Coronary artery bypass surgery versus medical therapy alone for ischaemic heart disease

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To assess the effects of coronary artery bypass surgery versus medical therapy alone in people with ischaemic heart disease.

Background

Description of the condition

Ischaemic heart disease, also known as coronary artery disease, is the biggest component of cardiovascular disease. According to a report from the World Health Organization, in 2018, ischaemic heart disease caused 9.46 million deaths, which makes it the most common cause of death globally (WHO 2018). Moreover, this number will keep increasing, along with the associated expenses (Downing 2016; Eswar 2018; Heidenreich 2011; Wong 2014).

The most common cause of ischaemic heart disease is atherosclerosis, which leads to coronary artery stenosis and obstruction (Ambrose 2015). Coronary artery stenosis may involve any of the three coronary arteries; the left anterior descending branch (LAD), the left circumflex branch (LCx), and the right coronary artery (RCA). We refer to stenosis as one, two, or three vessel coronary disease, depending on the number of branches involved. Obstruction of more than 70% of a coronary artery results in a lack of oxygen, leading to angina, especially when people are under mental stress or participating in physical activities (Ambrose 2015; Srikanth 2012).

Another cause of ischaemic heart disease is cardiac syndrome X. With cardiac syndrome X, there is an absence of coronary artery stenosis when people have an angiogram (Lanza 2006). The aetiology of cardiac syndrome X remains unknown, but there are some theories, including microvascular dysfunction and epicardial atherosclerosis (Erika 2012; Lanza 2006).

At the beginning, people with ischaemic heart disease only experience angina during intensive exercise. As the stenosis in the coronary artery progresses, they may have angina even at a rest. Chronic, severe stenosis in the coronary artery may result in transient occlusion, which leads to an acute myocardial infarction. In turn, this could lead to ventricular arrhythmia and death (Odonkor 2013).

Ischaemic heart disease can be classified into stable ischaemic heart disease and acute coronary syndrome according to different symptoms combined with imaging examination. Acute coronary syndrome (ACS) is also divided into three types: 1. unstable angina; 2. non‐ST‐segment elevation myocardial infarction (non‐STEMI); 3. ST‐segment elevation myocardial infarction (STEMI) (Ibanez 2017; Roffi 2016).

There are different treatments, depending on the degree and type of ischaemic heart disease, including medical therapy alone, coronary artery bypass surgery (CABS), and percutaneous coronary intervention (PCI). These interventions can relieve angina symptoms and reduce mortality (Jameson 2018).

A number of factors play important roles in the prognosis of people with ischaemic heart disease when they are given these two treatments. People with diabetes have a higher risk of events and death (Group 2009). People with left ventricular dysfunction indicate a higher risk of poorer survival (Allman 2002; Bruschke 1973; Ling 2013; Pigott 1985). And, this risk increases for people with a left ventricular ejection fraction (LVEF) of less than 30% (Roques 1999). People with left main or three vessel disease in particular benefit more from coronary artery bypass surgery than medical therapy alone when the proximal LAD is involved (Yusuf 1994).

Description of the intervention

Both medical therapy alone and CABS can manage ischaemic heart disease, especially when it is stable.

Medical therapy alone means therapeutic strategies without the use of PCI or CABS. This approach has changed considerably, as pharmacological treatment has expanded. Now, it mainly controls a variety of risk factors, through the use of nitrates, renin‐angiotensin system blockers, beta‐blockers, calcium channel blockers, aspirin, statins, and more recently, 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors (Pedersen 1994). With optimal medical therapy, cardiac‐related hospitalisations and mortality are reduced (Ho 2008).

Coronary artery bypass surgery (CABS), also known as coronary bypass graft surgery (CABG), is performed to restore blood flow by using autologous vessels, including the internal thoracic artery, radial artery, gastroepiploic artery, and great saphenous vein, to name a few (Shumacker 1992). Surgeons prefer to use either the left internal thoracic artery or the great saphenous vein, due to easy accessibility, lower injure risk, and acceptable patency rate (Kim 2014). For this, surgeons dissect the lower part of the left internal thoracic artery, maintaining its origin, and then connect it to the left anterior descending artery. They use the great saphenous vein to rebuild the pathway between the aorta and the distal part of coronary artery after the obstruction (Mohammadi 2008; Petrovic 2015).

Robert Goetz and his team from Bronx Municipal Hospital Center in the United States, performed the first coronary artery bypass surgery in 1960 (Konstantinov 2000; Mueller 1997). At that time, anastomosis was achieved with an inserted metal ring. However, the patient died nine months after the surgery (Goetz 1961). In 1964, Kolesov and his team performed the first successful coronary artery bypass surgery, using the internal mammary artery (Kolesov 1965). As technology and surgical procedures continued to improve and mature, in 1973, Benetti and Calafiore performed an anastomosis on a beating heart instead of using extracorporeal circulation during the procedure (Diodato 2014).

Common adverse events related to CABS include death, adverse neurological incidents (such as stroke, delirium, short‐term cognitive decline), nosocomial infections (for example, surgical site infections, deep sternal wound infections, respiratory infections), acute renal failure (often related to extracorporeal circulation, with a 2% to 3% incidence), myocardial dysfunction caused by the decrease of cardiac output, arrhythmias (such as atrial fibrillation, atrial flutter, ventricular fibrillation), nonunion of the sternum, acute graft block, due to thrombosis and graft failure, anticoagulation‐related complications (such as bleeding, reopened thoracotomy because of bleeding and thrombosis), acute myocardial infarction, and pleural effusion (Lopes 2012; Serruys 2009; SoS 2002).

Since 1973, the use of coronary artery bypass surgery increased rapidly. The procedure has changed a lot due to minimally invasive techniques, endoscopic vessel harvesting techniques, and robotic surgical techniques. After more than 50 years' development, the amount of coronary artery bypass surgery reached 395,000 cases in 2001 in the USA. The volume has declined recently because of improvements in medical treatment, secondary prevention, and stent technology with adjuvant medical therapy (Vedin 2013). However, morbidity and mortality have continued to decrease over the past 20 years. Mortality has declined from 3.9% in 1990, to 1.9% in 2009 (Elbardissi 2013; Ferguson 2002).

The European Society of Cardiology/European Association for Cardio‐Thoracic Surgery (ESC/EACTS) guidelines recommend CABS or CABG for ischaemic heart disease (stable ischaemic heart disease and acute coronary syndrome) in these circumstances.

For people with stable ischaemic heart disease, unstable angina, or non‐STEMI and:

1. Left main disease or proximal LAD with stenosis > 50%; two or three vessel disease with stenosis > 50% with impaired left ventricular function (left ventricular eject fraction ≤ 35%); or haemodynamically significant coronary stenosis in the presence of limiting angina or angina equivalent, with insufficient response to optimised medical therapy (Class I, Level of evidence A).

2. Large area of Ischaemia, detected by functional testing (> 10% left ventricular) or abnormal invasive fractional flow reserve (Class I, Level of evidence B).

3. Single remaining patent coronary artery with stenosis > 50% (Class I, Level of evidence C).

Further circumstances include:

1. One vessel with proximal LAD stenosis, left main disease, or three vessel disease (Class I, Level of evidence A).

2. One or two vessel disease without proximal LAD stenosis (Class IIb, Level of evidence A).

3. Two vessel disease with proximal LAD stenosis (Class I, Level of evidence B).

For ST elevation myocardial infarction (STEMI): CABG is recommended as a treatment option for failed PCI, or for someone with anatomy that is unsuitable for PCI but with persistent pain, or for haemodynamic instability (Sousa‐Uva 2018).

How the intervention might work

Coronary artery bypass surgery is a means of revascularisation therapy. Coronary blood flow is restored to the ischaemic area with a new pathway, in which one side of the harvested vessel is kept with its origin or attached to the aorta, and the other side is attached to the coronary artery, distal to the obstruction site (Shumacker 1992).

Why it is important to do this review

For the most part, current clinical trials focus on demonstrating the safety and efficacy of a strategy, not whether it is the optimal management for people. In the case of ischaemic heart disease, most studies are designed to compare PCI with CABS or CABG. This makes sense, since these are the most common treatments performed. However, this is based on the assumption that revascularisation is the treatment of choice for a person with ischaemic heart disease.

In 2016, a Cochrane Protocol, 'Non‐acute percutaneous coronary intervention versus medical therapy in patients with ischaemic heart disease' was published, which aimed to study the prognosis of participants with ischaemic heart disease after receiving non‐acute PCI or medical therapy alone (Nielsen 2016). Currently, there is no system review that explores the prognosis when comparing CABS or CABG with medical therapy alone. In our review, we want to explore this topic with a broader scope, and without the assumption that participants have to receive revascularisation. We hope to provide an analyses comparing current information of the effects of CABS or CABG compared. We hope to include a number of randomised controlled trials, and perform a series of subgroup analyses, so this review can inform evidence‐based decision‐making for clinicians, researchers, and policy makers, and people with ischaemic heart disease will have better and more appropriate treatments.

Objectives

To assess the effects of coronary artery bypass surgery versus medical therapy alone in people with ischaemic heart disease.

Methods

Criteria for considering studies for this review

Types of studies

We will include individual‐ and cluster‐randomised controlled trials (RCT), regardless of publication status, publication date, publication type, blinding, or publication language. We will exclude quasi‐randomised studies and observational studies.

Types of participants

We will include participants with ischaemic heart disease treated with guideline‐driven medical therapy alone, or first‐time isolated coronary artery bypass surgery.

We will include participants of all ages.

We will exclude trials that include participants with second‐time coronary bypass surgery, since these can result in higher mortality than first‐time surgery, and could influence our results.

If we find trials that include a subset of eligible participants for whom there are no separate data, we will contact the trial authors and try to get the primary data. If we can, we will include these trails. If we cannot, we will include trials that include a majority of eligible participants. Otherwise, we will exclude the trials. We will document these decisions in the review and perform sensitivity analyses to assess the impact of these decisions.

Types of interventions

We will include trials comparing coronary artery bypass surgery with medical therapy alone. We will include any type of co‐interventions if they are equal in two groups. We will exclude trials where coronary artery bypass surgery are performed with abandoned techniques or medical therapy are given without following the current guidelines (Fraker 2007; Ibanez 2017; Montalescot 2013; O'Gara 2012; Roffi 2016; Sousa‐Uva 2018; Wright 2011).

Types of outcome measures

Reporting one or more of the outcomes of interest is not an inclusion criterion for the review. If a published report does not appear to report one of these outcomes, we will access the trial protocol and contact the trial authors to ascertain whether the outcomes were measured but not reported. We will include relevant trials that measured these outcomes, but either did not report the data at all, or did not report them in a usable format, as part of the narrative.

We will asses the following outcomes, measured at the maximum follow‐up of the trial.

Primary outcomes

1. All‐cause mortality

2. Death due to a cardiac cause

3. Repeat revascularisation

Secondary outcomes

1. Myocardial infarction (defined as the presence of significant new Q waves on at least two ECG leads, or symptoms compatible with myocardial infarction associated with creatine kinase‐MB concentrations that were more than three times the upper limit of the reference range)

2. Cerebrovascular accident

3. Quality of life (QoL), based on the Seattle Angina Questionnaire (Hofer 2002), and the Medical Outcomes Study Short‐Form 36‐Item Health Survey (SF‐36 (Wyrwich 2003)).

4. Serious adverse events that result in death, are life‐threatening, require inpatient hospitalisation or prolongation of existing hospitalisation, or result in persistent or significant disability or incapacitation, including infection, acute kidney failure, bleeding

Search methods for identification of studies

Electronic searches

We will identify trials through systematic searches of the following bibliographic databases:

• Cochrane Central Register of Controlled Trials (CENTRAL; current issue) in the Cochrane Library

• MEDLINE Ovid (1946 to present)

• Embase Ovid (1980 to present)

• Web of Science Core Collection Clarivate Analytics – Conference Proceedings Citation Index‐Science (CPCI‐S; 1990 to present)

• China Biology Medicine (CBM)

We will adapt the preliminary search strategy for MEDLINE Ovid for use in the other databases (Appendix 1). We will apply the Cochrane sensitivity and precision maximising RCT filter MEDLINE Ovid and the adaptations of it to the other databases, except CENTRAL (Higgins 2019).

We will search the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.ClinicalTrials.gov), and the WHO International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/) for ongoing or unpublished trials.

We will search all databases from their inception to the present, and we will impose no restriction on language of publication or publication status.

We will not perform a separate search for adverse effects of interventions used for the treatment of ischaemic heart disease.

Searching other resources

We will check reference lists of all included studies and any relevant systematic reviews identified, for additional references to trials. We will also examine any relevant retraction statements and errata for included studies.

Data collection and analysis

Selection of studies

Two review authors (YC, LW) will independently screen titles and abstracts for inclusion of all the potential studies we identify as a result of the search, and code them as 'retrieve' (eligible or potentially eligible or unclear) or 'do not retrieve'. If there are any disagreements, they will ask a third review author (XY) to arbitrate. We will retrieve the full‐text study reports and publications, and two review authors (LW, XY) will independently screen the full‐text, identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person (YC). We will identify and exclude duplicates, and collate multiple reports of the same study, so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table.

Data extraction and management

We will use a data collection form for study characteristics and outcome data, which has been piloted on at least one study in the review. Two review authors (TB, SL) will independently extract study characteristics from included studies. We will extract the following study characteristics.

1. Methods: total duration of study, number of study centres and location, number of participants, primary author, and date of publication.

2. Participants: mean age, distribution of age and sex, history of MI, diabetes mellitus, stable angina, left ventricular ejection fraction, people with two vessel coronary disease, people with three vessel disease, people with proximal left anterior descending branch (LAD), inclusion criteria, and exclusion criteria.

3. Interventions: intervention, comparison, concomitant medications, and excluded medications.

4. Outcomes: primary and secondary outcomes specified and collected, and time points reported.

5. Notes: funding for trial, and notable conflicts of interest of trial authors.

Two review authors (TB, SL) will independently extract outcome data from included studies. We will resolve disagreements by consensus, or by involving a third person (LW). One review author (LW) will transfer data into the Review Manager 5 file (Revman5) (Review Manager 2014). We will double‐check the data in Revman5 with the publications. A second review author (LZ) will spot‐check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (YC, XY) will independently assess risk of bias for each study using version two of the Cochrane 'Risk of bias' tool (RoB2), outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019). We will resolve any disagreements by discussion, or by involving another review author (TB). We will resolve any disagreements by discussion or by involving another review author (PG). We will assess the risk of bias of trials that measure the outcomes that will be included in our 'Summary of findings' table according to the following domains:

1. Bias arising from the randomisation process.

2. Bias due to deviations from intended interventions.

3. Bias due to missing outcome data.

4. Bias in measurement of the outcome.

5. Bias in selection of the reported result.

We will perform an intention‐to‐treat (ITT) analysis to estimate the effect of assignment to intervention, when assessing the bias due to deviations from the intended interventions (Higgins 2019).

For cluster‐randomised trials, we will consider additional biases, according to table 23.1.a in Section 23.1.2 of the Handbook (Higgins 2019). We will assess if the reported data analysis had appropriately taken account of the aggregate nature of the data, the randomisation processes (including allocation sequence, timing, baseline imbalances), and blinding (containing recruitment bias, identification bias (Higgins 2019)).

We will use the signalling questions in the RoB2 tool and rate each domain as 'low risk of bias', 'some concerns', or 'high risk of bias'. We will summarise the risk of bias judgements across different studies for each of the domains listed for each outcome. The overall risk of bias for the result is the least favourable assessment across the domains of bias.

When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.

Assessment of bias in conducting the systematic review

We will conduct the review according to this published protocol, and report any deviations in the 'Differences between protocol and review' section of the review.

Measures of treatment effect

We will analyse dichotomous data as risk ratios (RR) with 95% confidence intervals (CI). We will analyse continuous data as mean differences (MD) with 95% CI, unless the same outcome is assessed in various ways, in which case, we will analyse as standardised mean differences (SMD) with 95% CI. We will enter data presented as a scale with a consistent direction of effect.

We will narratively describe skewed data reported as medians and interquartile ranges.

Unit of analysis issues

To analyse cluster‐randomised trials, especially for older trials that were analysed as if the randomisation was performed on individuals rather than clusters, we will perform an 'approximate analyses of cluster‐randomised trials: effective sample sizes', using an estimate of the intra‐cluster (or intra‐class) correlation coefficient (ICC) to calculate the design effect, from which we will calculate the effective sample size (Rao 1992). The effective sample size of a single intervention group in a cluster‐randomised trial is its original sample size divided by the design effect. For dichotomous outcomes, both the number of participants and the number experiencing the event should be divided. For continuous outcomes, only the sample size needs to be reduced; means and standard deviations should remain unchanged (Higgins 2019). Once trials have been reduced to their effective sample size, we will enter data into Review Manager 5 software (Review Manager 2014) according to the methods in the Handbook (Higgins 2019).

We will borrow ICC from external estimates, obtained from similar studies, when the ICC estimates are available in these trials. We will conduct sensitivity analyses to investigate the robustness of our conclusion in both situations (Higgins 2019).

To analyse multi‐arm trials, we will combine groups to create a single pair‐wise comparison, assuming they are similar groups. We will sum both samples sizes and the numbers of participants with events for dichotomous outcomes. For continuous outcomes, we will combine means and standard deviations, based on the methods in the Handbook (Higgins 2019). If we cannot combine multiple arms in a single pair‐wise comparison, we will include each pair‐wise comparison separately with shared intervention groups divided out approximately evenly among the comparisons.

Dealing with missing data

We will contact investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as abstract only). Where possible, we will use the Review Manager 5 calculator to calculate missing standard deviations, using other data from the trial, such as confidence intervals, based on methods outlined in the Handbook (Higgins 2019). Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by a sensitivity analysis.

Assessment of heterogeneity

We will use the I² statistic, which quantifies inconsistency across studies, to assess the impact of heterogeneity in the meta‐analysis. We will use an I² value of 50% or higher as a measure of substantial heterogeneity. If we identify substantial heterogeneity, we will report it, and explore possible causes by prespecified subgroup analysis.

We will also inspect forest plots visually for signs of heterogeneity.

Assessment of reporting biases

If we are able to pool more than 10 trials, we will create and examine a funnel plot to explore possible small study biases for the primary outcomes.

Data synthesis

We will undertake meta‐analyses only where this is meaningful, i.e. if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense.

We will use a random‐effects model to analyse primary analysis, as we expect the included studies to be different in participants and surgical procedures.

'Summary of findings' table

We will create a 'Summary of findings' table using the following outcomes:

1. All‐cause mortality;

2. Death due to a cardiac cause;

3. Repeat revascularization;

4. Myocardial infarction;

5. Cerebrovascular accident;

6. Quality of life (QoL);

7. Serious adverse events that result in death, are life‐threatening, require inpatient hospitalisation or prolongation of existing hospitalisation, or result in persistent or significant disability or incapacitation, including infection, acute kidney failure, bleeding.

We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data to each outcome. We will use methods and recommendations described in the Handbook, and use GRADEpro GDT software (GRADEpro GDT; Higgins 2019).

We will justify all decisions to downgrade the quality of the evidence using footnotes, and we will make comments to aid readers' understanding of the review, where necessary.

Two review authors (LZ, PS) will make independent judgments about the quality of the evidence, with disagreements resolved by discussion, or by involving a third review author (LZ). They will justify, document, and incorporate the judgements into the reporting of results for each outcome.

We plan to extract study data, format our comparisons in data tables, and prepare a 'Summary of findings' table before writing the results and conclusions of our review.

Subgroup analysis and investigation of heterogeneity

We plan to carry out the following subgroup analyses.

1. Type of grafts used for coronary artery bypass surgery

   1. total arterial revascularisation

   2. Combined arterial and venous revascularisation

   3. Total venous revascularisation

2. Length of maximum follow‐up time

   1. 12 months or less

   2. More than 12 months

3. Participants with diabetes compared with participants without diabetes

4. Participants with myocardial infarction compared with participants without myocardial infarction

5. Participants with stable angina compared with participants with acute coronary syndrome

6. Participants with one vessel diseases compared with participants with multi‐vessel diseases

7. Age of participants

   1. Age 60 or younger

   2. Age above 60

8. Gender of participants

   1. Female

   2. Male

9. Type of incision when performing the coronary artery bypass surgery

   1. Traditional median sternal incision

   2. Mini‐incision

10. Left ventricular ejection fraction

    1. > 30%

    2. < 30%

We will perform subgroup analysis for any outcome with substantial heterogeneity.

We will use the formal test for subgroup differences in Review Manager 5 (Review Manager 2014), and base our interpretation on this.

Sensitivity analysis

We plan to carry out the following sensitivity analyses, to test whether key methodological factors or decisions have affected the main result.

1. We will include only published trials.

2. We will include only studies published with complete reporting of all primary outcomes.

3. We will include only studies where all participants meet all inclusion criteria.

4. We will include only studies at low risk of bias.

Reaching conclusions

We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice; our implications for research will suggest priorities for future research and outline the remaining uncertainties in the area.

What's new

Date	Event	Description
11 November 2021	New citation required but no major changes	Re‐publication of protocol originally published in June 2020. No changes.

History

Protocol first published: Issue 6, 2020

Appendices

Appendix 1. Preliminary MEDLINE Ovid search strategy

1 Coronary Artery Bypass/

2 cabg.tw.

3 (coronary adj3 bypass*).tw.

4 (aortocoronary adj3 bypass*).tw.

5 1 or 2 or 3 or 4

6 Coronary Artery Disease/

7 Coronary Disease/

8 (coronary adj3 disease*).tw.

9 (multivessel adj2 disease).tw.

10 CAD.tw.

11 LMCAD.tw.

12 (Coronary adj2 atheroscleros*).tw.

13 (Coronary adj2 arterioscleros*).tw.

14 Coronary stenosis/

15 (coronary adj3 stenos*).tw.

16 exp Myocardial Ischemia/

17 (myocard* adj5 (ischaemia or ischemia)).tw.

18 (isch?emic adj disease*).tw.

19 (isch?emi* adj5 heart).tw.

20 IHD.tw.

21 Acute Coronary Syndrome/

22 (acute adj3 coronary adj3 syndrome*).tw.

23 ACS.tw.

24 Heart Diseases/

25 (heart adj3 disease*).tw.

26 Cardiovascular Diseases/

27 CHD.tw.

28 CVD.tw.

29 Acute Coronary Syndrome/

30 (acute adj3 coronary adj3 syndrome*).tw.

31 (myocard* adj5 infarct*).tw.

32 (heart adj5 infarct*).tw.

33 angina.tw.

34 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33

35 5 and 34

36 randomized controlled trial.pt.

37 controlled clinical trial.pt.

38 randomized.ab.

39 placebo.ab.

40 clinical trials as topic.sh.

41 randomly.ab.

42 trial.ti.

43 36 or 37 or 38 or 39 or 40 or 41 or 42

44 exp animals/ not humans.sh.

45 43 not 44

46 35 and 45

Contributions of authors

Long Zuo (LZ): Formulating the review question, drafting the protocol, approving and submitting the final version of the protocol

Xin Yue (XY): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Bian Tao (BT): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Yiqun Cai (YC): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Linning Wang (LW): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Linmiao Zeng (LZ): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Hongmei He (HH): Reviewing and correcting the statistical design in the original version of the protocol, and approving and submitting the final version of the protocol

Licheng Wang (LW): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Adam Ioannou (AI): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Shaoke Li (SL): Reviewing and correcting the original version of the protocol, and approving and submitting the final version of the protocol

Sources of support

Internal sources

• Zhengzhou Seventh People’s Hospital, China

  The office space, library and computers we used in the process of this project are supported by the Zhengzhou Seventh People's Hosptal.

External sources

• NIHR, UK

  This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Heart Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health and Social Care.

Declarations of interest

Long Zuo (LZ): no conflict of interest

Xin Yue (XY): no conflict of interest

Bian Tao (BT): no conflict of interest

Yiqun Cai (YC): no conflict of interest

Linning Wang (LW): no conflict of interest

Linmiao Zeng (LZ): no conflict of interest

Hongmei He (HH): no conflict of interest

Licheng Wang (LW): no conflict of interest

Adam Ioannou (AI): no conflict of interest

Shaoke Li (SL): no conflict of interest

Edited (no change to conclusions)