The SYNTAX Score: Usefulness, Limitations, and Future Directions

In 2009, the landmark Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial sought to establish whether coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) was the standard of care for patients with three-vessel or left main coronary artery disease.¹ The authors found that CABG, as compared with PCI, resulted in lower rates of major adverse cardiac or cerebrovascular events (MACCE) at 1 year; they also demonstrated that patients with less complex disease had equivalent outcomes to surgical and percutaneous revascularization at up to 3 years follow-up. SYNTAX highlighted the need for a multidisciplinary approach and appropriate risk stratification for patients with complex coronary disease in order to determine the optimal revascularization strategy.² The SYNTAX score (SXscore), a lesion-based angiographic scoring system, was introduced as a tool to grade the complexity of coronary artery disease. It was derived from a combination of the AHA classifications for coronary-tree segments, a modified Leaman score, the ACC/AHA lesion classification system, a combination of the Duke and ICPS bifurcation classification system, a chronic total occlusion classification system, and “consultation with experts.”³ The score was simple for interventional cardiologists and thoracic surgeons to use; physicians entered information on location, characteristics, tortuosity, and other factors for each lesion, which allowed the online calculator to generate a SXscore and a Kaplan-Meier curve showing what the cumulative event rate would have been for a patient at a similar risk level in the SYNTAX trial. The use of the SXscore was seen as not only a way to risk-stratify these complex patients using objective measurements, but also as a tool to encourage collaboration between surgeons and interventional cardiologists.³

Since the initial trial, a number of investigators have demonstrated that the SXscore can be used not only to risk-stratify patients with complex coronary disease, but also to predict clinical outcomes in various subsets of patients undergoing PCI. Across the board, studies have shown that patients with a relatively high SXscore have poorer outcomes, and that the score is an independent predictor of MACCE for PCI. As an example, Wykrzykowska et al demonstrated that the SXscore, when applied to an “all-comers” patient population treated with drug-eluting stents (DES), allowed for prospective risk stratification of patients undergoing PCI.⁴ Specifically, the authors looked at the subset of patients from the LEADERS (Limus Eluted from A Durable versus ERodable Stent coating) trial that had prospectively collected SXscore (1397 of the 1707 patients enrolled) and stratified their outcomes-based SXscore tertiles (<8, between 8 and 16, and >16). They were able to show a statistically significant increase in outcomes including death, myocardial infarction rate, and target vessel revascularization (TVR) in the higher tertiles at 1 year. Chakravarty et al looked at unprotected left-main artery PCI in a group of 120 patients and associated higher SXscores with lower survival rates (62.1% at SXscore of >36 vs 82.4% at SXscore of <36; P<.03) and target vessel revascularization-free (MACCE)survival (47.7% at SXscore >20 vs 76.6% at SXscore <20; P<.02), and an increase in all-cause mortality, myocardial infarction, and cerebrovascular events.⁵ Clinical outcomes at 5-year follow-up from the ARTS II trial, which included two- and three-vessel disease patients treated with PCI, also demonstrated a statistically significant separation of MACCE-free survival when patients were stratified according to SXscore tertiles, reinforcing the utility of the SXscore as an independent predictor of clinical outcomes in complex coronary patients undergoing PCI.⁶

Despite its initial promise and significant prognostic value, the SXscore, like other prediction tools, is not perfect. As a stand-alone lesion-based scoring system, which relies primarily on angiographic interpretation, it has been shown to have a lower ability to predict mortality when compared with scoring systems using clinical characteristics.⁷ As a result, a number of novel scores have been developed that include clinical and functional characteristics to improve predictive value. For example, the clinical SYNTAX score (CSS) combined the SXscore and a modified ACEF score, which is calculated using this formula: age/ejection fraction +1 point for every 10 ml/min reduction in creatinine clearance below 60 ml/min/1.73 m², up to a maximum of 6 points.^8,9 The ARTS II population was stratified by tertiles of the CSS, and the resultant risk model for predicting outcomes for MACCE and death at 5 years was found to be superior to the SXscore or modified ACEF score alone.⁷ The CSS, however, was still limited in its ability to differentiate between the clinical events for the low- and intermediate-risk tertiles. Another example is the functional SXscore, which implements the fractional flow reserve (FFR) technique as validated in the FFR versus Angiography for Guiding PCI in Patients with Multivessel Evaluation (FAME) study.¹⁰ When FFR data were incorporated into the SXscore, risk stratification of patients in the FFR-guided arm of FAME was improved when compared to use of the anatomical SXscore alone.¹¹

Another limitation of the early SXscore studies is their dependence on angiographic interpretation by experienced cardiologists, which resulted in over- and underestimation of lesion severity, as well as moderate interobserver variability.^12,13 The use of quantitative coronary angiography (QCA), which has been shown to be superior to visual estimates of vessel size, potentially addresses these inconsistencies.¹⁴ QCA uses a 3-step process to determine the severity of a coronary lesion: digitization, image calibration, and arterial contour detection.¹³ While QCA does have its own limitations (i.e., evaluating smaller diameter vessels and complex lesion morphology with irregular borders), this technology continues to improve with time. New applications for 2- and 3-dimensional QCA continue to emerge; recently, 3-dimensional QCA was validated as a methodology to predict functionally significant FFR in coronary lesions of intermediate severity.¹⁵

Looking to the future, the ideal tool to guide revascularization strategy and predict cardiovascular outcomes in coronary artery disease patients will require more than just visual anatomical assessment of coronary lesions. It will need to incorporate both angiographic and clinical variables, minimize intra- and interobserver variability, demonstrate “real-world” reproducibility, and perhaps above all, be user-friendly and minimize the number of input variables. With the increasing use of QCA, the availability of electronic medical records, and novel approaches to evaluating coronary stenosis such as that being evaluated in the DEFACTO trial (using coronary computed tomography angiograms to calculate virtual fractional flow reserves), a better tool is certainly within reach, and could lead to significant improvements in clinical outcomes and health care delivery.¹⁶

References

1. Serruys PW, Morice MC, Kappetein AP, et al. Percutaneous coronary intervention versus coronary artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009;360(10):961-972.
2. Evora PR, Bassetto S, Celotto AC, Capellini VK. The 2010 ESC/EACTS guidelines on myocardial revascularization does not present suggestions about disease-free saphenous vein grafts at the time of redo coronary artery bypass grafting. Eur J Cardiothorac Surgery. 2011 Jul 25 (Epub ahead of print).
3. Wood S. Syntax tool unvieled at EuroPCR: Now the trick is to use it. May 22, 2009. Accessed at https://www.theheart.org/article/973297.do
4. Wykrzykowska JJ, Garg S, Girasis C, et al. Value of the syntax score for risk assessment in the all-comers population of the randomized multicenter LEADERS (limus eluted from a durable versus erodable stent coating) trial. J Am Coll Cardiol. 2010;56(4):272-277.
5. Chakravarty T, Buch MH, Naik H, et al. Predictive accuracy of syntax score for predicting long-term outcomes of unprotected left main coronary artery revascularization. Am J Cardiol. 2011;107(3):360-366.
6. Serruys PW, Onuma Y, Garg S, et al. 5-year clinical outcomes of the ARTS II (arterial revascularization therapies study II) of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions. J Am Coll Cardiol.  2010;55(11):1093-1101.
7. Garg S, Sarno G, Garcia-Garcia HM, et al. A new tool for the risk stratification of patients with complex coronary artery disease: the clinical SYNTAX score. Circ Cardiovasc Interv. 2010;3(4):317-326.
8. Ranucci M, Castelvecchio S. The ACEF score one year after: a skeleton waiting for muscles, skin, and internal organs. EuroIntervention. 2010;6(5):549-553.
9. Ranucci M, Castelvecchio S, Menicanti L, Frigiola A, Pelissero G. Risk of assessing mortality risk in elective cardiac operations: age, creatinine, ejection fraction, and the law of parsimony. Circulation. 2009;119(24):3053-3061.
10. Pijls NH, Fearon WF, Tonino PA, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention in patients with multivessel coronary artery disease: 2-year follow-up of the fame (fractional flow reserve versus angiography for multivessel evaluation) study. J Am Coll Cardiol. 2010;56(3):177-184.
11. Nam CW, Mangiacapra F, Entjes R, et al. Functional SYNTAX score for risk assessment in multivessel coronary artery disease.  J Am Coll Cardiol. 2011;58(12):1211-1218.
12. Ibrahim TH, Mehmet E, Turgay I, Mustafa K, Ahmet K, Serdar S. Reproducibility of SYNTAX score: from core lab to real world. J Intervent Cardiol. 2011;24(4):302-306.
13. Ng VG, Lansky AJ. Novel QCA methodologies and angiographic scores. Int J Cardiovasc Imaging. 2011;27(2):157-165.
14. Farooq V, Brugaletta S, Serruys PW. Contemporary and evolving risk scoring algorithms for percutaneous coronary intervention. Heart. 2011;97(23):1902-1913.
15. Yong AS, Ng AC, Brieger D, Lowe HC, Ng MK, Kritharides L. Three-dimensional and two-dimensional quantitative coronary angiography, and their prediction of reduced fractional flow reserve. Eur Heart J. 2011;32(3):345-353.

16. Min JK, Berman DS, Budoff MJ, et al Rationale and design of the DeFACTO (determination of fractional flow reserve by anatomic computed tomographic angiography) study. J Cardiovasc Comput Tomogr. 2011;5(5):301-309.

____________________________________

From the Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center (AKC, CMG), Harvard Medical School, Boston, Massachusetts.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Address for correspondence: Anjan K. Chakrabarti, MD, Beth Israel Deaconess Medical Center, Division of Cardiology, 185 Pilgrim Road, Baker 4, Boston, MA 02215. Email: akchakra@bidmc.harvard.edu