Types of studies

We will include only randomized controlled trials comparing early invasive versus conservative treatment strategy for non‐IRA lesions in people with STEMI with multi‐vessel disease. We will include studies reported as full‐text, those published as abstract and unpublished data.

Types of participants

We will include adults aged 18 years and above, who underwent P‐PCI for management of STEMI, with concurrent non‐IRA significant lesions (as defined by the authors of the trial), identified at the time of the index procedure.

Types of interventions

People presenting with STEMI initially treated with a P‐PCI and coronary angiography to assess the extent of coronary vessel obstruction in the various branches of the coronary tree. We will identify the IRA and non‐IRA based on correlation with patient symptoms and dynamic changes on electrocardiograms. Following initial treatment of IRA lesion, participants randomized to either early invasive or conservative (medical) treatment. We will compare the following two treatment strategies:

1. early invasive strategy: involving revascularization of the clinically significant stenosed non‐IRA lesion(s) (at least 50% obstruction but less than 100%) at the index procedure or in a second intervention before discharge. This will be carried out in all eligible participants unless they had a contraindication;

2. conservative management: involving no invasive approach but rather medical management on all eligible participants with evidence of non‐IRA disease diagnosed at the time of P‐PCI, unless participant had clinical symptoms that warrant further testing and intervention (e.g. new onset chest pain, dynamic changes on electrocardiogram or a positive stress test).

Types of outcome measures

Electronic searches

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

1. Cochrane Central Register of Controlled Trials (Wiley);

2. MEDLINE (Ovid);

3. EMBASE (www.embase.com);

4. Database of Abstracts of Reviews of Effects (DARE; The Cochrane Library ‐ Wiley);

5. Health Technology Assessment Database (The Cochrane Library ‐ Wiley);

6. Conference Proceedings Citation Index (Web of Science).

We will apply the Cochrane sensitivity‐maximizing RCT filter (Lefebvre 2011) to MEDLINE (Ovid). For EMBASE, we will use the multi‐term EMBASE filter with the best balance of sensitivity and specificity (Wong 2006) translated from Ovid to embase.com syntax. For Conference Proceedings Citation Index (Web of Science), we will use a combination of keywords to try to limit retrieval to RCTs.

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

If we detect additional relevant key words during any of the electronic or other searches, we will modify the electronic search strategies to incorporate these terms and document the changes.

Searching other resources

In order to identify articles potentially missed through the electronic searches, we will:

1. handsearch reference lists of all included studies and of relevant reviews retrieved by electronic searching to identify other potentially eligible trials or ancillary publications;

2. conduct a search for other systematic reviews and Health Technology Assessment reports in Epistemonikos (www.epistemonikos.org). We will note the list of reviews and Health Technology Assessment reports screened as an appendix.

3. handsearch conference proceedings for the last five years from the following events: World Congress of Cardiology, European Society of Cardiology (ESC) Congress, ACC Annual Scientific Sessions, AHA Annual Scientific Sessions and Transcatheter Cardiovascular Therapeutics Abstracts;

4. if necessary, contact corresponding authors of included studies, local and foreign experts in the field, and pharmaceutical companies representatives that market coronary stents (e.g. Boston Scientific Corporation, Medtronic, Inc, Abbott Laboratories) for any additional published or unpublished data;

5. attempt to contact the authors of trials when information in the study report is either lacking or unclear.

We will also search the following trial registers:

1. ClinicalTrials.gov (www.clinicaltrials.gov/);

2. Current Controlled Trials MetaRegister (www.controlled‐trials.com/mrct/);

3. European (EU) Clinical Trials Register (www.clinicaltrialsregister.eu/);

4. WHO International Clinical Trials Registry Platform (apps.who.int/trialsearch/).

Selection of studies

Two review authors (SH and CB) will independently screen titles and abstracts for inclusion of all the potential studies that we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. If there are any disagreements, we will ask a third review author to arbitrate (JB or RP). We will retrieve the full‐text study reports/publication and two review authors (SH and CB) will independently screen the full‐text and 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 review author (JB or RP). 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 that will be piloted on at least one study in the review. One review author (SH and CB) will extract study characteristics from included studies. We will extract the following study characteristics.

1. Methods: study design, total duration of study, details of any 'run in' period, number of study centres and location, study setting, withdrawals and date of study.

2. Participants: number, mean age, age range, gender, severity of condition, diagnostic criteria, 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 (CB and RP) will independently extract outcome data from included studies. We will resolve disagreements by consensus or by involving a third review author (SH). One review author (CB) will transfer data into the Review Manager 5 (RevMan 2014). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (SH) will spot‐check study characteristics for accuracy against the trial report.

Assessment of risk of bias in included studies

Two review authors (SH and CB) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving a third review author (RP). We will assess the risk of bias according to the following domains (Wood 2008).

1. Random sequence generation.

2. Allocation concealment.

3. Blinding of participants and personnel.

4. Blinding of outcome assessment.

5. Incomplete outcome data.

6. Selective outcome reporting.

7. Other bias (e.g. industry funding).

We will grade each potential source of bias as high, low or unclear and provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We will summarize the risk of bias judgements across different studies for each of the domains listed. Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.

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

Measures of treatment effect

We will analyse dichotomous data as odds ratios or risk ratios with 95% confidence intervals and continuous data as mean difference or standardized mean difference with 95% confidence intervals. We will enter data presented as a scale with a consistent direction of effect.

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

Unit of analysis issues

We will take into account the level at which randomization occurred, such as multiple observations for the same outcome. Considering the nature of the intervention, it is unlikely that we will find cross‐over trials or cluster randomized trials. If these are found, we will take unit of analysis into account.

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 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 using a sensitivity analysis. 

Assessment of heterogeneity

We will examine heterogeneity using the I² statistic, which quantifies inconsistency across studies to assess the impact of heterogeneity on the meta‐analysis, where an I² statistic of 50% or more indicates a considerable level of inconsistency.

If we identify substantial heterogeneity, we will report it and explore possible causes by pre‐specified subgroup analysis and perform the analysis using a random‐effects model. In the event of substantial clinical, methodological or statistical heterogeneity, we will not report study results as meta‐analytically pooled effect estimates.

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

If there is evidence for homogeneous effects across studies, we will analyze the data using risk ratios and summarize all data using a fixed‐effect model (Riley 2011;Wood 2008). We will interpret fixed‐effect meta‐analyses with due consideration of the whole distribution of effects, ideally by presenting a prediction interval (Higgins 2011). In addition, we will perform statistical analyses according to the statistical guidelines contained in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Subgroup analysis and investigation of heterogeneity

We will carry out the following subgroup analyses and plan to investigate interaction.

1. Drug eluting stent versus bare metal stents.

2. Gender.

3. People with diabetes mellitus versus people without diabetes mellitus.

4. Non‐IRA and IRA intervention during the same procedure versus in separated intervention (staged).

5. Low risk of bias articles versus high risk of bias articles.

6. Participants on cardiogenic shock versus participants not on cardiogenic shock.

We will use the following outcomes in subgroup analyses.

1. Long term cardiovascular mortality: defined as death from cardiovascular cause at one year or greater after the intervention.

2. Long term non‐fatal myocardial infarction: spontaneous myocardial infarction measured at one year or greater after the intervention.

We will use the formal test for subgroup interactions in Review Manager 5 (RevMan 2014).

Sensitivity analysis

We will perform sensitivity analyses in order to explore the influence of the following factors on effect sizes.

1. Restricting the analysis to published studies.

2. Restricting the analysis by taking into low versus high risk of bias, as specified in Assessment of risk of bias in included studies.

3. Restricting the analysis to studies using the following filters: language of publication, source of funding (industry versus other) and country.