10 Years of SYNTAX

The SYNTAX trial randomized patients equally eligible for coronary artery bypass grafting or percutaneous coronary intervention using the Heart Team approach. The SYNTAXES study achieved a follow-up rate of 93.8% and reported the 10-year vital status. Factors associated with increased mortality at 10 years were pharmacologically treated diabetes mellitus, increased waist circumference, reduced left ventricular function, prior cerebrovascular and peripheral vascular disease, western Europe and North American descent, current smoking, chronic obstructive pulmonary disease, elevated C-reactive protein, anemia, and an increase in HbA1c. Procedural factors associated with higher 10 years mortality include periprocedural myocardial infarction, extensive stenting, small stents, ≥1 heavily calcified lesion, ≥1 bifurcation lesion, residual SYNTAX score >8, and staged percutaneous coronary intervention. Optimal medical therapy at 5 years, use of statins, on-pump coronary artery bypass grafting, multiple arterial grafts, and higher physical component score and mental component score were associated with lower mortality at 10 years. Numerous scores and prediction models were developed to help individualize risk assessment. Machine learning has emerged as a novel approach for developing risk models.

S electing the optimal mode of revascularization for individual patients with complex coronary artery disease (CAD) remains challenging.
Analysis of the risk benefit ratio of alternative strategies of revascularization is complex. It includes consideration of multiple issues and analysis includes interaction between these multiple issues ( Table 1).
Although study of the individual as well as the totality of these issues has been a goal of modern cardio-     Considering the size of the SYNTAX study and its allcomers design, with minimal exclusion, the cohort offers ample opportunity to try to identify a population that has most to gain from either CABG or PCI (Central Illustration). In the following is a summary of the results from prespecified analyses from SYNTAX and SYNTAXES.
SEX. At 5 years, morality following revascularization with PCI vs CABG differed significantly between females and males and based on this significant sextreatment interaction, female sex was incorporated into the SYNTAX score II (SSII). At 10 years, mortality was still higher with females compared with males (log-rank P ¼ 0.002); however, female sex was no longer an independent predictor of mortality (P ¼ 0.915) ( Figure 2A). Overall, 10-year mortality tended to be lower after CABG than after PCI, with a similar relative treatment effect between the sexes (P interaction ¼0.952), 11 such that female sex was no longer retained in the redeveloped and calibrated SYNTAX Score II 2020 (SSII-2020) risk model. 12 Of note, the significant mortality benefit with CABG observed in females at 5 years disappeared at 10 years ( Figure 2B, Table 3).    Table 3).
ELDERLY. Approximately a third of the study cohort were elderly (>70 years) and 10-year mortality did not differ significantly following PCI or CABG among elderly and nonelderly patients (P interaction ¼ 0.332) ( Figure 4). Elderly patients with 3VD and/or LMCAD had comparable 10-year mortality, life expectancy, 5-year MACCE, and 5-year quality of life status irrespective of the modality of revascularization. Of note, in elderly patients undergoing CABG fewer arterial conduits and more venous conduits were used compared with the nonelderly group. 15 SMOKING. Current smokers, who were on average 10 years younger than nonsmokers, made up approximately 20% of the study cohort, and had a significantly higher risk of 10-year all-cause mortality compared with those who had never smoked,

CENTRAL ILLUSTRATION Continued
SYNTAX trial used the Heart Team approach for the first time to randomize patients equally eligible for both CABG and PCI. Several clinical, procedural, and postprocedural variables and their impact on 10-year mortality have been assessed since then. Various scoring systems namely anatomical SYNTAX score and SYNTAX score II, and prediction models (SYNTAX score II) were developed during the course of the trial to individualize risk among patients undergoing revascularization.
Certainly, we have seen the evolution of risk factor assessment from conventional multivariable models to models based on the interaction for risk, to models based on calibration and treatment benefit, and now to models based on machine learning. BMI ¼ body mass index; CABG ¼ coronary artery bypass grafting; CVD ¼ cardiovascular disease; CEVD ¼ cerebrovascular disease; COPD ¼ chronic obstructive pulmonary disease; LAD ¼ left anterior descending coronary artery; LVEF ¼ left ventricular ejection fraction; LMCAD ¼ left main coronary artery disease; MI ¼ myocardial infarction; MVD ¼ multivessel disease; PCI ¼ percutaneous coronary intervention; PMAE ¼ periprocedural major adverse event(s); PVD ¼ peripheral vascular disease; WC ¼ waist circumference; SYNTAX ¼ Synergy Between percutaneous coronary intervention with Taxus and coronary artery bypass surgery. whereas former smokers did not. This suggests that the "smokers paradox" does not exist in stable patients with complex CAD. 16,17 Current smokers had a higher risk of all-cause mortality following PCI compared with CABG; however, no significant interaction was seen between revascularization strategy and smoking status (P interaction ¼ 0.910). In the CABG arm, the crude rates of all-cause mortality were similar irrespective of smoking status ( Figure 5). 18 However, in conjunction with data from FREEDOM, smoking status (current smoker) at the time of randomization was retained in the SSII-2020 as an independent predictor of all-cause mortality ( Table 3).  Figure 6). Overall, patients with an LVEF <50% had a poorer prognosis than those with pEF. Ten-year mortality in patients with rEF was higher with PCI than CABG, but this difference was not statistically significant (52.9% vs 39.6%; P ¼ 0.054) presumably due to the small sample size (n ¼ 168; PCI group: n ¼ 77; CABG group: n ¼ 91). The significant interaction for all-cause mortality between LVEF subgroups and revascularization modality at 5-year follow-up was no longer seen at 10 years ( Figure 6, Table 3).   Table 3). 19 10-year all-cause death (aHR: 1.07, 1.08, and 1.15).
Patients who did not have a history of diabetes at enrollment but had HbA1c $6% (42 mmol/mol) had higher mortality at 10 years (aHR: 1.38), especially after PCI (aHR: 1.82). In contrast, preprocedural HbA1c did not predict 10-year all-cause mortality in patients with medically treated diabetes at enrollment. Inclusion of biological markers into the SSII-2020 did not significantly improve predictivity. 20 As is discussed later in contrast to the SSII-2020, machine learning (ML) algorithms identified CRP as one variable able to predict 10-year mortality ( Table 3).  however, prior MI was not ( Table 3). 21 COPD. Approximately 9% of the study cohort had COPD, and regardless of revascularization strategy, these patients had a higher risk of 10-year all-cause death compared with those without (P < 0.001). The relative treatment effects of CABG vs PCI on 10-year all-cause death were not significantly different for patients with and without COPD, and although it was an independent predictor of 10-year all-cause death after CABG, it was not after PCI ( Table 3) (Figures 11 and 12).
The differences in 10-year mortality remained       Figure 14). The observed mortality rates after PCI and CABG were not significantly different in patients with a predicted absolute risk difference (ARD) in 5-year mortality <4.5%: observed ARD 2.1% (95% CI: À0.4% to 4.4%), whereas a significant difference in survival favoring CABG was observed in patients with a predicted ARD $4.5% (observed ARD: Recently, ML has emerged as a novel approach for developing risk models predictive of clinical outcomes. 28  P < 0.001) ( Figure 16A). 28 The 10 most important variables to predict 10-year mortality from the best performing model are shown in Figure 16B.

SECTION 5: EVIDENCE FROM SYNTAXES
The SYNTAXES study provides the first randomized data, that were meticulously collected, and achieved Other important takeaways were that patients with prior CEVD or COPD should not be precluded from  risks should be actionable, and must be implementable into practice. 26 We have seen a transition from use of the anatomical SXscore to SSII to SSII-2020 when individualizing revascularization decisions between PCI and CABG in patients with complex CAD. 12,27 The SSII-2020 has been validated in 4 randomized trials (BEST, PRECOMBAT, EXCEL, FREEDOM) and 1 large registry (CREDO-Kyoto PCI/ CABG). 30 Certainly we have seen the evolution of risk factor assessment from conventional multivariable models, to models based on the interaction for risk, to  (Top) In case 1, the patient has predicted 5-year mortality rates of 7.8% after PCI and 5.6% after CABG. The predicted ARD is 2.2% (<4.5%); therefore, the patient can be referred to either PCI or CABG. In case 2, the patient has predicted 5-year mortality rates of 53.5% after PCI and 40.6% after CABG. The predicted ARD is 12.9% ($4.5%). CABG should be recommended. (Bottom) The individual differences between the predicted mortality (individual scatterplots and solid smoothing curves) as well as the observed mortality (dashed smoothing curves) after PCI or CABG. Reproduced with permission from Hara et al. 30 ARD ¼ absolute risk difference; COPD ¼ chronic obstructive pulmonary disease; LMCAD ¼ left main coronary artery disease; LVEF ¼ left ventricular ejection fraction; PVD ¼ peripheral vascular disease; other abbreviations as in Figure 4.  and LM disease in the Asian population too. 12 The With Multivessel Disease-2) randomized controlled trial will be recruiting 1,800 patients with diabetes and multivessel disease in India. 44 The secondary objective of the study is to evaluate whether the pooled cohort of PCI provides similar clinical outcomes to CABG based on the performance goal derived from the CABG arm of the FREEDOM trial (historical cohort). The Asian population needs more trials like SYNTAX to better understand and address the interethnic differences in CVD and formulate its own guidelines for CAD, which is the need of the hour.

HIGHLIGHTS
Risk stratification among patients with complex CAD is central to decision making between CABG and PCI.
Revascularization strategy in complex CAD should consider multiple factors (clinical, procedural, postprocedural) and analysis includes interaction between these multiple factors.
We have seen evolution of risk factor assessment from conventional multivariable models to models based on the interaction for risk, to models based on calibration and treatment benefit, and now to models based on machine learning.