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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., Graphical Abstract The treatment effects of PCI versus CABG on all-cause death at 10 years in 3VD/LMCAD patients with pharmacologically treated diabetes and insulin-treated diabetes.

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 (>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 (>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 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 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

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

Background Periprocedural myocardial infarction (PMI) occurs frequently after both percutaneous coronary intervention (PCI) and bypass grafting surgery (CABG) in patients with complex coronary artery disease (CAD), and PMI has been shown to have a detrimental impact on mortality. On the other hand, long-term impact of PMI on mortality has not been fully evaluated. Purpose This study aimed to assess the impact of PMI according to SCAI definition on 10-year all-cause death in patients with complex CAD. Methods The SYNTAX Extended Survival (SYNTAXES) 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 treatment with CABG or PCI in the SYNTAX trial. Blood was sampled for creatine kinase (CK) pre- and post-revascularisation, and the cardiac specific MB iso-enzyme (CK-MB) was determined only if the CK ratio ≥2 x the upper limit of normal (ULN). If the CK ratio Results Of 1800 patients, 1679 (93.2%) patients were included. Of 877 patients treated with PCI, PMI occurred in 26 patients (3.0%), whereas 14 (1.7%) PMIs were observed in 802 patients treated with CABG. Compared with patients without PMI, patients with PMI presented with unstable angina more frequently (45.0% vs. 28.7, p=0.033), and had a higher rate of bifurcation lesion (87.5% vs. 72.5, p=0.046). PMI was associated with a higher all-cause mortality at 10 years compared with no PMI (55.3% vs. 25.4%; Log-rank p Conclusion PMI was associated with a poor prognosis at 10 years. The impact of PMI on mortality was strong within one year. Of note, the impact of PMI on mortality persisted beyond 1 year only in patients undergoing PCI. Patients who were treated with PCI and suffered PMI need careful follow-up beyond one year after revascularization. Figure 1 Funding Acknowledgement Type of funding source: None

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

Mitral regurgitation (MR) is one of the most prevalent valve disorders and has numerous etiologies, including primary (organic) MR, due to underlying degenerative/structural mitral valve (MV) pathology, and secondary (functional) MR, which is principally caused by global or regional left ventricular remodeling and/or severe left atrial dilation. Diagnosis and optimal management of MR requires integration of valve disease and heart failure specialists, MV cardiac surgeons, interventional cardiologists with expertise in structural heart disease, and imaging experts. The introduction of transcatheter MV therapies has highlighted the need for a consensus approach to pragmatic clinical trial design and uniform endpoint definitions to evaluate outcomes in patients with MR. The Mitral Valve Academic Research Consortium is a collaboration between leading academic research organizations and physician-scientists specializing in MV disease from the United States and Europe. Three in-person meetings were held in Virginia and New York during which 44 heart failure, valve, and imaging experts, MV surgeons and interventional cardiologists, clinical trial specialists and statisticians, and representatives from the U.S. Food and Drug Administration considered all aspects of MV pathophysiology, prognosis, and therapies, culminating in a 2-part document describing consensus recommendations for clinical trial design (Part 1) and endpoint definitions (Part 2) to guide evaluation of transcatheter and surgical therapies for MR. The adoption of these recommendations will afford robustness and consistency in the comparative effectiveness evaluation of new devices and approaches to treat MR. These principles may be useful for regulatory assessment of new transcatheter MV devices, as well as for monitoring local and regional outcomes to guide quality improvement initiatives. (C) 2015 by the American College of Cardiology Foundation.

This editorial refers to ‘Aortic valve replacement with mechanical vs. biological prostheses in patients aged 50–69 years’ by N. Glaser et al . doi:10.1093/eurheartj/ehv580 Since the Veterans Affairs landmark randomized trial on heart valve replacement with mechanical vs. bioprosthetic valves reported their long-term results,1 guidelines for aortic valve replacement (AVR) have recommended the use of mechanical valves in patients younger than 60 years of age and the use of bioprosthetic valves in patients above the age of 65 or 70 years, depending on the European or North American guidelines, respectively, with a grey area from 60 to 65–70 years in which both valves can be considered.2–3 However, despite these recommendations, studies on trends of mechanical and bioprosthetic valve implantations have found increasingly higher usage of bioprosthetic valves, particularly in patients aged 55–70 years.4 The evidence base to support lowering of the age cut-off for implanting bioprosthetic valves is limited and this increase is therefore potentially concerning.5 The susceptibility for bioprosthetic valve failure is particularly prominent in younger patients and may be related to higher rates of mortality during long-term follow-up. There is a constant debate regarding whether mechanical or bioprosthetic valves should be used in patients aged 50–70 years. The choice of implanting a bioprosthetic over a mechanical valve is particularly influenced by (i) the risk of stroke and bleeding related to the thrombogenicity of mechanical valves and the use of oral anticoagulation; (ii) the perceived lower risk of valve dysfunction with newer bioprosthetic valves as compared with older ones; and (iii) reductions in operative complications, including mortality, of reoperations that renders such procedures a less important outcome to consider. …

Mechanical valves used for aortic valve replacement (AVR) continue to be associated with bleeding risks because of anticoagulation therapy, while bioprosthetic valves are at risk of structural valve deterioration requiring reoperation. This risk/benefit ratio of mechanical and bioprosthetic valves has led American and European guidelines on valvular heart disease to be consistent in recommending the use of mechanical prostheses in patients younger than 60 years of age. Despite these recommendations, the use of bioprosthetic valves has significantly increased over the last decades in all age groups. A systematic review of manuscripts applying propensity-matching or multivariable analysis to compare the usage of mechanical vs. bioprosthetic valves found either similar outcomes between the two types of valves or favourable outcomes with mechanical prostheses, particularly in younger patients. The risk/benefit ratio and choice of valves will be impacted by developments in valve designs, anticoagulation therapy, reducing the required international normalized ratio, and transcatheter and minimally invasive procedures. However, there is currently no evidence to support lowering the age threshold for implanting a bioprosthesis. Physicians in the Heart Team and patients should be cautious in pursuing more bioprosthetic valve use until its benefit is clearly proven in middle-aged patients.

Aims Numerous studies have linked prosthesis–patient mismatch (PPM) after aortic valve replacement (AVR) to adverse outcomes. Its correlation with long-term survival has been described but with contradicting results. This systematic review and meta-analysis of observational studies aims to determine the hazard of PPM after AVR. Methods and results The Medline and EMBase databases were searched for English-language original publications. Two researchers independently screened studies and extracted data. Pooled estimates were obtained by random effects model. Subgroup analyses were performed to detect sources of heterogeneity. The search yielded 348 potentially relevant studies; 34 were included comprising 27 186 patients and 133 141 patient-years. Defined by the universally accredited indexed effective orifice area

Aims Coronary artery bypass grafting (CABG) has been considered the standard of care for patients with three-vessel disease (3VD), but long-term comparative results from randomized trials of CABG vs. percutaneous coronary intervention (PCI) using drug-eluting stents (DES) remain limited. Methods and results Patients with de novo 3VD or left main disease were randomly assigned to PCI with the paclitaxel-eluting first-generation stent or CABG in the SYNTAX trial. This pre-specified analysis presents the 5-year outcomes of patients with 3VD (n = 1095). The rate of major adverse cardiac and cerebrovascular events (MACCE) was significantly higher in patients with PCI compared with CABG (37.5 vs. 24.2%, respectively; P < 0.001). Percutaneous coronary intervention as opposed to CABG resulted in significantly higher rates of the composite of death/stroke/myocardial infarction (MI) (22.0 vs. 14.0%, respectively; P < 0.001), all-cause death (14.6 vs. 9.2%, respectively; P = 0.006), MI (9.2 vs. 4.0%, respectively; P = 0.001), and repeat revascularization (25.4 vs. 12.6%, respectively; P < 0.001); however, stroke was similar between groups at 5 years (3.0 vs. 3.5%, respectively; P = 0.66). Results were dependent on lesion complexity (P for interaction = 0.12); in patients with a low (022) SYNTAX score, PCI vs. CABG resulted in similar rates of MACCE (33.3% vs. 26.8%, respectively; P = 0.21) but significantly more repeat revascularization (25.4% vs. 12.6%, respectively; P = 0.038), while in intermediate (2332) or high (>= 33) SYNTAX score terciles, CABG demonstrated clear superiority in terms of MACCE, death, MI, and repeat revascularization. Differences in MACCE between PCI and CABG were larger in diabetics [hazard ratio (HR) = 2.30] than non-diabetics (HR = 1.51), although the P for interaction failed to reach significance for MACCE (P for interaction = 0.095) or any of the other endpoints. Conclusion Five-year results of patients with 3VD treated with CABG or PCI using the first-generation paclitaxel-eluting DES suggest that CABG should remain the standard of care as it resulted in significantly lower rates of death, MI, and repeat revascularization, while stroke rates were similar. For patients with low SYNTAX scores, PCI is an acceptable revascularization strategy, although at a price of significantly higher rates of repeat revascularization.

Transcatheter aortic valve implantation (TAVI) has been increasingly recognized as a curative treatment for severe aortic stenosis (AS). Despite important improvements in current device technology and implantation techniques, specific complications still remain and warrant consideration. Vascular complications and peri-procedural neurological events were the first concerns to emerge with this new technology. Recently, significant post procedural para-valvular leak has been shown to be more frequent after TAVI than after surgical aortic valve replacement (SAVR), and its potential association with worse long-term prognostic has raised concerns. In moving toward treatment of lower risk populations, structural integrity and long-term durability of heat valve prosthesis are becoming of central importance. Emerging technologies and newer generations of devices seem promising in dealing with these matters.

The non-inferiority trial design has gained popularity within the last decades to compare a new treatment to the standard active control. In contrast to superiority trials, this design is complex and is based on assumptions that cannot be validated directly. Many readers and even investigators, therefore, have difficulty grasping the full methodological nature of non-inferiority trials. Non-inferiority margins are often arbitrarily chosen such that a favourable margin can bias a trial towards declaring non-inferiority. Pitfalls of non-inferiority trials are not fully appreciated, and without having identified these shortcomings, objective conclusions from non-inferiority trials cannot be made. This methodological review elaborates on what is a non-inferiority trial, why such a trial is performed, what the hazards are, and how conclusions from non-inferiority trials are derived, by providing examples of recent cardiovascular trials.