Author + information
- Received January 23, 2018
- Revision received February 16, 2018
- Accepted February 17, 2018
- Published online May 2, 2018.
- Vincenzo Pasceri, MD, PhDa,b,∗ (, )
- Giuseppe Patti, MDc,
- Francesco Pelliccia, MD, PhDb,
- Carlo Gaudio, MDb,
- Giulio Speciale, MDa,b,
- Roxana Mehran, MDd,e and
- George D. Dangas, MDd,e
- aSan Filippo Neri Hospital, Rome, Italy
- bLa Sapienza University, Rome, Italy
- cCampus Bio-Medico University, Rome, Italy
- dZena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- eCardiovascular Research Foundation, New York, New York
- ↵∗Address for correspondence:
Dr. Vincenzo Pasceri, Emodinamica, San Filippo Neri Hospital, Via G. Martinotti, 20, 00135 Rome, Italy.
Objectives The aim of this study was to compare complete revascularization with a culprit-only strategy in patients presenting with ST-segment elevation myocardial infarction (MI) and multivessel disease by a meta-analysis of randomized trials.
Background Although several trials have compared complete with culprit-only revascularization in ST-segment elevation MI, it remains unclear whether complete revascularization may lead to improvement in hard endpoints (death and MI).
Methods Randomized trials comparing complete revascularization with culprit-only revascularization in patients with ST-segment elevation MI without cardiogenic shock were identified by a systematic search of published research. Random-effects meta-analysis was performed, comparing clinical outcomes in the 2 groups.
Results Eleven trials were identified, including a total of 3,561 patients. Compared with a culprit-only strategy, complete revascularization significantly reduced risk for death or MI (relative risk [RR]: 0.76; 95% confidence interval [CI]: 0.58 to 0.99; p = 0.04). Meta-regression showed that performing complete revascularization at the time of primary percutaneous coronary intervention (PCI) was associated with better outcomes (p = 0.016). The 6 trials performing complete revascularization during primary PCI (immediate revascularization) were associated with a significant reduction in risk for both total mortality (RR: 0.62; 95% CI: 0.39 to 0.97; p = 0.03) and MI (RR: 0.40; 95% CI: 0.25 to 0.66; p < 0.001), whereas the 5 trials performing only staged revascularization did not show any significant benefit in either total mortality (RR: 1.02; 95% CI: 0.65 to 1.62; p = 0.87) or MI (RR: 1.04; 95% CI: 0.48 to 1.68; p = 0.86).
Conclusions When feasible, complete revascularization with PCI can significantly reduce the combined endpoint of death and MI. Complete revascularization performed during primary PCI was also associated with significant reductions in both total mortality and MI, whereas staged revascularization did not improve these outcomes.
- coronary interventions
- multivessel disease
- ST-segment elevation myocardial infarction
Multivessel coronary disease is found in up 40% to 50% of patients with ST-segment elevation myocardial infarction (STEMI) undergoing revascularization by primary percutaneous coronary intervention (PCI) and is associated with worse clinical outcomes and increased mortality (1–3). Although observational studies have reported conflicting results (4), most recent randomized trials have reported that complete revascularization during the acute phase may have significant beneficial effects (5). However, clinical trials were small (from 69 to 885 patients) and undersized for major clinical endpoints, and most trials have reported significant reductions only in major adverse cardiac events (MACE) (driven largely by reduced need for new revascularizations) (5–10), but no significant reduction in death or myocardial infarction (MI) (5,6,8–10), whereas others did not even report significant reductions in MACE (11–15). Trials have also used different strategies, either immediate revascularization during primary PCI or staged revascularization, and it is unclear whether these different approaches may influence trial results.
Thus, the aims of the present study were to assess whether complete revascularization can reduce total mortality and MI by performing a comprehensive meta-analysis including the most recent trials and to determine the possible role of the timing of complete revascularization in explaining differences in trial results.
This analysis was planned in accordance with current guidelines for systematic reviews and meta-analyses with regression, in particular the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (16). The review protocol was registered at the PROSPERO international prospective register of systematic reviews (Centre for Reviews and Dissemination, University of York, registration number CRD42017076726).
We searched PubMed, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials using the terms “coronary angioplasty” or “coronary intervention” and “myocardial infarction” and “multivessel” (or “multi-vessel”). A thorough search through the reference lists of published trials, meta-analysis, and reviews was also performed, including studies presented at major cardiovascular scientific sessions.
Eligible trials had to fulfil the following criteria: 1) randomized controlled trials comparing complete versus culprit-only revascularization in patients with STEMI without cardiogenic shock admitted within 24 h of symptom onset; 2) complete revascularization performed within 30 days of admission in the majority of patients in the complete group; and 3) main outcomes of interest (including mortality, MI, and revascularization) reported. Trials not including culprit-only control groups were not included.
Two reviewers independently assessed trials for eligibility on the basis of the aforementioned inclusion criteria (G.S. and G.P.). Disagreement was resolved by consensus with third-party adjudication.
Data were extracted to standard spreadsheets by the 2 reviewers (V.P. and F.P.) and included date of trial publication; years of enrollment; whether single center or multicenter; duration of follow-up; randomization protocol (including time of randomization, before or after primary PCI); definitions of endpoints used in each study; demographics; prevalence of diabetes, previous MI, 3-vessel disease, and anterior STEMI; mean ejection fraction before discharge; Killip class; duration of the index procedure and volume of contrast used; use of glycoprotein IIb/IIIa inhibitors; use of drug-eluting stents; prevalence of complete revascularization performed during the index procedure and the median or average timing of complete revascularization when performed after STEMI; the method used to assess the severity of nonculprit significant stenosis; and clinical outcomes (including MACE, total death, MI, revascularization, stent thrombosis, contrast-induced nephropathy [CIN], and major bleeding). For diagnosis of MI, a definition using an increase of creatine kinase or creatine kinase–MB >3 times the upper limit of normal was used whenever possible.
Bias risk was determined according to the Cochrane Collaboration’s “risk of bias” tool. Trials with low risk for bias in at least 4 components were classified as having low risk for bias. Bias risk was assessed by 2 reviewers (G.S. and G.P.) independently from data extraction.
The main endpoints for our analysis were: 1) the combined outcome of total death and MI; and 2) the individual endpoints of death and MI. Secondary safety outcomes included stent thrombosis, major bleeding, and CIN, as defined by the original trials. The effect of timing of complete revascularization on trial outcomes was also assessed with a pre-specified subgroup analysis dividing trials into 2 groups: trials with >50% complete revascularization during the index procedure (immediate group) and those in which complete revascularization was performed 1 to 30 days later in ≥50% of cases (staged group). Another pre-specified subgroup analysis was performed according to the method used for assessing nonculprit coronary stenosis (angiography or fractional flow reserve [FFR]).
Statistical analyses were performed using R version 3.4.0 (R Foundation for Statistical Computing, Vienna, Austria) using the Metafor Package (17). For dichotomous variables, pooled statistics were calculated as weighted relative risks (RRs) with 95% confidence intervals (CIs) using the random-effects DerSimonian and Laird model (18).
We tested heterogeneity of the included studies with Q statistics and the extent of inconsistency between results using I2 statistics (significant heterogeneity was considered present for p values <0.10 and/or I2 values >50%). Random-effects meta-regression analysis was performed to measure the impact of baseline characteristics on the effect size for the major outcome (death or MI). Specifically, we performed an analysis for the following outcomes: age, male sex, diabetes mellitus, ejection fraction, and year of publication of the study. The possible association between completing revascularization during the index procedure and the effect size was also assessed by meta-regression (19).
Sensitivity analysis included a subgroup analysis of trials including only trials with low risk for bias according to the Cochrane Collaboration’s tool, using a leave-one-out analysis to assess whether the pooled results were influenced by a single trial, by excluding trials with <100 patients per group, and by excluding trials published before 2010. Presence of publication bias was estimated using Rucker’s test (with arcsine transformation), which is best suited for binary outcomes and funnel plot graph. Statistical significance was set at p < 0.05 (2-tailed).
In total, 2,843 studies were identified, and 427 abstracts were screened. Eleven randomized trials enrolling 3,561 patients met the inclusion criteria and were included in the analysis (5–15); 1,660 patients were randomized to complete revascularization and 1,901 to culprit-only revascularization. Nine trials were identified through PubMed search (5–12,14) and 2 by analysis of presentations at major cardiology meetings (13,15). One trial was presented only as an abstract (13), and 2 were published in languages other than English (14,15). Figure 1 outlines the results of the search strategy. One trial was excluded because it did not include patients with STEMI (20) and 1 small trial because it included only a comparison between immediate and staged revascularization, without a culprit-only comparison group (21). A study by Politi et al. (6) had 3 randomized arms: immediate complete revascularization, culprit-only revascularization, and staged complete revascularization performed an average of 60 days after the first procedure; according to our inclusion criteria, only the first 2 arms were included.
Tables 1 and 2⇓⇓ describe main features of the included studies. Common exclusion criteria were cardiogenic shock, left main coronary artery disease, and presence of chronic total occlusion. Nine trials were performed in Europe, 1 in China, and 1 in Egypt.
Weighted analysis across all studies showed that baseline characteristics were similar between complete and culprit-only groups for the following variables: age, sex, ejection fraction, previous MI, anterior STEMI, use of glycoprotein IIb/IIIa inhibitors, prevalence of 3-vessel coronary disease, Killip class, and use of drug-eluting stents (Table 3), although there was a trend toward lower prevalence of diabetes in the complete revascularization group. Duration of the index procedure and volume of contrast used were reported by 5 trials (5,7,8,9,11), and as expected, the index procedure was longer (mean difference 17.6 min; 95% CI: 7.9 to 27.5 min; p = 0.00004) and more contrast was used (mean difference 76 ml; 95% CI: 35 to 117 ml; p = 0.0003) in patients with complete versus culprit-only revascularization (Table 3).
Definitions of endpoints and randomization protocol in each trial are summarized in Online Tables 1 and 2.
Same-setting (immediate) complete revascularization was used in 6 trials: 3 trials had mandatory immediate revascularization (100% of cases, no exceptions reported) (6,7,11), and 3 had same-setting PCI by protocol, but early staged revascularization was allowed (58% to 83% of patients had immediate revascularization) (5,8,10); the remaining 5 trials used an early staged revascularization strategy (average delay from 2 days in DANAMI [Danish Multicenter Randomized Study on Fibrinolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction] to 20 days in PRAGUE-13 [Multivessel Disease Diagnosed at the Time of PPCI for STEMI: Complete Revascularization Versus Conservative Strategy], with a weighted average delay of 7.1 days) (9,12–15). Average follow-up was 20.1 months.
Compared with culprit-only revascularization, complete revascularization significantly reduced the risk for death and MI (RR: 0.76; 95% CI: 0.58 to 0.99; p = 0.04) (Figure 2). Only 1 trial (7) reported a significant reduction in this endpoint, whereas 5 trials showed a nonsignificant trend in reduction of events (5,6,8,10,12), with modest heterogeneity of the results (I2 = 13%, p = 0.32). However, the 6 trials performing immediate complete revascularization had significant reductions in risk for death or MI (RR: 0.53; 95% CI: 0.38 to 0.74; p = 0.0002; no evidence of heterogeneity: p = 0.96, I2 = 0%), whereas the 5 trials performing staged revascularization did not report any beneficial effect (RR: 1.06; 95% CI: 0.78 to 1.45; p = 0.71; no evidence of heterogeneity: p = 0.58, I2 = 0%) (Figure 2).
There was a trend toward a reduction in all-cause mortality with complete revascularization (RR: 0.79; 95% CI: 0.56 to 1.09; p = 0.16) and no evidence of heterogeneity among trials (I2 = 0%, p = 0.75) (Figure 3). Trials performing complete revascularization during primary PCI had a significant reduction in total mortality (RR: 0.62; 95% CI: 0.39 to 0.97; p = 0.03; no evidence of heterogeneity of the results: p = 0.87, I2 = 0%), whereas trials performing staged revascularization did not report any beneficial effect (RR: 1.02; 95% CI: 0.65 to 1.62; p = 0.87; no signs of heterogeneity: p = 0.67, I2 = 0%) (Figure 3).
There was a reduction in the risk for MI with complete revascularization (RR: 0.69; 95% CI: 0.48 to 0.99; p = 0.048) (Figure 4), with moderate heterogeneity among trials (I2 = 14%, p = 0.31) (Figure 4). Again, trials performing complete revascularization during primary PCI had a significant reduction in the risk for MI (RR: 0.40; 95% CI: 0.25 to 0.66; p < 0.001; no evidence of heterogeneity: p = 0.99, I2 = 0%), whereas trials performing staged revascularization did not report any beneficial effect (RR: 1.04; 95% CI: 0.68 to 1.58; p = 0.86; no evidence of heterogeneity: p = 0.56, I2 = 0%).
Unplanned revascularization was significantly reduced by complete revascularization (RR: 0.39; 95% CI: 0.32 to 0.47; p < 0.0001; no evidence of heterogeneity of the results: p = 0.80, I2 = 0%). Trials using immediate revascularization (RR: 0.36; 95% CI: 0.27 to 0.48; p < 0.0001) and those using a staged strategy (RR: 0.42; 95% CI: 0.31 to 0.56; p < 0.001) had similar results (Online Figure 1).
Incidence of CIN was reported by 5 trials (6–10). The overall incidence of CIN was very low (1.7% vs. 1.8%), with no difference between complete and culprit-only groups (RR: 0.84; 95% CI: 0.39 to 1.81; p = 0.66) (Online Figure 2).
The incidence of major bleeding was reported by 6 trials (5,7–10,12) and was very low in both groups (1.3% vs. 1.8% in the complete vs. culprit-only group; RR: 0.82; 95% CI: 0.44 to 1.56; p = 0.55; no heterogeneity of the results: p = 0.69, I2 = 0%); the 4 trials performing immediate revascularization (RR: 0.82) and the 2 trials performing staged revascularization (RR: 0.80) reported similar results (Online Figure 2). Definitions of CIN and major bleeding used in each trial are shown in Online Table 3.
Stent thrombosis was reported by only 3 trials (5,8,12), with a total of only 10 events, so analysis for this endpoint was not feasible. Data on radial versus femoral approach were not available in any trial.
Meta-regression and other subanalysis
Meta-regression showed that age (p = 0.18), sex (p = 0.33), diabetes mellitus (p = 0.72), ejection fraction (p = 0.58), use of drug-eluting stents (p = 0.94), prevalence of 3-vessel disease (p = 0.55), and year of publication of the study (p = 0.34) were not associated with trial results. Data on chest pain duration were available from only 5 trials, insufficient for meta-regression analysis. Prevalence of complete revascularization during primary PCI was significantly associated with death or MI (p = 0.016) (Figure 5), with trials with a higher prevalence of complete revascularization during the index procedure reporting better outcomes. Meta-regression also showed that the average time delay (from 0 to 20 days) for performing complete revascularization was significantly associated with trial results, with earlier complete revascularization associated reduced risk for death or MI (p = 0.025) (Figure 5).
Eight trials used only angiography to define the significance of nonculprit coronary stenosis (6–8,10,11,13–15), whereas 3 trials also used a functional assessment of nonculprit lesions using FFR (5,9,12). Trials using angiography had a significant risk reduction in risk for death or MI (RR: 0.70; 95% CI: 0.52 to 0.96; p = 0.03), whereas trials using FFR had a nonsignificant trend for risk reduction (RR: 0.90; 95% CI: 0.47 to 1.70; p = 0.70) (Online Figure 3).
Including only the 7 studies (5,7–10,12,14) with low risk for bias did not change the results of the meta-analysis (for death or MI, RR: 0.71; 95% CI: 0.51 to 0.98; p = 0.04) (Online Figure 4, Online Table 4). Also, a leave-one-out analysis showed that the pooled results were not influenced by a single trial, not even the larger COMPARE-ACUTE (Comparison Between FFR Guided Revascularization Versus Conventional Strategy in Acute STEMI Patients With MVD) (Online Figure 5). Excluding studies with <100 patients per group, studies with longer follow-up, and studies published before 2010 also did not change results of the meta-analysis. Rucker’s test did not suggest publication bias (p = 0.41 for death or MI). Examination of the funnel plot also did not reveal a significant risk for publication bias for any of the clinical outcomes (Online Figure 6).
This meta-analysis of studies comparing complete with culprit-only revascularization for patients with STEMI and multivessel disease provides a comprehensive aggregate analysis of the available randomized trials to date. Complete revascularization significantly reduced the risk for death or MI; trials performing complete revascularization during primary PCI also showed a significant benefit for both total mortality and MI, whereas those using a staged revascularization strategy did not show any benefit on these outcomes.
Early observational studies did not show signs of benefit from complete revascularization in patients with STEMI; actually, complete revascularization was associated with increased risk (4). Thus, routine complete revascularization in STEMI was contraindicated in both American College of Cardiology/American Heart Association and European Society of Cardiology guidelines (with the exception of patients with symptoms or ongoing ischemia). Results of recent randomized trials have changed these indications, with several trials showing a significant reduction of MACE and no trial showing an increase in adverse events; accordingly, the 2012 European Society of Cardiology guidelines allowed complete revascularization as a Class IIb indication, and the current 2017 guidelines give this strategy a Class IIa indication (22), whereas the American College of Cardiology/American Heart Association guidelines have moved from Class III (2012) to Class IIb (2015) (3). Selection bias is likely to be the main reason for the different results of observational studies compared with randomized trials, because in everyday practice, clinicians are more disposed to perform complete revascularization in higher risk patients (23). Although several trials were able to find a significant reduction in the composite endpoint of MACE (using different definitions, but always including new revascularizations), all trials were largely undersized for mortality and MI as endpoints. The knowledge that patients treated with a culprit-only strategy have significant coronary stenosis left untreated may by itself trigger indication for new revascularizations, whereas the preventive treatment of significant coronary stenosis in the acute phase should predictably reduce the need for further revascularization (24). For these reasons, it is important to focus on total mortality, the only endpoint that cannot be influenced by bias or different definitions (24).
Even the most recent meta-analyses did not show a reduction in death or MI, but only in MACE (25–27), possibly because they did not include more recent trials, in particular the recent large COMPARE-ACUTE trial (25–27), or included both randomized trials and observational studies (25). More important, recent meta-analyses have not focused on the different results of trials performing immediate versus staged complete revascularization, which was the main source of heterogeneity in trial results (whereas differences in age, use of FFR, glycoprotein IIb/IIIa inhibitors, and diabetes were not associated with outcomes). As a consequence, this is the first meta-analysis to show that immediate complete revascularization is associated with significant reductions in both total mortality and MI. Interestingly, an earlier meta-analysis including only trials using an immediate revascularization strategy showed a benefit for death or MI (28), showing how results of meta-analyses are influenced by the types of trials included and how, by putting together trials with different designs, it is possible to dilute evidence of benefit.
The present analysis may seem at variance with the recent CULPRIT-SHOCK (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock) trial, which found increased total mortality (mostly noncardiac) in patients with cardiogenic shock and acute MI (62% STEMI and 38% non–STEMI) treated with immediate complete revascularization (29). It is important to note that patients with high-risk features, including cardiogenic shock and left main coronary artery disease, were excluded by trials on complete revascularization in STEMI. In the CULPRIT-SHOCK trial, revascularization of chronic total occlusion was attempted in the acute phase in 24% of patients in cardiogenic shock, whereas attempting chronic total occlusion PCI in the acute or staged phase was banned in other trials of complete revascularization in STEMI. Indeed, all trials included patients with multivessel disease, which was judged feasible for complete revascularization by the operator. This is an important point when trying to extrapolate results of these trials into clinical practice.
Clinical trials tend to include lower risk patients who may be different from those patients presenting in everyday clinical practice. Patients included in the present analysis had low-risk features, with only 6.5% of patients with a Killip class ≥II, good average ejection fraction, and average mortality <5%. Thus, data from these trials cannot directly extrapolated into sicker patients (in particular patients with Killip class ≥II at presentation, lower ejection fraction, or other higher risk features) and in particular to patients with cardiogenic shock (29).
Current guidelines either support (Class IIa indication in European Society of Cardiology guidelines) (22) or allow (Class IIb in American Heart Association/American College of Cardiology guidelines) (3) complete revascularization before hospital discharge, without supporting either an immediate or a staged strategy. However, our data show that the evidence supporting complete revascularization comes only from trials using an immediate complete revascularization strategy, which is not associated with increased risk and may significantly reduce total mortality and MI. Accordingly, a strategy of complete revascularization in the same setting should be considered when technically feasible: for instance, a patient with inferior STEMI and a tight stenosis in the proximal left anterior descending coronary artery is likely to benefit most from immediate complete revascularization. Conversely, patients with complex bifurcations or calcified lesions may be treated with staged revascularization. Meta-regression analysis (Figure 5) suggests that trials showing significant benefit performed immediate revascularization in more than 50% of cases or early staged revascularization <5 days after STEMI; thus, it is possible that trials using very early staged revascularization may still provide significant benefit compared with culprit-only strategy, whereas a late staged revascularization strategy does not seem to be associated with clinical benefits.
We found only 2 small trials (6,21) (including only 224 patients) that directly compared immediate versus staged revascularization in the setting of STEMI, so it is not possible yet to directly compare these 2 strategies from randomized data.
The mechanisms by which early complete revascularization may improve prognosis and reduce hard events in patients with multivessel disease are probably related to the pathophysiology of coronary disease. In STEMI the risk for adverse events (in particular death and MI) is higher in the first days and weeks and then decreases after the first month, and early mortality is significantly higher in patients with multivessel disease (1,2). Achieving complete revascularization as soon as possible may help reduce the risk for death and MI when this risk is higher (i.e., in the early phase of acute MI). Several studies have also shown that multiple unstable plaques are common in patients with STEMI. Complex coronary plaques on angiography were found in up to 39% of patients presenting with STEMI and were associated with increased risk for acute coronary events during follow-up (30). More recent studies have found plaque ruptures in nonculprit lesions in 17% of patients using intravascular ultrasound (31) and in up to 38% of patients using optical coherence tomography (32). Early treatment of high-risk coronary plaques might contribute to explain the reduction in death and MI observed with an immediate complete revascularization strategy.
Ongoing, larger randomized trials will compare complete revascularization (either early staged as in the COMPLETE [Complete vs Culprit-only Revascularization to Treat Multi-vessel Disease After Primary PCI for STEMI] trial of 3,900 patients or both immediate and staged FFR guided as in the FULL REVASC [FFR-Guidance for Complete Non-Culprit Revascularization] trial of 4,000 patients) with a culprit-only strategy and will provide important data on the best strategy to be used in a larger unselected population; interestingly both trials allow only either immediate or early staged revascularization protocol (within 72 h for COMPLETE and during the index admission for FULL REVASC), which, according to our analysis, are likely to provide beneficial effects.
Our meta-analysis shows that in patients with STEMI and multivessel disease, complete revascularization in the same setting of primary PCI is associated with significant reductions in both total mortality and MI. When feasible, complete immediate revascularization should be considered in patients with STEMI and multivessel disease.
WHAT IS KNOWN? Patients with STEMI treated with primary PCI frequently have significant multivessel coronary disease. These patients can be treated with complete revascularization (either immediate or staged) or with a culprit-only strategy (with revascularization limited to the culprit artery). The best interventional treatment for these patients is still unclear.
WHAT IS NEW? Our meta-analysis of clinical trials shows that complete revascularization at the time of primary PCI significantly reduces both total death and MI during follow-up; conversely trials performing complete staged revascularization did not show significant reduction in death or MI.
WHAT IS NEXT? Appropriate timing of complete revascularization (during primary PCI or staged) and the methods to be used for determining significance of nonculprit lesions should be addressed in appropriately designed and sized randomized trials.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- contrast-induced nephropathy
- fractional flow reserve
- major adverse cardiac event(s)
- myocardial infarction
- percutaneous coronary intervention
- relative risk
- ST-segment elevation myocardial infarction
- Received January 23, 2018.
- Revision received February 16, 2018.
- Accepted February 17, 2018.
- 2018 American College of Cardiology Foundation
- Levine G.N.,
- Bates E.R.,
- Blankenship J.C.,
- et al.
- Vlaar P.J.,
- Mahmoud K.D.,
- Holmes D.R. Jr..,
- et al.
- Smits P.C.,
- Abdel-Wahab M.,
- Neumann F.J.,
- et al.
- Politi L.,
- Sgura F.,
- Rossi R.,
- et al.
- Gershlick A.H.,
- Khan J.N.,
- Kelly D.J.,
- et al.
- Engstrom T.,
- Kelbaek H.,
- Helqvist S.,
- et al.
- Hamza M.,
- Mahmoud A.N.,
- Elgendy I.Y.
- Estevez Loureiro R.,
- Calvino-Santos R.,
- Peteiro J.,
- Bouzas-Mosquera A.,
- Salgado-Fernandez J.,
- Soler-Martin M.R.
- Zhang J.,
- Wang Q.,
- Yang H.,
- et al.
- Hlinomaz O.,
- Grouch L.,
- Polokova L.,
- et al.
- Shamseer L.,
- Moher D.,
- Clarke M.,
- et al.
- Viechtbauer W.
- Ibanez B.,
- James S.,
- Agewall S.,
- et al.
- Ahmad Y.,
- Cook C.,
- Shun-Shin M.,
- et al.
- Køber L.
- Tarantini G.,
- D’Amico G.,
- Brener S.J.,
- et al.
- Elgendy I.Y.,
- Mahmoud A.N.,
- Kumbhani D.J.,
- Bhatt D.L.,
- Bavry A.A.
- Bangalore S.,
- Toklu B.,
- Wetterslev J.
- El-Hayek G.E.,
- Gershlick A.H.,
- Hong M.K.,
- et al.
- Thiele H.,
- Akin I.,
- Sandri M.,
- et al.
- Hong M.K.,
- Mintz G.S.,
- Lee C.W.,
- et al.