Impact of Chronic Total Occlusions on Revascularization Scores and Outcome Prediction

Abstract: Objectives. To evaluate the contribution of chronic total occlusion (CTO)-related SYNTAX score (SS) to the overall SS for patients with CTO and compare the traditional SS to a simplified variant. The SS algorithm assigns CTO lesions a greater weight (5× points) than non-CTO lesions (50% to <100% diameter stenosis; 2× points). Methods. We calculated the SS and the simplified SS (2× points also to CTO lesions) for 4356 patients from the angiographic substudy of the Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial. We compared the association between SS and 1-year mortality and major adverse cardiac events for patients with and without a CTO. We also compared the simplified SS with the traditional SS. Results. The median SS was 20 (interquartile range, 13-27.5) for patients with a CTO and 8 (interquartile range, 2-16) for patients without a CTO. For patients with a CTO, the CTO lesion(s) contributed 67 ± 26% of the total SS. The simplified SS reclassified 187/603 (31.0%) of patients with a SS >22 to a SS ≤22. The traditional SS did not improve discrimination indices for predicting outcomes compared with the simplified SS. Conclusions. CTO lesions contribute considerably to the total SS in patients with a CTO. A simplified SS that does not differentiate between CTO and non-CTO lesions appeared equivalent to the traditional SS for risk prediction, but reclassified a substantial proportion of patients to a SS ≤22 and may impact choice of revascularization strategy for patients with complex coronary artery disease involving a CTO lesion.

J INVASIVE CARDIOL 2017;29(4):123-131. Epub 2017 March 15.

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

The SYNTAX score (SS) quantifies the severity and extent of coronary artery disease (CAD) and is used for predicting risk and guiding revascularization decisions.^1,2 The SS assigns a point value to each coronary lesion with a diameter stenosis ≥50% within a vessel ≥1.5 mm based on the amount of myocardium at risk (proximal vs distal) and its complexity (bifurcation, calcification, total occlusion, etc). The SS algorithm arbitrarily gives a greater weight (5×) to lesions with a chronic total occlusion (CTO; diameter stenosis 100%) compared with non-CTO lesions (2×; diameter stenosis 50% to <100%), aiming to reflect the difficulty of the percutaneous coronary intervention (PCI). Because of this, a CTO considerably increases a patient’s SS.^1,2 While CTO lesions are known to be more challenging for PCI revascularization and are associated with a lower rate of procedural success, giving CTO lesions a greater weight than non-CTO lesions might be questionable given that the SS already takes into account the myocardium at risk and gives a greater weight to proximal lesions compared with distal lesions. Actually, this might partially explain why the SS predicts adverse events after surgical revascularization inconsistently, since the complexity of the targeted lesion has no influence on the success of surgical revascularization.^3,4 Herein, we describe the impact of CTO-related SS on the total SS and the relationship between CTO-related SS and adverse outcomes using data from the multicenter, prospective, randomized ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial.

Methods

Study protocol. The ACUITY trial design has been reported in detail.⁵ Briefly, ACUITY was a multicenter, prospective, randomized trial of patients with moderate and high-risk non-ST elevation acute coronary syndromes 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, coronary artery bypass graft (CABG) surgery, 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.

Objectives, patients, and angiographic analysis. Our primary objectives were: (1) describe the proportion of the SS that is accounted for by the CTO lesion in patients with a CTO; (2) compare the association between SS and outcomes between patients with and without a CTO; and (3) compare the association between SS calculated with vs without CTO-specific extra weight and adverse outcomes for patients with a CTO. All patients who were enrolled in the quantitative coronary angiography substudy of the ACUITY trial were included regardless of whether the treatment strategy was PCI, CABG, or medical therapy. We performed separate analyses for each of these three patient cohorts. Patients who were treated with PCI were defined as the primary study population. Quantitative coronary angiographic analysis was performed by experienced angiographic core laboratory technicians at the Cardiovascular Research Foundation (New York, New York) who were blinded to treatment assignment and clinical outcomes.⁶

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.⁷ Each lesion with ≥50% diameter stenosis in vessels ≥1.5 mm in diameter was scored using the SS algorithm fully described elsewhere.¹ Interobserver (κ = 0.76; 95% confidence interval [CI], 0.64-1.00) and intraobserver (κ = 0.88; 95% CI, 0.66-0.89) reproducibility was at least substantial. For patients with a CTO, we calculated an alternative SS in which each CTO lesion was treated as if it was a non-CTO lesion (lesion weighted by a factor of 2 for both), ie, no CTO-related points were assigned (simplified SS) (Figure 1).

Statistical analysis. Continuous data are presented as mean ± standard deviation and were compared using analysis of variance and modified Student's t-test or the Kruskal-Wallis test, as appropriate. Categorical variables were compared using the Chi² test or Fisher's exact test. We defined the endpoint of major adverse cardiac event (MACE) as a composite of all-cause mortality, myocardial infarction, or unplanned revascularization. 

We constructed receiver-operator characteristic (ROC) curves to assess the predictive power of SS for 1-year death or MACE. For each treatment strata, we constructed three separate ROC curves: (1) all patients; (2) patients without a CTO; and (3) patients with a CTO. We report the 95% CIs for each estimate. For CTO patients, we compared ROC curves and calculated the net reclassification index (NRI) and the integrated discrimination index (IDI) for the association between SS with (traditional SS) and without (simplified SS) CTO-specific points and the risks for MACE and death. 

We also performed stratified univariate and multivariable Cox proportional hazards regression to assess whether the presence of a CTO influenced the association of SS with death and MACE. We included in the models SS as a continuous variable and fitted separate models for patients with and without CTO. In the adjusted models, we added the covariates age, insulin-treated diabetes mellitus, current smoking, sex, whether or not the patients had a diseased left anterior descending (LAD) coronary artery, and whether or not cardiac biomarkers (troponin or creatinine kinase-MB) were elevated. 

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. The SS was calculated for 4356 patients. Of these, 810 (19%) had a CTO (Figure 2). Among the entire study cohort, the median SS was 8 (interquartile range [IQR], 2-16). Among patients who had a CTO, the median SS was 19.5 (IQR, 13-27.5) vs 6 (IQR, 2-10) for patients with no CTO. Among CTO patients, the proportion of SS related to the CTO lesion was 67 ± 26%. The proportion of CTO patients among those with low SS (<22), intermediate SS (≥22 and <32), and high SS (≥32) was 12% (478/3838), 54% (240/445), and 64% (116/180). Among 563 CTO patients who underwent PCI, the CTO was left untreated in 187 patients (33%).

Clinical and angiographic characteristics are presented for patients with and without CTOs in Table 1. CTO patients were more likely to be men and have diabetes. They were also more likely to present with elevated cardiac biomarkers and were more likely to have triple-vessel disease. The coronary location of each lesion that was scored according to the SS algorithm is presented in Supplemental Table 1. Non-CTO patients had higher ejection fractions and were more likely to have hyperlipidemia and to previously have had a PCI. Medications used during the study period are presented in Table 2. Patients with a CTO were less likely to have antiplatelet drugs, beta-blockers, angiotensin-converting enzyme inhibitors, or statins at admission, but were more likely to use these drugs post discharge.

One-year clinical outcomes. In-hospital, 1-month, and 1-year clinical outcomes are presented in Table 3. Event rates were higher for CTO patients vs non-CTO patients. Higher SS was associated with higher risk of death or MACE for patients who were treated with PCI or medical therapy, but not for patients treated by CABG (Table 4).

The association between SS and MACE or death was similar for patients with and without a CTO, regardless of treatment strategy and for both unadjusted and adjusted Cox proportional hazards models (Table 5). ROC curves for the predictive ability of the SS in regard to death or MACE were similar regardless of whether or not a CTO was present (Supplemental Table 2). 

Traditional vs simplified SS related to CTO. Among patients with CTO lesions, the median simplified SS (CTO lesion weighted by a factor of 2) was 13.0 (IQR, 7.0-19.0) compared with the median traditional SS (CTO lesion weighted by a factor of 5) of 19.5 (IQR, 13.0-27.5). Among the 603 patients initially classified as having a SS >22 using the traditional SS scoring system for CTO, 189 (31%) were reclassified to a SS ≤22 when using the simplified SS. ROC curves were similar for traditional and simplified SS in regard to both death and MACE (Supplemental Table 3). Neither NRI nor IDI improved with the traditional SS vs the simplified SS (Table 6). 

Discussion 

To the best of our knowledge, this is the first study to address the contribution of CTO-related SS to total SS and its impact on risk prediction in patients undergoing PCI, CABG, or medical therapy. Using data from 4356 patients, we demonstrated that: (1) CTO lesions contribute a considerable proportion (more than two-thirds) of the total SS in patients with a CTO; (2) SS has similar predictive power for adverse events in patients with and without a CTO; and (3) a simplified SS that considers all lesions as non-CTO lesions appears to be equivalent to the traditional SS for risk prediction and reclassified approximately one-third of patients from a SS >22 to a SS ≤22.

The selection of the most appropriate revascularization strategy for patients presenting with complex CAD is still a matter of active debate.^8-11 CTO is a frequent subtype of lesion present among patients with complex CAD and is a well-known factor that influences many operators to refer patients to CABG. The SS is a well-recognized tool to risk stratify and guide the therapeutic decision-making process when facing complex CAD.¹ The SS has been shown to be predictive of ischemic events regardless of clinical presentation in patients undergoing PCI^12-20 or who are managed medically,²¹ but not in patients undergoing CABG.^3,4,12,22-24 The currently available SS algorithm assigns CTO lesions a higher score (weighted by a factor of 5) than non-CTO lesions (weighted by a factor of 2). Given that approximately two-thirds of the SS is explained by CTO lesions when present, patients with CTO lesions are intuitively and “mathematically” more prone to be sent to CABG.^25,26 In the current report, we demonstrated that among patients with a CTO, eliminating weighting CTO lesions by a factor of 5 for CTO lesions resulted in reclassification of approximately one-third of patients from a SS >22 to a SS ≤22, potentially impacting the selection of the most appropriate revascularization strategy for a given patient without compromising its prognostic capability for adverse ischemic events. This finding is important and, assuming high success rates (ie, >90%) in revascularizing CTO lesions percutaneously, may impact therapeutic strategy. Indeed, if an operator first succeeds in revascularizing a CTO lesion by PCI, patients may potentially have non-CTO residual disease that could either be treated by PCI or be treated medically if judged reasonable,^27-29 switching the balance in favor of PCI revascularization. Current effort and enthusiasm in developing expert CTO teams to increase the PCI success rate of CTO lesions is also expected to change the stratification algorithm of complex CAD and the revascularization strategy.^26,30-36 That being said, whether such a high CTO revascularization success rate (ie, >90%) could be achieved among non-CTO experts remains to be seen. 

In the current study, the association between SS and risk of death or MACE was similar for patients with and without a CTO. This relationship appears to hold true regardless of whether the patients were treated with PCI, CABG, or medical therapy. A similar association between the SS and outcome regardless of the presence of a CTO implies that the presence of a CTO does not influence the predictive ability the SS; however, the current scoring algorithm, although adequate, may not be optimal. In fact, not giving CTO lesions a greater weight did not result in a weaker association with outcome, implying that CTO lesions should be considered as a non-CTO lesion from a risk stratification point of view. ROC curves were poor for both the standard SS and the simplified SS (scoring all lesions as if they were non-CTOs), with no sign of a benefit with the traditional score. Furthermore, neither NRI nor IDI improved with the traditional SS vs the simplified SS. This implies that a simpler variant of the SS performs similarly in terms of risk prediction and that the aim in revascularization strategy should be the achievement of complete revascularization (or reasonably incomplete revascularization)^27-29 independent of the nature and complexity of the lesions involved. 

The location (proximal vs distal), amount of myocardium at risk, and the extent of CAD are potentially more important factors, prognostically speaking, than the complexity of a given lesion. Indeed, a CTO lesion involving a small vessel (eg, the third obtuse marginal) is most likely of little importance, whereas a significant lesion (CTO or not) involving the proximal LAD will be associated with poor outcomes if not revascularized. In fact, most studies show a greater effect on prognosis with CTO-PCI of the LAD than non-LAD CTO.^37,38 Considering that the SS already takes into account the location of the lesion (proximal vs distal) and scores lesions associated with a greater amount of jeopardized myocardium higher, any additional increment in score related to lesion complexity (ie, CTO) is probably not necessary.^1,2,39

Study limitations. As a retrospective analysis from a prospective, randomized trial, the results should be considered hypothesis generating. Our findings need to be reproduced in a prospective study. The complexity of the coronary disease in the ACUITY trial and the number of patients who had a CTO were relatively low. Our findings therefore need to be validated in a contemporary cohort of patients with more complex disease. However, to our knowledge, this is the largest cohort of patients with non-ST elevation acute coronary syndromes in whom the predictive ability of the SS has been studied and the first in which CTO importance and impact on prognosis was statistically assessed and challenged.

Conclusion

CTO lesions contribute considerably to the total SS in patients with CTOs. A simplified variant of the SS that does not differentiate between CTO and non-CTO lesions is equivalent to the traditional SS for risk prediction, reclassified a substantial proportion of patient to a SS ≤22, and may impact the selection of revascularization strategy for patients with complex CAD involving a CTO lesion.

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From the ¹Cardiovascular Research Foundation, New York, New York; ²Dipartimento Cardiovascolare, Policlinico S. Orsola, Bologna, Italy; ³Hospital Israelita Albert Einstein, São Paulo, Brazil; ⁴Icahn School of Medicine at Mount Sinai, New York, New York; ⁵VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas, Texas; ⁶Minneapolis Heart Institute, Minneapolis, Minnesota; ⁷NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, New York; ⁸Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada; and ⁹Gagnon Cardiovascular Institute, Morristown Medical Center, Morristown, New Jersey.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Mehran reports institutional research grants from Eli Lilly/DSI, 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 from Watermark Research Partners; consulting fees from Medscape, The Medicines Company, Boston Scientific, Merck, CSI, Sanofi USA, Shanghai BraccoSine Pharmaceutical, and AstraZeneca. Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, Asahi Intecc, Boston Scientific, Elsevier, Somahlution, St Jude Medical, and Terumo; research support from Boston Scientific and InfraRedx; spouse is employee of Medtronic. Dr Kirtane reports institutional research grants from Boston Scientific, Medtronic, Abbott Vascular, Abiomed, St. Jude Medical, Vascular Dynamics, and Eli Lilly. Dr Karmpaliotis reports speaker’s bureau fees from Boston Scientific, Abbott Vascular, and Medtronic; consultant fees from Vascular Solutions. Dr Stone reports consultant fees from St. Jude, Toray, Matrizyme, Ablative Solutions, Claret, Reva, V-wave, Vascular Dynamics, Miracor, Neovasc, Medical Development Technologies, BackBeat Medical, Valfix, and TherOx; equity/options from Cagent, Qool Therapeutics, Caliber, Aria, Biostar family of funds, MedFocus family of funds, Guided Delivery Systems, Micardia, and Vascular Nanotransfer Technologies. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted October 11, 2016; provisional acceptance given November 22, 2016; final version accepted November 30, 2016.

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