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Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NYSection of Cardiac Surgery, Yale University School of Medicine, New Haven, Conn
The evidence supporting the use of the Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) score for risk stratification is controversial. We performed a systematic review and meta-analysis of all the randomized controlled trials comparing percutaneous coronary intervention versus coronary artery bypass grafting that reported their outcomes stratified by SYNTAX score, focusing on between-strata comparisons.
Methods
A systematic review of MEDLINE, EMBASE, Cochrane Library databases was performed. Incidence rate ratios were pooled with a random effect model. Between-group statistical heterogeneity according to accepted SYNTAX score tertiles was computed in the main analysis. Ratios of incidence rate ratios were computed to appraise between-strata effect, as sensitivity analysis. Primary and secondary outcomes were major adverse cardiac and cerebrovascular events and all-cause mortality, respectively. Separate sub-analyses were performed for left main and multivessel disease.
Results
From 425 citations, 6 trials were eventually included (8269 patients [4134 percutaneous coronary interventions, 4135 coronary artery bypass graftings]; mean follow-up: 6.2 years [range: 3.8-10]). Overall, percutaneous coronary intervention was associated with a significant increase in major adverse cardiac and cerebrovascular events (incidence rate ratio, 1.39, 95% confidence interval, 1.27-1.51) and nonsignificant increase in all-cause mortality (incidence rate ratio, 1.17, 95% confidence interval, 0.98-1.40). There was no significant statistical heterogeneity of treatment effect by SYNTAX score for major adverse cardiac and cerebrovascular events or mortality (P = .40 and P = .34, respectively). Results were consistent also for patients with left main and multivessel disease (major adverse cardiac and cerebrovascular events: P = .85 in left main, P = .78 in multivessel disease 0.78; mortality: P = .12 in left main; P = .34 in multivessel disease). Results of analysis based on ratios of incidence rate ratios were consistent with the main analysis.
Conclusions
No significant association was found between SYNTAX score and the comparative effectiveness of percutaneous coronary intervention and coronary artery bypass grafting. These findings have implications for clinical practice, future guidelines, and the design of percutaneous coronary intervention versus coronary artery bypass grafting trials.
Our findings have implications for clinical practice, as well as future guidelines and the design of trials comparing PCI and CABG. The use of the SYNTAX score as the primary approach to stratify patients with coronary artery disease and to identify the most appropriate revascularization method in the individual patient is not explicitly supported by the current analysis.
See Commentaries on pages 1414 and 1415.
The Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) score was initially described in the eponymous study to grade the angiographic complexity of coronary artery disease and obtain objective data to guide the choice of the revascularization technique.
In their original publication, the SYNTAX authors clearly highlighted the fact that stratification of outcomes based on the SYNTAX score was a post hoc unadjusted analysis that had to be considered hypothesis generating, especially in light of inclusion of some features (eg, chronic total occlusion, trifurcation) which may impact percutaneous coronary interventions (PCIs), but not coronary artery bypass grafting (CABG), safety and efficacy. In the following years, several trials performed similar post hoc analyses, but no formal validation of the score as a determinant of the revascularization strategy in patients with coronary artery disease was published.
Despite this lack of solid supporting evidence, the stratification of patients by SYNTAX score has become standard practice and the current myocardial revascularization guidelines are largely based on this approach, explicitly recommending to consider PCI in patients with lower SYNTAX scores.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
We hypothesized that there is no significant correlation between the SYNTAX score and the comparative effectiveness of PCI and CABG. Most explicitly, we hypothesized that the overall benefit of CABG versus PCI does not vary substantially in patients with different SYNTAX scores. Thus, we performed a systematic review and meta-analysis of all the randomized controlled trials (RCTs) comparing PCI versus CABG that reported their outcomes stratified by SYNTAX score, focusing on groups of patients belonging to different SYNTAX score tertiles.
Materials and Methods
The Institutional Review Board did not approve this study due to the lack of individual patients' information. Patient written consent for the publication of the study was not received due to the lack of individual patients' information.
Search Strategy
A medical librarian performed comprehensive searches to identify all randomized controlled trials comparing PCI versus CABG. Searches were run on November 24, 2019 in the following databases: Ovid MEDLINE (1946 to present); Ovid EMBASE (1974 to present); and The Cochrane Library (Wiley). The full search strategy for Ovid MEDLINE is available in Table E1.
Study Selection and Data Extraction
Trials were considered for inclusion if they compared PCI with drug-eluting or bare-metal stents with CABG for the treatment of coronary artery disease and reported outcomes stratified by low (≤22), intermediate (23-32), and high (≥33) SYNTAX scores. PCI trials involving balloon angioplasty were excluded. For each included trial, the publication with the longest follow-up duration for each outcome was selected. Animal studies, case reports, conference presentations, editorials, expert opinions, and observational studies were excluded.
Full text was pulled for the selected studies for a second round of eligibility screening. Reference lists of articles were also searched to identify other relevant trials. The full Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
outlining the study selection process is available in Figure E1. Two investigators performed data extraction independently, and the extracted data were verified by a third investigator for accuracy. All articles were reviewed and analyzed for data by 2 independent investigators and disagreements were resolved by a third author.
The following variables were extracted: trial data (number of enrolling centers, location, study period, number of patients randomized, and mean follow-up), major adverse cardiac and cerebrovascular events (MACCE) definition, patient demographics (age, sex, body mass index, New York Heart Association Class, European System for Cardiac Operative Risk Evaluation, SYNTAX score, comorbidities/past treatment [diabetes, insulin therapy, statin therapy, smoking, hypertension, hypercholesterolemia/hyperlipidemia, peripheral vascular disease, carotid artery disease, stroke, myocardial infarction, heart failure, previous PCI/CABG, stable/unstable angina pectoris, acute coronary syndrome]), procedure-related factors (number of stents, type of stent, total stent length, stent diameter, left main bifurcation stent technique, intravascular ultrasound, use of left or bilateral internal mammary arteries, off-pump CABG, number of arterial and venous grafts, use of epi-aortic or transesophageal ultrasound, and completeness of revascularization), details of medical therapy, details of SYNTAX score assessment in the included trials, inclusion and exclusion criteria, all-cause and cause-specific mortality in the CABG and PCI arm. The quality of the included studies was assessed using the Cochrane Collaboration's tool for assessing Risk of Bias Version 2 in randomized trials.
The primary outcome was the composite end point of MACCE as defined in the individual trials. The secondary outcome was all-cause mortality.
Statistical Analyses
We first computed incidence rate ratios (IRRs) as an estimator of hazard ratios according to established methods by extracting data on event count and person-time at risk per each treatment (Figures E2 and E3).
IRR were then pooled with a random-effects model using inverse variance weighting, whereby each study estimate of the relative treatment is given a weight that is equal to the inverse of the variance of the effect estimate.
Overall and subgroup effect estimates were generated, dividing the patient populations according to accepted SYNTAX tertiles. Separate sub-analyses were performed for trials on left main disease and multi-vessel disease patients. Between-strata statistical heterogeneity was appraised using established methods.
In addition, as sensitivity analysis, we used ratios of IRR according to Bland–Altman (ie, ratio of the stratum-specific effects); this methodology allows the generation of interaction effect estimates to compare subgroups of interest, thus enabling the comparison of high versus intermediate, high versus low, and intermediate versus low SYNTAX score groups.
Statistical significance was set at the 2-tailed 0.05 level for hypothesis testing, and at the 2-tailed 0.10 level for heterogeneity testing. Computations were performed with the “metafor” and “meta” packages
Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial.
Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial.
Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.
Two trials involved centers located in different continents (Evaluation of XIENCE vs Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization,
Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial.
Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.
Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial.
Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial.
Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.
BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery.
Details on the number of events, number of patients at risk, and follow up duration stratified according to the SYNTAX score groups in the included trials for the primary and secondary outcome are reported in Table 2.
Table 2Number of events, number of patients at risk, and follow up duration stratified according to the SYNTAX score groups in the included trials for the primary and secondary outcomes
Trial
SYNTAX score 1-low 2-intermediate 3-high
No. of events CABG
Total no. of patients CABG
Follow up in years CABG
No. of events PCI
Total no. of patients PCI
Follow-up in years PCI
Patients at risk × follow up CABG
Patients at risk × follow-up PCI
Primary outcome (major adverse cardiac and cerebrovascular events)
Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial.
Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.
Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.
SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease.
Details of MACCE definitions, patient characteristics, procedural characteristics, medical therapy, SYNTAX score assessment, and inclusion/exclusion criteria in the included trials are reported in Table E2, Table E3, Table E4, Table E5, Table E6, Table E7, Table E8, Table E9. All trials used all-cause mortality in their composite primary end point (Table E2).
A total of 8269 patients were included (PCI: 4134; CABG: 4135). The number of patients in the individual trials ranged from 600 to 1905. The mean follow-up duration was 6.2 years (range, 3.8-10 years). The mean age ranged from 61.8 ± 10.0 to 66.2 ± 9.9 years for patients who underwent PCI patients and 62.7 ± 9.5 to 66.2 ± 9.4 years for patients who underwent CABG. Female patients ranged from 20.0% to 30.6% for PCI and 21.1% to 26.5% for CABG. The prevalence of diabetes ranged from 15.05% to 100% for PCI and 15.0% to 100% for CABG. The weighted mean follow-up was 6.6 years. The assessment of the quality of the individual studies and the evidence is reported in the Online Data Supplement.
Meta-analysis
Overall, PCI was associated with a significant increase in MACCE (IRR, 1.39, 95% CI, 1.27-1.51, Figure 1) and nonsignificant increase in all-cause mortality (IRR, 1.17, 95% CI, 0.98-1.40, Figure 2). In the low SYNTAX score subgroup, PCI was associated with significantly higher incidence of MACCE (IRR, 1.25, 95% CI, 1.02-1.54), and nonsignificant increase in all-cause mortality (IRR, 1.07, 95% CI, 0.76-1.50). In the intermediate SYNTAX score subgroup, PCI was associated with significantly higher incidence of both MACCE (IRR, 1.48, 95% CI, 1.30-1.69) and all-cause mortality (IRR, 1.38, 95% CI, 1.07-1.77). In the high SYNTAX score subgroup, PCI was associated with significantly higher incidence of MACCE (IRR, 1.39, 95% CI, 1.18-1.63), and nonsignificant increase in all-cause mortality (IRR, 1.03, 95% CI, 0.70-1.52).
Figure 1Comparison of the risk of major adverse cardiac and cerebrovascular events in different SYNTAX score groups in randomized trials comparing PCI versus CABG, using IRR (an estimator of the hazard ratio) as effect of choice. CI, Confidence interval; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; I2, inconsistency; df, degrees of freedom; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting.
Figure 2Comparison of the risk of all-cause mortality in different SYNTAX score groups in randomized trials comparing PCI versus CABG, using IRR (an estimator of the hazard ratio) as effect of choice. CI, Confidence interval; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; I2, inconsistency; df, degrees of freedom; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting.
Formal testing for between-strata heterogeneity of treatment effect by SYNTAX score for the primary outcome of MACCE and for mortality did not yield significant results (pinteraction 0.40 and 0.34 respectively). Furthermore, the results were consistent for patients with left-main and multi-vessel disease (MACCE: pinteraction in left main disease 0.85; pinteraction in multi-vessel disease 0.78; all-cause mortality pinteraction in left main disease 0.12; pinteraction in multi-vessel disease 0.34).
The results of the sensitivity analysis based on ratios of IRR confirmed the overall results based on between-strata heterogeneity (Figures 3 and 4). The main findings of this meta-analysis are summarized in Figure 5. Funnel plots for MACCE and mortality are displayed in Figures E4 and E5, respectively.
Figure 3Ratio of risk estimates detailed in Figure 1 to explore the interaction between SYNTAX score groups and the risk of major adverse cardiac and cerebrovascular events in randomized trials comparing PCI versus CABG, using IRR (an estimator of the hazard ratio) as effect of choice. CI, Confidence interval; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; I2, inconsistency; df, degrees of freedom; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting.
Figure 4Ratio of the risk estimates detailed in Figure 2 to explore the interaction between SYNTAX score groups and the risk of all-cause mortality in randomized trials comparing PCI versus CABG, using IRR (an estimator of the hazard ratio) as effect of choice. CI, Confidence interval; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; I2, inconsistency; df, degrees of freedom; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting.
Figure 5Summary of the findings of this systematic review and meta-analysis, highlighting the use of IRR (an estimator of the hazard ratio) and their ratios, as a means to test the comparative between-strata effects of PCI versus CABG in randomized trials according to different groups of SYNTAX angiographic score. CI, Confidence interval; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; I2, inconsistency; MACCE, major adverse cardiac and cerebrovascular events; df, degrees of freedom.
An important feature introduced by the trials' investigators was the stratification of patients according to the complexity of the CAD, expressed using the SYNTAX score.
Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial.
The SYNTAX score is based on the angiographic assessment of coronary lesions and is calculated by summing the points assigned to each lesion causing more than 50% diameter narrowing in vessels with more than 1.5 mm diameter.
Based on this score, the SYNTAX authors stratified patients in tertiles of CAD complexity: low (score ≤22), intermediate (score 23-32) or severe (score >32). Since the publications of the results of the SYNTAX trial, this type of patients stratification has become standard practice, and is adopted by current myocardial revascularization guidelines.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
However, no prospective validation of the prognostic role of the SYNTAX score in patients with CAD has been published to date, and the available evidence seems to deny, rather than support the use of the SYNTAX score for risk stratification.
In a recent pooled analysis of individual patient data from 11 randomized trials (11,518 total patients), Head et al. found similar 5-year all-cause mortality between patients with left main disease undergoing PCI versus CABG (10.7% vs 10.5%, respectively; P = .52), regardless of SYNTAX score.
Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data.
The prospective, randomized, Nordic-Baltic-British left main revascularization study (NOBLE) trial enrolled 1201 patients with left main coronary artery disease undergoing PCI or CABG in 36 centers in northern Europe. At 5-year follow-up, patients had worse outcome after PCI compared with CABG, irrespective of the SYNTAX score; of note, in NOBLE better outcomes after CABG were reported in the low, rather than high, SYNTAX score tertile.
Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.
Similarly, in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial at 7.5-year median follow-up, the benefit of CABG versus PCI was consistent across all SYNTAX score tertiles.
Kim et al. performed a prospective observational study of 1580 patients with left main CAD undergoing PCI or CABG. At 3 years, the incidence of MACCE in both the PCI and CABG groups did not differ among the SYNTAX tertiles (P = .08 and P = .594 for the PCI and CABG groups, respectively) and no significant interaction between treatment type and SYNTAX score tertiles was found with regard to MACCE (P = .66).
Validation of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score for prediction of outcomes after unprotected left main coronary revascularization.
In another study of 320 consecutive patients with multivessel disease undergoing CABG, no statistical difference was found for the composite outcome of death, myocardial infarction, or stroke at 1-year follow-up between SYNTAX score tertiles (P = .75).
Validation of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score for prediction of outcomes after unprotected left main coronary revascularization.
First, while the SYNTAX score is based on a purely angiographic assessment, clinical risk profiles have consistently been shown to be more closely related with both short- and long-term outcomes following revascularization with PCI or CABG.
Validation of the Mayo clinic risk score for in-hospital mortality after percutaneous coronary interventions using the national cardiovascular data registry.
Second, the SYNTAX score attribution suffers from significant interobserver variations, resulting in heterogeneous outcomes across studies. In the Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization trial when angiographies were analyzed by an independent core laboratory, the mean SYNTAX score of the enrolled patients was significantly higher than by site assessment (26.5 ± 9.3 vs 20.6 ± 6.2, P < .0001) and 24% of the enrolled patients had a SYNTAX score above the trial exclusion criteria of 32.
Differences and level of agreement in syntax score assessment between site operators and angiographic core laboratory readers: insights from the Excel Trial.
Finally, with particular reference to CABG surgery, because the grafts are bypassed downstream of the lesions, angiographic complexity might have limited clinical impact, unless the degree of target vessel stenosis is diligently used to guide the choice of the most appropriate conduits.
The results of our meta-analysis confirm the lack of interaction between the SYNTAX score and the outcomes of PCI versus CABG trials and are concordant with those of the published studies.
The limitations of SYNTAX are overcome by other scores, which expand multidimensionally patient appraisal including nonangiographic features, such as the Society of Thoracic Surgeons and SYNTAX II scores.
Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II.
Our study shares the usual limitations of aggregate data meta-analyses. In particular heterogeneity in the definitions of the outcomes used by the different studies, in the surgical protocols, type of stents, use of arterial grafts, medical therapy, postprocedural management and follow-up protocol exists among the included trials. Like in all meta-analyses, ecological fallacy is also a concern. Importantly, the IRR is based on several assumptions, including constant hazard, which may not hold true in all included randomized trials.
Conclusions
We found no association between the SYNTAX score and the outcome of the trials comparing PCI and CABG. Our findings have implications for clinical practice, as well as future guidelines and the design of trials comparing PCI and CABG. The use of the SYNTAX score as the primary approach to stratify patients with coronary artery disease and to identify the most appropriate revascularization method in the individual patient is not supported by the current evidence.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Figure E3Details on how events and person years were computed, and how they were used to generate incidence ratio, IRRs, and interaction IRR. RCT, Randomized clinical trial.
(percutaneous coronary intervention∗ or percutaneous coronary revascularization∗ or PCI or percutaneous coronary angioplasty or stent or stents or stenting).
3
Angioplasty, Balloon, Coronary
4
(coronary balloon angioplasties or coronary balloon angioplasty or transluminal coronary balloon dilation or coronary artery balloon dilation or percutaneous transluminal coronary angioplasty or coronary angioplasty or coronary angioplasties or PTCA).
5
or/1-4
6
Coronary Artery Bypass/
7
(coronary adj2 (bypass or graft)).
8
(CABG or aorticocoronary anastomosis or total arterial revascularization or total arterial revascularization or Multiple arterial revascularization or multiple arterial revascularization).
9
Coronary Artery Bypass, Off-Pump/
10
Internal Mammary-Coronary Artery Anastomosis/
11
((Right Internal Mammary Artery or RIMA or Coronary Internal Mammary Artery or arteria mammaria interna or arteria thoracica interna or internal thoracic artery or mammary internal artery) and (transplant∗ or graft∗ or anastomosis)).
12
(surgical revascularization or cardiac muscle revascularization or cardiac muscle revascularization or coronary revascularization or coronary revascularization or heart muscle revascularization or heart myocardium revascularization or heart revascularization or heart revascularization or internal mammary arterial anastomosis or internal mammary arterial implantation or internal mammary artery anastomosis or internal mammary artery graft or internal mammary artery implant or internal mammary artery implantation or internal mammary-coronary artery anastomosis or myocardial revascularization or myocardial revascularization or myocardium revascularization or myocardium revascularization or transmyocardial laser revascularization or transmyocardial laser revascularization or vineberg operation).
13
or/6-12
14
“randomized controlled trial”.pt.
15
(random$ or placebo$ or single blind$ or double blind$ or triple blind$).ti,ab
16
(retraction of publication or retracted publication).pt.
17
or/14-16
18
(animals not humans).sh.
19
((comment or editorial or meta-analysis or practice-guideline or review or letter) not “randomized controlled trial”).pt.
20
(random sampl$ or random digit$ or random effect$ or random survey or random regression).ti,ab. not “randomized controlled trial”.pt.
Table E2Definition of the composite of major adverse cardiac and cerebrovascular events used in the included trials
Trial
MACCE definition
BEST
Death, myocardial infarction, or target-vessel revascularization
EXCEL
Death from any cause, stroke, or myocardial infarction
FREEDOM
Death from any cause, nonfatal myocardial infarction, and nonfatal stroke
NOBLE
Death from any cause, nonprocedural myocardial infarction, repeat revascularization, or stroke
PRECOMBAT
Death from any cause, myocardial infarction, stroke, and ischemia-driven target-vessel revascularization
SYNTAX
Death from any cause, stroke, myocardial infarction, or repeat revascularization
References are provided in the main text. MACCE, Major adverse cardiac and cerebrovascular events; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery.
Table E3Details of patient characteristics (continues)
Trial
Treatment
Age, mean (SD), median [IQR]
Female (%)
BMI (SD) [IQR]
Smoking (%)
DM (%)
Insulin (%)
CAD, family history (%)
Statin (%)
HTN (%)
HCL/HLD (%)
PVD (%)
Carotid artery disease (%)
Prior stroke (%)
Prior MI (%)
Prior TIA (%)
Prior CHF (%)
Prior PCI (%)
Prior CABG (%)
LVEF (SD) [IQR]
SA (%)
UA (%)
ACS (%)
BEST
PCI
64.0 (9.3)
30.6
24.7 (2.9)
20.1
40.4
4.6
-
-
67.6
54.6
3.4
-
8.4
5.7
-
3.7
6.8
-
59.1 (8.5)
47.9
42.1
-
CABG
64.9 (9.4)
26.5
25.0 (2.9)
20.1
42.1
4.1
-
-
66.7
50.2
2.7
-
7.5
6.6
-
2.7
8.6
-
59.9 (8.1)
46.2
45.0
-
EXCEL
PCI
66.0 (9.6)
23.8
28.6 (5.0)
23.4
30.2
7.7
-
-
74.2
70.5
10.2
-
-
17.8
5.5
7.1
18.4
0
57.0 (9.6)
52.7
24.1
-
CABG
65.9 (9.5)
22.5
28.8 (4.9)
20.2
28.0
7.7
-
-
73.2
68.1
8.8
-
-
16.8
7.0
6.2
15.9
0
57.3 (9.0)
52.8
24.5
-
FREEDOM
PCI
63.2 (8.9)
26.8
29.6 (5.4)
14.8
100
33.8
-
82.1
84.6
-
-
-
3.9
26.2
-
-
-
-
65.7 (12.1)
-
-
31.9
CABG
63.1 (9.2)
30.5
29.8 (5.3)
16.6
100
30.9
-
82.6
85.1
-
-
-
3.0
25.0
-
-
-
-
66.6 (10.5)
-
-
29.5
NOBLE
PCI
66.2 (9.9)
20.0
27.9 (4.5)
19
15
-
58
82
65.2
-
-
-
-
-
-
-
19.6
0.7
60 [55-65]
82.1
-
17.9
CABG
66.2 (9.4)
24.0
28.1 (4.4)
22
15
-
56
78
65.7
-
-
-
-
-
-
-
19.9
0.3
60 [52-64]
82.9
-
16.9
PRECOMBAT
PCI
61.8 (10.0)
24.0
24.6 (2.7)
-
34
3.3
-
-
54.3
42.3
5.0
-
-
3.4
-
0.0
12.7
-
61.7 (8.3)
53.3
42.7
-
CABG
62.7 (9.5)
23.0
24.5 (3.0)
-
30
3.0
-
-
51.3
40.0
2.3
-
-
6.7
-
0.7
12.7
-
60.6 (8.5)
45.7
48.0
-
SYNTAX
PCI
65.2 (9.7)
23.6
28.1 (4.8)
18.5
25.6
24.6
-
-
68.9
78.7
-
8.1
3.9
31.9
4.3
4.0
-
-
-
56.9
28.9
-
CABG
65.0 (9.8)
21.1
27.9 (4.5)
22.0
24.6
9.9
-
-
64.0
77.2
-
8.4
4.8
33.8
5.2
5.3
-
-
-
57.2
28.0
-
References are provided in the main text. SD, Standard deviation; IQR, interquartile range; BMI, body mass index; DM, diabetes mellitus; CAD, coronary artery disease; HTN, hypertension; HCL, hypercholesterolemia; HLD, hyperlipidemia; PVD, peripheral vascular disease; MI, myocardial infarction; TIA, transient ischemic attack; CHF, chronic heart failure; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; LVEF, left ventricular ejection fraction; SA, stable angina pectoris; UA, unstable angina; ACS, acute coronary syndrome; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery.
Table E4Details of patient characteristics (continued)
Trial
Treatment
Bifurcation (%)
Bifurcation or trifurcation of the distal left artery (%)
Diseased non-left main coronary arteries (0, 1, 2, 3) (%)
NYHA Class I (%)
NYHA Class II (%)
NYHA Class III (%)
NYHA Class IV (%)
euroSCORE (SD) [IQR]
SYNTAX score (SD) [IQR]
BEST
PCI
57.5
-
-
-
-
-
-
2.9 (2.0)
24.2 (7.5)
CABG
58.8
-
-
-
-
-
-
3.0 (2.1)
24.6 (8.1)
EXCEL
PCI
-
81.3
(17.2, 30.8, 34.3, 17.)
-
-
-
-
-
32.2% (<22); 42.8% (23-32); 25.1% (>33)
CABG
-
77.4
(17.5, 30.5, 30.8, 19.0)
-
-
-
-
-
39.3% (<22); 37.3% (23-32); 23.4% (>33)
FREEDOM
PCI
-
-
-
-
-
-
-
2.7 (2.4)
26.2 (8.4)
CABG
-
-
-
-
-
-
-
2.8 (2.5)
26.1 (8.8)
NOBLE
PCI
-
-
-
53
29.6
13
5
2 [2-4]
22.5 (7.5)
CABG
-
-
-
43
33.0
17
7
2 [2-4]
22.4 (8.0)
PRECOMBAT
PCI
66.7
-
(9.0, 17.7, 33.7, 40.7)
-
-
-
-
2.6 (1.8)
24.4 (9.4)
CABG
61.0
-
(11.3, 17.7, 30.0, 41.0)
-
-
-
-
2.8 (1.9)
25.8 (10.5)
SYNTAX
PCI
72.4
-
-
-
-
-
-
3.8 (2.6)
28.4 (11.5)
CABG
73.3
-
-
-
-
-
-
3.8 (2.7)
29.1 (11.4)
References are provided in the main text. NYHA, New York Heart Association; euroSCORE, European System for Cardiac Operative Risk Evaluation; SD, standard deviation; IQR, interquartile range; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease.
References are provided in the main text. GP, Glycoprotein IIa IIb; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blockers; SD, standard deviation; IQR, interquartile range; CR, complete revascularization; DES, drug-eluting stent; LMCA, left main coronary artery; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery.
Ultrasound (epi-aortic or transesophageal-aortic, epi-aortic, transesophageal)
BEST
PCI
-
-
-
-
-
-
-
-
-
CABG
90.0
-
58.4
-
3.1 (0.9)
2.1 (1.1)
1.0 (0.8)
-
-
EXCEL
PCI
-
-
-
-
-
-
-
-
-
CABG
94.9
27.7
28.3
-
2.6 (0.8)
1.4 (0.6)
1.2 (0.9)
-
(43.6, 12.6, 40.8)
FREEDOM
PCI
-
-
-
-
-
-
-
-
-
CABG
89.5
-
17.4
-
2.9 (0.8)
-
-
-
-
NOBLE
PCI
-
-
-
-
-
-
-
-
-
PCI
-
-
-
-
-
-
-
-
-
PRECOMBAT
PCI
-
-
-
-
-
-
-
-
-
CABG
77.7
-
51.7
-
2.7 (0.9)
2.1 (0.9)
0.7 (0.8)
-
-
SYNTAX
PCI
-
-
-
-
-
-
-
-
-
CABG
-
24.1
14.3
-
2.8 (0.7)
-
-
-
-
References are provided in the main text. LITA, Left internal thoracic artery; BITA, bilateral internal thoracic artery; OPCAB, off-pump coronary artery bypass grafting; SV, saphenous vein; SD, standard deviation; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery.
References are provided in the main text. PCI, Percutaneous coronary intervention; CABG, coronary artery bypass grafting; ACE, angiotensin-converting enzyme; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery.
Table E8SYNTAX score assessment details in the included trials
Trial
SYNTAX score assessment
BEST
All angiographic data were analyzed in the angiographic core laboratory of the Cardio-Vascular Research Foundation, Seoul, South Korea.
EXCEL
Site-determined quantification of the coronary anatomy with the SYNTAX score; plus, an independent angiographic core laboratory was used to assess the extent of disease and the SYNTAX score at baseline, the residual SYNTAX score after PCI (and CABG, according to operative reports), and the degree of completeness of anatomic and ischemic revascularization.
FREEDOM
A core laboratory reading of all qualifying angiograms was conducted at the Cardiovascular Research Foundation in New York.
NOBLE
The SYNTAX score was calculated on site by investigators and post hoc by the independent corelab at Cardiovascular European Research Center, Massy, France. Due to missing projections of the right coronary artery, missing angiograms, or un-analyzable angiograms, the corelab analysis was performed for 1116 patients. In remaining 68 patients, the site SYNTAX analysis was applied for the subgroup analysis. The missing individual projections and angiograms was due to the late collection of data for the post hoc corelab analysis.
PRECOMBAT
Analyses of all angiographic data were performed in the angiographic core laboratory of the Cardiovascular Research Foundation.
SYNTAX
Diagnostic angiograms were scored, according to the SYNTAX score algorithm, at the site and at the core laboratory.
References are provided in the main text. SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease.
Table E9Inclusion and exclusion criteria for patient enrollment in the included trials
Trial
Selection criteria
BEST
Inclusion criteria
1.
Age ≥ 18 y.
2.
Angiographically confirmed multivessel CAD critical (>70%) lesions in at least 2 major epicardial vessels (≥2.0 mm in diameter) in at least 2 separate coronary artery territories expected to be equally treatable with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) by clinicians at the investigating site.
3.
Indication for revascularization based on symptoms of angina and/or objective evidence of myocardial ischemia.
4.
Geographically accessible and willing to come in for required study visits.
5.
Agreement by the patient or guardian to the study protocol and the clinical follow-up schedule, including the provision of written informed consent, as approved by the appropriate Institutional Review Board/Ethical Committee at the respective clinical site.
Exclusion criteria
1.
Known hypersensitivity or contraindication to any of the following:
•
Heparin
•
Aspirin
•
Clopidogrel
•
Everolimus
•
Stainless steel and/or
•
Contrast media (patients with documented sensitivity to contrast who can be effectively premedicated with steroids and diphenhydramine [eg, for rash] may be enrolled. Patients with true anaphylaxis to prior contrast media, however, should not be enrolled).
2.
Severe congestive heart failure (class III or IV according New York Heart Association, or pulmonary edema) at the time of enrollment. The left ventricular ejection fraction was not considered a criterion for exclusion.
3.
Planned simultaneous surgical procedure unrelated to coronary revascularization (eg, valve repair/replacement, aneurysmectomy, carotid endarterectomy or carotid stent).
4.
Previous bypass surgery.
5.
Prior PCI with drug eluting stent (DES) implantation within 1 y.
6.
Two or more chronic total occlusions in major coronary territories.
7.
Acute ST-elevation myocardial infarction (MI) (Q-wave) within 72 h prior to enrollment requiring revascularization.
8.
Abnormal creatine kinase (CK > 2x normal) and/or abnormal CK-MB levels and/or elevated troponin levels at the time of randomization. Enrollment was allowed when these cardiac enzymes returned to normal.
9.
Previous stroke within 6 mo or stroke at more than 6 mo with significant residual neurologic involvement.
10.
Extra-cardiac illness expected to limit survival to less than 2 y, eg, oxygen dependent chronic obstructive pulmonary disease, active hepatitis, significant hepatic failure, or severe renal disease.
11
Prior history of significant bleeding (within the previous 6 mo) that might be expected to recur during CABG or PCI/DES-related anticoagulation.
12.
Contraindication to either CABG or PCI/DES due to a coexisting clinical condition.
13.
Intolerance or contraindication to aspirin or clopidogrel.
14.
Suspected pregnancy.
15.
Concurrent enrollment in another clinical trial.
16.
Left main coronary artery stenosis (≥50% diameter).
EXCEL
Inclusion criteria
1a.
Unprotected left main coronary artery disease (ULMCAD) with angiographic diameter stenosis ≥70% (visually estimated), or with angiographic diameter stenosis ≥50% but <70% with 1 or more of the following present:
•
Non-invasive evidence of ischemia referable to a hemodynamically significant left main lesion, and/or
•
Intravascular ultrasound minimum lumen area (IVUS MLA) ≤6.0 mm2, and/or
•
Fractional flow reserve (FFR) ≤0.80
OR
1b.
LM equivalent disease: LM distal bifurcation Medina 0,1,1 disease, in the absence of significant angiographic stenosis in the left main coronary artery, may also be randomized if either of the following conditions are present:
•
Both the ostial left anterior descending (LAD) and ostial left circumflex (LCX) stenoses are ≥70% stenotic by visual estimation, or
•
If 1 or both of the ostial LAD and ostial LCX stenoses are ≥50%-<70% stenotic by visual estimation, then this lesion(s) is demonstrated to be significant either by:
-
noninvasive evidence of ischemia in its myocardial distribution; and/or
-
FFR ≤0.80; and/or
-
IVUS MLA ≤4.0 mm2 (FFR is preferred).
2.
Clinical and anatomic eligibility for both PCI and CABG as agreed to by the local Heart Team (interventionalist determines PCI appropriateness and eligibility; cardiac surgeon determines surgical appropriateness and eligibility)
3.
≥18 y of age
4.
Ability to sign informed consent and comply with all study procedures, including follow-up for at least 3 y
Exclusion criteria
1.
Prior
•
PCI of the left main trunk at any time prior to randomization
•
PCI of any other (non-left main) coronary artery lesions within 1 y prior to randomization
•
CABG at any time prior to randomization
2.
Need for any concomitant cardiac surgery other than CABG (eg, valve surgery, aortic repair, etc.), or intent that if the subject randomizes to surgery, any cardiac surgical procedure other than isolated CABG will be performed
3.
The presence of any clinical condition(s) which leads the participating interventional cardiologist to believe that clinical equipoise is not present (ie, the subject should not be treated by PCI, but rather should be managed with CABG or medical therapy)
4.
The presence of any clinical condition(s) which leads the participating cardiac surgeon to believe that clinical equipoise is not present (ie, the subject should not be treated by CABG, but rather should be managed with PCI or medical therapy)
5.
Subjects unable to tolerate, obtain or comply with dual antiplatelet therapy for at least 1 y
6.
Subjects requiring or who may require additional surgery (cardiac or noncardiac) within 1 y
7.
CK-MB greater than the local laboratory upper limit of normal, or recent MI with CK-MB levels still elevated
8.
Pregnancy or intention to become pregnant
9.
Noncardiac comorbidities with life expectancy <3 y
10.
Current participation in other investigational drug or device studies that have not reached their primary end point
11.
Angiographic exclusion criteria:
•
LM diameter stenosis <50%, unless left main equivalent disease is present
•
SYNTAX score ≥33, as determined by the local Heart Team
•
Visually estimated LM reference vessel diameter <2.25 mm or >4.25 mm
•
The presence of specific coronary lesion characteristics or other cardiac condition(s) which leads the participating interventional cardiologist or cardiac surgeon to believe that clinical equipoise is not present
FREEDOM
Inclusion criteria
1.
Man or woman aged ≥18 y
2.
Diabetes mellitus (type 1 or type 2): defined according to American Diabetes Association as history of either:
•
Presence of classic symptoms of diabetes mellitus with unequivocal elevation of plasma glucose (2 h postprandial or random of >200 mg/dL [11 mmol/L]) or
•
Fasting plasma glucose elevation on (>1 occasion of ≥126 mg/dL [7 mmol/L]) and currently undergoing pharmacologic or nonpharmacologic treatment
3.
Angiographically confirmed multivessel CAD (critical [≥70%] lesions in ≥2 major epicardial vessels and in ≥2 separate coronary artery territories)
4.
Angiographic characteristics amenable to both PCI/DES and CABG
5.
Indication for revascularization based upon symptoms of angina or objective evidence of myocardial ischemia
6.
Willing to comply with all follow-up required study visits
7.
Signed and received copy of informed consent
Exclusion criteria
1.
Severe congestive heart failure (class III or IV according to New York Heart Association or pulmonary edema) at time of enrolment
2.
Prior CABG surgery
3.
Prior cardiac valve surgery
4.
Prior PCI with stent implantation within 6 m
5.
Previous stroke within 6 m or patients with stroke at >6 m with significant residual neurologic involvement, as reflected in Rankin score >1
6.
Prior history of significant bleeding (within previous 6 m) that might be expected to occur during CABG- or PCI/DES-related anticoagulation
7.
In-stent restenosis of target vessel
8.
≥2 chronic total occlusions in major coronary territories which are considered targets for revascularization
9.
LM stenosis (≥50% diameter stenosis)
10.
Acute ST-elevation MI (Q wave) within 72 h before enrollment requiring revascularization
11.
Abnormal CK (>2x normal) at time of randomization
12.
Planned simultaneous surgical procedure unrelated to coronary revascularization (eg, valve repair/replacement, aneurysmectomy, carotid endarterectomy, or carotid stent)
13.
Contraindication to either CABG or PCI/DES because of coexisting clinical condition
14.
Significant leukopenia, neutropenia, thrombocytopenia, anemia, or known bleeding diathesis
15.
Intolerance or contraindication to aspirin or both clopidogrel and ticlopidine.
16.
Dementia with Mini Mental Status Examination (MMSE) score <20
17.
Extracardiac illness that is expected to limit survival to <5 y, for example oxygen-dependent chronic obstructive pulmonary disease, active hepatitis or significant hepatic failure, severe renal disease
18.
Suspected pregnancy: pregnancy test (urine or serum) will be administered prerandomization to all women not clearly menopausal
19.
Concurrent enrollment in another clinical trial
20.
Geographically inaccessible for follow-up visits required by protocol
NOBLE
Inclusion criteria for study enrolment were stable angina pectoris, unstable angina pectoris, or acute coronary syndrome, together with a lesion with visually assessed stenosis diameter ≥50% or fractional flow reserve ≤0.80 in the left main coronary artery ostium, mid-shaft, or bifurcation, with no more than 3 additional noncomplex lesions. Complex lesions were defined as chronic total occlusions: bifurcation lesions requiring 2 stent techniques or lesions with calcified or tortuous vessel morphology. Exclusion criteria were ST-elevation infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 y. Patients were enrolled in the study by site investigators or designated staff. A screening log was maintained in 5 centers, which recruited 506 of the 1201 patients.
PRECOMBAT
Inclusion Criteria
1.
The patient must be at least 18 y of age.
2.
The patient must have significant de novo ULMCA stenosis (>50% by visual estimation) with or without any additional target lesions (>70% by visual estimation). “Unprotected” in this context means that no perfusion distal to the left main stenosis is supplied by either a patent bypass graft or a collateral vessel.
3.
Left main lesions and lesions outside ULMCA (if present) must be potentially comparably treatable with coronary stenting and CABG.
4.
Patients with stable (CCS class 1 to 4) or acute coronary syndromes (unstable angina pectoris Braunwald class IB, IC, IIB, IIC, IIIB, IIIC or Non-ST elevation MI) or patients with atypical chest pain or without symptoms but having documented myocardial ischemia may be enrolled.
5.
The patient or guardian must agree to the study protocol and the schedule of clinical and angiographic follow-up, and must provide informed, written consent, as approved by the appropriate Institutional Review Board/Ethical Committee of the respective clinical site.
Exclusion Criteria
1.
Known hypersensitivity or contraindication to any of the following medications:
•
Heparin
•
Aspirin
•
Both clopidogrel and ticlopidine
•
Sirolimus
•
Stainless steel and/or
•
Contrast media (patients with documented sensitivity to contrast which can be effectively pre-medicated with steroids and diphenhydramine [eg, rash] may be enrolled. Patients with true anaphylaxis to prior contrast media, however, should not be enrolled).
2.
Systemic (intravenous) sirolimus use within 12 mo.
3.
Any previous PCI within 1 y
4.
Previous bypass surgery
5.
Any previous PCI of a ULMCA or ostial left circumflex artery or ostial left anterior descending artery lesion within 1 y
6.
Intention to treat more than 1 totally occluded major epicardial vessel
7.
Acute MI within 1 wk
8.
Ejection fraction <30%.
9.
Cardiogenic shock
10.
Any stroke with a persistent neurological deficit or any cerebrovascular accident within 6 mo
11.
Creatinine level ≥2.0 mg/dL or dependence on dialysis.
12.
Severe hepatic dysfunction (AST and ALT ≥3 times upper normal reference values).
13.
Gastrointestinal or genitourinary bleeding within the prior 3 mo, or major surgery within 2 mo.
14.
History of bleeding diathesis or known coagulopathy (including heparin-induced thrombocytopenia), or will refuse blood transfusions.
15.
Current known current platelet count <100,000 cells/mm3 or Hgb <10 g/dL.
16.
A planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 1 y postenrollment.
17.
Noncardiac comorbid conditions with life expectancy <1 y or that may result in protocol noncompliance (per site investigator's medical judgment).
18.
Active participation in another drug or device investigational study, which has not completed the primary end point follow-up period.
19.
Unable or unwilling to follow-up with visits required by protocol
20.
Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plan to pregnant any time after enrollment into this study
SYNTAX
Inclusion criteria included de novo (previously untreated) lesions, ≥50% target vessel stenosis with stable/unstable angina or atypical chest pain. If asymptomatic, positive evidence of myocardial ischemia was required. Exclusion criteria included previous PCI or CABG, acute MI, or the need for concomitant cardiac surgery.
References are provided in the main text. BEST, Randomized Comparison of Coronary Artery Bypass Surgery and Everolimus-Eluting Stent Implantation in the Treatment of Patients With Multivessel Coronary Artery Disease; CAD, coronary artery disease; CK-MB, creatine kinase-MB; EXCEL, Evaluation of XIENCE versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; LM, left main; SYNTAX, Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery; FREEDOM, Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease; NOBLE, Nordic-Baltic-British left main revascularization study; PRECOMBAT, Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease; CCS, Canadian Cardiovascular Society; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial.
Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised, non-inferiority NOBLE trial.
Percutaneous coronary intervention versus coronary artery bypass grafting in patients with three-vessel or left main coronary artery disease: 10-year follow-up of the multicentre randomised controlled SYNTAX trial.
Mortality after coronary artery bypass grafting versus percutaneous coronary intervention with stenting for coronary artery disease: a pooled analysis of individual patient data.
Percutaneous coronary angioplasty versus coronary artery bypass grafting in treatment of unprotected left main stenosis (NOBLE): a prospective, randomised, open-label, non-inferiority trial.
Validation of SYNTAX (Synergy between PCI with Taxus and Cardiac Surgery) score for prediction of outcomes after unprotected left main coronary revascularization.
Validation of the Mayo clinic risk score for in-hospital mortality after percutaneous coronary interventions using the national cardiovascular data registry.
Differences and level of agreement in syntax score assessment between site operators and angiographic core laboratory readers: insights from the Excel Trial.
Anatomical and clinical characteristics to guide decision making between coronary artery bypass surgery and percutaneous coronary intervention for individual patients: development and validation of SYNTAX score II.
The Institutional Review Board did not approve this study because of the lack of individual patients' information. Patient written consent for the publication of the study was not received because of the lack of individual patients' information.
Scoring systems serve a common goal to standardize the classification of complex conditions to improve decision-making. When properly built, they can predict outcomes and assist in patient stratification for clinical trials. In the field of coronary artery disease (CAD), the SYNTAX (Synergy Between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) score has become widely used to classify the severity of coronary lesions, and it has been integrated into a culture that guides the choice of revascularization strategy between percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG).
The advent of revascularization trials comparing drug-eluting stents (DES) with coronary artery bypass grafting (CABG) prompted the need to more accurately quantify the complexity of coronary artery disease (CAD). In the design of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial of DES versus CABG for multivessel CAD, the realization that CAD severity measured by the number of diseased epicardial vessels alone was not sufficient gave way to the development of the SYNTAX score.
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