality assessment by RoB 2.0 and GRADE, publication bias assessment by funnel plots and Egger’s regression test will be performed.

The limitations of our systematic review are as follows: first, participants with different comorbidities, different RIPC and anaesthesia protocols, different artificial valve types, various access routines and different aortic valve diseases will be included in the analysis, leading to potential heterogeneity. Second, the sample size of each included study may be small, and the data for subgroup analyses may also be limited. Relevant studies with large samples may emerge in the future, as the volume of TAVR increases. Third, double-blind designed RCTs may be limited, as it is hard to perform double-blinding for different RIPC techniques. Fourth, it is difficult to define a significant clinical value of MD and RR due to the limited clinical data of RIPC on TAVR, which will influence the evidence quality of the TSA.

Ethics and dissemination

Ethical approval was not required for this systematic review protocol. The findings will be disseminated through peer-reviewed publications.

Timelines

Formal screening of search results will begin in December 2023. Data extraction will begin in July 2025. The project will be completed in December 2025.

Data availability statement

Not applicable for this protocol.

Ethics statements

Patient consent for publication

References

Footnotes

  • Timelines Formal screening of search results will begin in December 2023. Data extraction will begin in July 2025. The project will be completed in December 2025.

  • Contributors Z-JQ and DL conceived the idea for this systematic review. All authors (Z-WY, DL, CG, DB, ZL and Z-JQ) developed the methodology for the systematic review. The manuscript was drafted by Z-JQ and Z-WY and revised by all authors. Z-WY and DL will screen potential studies and extract the data. CG and DB will undertake a risk of bias assessment and assess the evidence quality. ZL and Z-JQ will conduct the data synthesis. All authors contributed to the research and agreed to be responsible for all aspects of the work.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

  • ETHICS AND DISSEMINATION Ethical approval was not required for this systematic review protocol. The findings will be disseminated through peer-reviewed publications.

  • Provenance and peer review Not commissioned; externally peer reviewed.