Original Contribution

The SYNTAX Score Does Not Predict Risk of Adverse Events in Patients With Non-ST Elevation Acute Coronary Syndrome Who Undergo Coronary Artery Bypass Graft Surgery

Bj√∂rn Redfors, MD, PhD1;  Chun-Hui He, MD, PhD1,2;  Tullio Palmerini, MD3;  Adriano Caixeta, MD, PhD4;  Gennaro Giustino, MD5;  Girma Minalu Ayele, PhD1;  Ajay J. Kirtane, MD, SM1,6;  Roxana Mehran, MD1,5;  Gregg W. Stone, MD1,6;  Philippe G√©n√©reux, MD1,7,8

Bj√∂rn Redfors, MD, PhD1;  Chun-Hui He, MD, PhD1,2;  Tullio Palmerini, MD3;  Adriano Caixeta, MD, PhD4;  Gennaro Giustino, MD5;  Girma Minalu Ayele, PhD1;  Ajay J. Kirtane, MD, SM1,6;  Roxana Mehran, MD1,5;  Gregg W. Stone, MD1,6;  Philippe G√©n√©reux, MD1,7,8

Abstract: Objectives. We tested the ability of the SYNTAX score (SS) to predict 1-year adverse outcomes for patients with non–ST segment elevation acute coronary syndromes (NSTE-ACS) who undergo coronary artery bypass graft (CABG) surgery. Background. The SS effectively risk stratifies patients who undergo percutaneous coronary intervention, but not patients with stable coronary disease who undergo CABG. Methods. We calculated the SS for 457 patients with NSTE-ACS in the angiographic substudy of the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial who underwent CABG. We stratified and compared patients according to SS tertiles. We tested the ability of the SS, as a linear covariate, to predict adverse events by univariate analyses and by univariate and multivariable Cox proportional hazards model. We also tested the predictive abilities of the Age, Creatinine Clearance, and Ejection Fraction (ACEF) score, the clinical SS, and the logistic clinical SS. Results. The median SS was 23 (interquartile range, 15-30). Baseline clinical characteristics were similar among the groups. One-year mortality and major adverse cardiovascular events (all-cause death, myocardial infarction, any stroke, or urgent revascularization) were similar between the groups (P=.13 and P=.62, respectively). Receiver operating characteristic curves, net reclassification indices, and integrated discrimination indices did not improve with SS, clinical SS, or logistic clinical SS compared with the ACEF score. Conclusions. The anatomical SS does not appear to be useful in risk stratifying patients with NSTE-ACS who undergo CABG. Clinical variables may better risk stratify patients with complex coronary artery disease considered for CABG.

J INVASIVE CARDIOL 2017;29(2):42-49. Epub 2016 December 15.

Key words: coronary artery bypass graft surgery, non–ST elevation acute coronary syndromes, SYNTAX score


The Synergy Between PCI With TAXUS and Cardiac Surgery (SYNTAX) score (SS) has been shown to predict the risk of major ischemic events in many patient subsets undergoing percutaneous coronary intervention (PCI).1-3 Recently, we also demonstrated the utility of the SS to risk stratify patients undergoing coronary angiogram and medical treatment;4 however, conflicting data exist regarding the ability of the SS to predict risk for patients undergoing coronary artery bypass graft (CABG) surgery.5-10 Most importantly, the SS failed to predict adverse events within the large SYNTAX trial among the CABG cohort. This lack of predictability of the SS was never confirmed among a population of patients with non-ST segment elevation acute coronary syndromes (NSTE-ACS) undergoing CABG. Therefore, we assessed the ability of the SS to predict ischemic outcomes in patients with NSTE-ACS who were treated with CABG, using data from the multicenter, prospective, randomized ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial.

Methods

Study population. The ACUITY trial design has been reported in detail.11 Briefly, the ACUITY trial was a multicenter, prospective, randomized trial of patients with moderate-risk and high-risk NSTE-ACS who were managed with an early invasive strategy. Patients were randomly assigned before coronary angiography to heparin (unfractionated or low molecular weight) plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin monotherapy with provisional glycoprotein IIb/IIIa inhibitor use. Angiography was performed in all patients within 72 hours of randomization. Depending on coronary anatomy, patients were then treated with PCI, CABG, or medical therapy. Dual-antiplatelet therapy with aspirin and clopidogrel was strongly recommended for at least 1 year. All patients were anticoagulated during CABG with unfractionated heparin, with dosing per standard institutional practice. The study was approved by the institutional review board or ethics committee at each center, and all patients provided written informed consent. All major adverse events were adjudicated by an independent clinical events committee blinded to treatment assignment.

Study objectives. Our primary objective was to evaluate the impact of the SS on the risk of all-cause death within 1 year in patients with NSTE-ACS who underwent CABG. We limited the study to the subgroup of patients who had CABG and were enrolled in the quantitative coronary angiography substudy of the ACUITY trial. Quantitative coronary angiographic analysis was performed by experienced angiographic core laboratory technicians at the Cardiovascular Research Foundation in New York, New York who were blinded to treatment assignment and clinical outcomes.12

Angiographic analysis. Three experienced interventional cardiologists (PG, TP, AC) who were also blinded to treatment assignment and clinical outcomes assessed the SS for each angiogram. In order to minimize interobserver variability, these cardiologists were first trained by expert core lab technicians.13 Each lesion with ≥50% diameter stenosis in vessels ≥1.5 mm in diameter was scored using the SS algorithm fully described elsewhere.1 Interobserver (kappa, 0.76; 95% confidence interval [CI], 0.64-1.00) and intraobserver (kappa, 0.88; 95% CI, 0.66-0.89) reproducibility was at least substantial.13,14

Statistical analysis. Continuous data are presented as mean ± standard deviation and were compared using analysis of variance (ANOVA) and modified Student’s t-test or the Kruskal-Wallis test, as appropriate. Categorical variables were compared by the χ2 or the Fisher exact test. The composite endpoints were major adverse cardiovascular events, defined as any all-cause mortality, MI, stroke, or unplanned revascularization, and net adverse clinical events, defined as any all-cause mortality, MI, stroke, unplanned revascularization, or major non-CABG related bleeding. We grouped patients into SS tertiles, and 1-year outcomes for each group were determined using Kaplan-Meier methodology and compared using the log-rank test.

We performed univariate and multivariable Cox proportional hazards regression to assess independent predictors of 1-year mortality. To avoid overfitting of the model, we included only SS and the composite clinical variable Age, Creatinine Clearance, and Ejection Fraction (ACEF) score, which is calculated as [age/ejection fraction] + 1 if serum creatinine >2 mg/mL) in the model. We constructed receiver operating characteristic (ROC) curves to assess the predictive power of SS for 1-year death. We compared ROC curves for the modified ACEF with the clinical SS, which is calculated as SS multiplied by ACEF.15,16 We calculated net reclassification index and integrated discrimination index using a Cox proportional hazards model for SS, clinical SS, and log clinical SS as compared with ACEF. We performed statistical analyses using SAS version 9.1 (SAS Institute). A P-value <.05 was considered statistically significant.

Results

The quantitative angiographic substudy of the ACUITY trial included 6921 patients, 755 of whom had CABG (Figure 1). After excluding patients for whom the SS could not be calculated due to technical reasons (n = 298), 457 patients remained.

The median SS was 23 (interquartile range [IQR], 15-30). Clinical and angiographic characteristics of patients stratified by SS tertiles are shown in Table 1. Compared to patients with lower SS, patients with higher SS were more likely to have higher baseline biomarker elevation, ST-segment deviation, and a lower left ventricular ejection fraction. They were also more likely to have longer lesions, multivessel disease, and thrombus-containing lesions. There were no significant differences in discharge medications, ie, use of aspirin, clopidogrel, or ticlopidine, among the groups (Table 2).

At 30-day follow-up, the rates of all-cause death, cardiac death, MI, and unplanned revascularization in the overall cohort were 3.3%, 3.1%, 14.3%, and 1.1%, respectively. Event rates were not significantly different among the SS groups (Table 3). 

The rates of all-cause death, cardiac death, MI, and unplanned revascularization within 1 year in the overall cohort were 5.3%, 4.0%, 15.2%, and 3.7%, respectively (Table 3 and Figure 2). Event rates were not significantly different between the groups. When stratified by traditional SS categories (<22, 22-32, and >32), higher SS was not associated with increased risk of death (Figure 4). Univariate predictors of death within 1 year are shown in Table 4. SS was not associated with increased risk of death in a univariable Cox proportional hazards model (hazard ratio [HR], 1.03; 95% CI, 0.99-1.06; P=.12). In a multivariable Cox proportional hazards model, ACEF (HR, 1.85; 95% CI, 1.26-2.73; P=.01) but not SS (HR, 1.01; 95% CI, 0.97-1.05; P=.57) was associated with increased risk. None of the ROC curves for SS, clinical SS, or log clinical SS were better than for ACEF alone (Figure 3). SS, clinical SS, and log clinical SS were associated with negative net reclassification index and integrated discrimination index when compared with ACEF (Table 5). Hosmer-Lemeshow tests were acceptable for all ROC models (P>.10).

Discussion

To the best of our knowledge, this is the first study to test SS for risk prediction in patients with NSTE-ACS who undergo CABG. We show that the SS was not predictive of death within 1 year for these patients and added no incremental value over clinical predictors.

In this study, the SS did not predict death. This was true regardless of whether patients were divided into true tertiles based on the current SS distribution, whether traditional SS grouping was used (<22, 22-32, >32), or whether the SS was used as a continuous variable. In contrast, several previously established clinical predictors were associated with increased risk of death. These included previous CABG, older age, weight, and renal insufficiency.2,15 The ROC curve for SS was nominally worse than for the clinical ACEF score. Combinations of SS and ACEF, including the clinical SS, had no incremental value over ACEF alone. Hosmer-Lemeshow tests were acceptable for all ROC models (calibration) and the clinical SS, when compared with ACEF, did not improve ROC characteristics, net reclassification index, or integrated discrimination index (discrimination). Hence, the SS had little value for risk stratifying patients who underwent CABG in the ACUITY trial.

Since the SS has been recognized as an integral part of the decision algorithm when facing complex multivessel coronary artery disease,17,18 our findings are important and suggest that some improvement and refinement to the purely angiographic SS is needed if its predictability is to be improved among patients managed surgically. One way to improve the predictability of the SS is to consider the addition of clinical variables known to be associated with adverse events after CABG. To that extent, the SYNTAX score II (SS-II) was recently developed and combines the anatomical SS with anatomical and clinical variables that were shown to alter the threshold value of the anatomical SS, so that equipoise was achieved between CABG and PCI for long-term mortality.10 In the current study, the ACEF score, composed of age, ejection fraction, and creatinine clearance, was a considerably better predictor of death than SS.

A second way to improve the predictability of the SS for patients undergoing CABG would be to enhance the SS of angiographic variables that impact prognosis after CABG. Indeed, the poor predictive value of SS after CABG could be explained by the fact that surgical revascularization bypasses the most severe coronary lesions. In contrast to PCI, which attempts to restore the patency of the culprit lesion (the success of which depends in part on lesion characteristics), CABG diverts blood flow away from the lesion. Therefore, the complexity of the lesion (ie, tortuosity, calcification, chronic total occlusion) per se may be less if not at all important after CABG, at least as long as the graft remains open. This theory is supported by the observation that residual SS, based on the remaining untreated coronary artery disease, is more important than baseline SS in patients after PCI.19-21 Unfortunately, evaluation of residual disease may be challenging in patients post CABG, particularly in the absence of a post-CABG coronary angiogram. A more complex CABG-specific variant of the SS was recently developed in an attempt to account for functional grafts anastomosed distal to high-grade lesions;20 however, this score has not been validated and did not reach wide acceptance. 

Factors associated with graft failure are diverse and differ according to the timing of occlusion (periprocedural vs mid-term or long-term).22,23 Suitability and quality of the distal bed for bypass is probably one of the most important factors leading to graft failure. While at the center of every heart team discussion when debating the best option (PCI vs CABG) for a given patient, distal bed quality is absent from both the SS and the SS-II. Actually, only 1 variable in the SS may relates to CABG suitability, which is the “small/diseased” vessel variable, adding only 1 point when present in a given diseased segment. This variable may not be sufficiently elaborated to be associated to graft failure, and has been shown to be the SS variable with the most important reproducibility issue.13 Integration of a more elaborated variable related to distal bed quality into the SS could, by itself, substantially enhance the predictability of the SS among patients undergoing CABG. More data are needed to confirm this hypothesis.

Another important reason that might explain the failure of the SS to predict adverse events among CABG patients is the short length of follow-up. Indeed, although some grafts may fail within the first year, most graft failures are expected to occur approximately 10 to 15 years after the initial procedure.23,24 While bleeding and neurological events occurred periprocedurally after CABG, any follow-up shorter than 10 years will invariably lead to underdetection of any adverse ischemic events related to graft occlusion. On the other hand, if a proper follow-up is performed (eg, >15 years), the SS will most likely become an extremely important variable, knowing that the complexity of the coronary disease involving the native coronary artery is expected to increase with time.23,25 This concept will become even truer in situations when the native coronary artery becomes the only viable option of revascularization. This hypothesis has yet to be proven.

Study limitations. As a retrospective analysis from a prospective, randomized trial, the results of the current study should be considered hypothesis generating. Because patients were not randomized to the group assignment (SS), we cannot rule out the presence of unmeasured confounders. The SS could not be calculated for a considerable number of patients due to technical reasons. We cannot rule out that the exclusion of these patients from the analyses led to bias. Only 24 patients died; this increased the risk of committing type II statistical errors. Furthermore, we did not have enough statistical power to address the value of the different risk scores in multivariable models; however, this is the largest cohort of patients with NSTE-ACS treated with CABG in whom the predictive ability of the SS has been studied. Given the current lack of an online calculator, we could not reliably calculate the SS-II.10 Therefore, we cannot rule out the possibility that the SS-II would perform better than the other SS-based risk scores. Similarly, systematic angiography is rarely performed post CABG and details on the nature and extent of surgical revascularization were not collected in the ACUITY trial. Therefore, we could not assess the prognostic impact of the residual SS, which quantifies the degree of incompleteness or revascularization and which is associated with outcomes after PCI.19 We did not have data on the necessary variables for calculating the EuroSCORE or the Society of Thoracic Surgeons score. Very high SS (~50-60) has been shown to be associated with worse prognosis in patients with CABG in one study.7 The SS was lower in our study, and it is possible that the predictability of the SS improves when assessed among a surgical cohort of patients with more extensive coronary artery disease. Finally, longer follow-up could have led to different results.

Conclusion

The SS did not predict 1-year mortality and adverse events in patients with high-risk NSTE-ACS who underwent CABG in the ACUITY trial. 

References

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From the 1Cardiovascular Research Foundation, New York, New York; 2The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China; 3Dipartimento Cardiovascolare, Policlinico S. Orsola, Bologna, Italy; 4Hospital Israelita Albert Einstein, São Paulo, Brazil; 5Icahn School of Medicine at Mount Sinai, New York, New York; 6NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York; 7Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada; 8Morristown Medical Center, Morristown, New Jersey.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kirtane reports research grants to his institution from Medtronic, Boston Scientific, Vascular Dynamics, St. Jude Medical, Abiomed, Abbott Vascular, and Eli Lilly. Dr Mehran reports research grants to her institution from Eli Lilly/SKI, BMS, AstraZeneca, The Medicines Company, OrbusNeich, Bayer, CSL Behring, Abbott Laboratories, Watermark Research Partners, Novartis Pharmaceuticals, Medtronic, AUM Cardiovascular, Inc, and Beth Israel Deaconess Medical Center; executive committee fees from Janssen Pharmaceuticals and Osprey Medical; DSMB fees from Watermark Research Partners; and consulting fees from Medscape, The Medicines Company, Boston Scientific, Merck & Company, CSI, Sanofi USA, Shanghei BraccoSine Pharmaceutical, and AstraZeneca. Dr Stone reports consultant fees from Velomedix, Toray, Matrizyme, Miracor, TherOx, Reva, V-wave, Vascular Dynamics, Ablative Solutions, Neovasc, and Medical Development Technologies; equity/options in MedFocus family of funds, Guided Delivery Systems, Micardia, Vascular Nonotransfer Technologies, Cagent, Qool Therapeutics, Caliber, Aria, and Biostar family of funds. Dr Genereux reports speaker fees from Abbott Vascular, grant support from Boston Scientific, and speaker/consultant fees from CSI. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted August 22, 2016 and accepted August 29, 2016.

Address for correspondence: Philippe Généreux, MD, Cardiovascular Research Foundation, 1700 Broadway, 9th Floor, New York, NY 10019. Email: pgenereux@crf.org

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