Serruys, Patrick W.

Abstract Aims The aim of this article was to compare rates of all-cause death at 10 years following coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in patients with or without diabetes. Methods and results The SYNTAXES study evaluated up to 10-year survival of 1800 patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to receive either PCI or CABG in the SYNTAX trial. Ten-year all-cause death according to diabetic status and revascularization strategy was examined. In diabetics (n = 452), the risk of mortality was numerically higher with PCI compared with CABG at 5 years [19.6% vs. 13.3%, hazard ratio (HR): 1.53, 95% confidence interval (CI): 0.96, 2.43, P = 0.075], with the opposite seen between 5 and 10 years (PCI vs. CABG: 20.8% vs. 24.4%, HR: 0.82, 95% CI: 0.52, 1.27, P = 0.366). Irrespective of diabetic status, there was no significant difference in all-cause death at 10 years between patients receiving PCI or CABG, the absolute treatment difference was 1.9% in diabetics (PCI vs. CABG: 36.4% vs. 34.5%, difference: 1.9%, 95% CI: −7.6%, 11.1%, P = 0.551). Among insulin-treated patients (n = 182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%, difference: 8.2%, 95% CI: −6.5%, 22.5%, P = 0.227). Conclusions The treatment effects of PCI vs. CABG on all-cause death at 10 years in patients with 3VD and/or LMCAD were similar irrespective of the presence of diabetes. There may, however, be a survival benefit with CABG in patients with insulin-treated diabetes. The association between revascularization strategy and very long-term ischaemic and safety outcomes for patients with diabetes needs further investigation in dedicated trials. Trial registration SYNTAX: ClinicalTrials.gov reference: NCT00114972 and SYNTAX Extended Survival: ClinicalTrials.gov reference: NCT03417050.

Abstract OBJECTIVES This study sought to evaluate the long-term differences in survival between multiple arterial grafts (MAG) and single arterial grafts (SAG) in patients who underwent coronary artery bypass grafting (CABG) in the SYNTAX study. METHODS The present analysis included the randomized and registry-treated CABG patients (n = 1509) from the SYNTAX Extended Survival study (SYNTAXES). Patients with only venous (n = 42) or synthetic grafts (n = 1) were excluded. The primary end point was all-cause death at the longest follow-up. Multivariable Cox regression was used to adjust for differences in baseline characteristics. Sensitivity analysis using propensity matching with inverse probability for treatment weights was performed. RESULTS Of the 1466 included patients, 465 (31.7%) received MAG and 1001 (68.3%) SAG. Patients receiving MAG were younger and at lower risk. At the longest follow-up of 12.6 years, all-cause death occurred in 23.6% of MAG and 40.0% of SAG patients [adjusted hazard ratio (HR) 0.74, 95% confidence interval (CI) (0.55–0.98); P = 0.038], which was confirmed by sensitivity analysis. MAG in patients with the three-vessel disease was associated with significant lower unadjusted and adjusted all-cause death at 12.6 years [adjusted HR 0.65, 95% CI (0.44–0.97); P = 0.033]. In contrast, no significance was observed after risk adjustment in patients with the left main disease, with and without diabetes, or among SYNTAX score tertiles. CONCLUSIONS In the present post hoc analysis of all-comers patients from the SYNTAX trial, MAG resulted in markedly lower all-cause death at 12.6-year follow-up compared to a SAG strategy. Hence, this striking long-term survival benefit of MAG over SAG encourages more extensive use of multiple arterial grafting in selected patients with reasonable life expectancy. Trial registration SYNTAXES ClinicalTrials.gov reference: NCT03417050; SYNTAX ClinicalTrials.gov reference: NCT00114972.

Abstract Aim The aim of this study was to compare long-term all-cause mortality between patients receiving percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) using multiple (MAG) or single arterial grafting (SAG). Methods and results The current study is a post hoc analysis of the SYNTAX Extended Survival Study, which compared PCI with CABG in patients with three-vessel (3VD) and/or left main coronary artery disease (LMCAD) and evaluated survival with ≥10 years of follow-up. The primary endpoint was all-cause mortality at maximum follow-up (median 11.9 years) assessed in the as-treated population. Of the 1743 patients, 901 (51.7%) underwent PCI, 532 (30.5%) received SAG, and 310 (17.8%) had MAG. At maximum follow-up, all-cause death occurred in 305 (33.9%), 175 (32.9%), and 70 (22.6%) patients in the PCI, SAG, and MAG groups, respectively (P < 0.001). Multiple arterial grafting [adjusted hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.49–0.89], but not SAG (adjusted HR 0.83, 95% CI 0.67–1.03), was associated with significantly lower all-cause mortality compared with PCI. In patients with 3VD, both MAG (adjusted HR 0.55, 95% CI 0.37–0.81) and SAG (adjusted HR 0.68, 95% CI 0.50–0.91) were associated with significantly lower mortality than PCI, whereas in LMCAD patients, no significant differences between PCI and MAG (adjusted HR 0.90, 95% CI 0.56–1.46) or SAG (adjusted HR 1.11, 95% CI 0.81–1.53) were observed. In patients with revascularization of all three major myocardial territories, a positive correlation was observed between the number of myocardial territories receiving arterial grafts and survival (P trend = 0.003). Conclusion Our findings suggest that MAG might be the more desirable configuration for CABG to achieve lower long-term all-cause mortality than PCI in patients with 3VD and/or LMCAD. Trial registration Registered on clinicaltrial.gov. SYNTAXES: NCT03417050 (https://clinicaltrials.gov/ct2/show/NCT03417050); SYNTAX: NCT00114972 (https://www.clinicaltrials.gov/ct2/show/NCT00114972).

Background: Cardiovascular risk factors have an impact on coronary atherosclerosis evolution. However, there is only limited information about the relationship between risk and atherosclerotic plaque as measured invasively by Intravascular Ultrasound Radiofrequency (IVUS-RF) analysis. The Aim of this study was to assess the impact of cardiovascular risk factors not only on overall coronary plaque volume but on coronary plaque composition. Methods: 990 patients from 42 centers were enrolled in the prospective, multicenter, non randomized, global VH-IVUS registry. Coronary lesions were measured by conventional and IVUS-VH parameters using 20MHz Intravascular Ultrasound catheter. The four IVUS-VH plaque components (Dense Calcium-DC, Necrotic Core-NC, Fibrous tissue-F, Fibro Fatty-FF) were analyzed in every recorded frame. The results were expressed as mean cross-sectional areas, and percentage of total plaque volume. Risk factor assessment included correlation with family history of myocardial infarction, past or current smoking, diabetes mellitus, hypertension, and laboratory measurements. Results: Patients with diabetes have an increased relative amount of NC (6.47±0.28% vs. 5.86±0.14%, p=0.037) and DC (4.58±0.27% vs. 3.90±0.14%, p=0.017), Patients with hypertension have an increased relative amount of FF, DC (4.35±0.16% vs. 3.57±0.17%, p=0.02) and NC (6.24±0.17% vs. 5.60±0.19%, p=0.01). Compared with patients with LDL cholesterol 160 mg/dl had higher plaque volume (342.1±26.2mm 3 vs. 318.6±10.7mm 3 ). Linear Regression Analysis showed a correlation between the level of HDL and F (r=−0.149, p<0.01), FF (r=−0 –106, p< 0.01), and NC (r=−0.90, p<0.05). The level of LDL correlated with F (r = 0.110, p < 0.01). Patients with prior MI have an increased percentage of F (30.03±0.59 % vs. 28.20±0.37 %, p<0.009). Smoking had no relevant effect on plaque composition. Conclusion: IVUS-RF analysis detects marked differences in coronary plaque depending on the risk factor profile with particular focus on lipid levels. Patients with greater amounts of necrotic core were associated with hypertension, myocardial infarction, and low HDL. This may have implications for prognosis and systemic treatment of patients with coronary artery disease.

Background: Ten-year all-cause death according to incomplete (IR) versus complete revascularization (CR) has not been fully investigated in patients with 3-vessel disease and left main coronary artery disease undergoing percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). Methods: The SYNTAX Extended Survival study (Synergy Between PCI With TAXUS and Cardiac Surgery: SYNTAX Extended Survival [SYNTAXES]) evaluated vital status up to 10 years in patients who were originally enrolled in the SYNTAX trial. In the present substudy, outcomes of the CABG CR group were compared with the CABG IR, PCI CR, and PCI IR groups. In addition, in the PCI cohort, the residual SYNTAX score (rSS) was used to quantify the extent of IR and to assess its association with fatal late outcome. The rSS of 0 suggests CR, whereas a rSS>0 identifies the degree of IR. Results: IR was more frequently observed in patients with PCI versus CABG (56.6% versus 36.8%) and more common in those with 3-vessel disease than left main coronary artery disease in both the PCI arm (58.5% versus 53.8%) and the CABG arm (42.8% versus 27.5%). Patients undergoing PCI with CR had no significant difference in 10-year all-cause death compared with those undergoing CABG (22.2% for PCI with CR versus 24.3% for CABG with IR versus 23.8% for CABG with CR). In contrast, those with PCI and IR had a significantly higher risk of all-cause death at 10 years compared with CABG and CR (33.5% versus 23.7%; adjusted hazard ratio, 1.48 [95% CI, 1.15–1.91]). When patients with PCI were stratified according to the rSS, those with a rSS≤8 had no significant difference in all-cause death at 10 years as the other terciles (22.2% for rSS=0 versus 23.9% for rSS>0–4 versus 28.9% for rSS>4–8), whereas a rSS>8 had a significantly higher risk of 10-year all-cause death than those undergoing PCI with CR (50.1% versus 22.2%; adjusted hazard ratio, 3.40 [95% CI, 2.13–5.43]). Conclusions: IR is common after PCI, and the degree of incompleteness was associated with 10-year mortality. If it is unlikely that complete (or nearly complete; rSS<8) revascularization can be achieved with PCI in patients with 3-vessel disease, CABG should be considered. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00114972. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03417050.

AbstractObjectivesWe investigated the impact of total stent length (TSL) and average nominal stent diameter (ASD) on 10‐year mortality after percutaneous coronary intervention (PCI) in the SYNTAXES trial.BackgroundTSL and ASD in patients treated with PCI are associated with major adverse cardiovascular events. However, the treatment effect of PCI with extensive and/or small stenting as compared with coronary artery bypass grafting (CABG) for complex coronary artery disease has not been fully evaluated.MethodsImpacts on mortality of extensive stenting defined as TSL >100 mm and small stenting as ASD <3 mm were analyzed in 893 PCI patients and were compared to 865 CABG patients.ResultsTSL as a continuous variable was significantly associated with 10‐year mortality (adjusted hazard ratio [HR], 1.05 [1.01–1.09] per 10 mm increase). PCI patients with extensive stenting had a higher 10 year mortality than CABG patients (adjusted HR, 1.97 [1.41–2.74]) or not‐ extensive stenting PCI (adjusted HR, 1.94 [1.36–2.77]). Although ASD did not have a significant association with 10 year mortality (adjusted HR, 0.97 [0.85–1.11] per 0.25 mm increase), PCI with small stents was associated with a higher 10 year mortality, compared to CABG (adjusted HR, 1.66 [1.23–2.26]) and PCI performed with large stents (adjusted HR, 1.74 [1.19–2.53]). Patients treated with not‐extensive and large stents had similar mortality rates (24.0 versus 23.8%) as those treated with CABG.ConclusionsExtensive and small stenting were associated with higher 10 year mortality, compared with CABG. When patients have to be treated with extensive or small stenting, revascularization with CABG should be preferred.

Abstract Aims To evaluate the impact of various smoking status on 10-year all-cause mortality and to examine a relative treatment benefit of coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI) according to smoking habits. Methods and results The SYNTAX Extended Survival study evaluated vital status up to 10 years in 1800 patients with de novo three-vessel disease and/or left main coronary artery disease randomized to CABG or PCI in the SYNTAX trial. In the present analysis, patients were divided into three groups (current, former, or never smokers), and the primary endpoint of 10-year all-cause mortality was assessed according to smoking status. Smoking status was available in 1793 (99.6%) patients at the time of randomization, of whom 363 were current smokers, 798 were former smokers, and 632 were never smokers. The crude rates of 10-year all-cause mortality were 29.7% in current smokers, 25.3% in former smokers, and 25.9% in never smokers (Log-rank P = 0.343). After adjustment for imbalances in baseline characteristics, current smokers had a significantly higher risk of 10-year all-cause mortality than never smokers [adjusted hazard ratio (aHR): 2.29; 95% confidence interval (CI): 1.60–3.27; P &lt; 0.001], whereas former smokers did not. PCI was associated with a higher risk of all-cause mortality than CABG among current smokers (HR: 1.60; 95% CI: 1.09–2.35; P = 0.017), but it failed to show a significant interaction between revascularization strategies and smoking status (Pinteraction = 0.910). Conclusion Current smokers had a higher adjusted risk of 10-year all-cause mortality, whereas former smokers did not. The treatment effect of CABG vs. PCI did not differ significantly according to smoking status. Clinical trial registration SYNTAX: ClinicalTrials.gov reference: NCT00114972; SYNTAX Extended Survival. ClinicalTrials.gov reference: NCT03417050.

Abstract Background Coronary artery disease is the leading cause of death among elderly men and women worldwide. The aging society worldwide will lead to increasing numbers of elderly patients with multivessel coronary artery disease. Although age is recognized as one of the most important factors in a decision-making for revascularization of multivessel coronary artery disease, the very long-term outcomes in patients undergoing revascularization by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) is still unclear. Objectives The aim of the present study was to investigate the association between revascularization strategies and 10-year outcomes in elderly patients. Methods The SYNTAX Extended Survival (SYNTAXES) study (NCT 03417050) is an investigator-driven extension of follow-up of a multicentre, randomised controlled trial done in 85 hospitals across 18 North American and European countries, enrolling 1,800 patients with de novo three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to revascularization strategy with CABG versus PCI in the SYNTAX trial. Patients were divided into two groups according to the prespecified threshold of 70 years old; elderly patients (&gt;70 years) and non-elderly patients (≤70 years). The primary endpoint of this study was all-cause death at 10 years. Results Out of 1,800 patients, 575 patients (31.9%) were classified as elderly (&gt;70 years). The mean age ± standard deviation (SD) of the elderly patients and the non-elderly patients was 75.8±3.6 years and 60.1±7.4 years, respectively. Of note, elderly patients were more frequently female than non-elderly patients (33.6% vs. 17.1%, p&lt;0.001). As expected, the elderly patients had higher prevalence of chronic kidney disease (43.4% vs. 7.9%, p&lt;0.001), had higher anatomical SYNTAX score (30.2±11.8 vs 28.0±11.2 p&lt;0.001) when compared to those of the non-elderly patients. Up to 10 years, all-cause death occurred in 42.7% and 18.9% in the elderly and non-elderly patients, respectively (Log-rank p&lt;0.001). The cubic spline curve showed an exponentially increase in all-cause death at 10 years according to the increase of age both in the PCI arm and the CABG arm. At 10 years, there was no significant difference in the risk of all-cause death between CABG vs. PCI either in elderly patients (41.5% vs. 44.0%; Log-rank p=0.53) or non-elderly patients (16.6% vs. 21.1%; Log-rank p=0.051). Conclusion CABG and PCI were equipoise in terms of risk of all-cause death at 10 years in patients with de novo 3VD and/or LMCAD irrespective of their age when stratified according to the prespecified threshold of 70 years old. Kaplan-Meier curves Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Foundation of Heart Research

Abstract Background The SYNTAX Extended Survival (SYNTAXES) study is an investigator-driven extension of follow-up of the SYNTAX trial, which was a non-inferiority trial that compared percutaneous coronary intervention (PCI) using first-generation paclitaxel-eluting stents with coronary artery bypass grafting (CABG) in patients with de-novo three-vessel and left main coronary artery disease. The SYNTAXES study is the first randomized trial that reported the complete 10-year data on all-cause death in patients with complex coronary artery disease. Purpose Patients with coronary artery disease (CAD) and concomitant diabetes mellitus (DM) or chronic kidney disease (CKD) are more susceptible to major adverse cardiovascular and cerebrovascular events. However, to date, the long-term prognosis and which revascularization strategy was associated with better clinical outcomes for patients with complex coronary artery disease and concomitant with DM and CKD have not been documented. Methods In this sub-analysis of the SYNTAXES trial, a total of 1,638 patients were classified into four subgroups according to the DM and CKD status: DM−/CKD− (n=999, 60.1%), DM+/CKD− (n=323, 19.7%), DM−/CKD+ (n=231, 14.1%), and DM+/CKD+ (n=85, 5.2%). The treatment effects of PCI and CABG were analyzed in each subgroup. The primary endpoint was all-cause death at 10 years. Results Compared with the DM−/CKD− patients, patients with DM+/CKD+ were older, more often had a history of stroke, hypertension, heart failure, and were more frequently presented with total occlusion, bifurcation lesion and three-vessel disease. At 10 years, patients with DM+/CKD+ had a 3.94-fold higher incidence of all-cause mortality compared with DM−/CKD− individuals (54.1% versus 18.9%, 95% CI [2.85–5.44]). Patients with DM−/CKD+ (38.1%, HR 2.36; 95% CI [1.83–5.44]) or DM+/CKD− (28.2%, HR 1.61; 95% CI [1.26–2.07]) had intermediate risk profile. For DM+/CKD+ patients, compared with PCI, those who underwent CABG were associated with lower incidence of all-cause mortality (64.3% versus 44.2%, adjusted HR 0.52; 95% CI [0.27–0.99], p=0.047, pinteraction=0.443). The number of needed-to-treat to reduce mortality for CABG was 12. Conclusion In the SYNTAX population, patients with DM and CKD are at markedly increased risk of long-term mortality rate compared with patients one or neither of these risk factors. For patients with both comorbidities, CABG was associated with better clinical outcome compared with PCI. These findings should be interpreted as hypothesis-generating. Figure 1. Kaplan-Meier curves showing the clinical events according to treatment and DM/CKD status. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Boston Scientific Corporation

Abstract Background In patients with complex coronary artery disease (CAD), women favored coronary artery bypass grafting surgery (CABG) compared to percutaneous coronary intervention (PCI) at 5 years in the SYNTAX trial, whereas mortality rates after PCI and CABG were not different in men. On the other hand, poor outcomes of women undergoing PCI were not observed in the PRECOMBAT and BEST trials. The long-term optimal revascularization strategy according to gender has not been fully evaluated. Purpose In the SYNTAX Extended Survival (SYNTAXES) study, no significant difference existed in all-cause death between PCI and CABG at 10 years. This study aimed to assess treatment effect of PCI and CABG for 10-year all-cause death according to gender. Methods The SYNTAXES study evaluated vital status up to 10 years in 1,800 patients with de novo three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) randomized to treatment with CABG or PCI in the SYNTAX trial, and the pre-specified primary endpoint was all-cause death at 10 years. In this prespecified analysis, all-cause death at 10 years according to gender in patients undergoing PCI or CABG was evaluated. Results Of 1800 patients, 402 (22.3%) were women and 1398 (77.7%) were men. In women, the rate of mortality was significantly higher in the PCI arm at 5 years than in the CABG arm (19.3% vs. 10.3%; Log-rank p=0.010, Figure A), but the rates of mortality were not different at 10 years between the PCI and CABG arms (33.0% vs. 32.5%; Log-rank p=0.600, Figure A). In men, the mortality rate tended to be higher in the PCI arm at 10 years than in the CABG arm (27.0% vs. 22.5%; Log-rank p=0.082, Figure B), although the mortality rates were not different at 5 years between the PCI and CABG arms (12.4% vs. 12.3%; Log-rank p=0.957, Figure B). Conclusion The efficacy of CABG observed at 5 years disappeared at 10 years in women, whereas the efficacy of CABG became apparent after 5 years in men. Figure 1 Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Erasmus University Medical Centre, Rotterdam, Netherlands, reference: MEC-2016-716