SCOPE II: A randomized trial of two self-expanding TAVR bioprostheses
Reported from the TCT Congress 2020
At TCT Connect 2020, Late-Breaking Trial Session II, the primary results of the Safety and Efficacy Comparison of Two TAVI Systems in a Prospective Randomized Evaluation (SCOPE) 2 trial were presented and simultaneously published in Circulation. Daniele Giacoppo provides a summary of the trial.
Why this study – the rationale/objective?
In randomized clinical trials, transcatheter aortic valve replacement with self- or balloon-expandable bioprosthesis has shown overall at least comparable safety and efficacy to surgery across different surgical risk settings. Procedural and mid-term outcomes of transcatheter aortic valve replacement have improved over the years as a result of several factors including substantial advances in bioprostheses technology. However, the number of randomized trials comparing contemporary bioprostheses is very limited and most of data on differential clinical and functional performance between transcatheter valves derive from observational studies.
The SCOPE 2 trial was designed with the objective of comparing the ACURATE neo valve with the CoreValve Evolut R / Pro valve.
How was it executed – the methodology?
SCOPE 2 is a multicenter, noninferiority, open-label, randomized clinical trial conducted at 23 centres in Europe. The trial compared two self-expandable supra-annular bioprostheses, the ACURATE neo and the CoreValve Evolut R / Pro.
The ACURATE neo bioprosthesis consists of three porcine pericardial leaflets mounted on a two-crown self-expandable nitinol frame with the inflow tract covered by porcine pericardium fabric. Two subsequently marketed iterations of the CoreValve Evolut system, the Evolut R and Evolut Pro, were used during the study. The CoreValve Evolut R / Pro bioprosthesis is a recapturable and repositionable valve also consisting of three porcine pericardial leaflets mounted on a self-expanding nitinol frame. The main difference between the Evolut R and Pro systems is the nitinol frame skirt, made from a single and a double layer of porcine pericardium, respectively.
Patients were eligible for inclusion when aged 75 years or older, suffering from symptomatic severe aortic valve stenosis, and deemed to be at increased risk of death with conventional surgical treatment as assessed by the heart team. Patients were excluded if they had <20% of left ventricular ejection fraction, pre-existing aortic and/or mitral prosthetic valve, bicuspid or unicuspid native valve, severe mitral regurgitation, and peripheral anatomy unfavourable for transfemoral implantation.
Prosthesis size, pre- and post-dilation, and type of anaesthesia were left at the operator’s discretion. Dual antiplatelet therapy was recommended for at least 3 months, followed by single antiplatelet therapy. In patients with an indication for oral anticoagulation or recent percutaneous coronary intervention, combination of antithrombotic medications and their duration were at the operator’s discretion.
The primary endpoint was a composite of all-cause death or stroke at 1 year. The key secondary endpoint was new permanent pacemaker implantation at 30 days. An independent clinical events committee adjudicated all events. Echocardiography recordings were assessed by an independent core laboratory. Primary analysis was conducted according to the intention-to-treat principle.
What is the main result?
A total of 796 patients were allocated in a 1:1 ratio to the ACURATE neo valve or the CoreValve Evolut R / Pro valve from April 2017 to April 2019. Clinical follow-up was available for 98% of patients.
Patients had mean age of 83.2 ± 4.3 years, were prevalently female (68%), and showed mean Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score of 4.6% ± 2.9. Pre-dilation and post-dilation were more common in the ACURATE neo group. Procedural complications were similar between treatment groups.
The primary composite endpoint of all-cause death or stroke at 1 year occurred in 59 (15.8%) patients in the ACURATE neo group and in 52 (13.9%) patients in the CoreValve Evolut R / Pro group, with an absolute risk difference of 1.8% and a one-sided 95% upper confidence limit of 6.1% that did not meet noninferiority of the ACURATE neo valve compared with the CoreValve Evolut R / Pro valve (p=0.055 for noninferiority).
In the sensitivity analysis of the primary endpoint by stratification across STS-PROM score categories (≤4%, 5-8%, >8%) using Mantel-Haenszel weights, conclusions did not change (p=0.069 for noninferiority). However, a predefined subgroup analysis by STS-PROM categories showed a significant interaction and the subgroup with STS-PROM ≤4% mainly driven primary results. In the per-protocol analysis, the primary endpoint occurred in 55 (15.3%) patients in the ACURATE neo group and in 50 (14.3%) patients in the CoreValve Evolut R / Pro group, with a one-sided 95% upper confidence limit of 5.4% (p=0.031 for noninferiority).
The key secondary endpoint of new permanent pacemaker implantation at 30 days occurred in 41 (10.5%) patients in the ACURATE neo group and in 70 (18.0%) patients in the CoreValve Evolut R / Pro group, with an absolute risk difference of -7.5% (95% confidence interval -12.4% to -2.6%, p=0.003). At 1 year, the proportion of patients who received new permanent pacemaker implantation remained significantly lower in the ACURATE neo group compared with the CoreValve Evolut R / Pro group (11% vs. 18%; -7.2%, 95% confidence interval -12.2% to -2.3%; p=0.004). At 1 year, also new left bundle branch block occurred less frequently in the ACURATE neo group compared with the CoreValve Evolut R / Pro group (14% vs. 19%; -5.2%, 95% confidence interval -10.3% to -0.04%; p=0.048).
No statistically significant differences were observed for the two components of the primary endpoint at both 30 days and 1 year. However, cardiac death incidence resulted to be higher in the ACURATE neo group compared with the CoreValve Evolut R / Pro group at both 30 days (2.8% vs. 0.8%; 2.1%, 95% confidence interval 0.2% to 3.9%; p=0.03) and 1 year (8.4% vs. 3.9%; 4.5%, 95% confidence interval 1.0% to 8.0%; p=0.01). Stroke incidences were comparable between groups at both 30 days (3% vs. 4%; -1.0%, 95% confidence interval -3.7% to 1.7%; p=0.45) and 1 year (5% vs. 6%; -1.6%, 95% confidence interval -4.9% to 1.6%; p=0.33). No significant differences in hospitalization for valve-related symptoms or worsened heart failure, myocardial infarction, life-threatening or major bleeding, valve endocarditis, and repeat intervention between groups were observed at both 30 days and 1 year. No valve thrombosis occurred in the two groups over time.
Echocardiographic assessment was available in 71% of patients at 1- to 7 days, 58% of patients at 30 days and 46% at 1 year. At 30 days, Valve Academic Research Consortium (VARC)-2-defined structural valve deterioration (14% vs. 6%; p=0.007) and moderate or severe aortic regurgitation (10% vs. 3%; p=0.002) were significantly more frequent in the ACURATE neo group compared with the CoreValve Evolut R / Pro group. Regurgitation was paravalvular in 96% of patients. At 1 year, the difference in moderate or severe aortic regurgitation was no longer significant.
Critical reading and the relevance for clinical practice
The main results of the SCOPE 2 trial are that, compared with the CoreValve Evolut R / Pro valve, the ACURATE neo valve did not result to be noninferior in terms of the primary endpoint of all-cause death or stroke at 1 year and was associated with a significantly higher incidence of moderate or severe aortic regurgitation at 30 days, though it also required less frequently new permanent pacemaker implantation.
The results of this trial highlight a novel, emerging area of need in structural heart interventions which is the comprehensive definition by high-quality comparative investigations of virtues and vices of each of the increasing number of currently available transcatheter aortic bioprosthetic valves.
As already occurred in the SCOPE 1 trial, the self-expanding ACURATE neo valve did not meet noninferiority compared with the balloon-expandable SAPIEN 3 valve in terms of early safety and clinical efficacy outcomes. The results of the SCOPE 1 trial might have been interpreted as a result of the differential performance between self- and balloon-expandable technologies. However, findings from the SCOPE 2 trial may reveal that outcomes between contemporary transcatheter bioprostheses primarily depend on the individual features of each valve rather than the underlying implantation technology. Of note, in the SOLVE-TAVI trial, the second-generation SAPIEN and CoreValve bioprostheses were equivalent with respect to the composite efficacy endpoint at 30 days.
The results of the SCOPE 2 trial are mainly driven by a significant excess in cardiac death in the ACURATE neo group compared with the CoreValve Evolut R / Pro group, that translated in a numerical imbalance in all-cause death between treatment groups. The supplementary finding of an increased proportion of moderate or severe aortic regurgitation at 30-day echocardiography might provide an explanation for the increased mortality from cardiac cause observed in the ACURATE neo group. Indeed, it is known that there is a link between paravalvular regurgitation degree and long-term mortality in literature. In addition, the observation of comparable rates of moderate or severe regurgitation at 1 year does not invalidate this speculative view and it can be likely explained by survival bias and low completeness of echocardiography follow-up. On the other hand, in the SCOPE 2 trial, moderate or severe aortic regurgitation was infrequent in patient who died from cardiac cause and, in light of the limited statistical power for individual endpoints, an effect of chance cannot be formally excluded.
Finally, the ACURATE neo valve was also associated with lower incidences of new permanent pacemaker implantation at 30 days and 1 year. These favourable outcomes may be explained by a lower radial force of the ACURATE neo valve at the level of the left outflow valve tract. This feature, however, may at the same time provide justification for a more frequent incomplete paravalvular sealing with resulting moderate or severe paravalvular regurgitations in patients who received the ACURATE neo valve compared with those who received the CoreValve Evolut R / Pro valve. In conclusions, design improvements are necessary to mitigate the risk of paravalvular regurgitation with the ACURATE neo valve and improve clinical outcomes.
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