Design and rationale of the COMPARE-TAVI 2 trial: An all-comers head-to-head comparison of Evolut FX+ and Sapien 3 Ultra Resilia transcatheter heart valves

Highlights

•
Majority of previous studies have indicated more aortic regurgitation with self-expandable compared to balloon-expandable transcatheter heart valves (THVs).
•
COMPARE-TAVI 2 study question: Is the Evolut FX+ noninferior to the Sapien 3 Ultra Resilia regarding death, stroke, aortic regurgitation or hemodynamic THV-deterioration?
•
Patients: All comers for transfemoral aortic valve implantation.
•
Follow-up: Combined primary endpoint at 1 year and long-term follow-up included in secondary endpoints.

ABSTRACT

Introduction

The COMPARE-TAVI trial framework was launched for direct comparison of transcatheter aortic valve implantation (TAVI) valves. The COMPARE-TAVI 1 trial, comparing Myval/Myval Octacor versus Sapien 3/Sapien 3 Ultra transcatheter heart valves (THVs), was recently published. Here, we present the design and rationale for the COMPARE-TAVI 2 trial comparing the Evolut FX+ self-expandable THV with the Sapien 3 Ultra Resilia balloon-expandable THV.

Methods and analysis

In the COMPARE-TAVI 2 trial (ClinicalTrials.gov NCT06470022), patients will be randomized 1:1 between the THVs. The trial will test whether the Evolut FX+ self-expandable THV is noninferior to the Sapien 3 Ultra Resilia balloon-expandable THV in terms of the combined 1-year primary composite endpoint of all-cause mortality, stroke, moderate/severe total aortic regurgitation, or moderate/severe hemodynamic THV deterioration, according to VARC-3 criteria. If noninferiority is proven, superiority analyses may apply. Based on a power of 80%, alpha level of 0.05, 1-sided test, noninferiority margin of 4.5%, and expected event rate of 12%, the necessary sample size has been estimated to be 1,364 patients. Prespecified secondary endpoints, including long-term follow-up for 10 years, will also be investigated.

Summary

The COMPARE-TAVI 2 will provide important information on the short- and long-term outcomes among patients treated with the Evolut FX+ self-expandable and the Sapien 3 Ultra Resilia balloon-expandable THVs.

Graphical abstract

Background

The COMPARE-TAVI trial framework for direct comparison of transcatheter aortic valve implantation (TAVI) valves has previously been presented. The framework allows for head-to-head comparison of transcatheter heart valves (THVs). The first head-to-head comparison of Myval/Myval Octacor versus Sapien 3/Sapien 3 Ultra THVs was recently published as the COMPARE-TAVI 1 trial.

Here, we present the design and rationale for the COMPARE-TAVI 2 trial (ClinicalTrials.gov NCT06470022 ), comparing the Evolut FX+ self-expandable THV with the Sapien 3 Ultra Resilia balloon-expandable THV in all comers undergoing transfemoral TAVI (Graphical abstract).

Methods

Trial design and setting

Patients scheduled for transfemoral TAVI will be randomized 1:1 to treatment with either the Evolut FX+ THV or the Sapien 3 Ultra Resilia THV ( Figure 1 ).

European centers performing more than 75 TAVI procedures per year will be eligible to participate, and operators will be required to have implanted at least 15 of each valve before including patients in the trial.

Computed tomography (CT) and cardiac magnetic resonance (CMR) substudies will be conducted ( Figure 2 ).

The trial is registered with ClinicalTrials.gov (NCT06470022).

Patients and recruitment

Patients 18 years or older who are scheduled for transfemoral TAVI will be eligible for inclusion in the trial. Patients must be candidates for treatment with both valves, according to a technical evaluation in agreement with instructions for use of the THVs.

Interventions

The TAVI procedures will be performed according to usual clinical practice at the participating centers in general agreement with the instructions for use of the THVs. Procedural characteristics will be recorded.

Endpoints and timeline

The primary and secondary endpoints are presented in Table 1 . The endpoint definitions are consistent with VARC-3 and BARC criteria, as specified. ^,

Table 1

COMPARE-TAVI 2 trial endpoints.

Primary composite endpoint

All-cause mortality, stroke, moderate/severe total aortic regurgitation, or moderate/severe hemodynamic transcatheter heart valve (THV) deterioration at 1 year, according to VARC-3 criteria.
The individual components of the primary outcome will be presented, to describe their contribution to the primary endpoint. The primary composite endpoint and each component will be re-analyzed at 3-, 5-, and 10-year follow-up.

Secondary safety and efficacy endpoints (Bonferroni correction for multiple testing):

1.
TAVI-related complications: These complications comprise conversion to open surgery during implantation, unplanned use of cardiopulmonary support, coronary artery obstruction, ventricular septal defect, mitral valve apparatus damage or dysfunction, cardiac tamponade/pericardial effusion resulting in pericardiocentesis, valve embolization, valve migration, and need for TAVI-in-TAVI deployment, according to VARC-3 criteria, or annulus rupture, aortic rupture/perforation, aortic dissection, or shunts other than ventricular septal defect.
2.
Proportion with successful implantation of the chosen valve. This proportion is defined according to no need for more than 1 TAVI valve; no change to an unplanned valve during the procedure, because implanting the planned valve was impossible; and no conversion to surgery or procedure-related death.
3.
SMART criteria for bioprosthetic valve dysfunction through 1-year: These criteria comprise (1) hemodynamic structural valve dysfunction, defined as an aortic valve mean gradient ≥20 mmHg at any time up to the 1-year visit echocardiography; (2) nonstructural valve dysfunction, defined as severe prosthesis-patient mismatch or moderate to severe total aortic regurgitation at any time until the 1-year visit echocardiography; (3) clinical valve thrombosis; (4) endocarditis; or (5) aortic valve reintervention.
4.
Pacemaker implantation: New pacemaker implantation within 1 year after TAVI.

Exploratory secondary endpoints for the main trial (hypothesis-generating only):
Procedural and early in-hospital complications:

1.
Major vascular access site and access-related complications resulting in endovascular or open surgery, according to VARC-3 criteria, during admission and within 30 days.
2.
Major bleeding resulting in a decrease in hemoglobin level ≥1.86 mmol/l and/or erythrocyte transfusion ≥2 units, during admission and within 30 days, modified from BARC type 3 to 5 criteria. This endpoint will be adjudicated and presented as VARC-3 type 2, 3, or 4 bleeding.

Bioprosthetic valve dysfunction:

1.
Endocarditis at 30 days, and 1, 3, 5, and 10 years.
2.
Reoperation (TAVI, surgical aortic valve replacement, or balloon aortic valvuloplasty) at 30 days, and 1, 3, 5, and 10 years, according to VARC-3 criteria.
3.
Moderate/severe prosthesis-patient mismatch: Effective orifice area (EOA)/body surface area ≤0.85 cm ²/m ² if BMI <30 kg/m ² or ≤0.70 cm ²/m ² if BMI ≥30 kg/m ², at 30 days, according to VARC-3 criteria.
4.
EOA at 30 days, and 1, 3, 5, and 10 years, as evaluated by the echocardiography core laboratory.
5.
Mean gradient at 30 days, and 1, 3, 5, and 10 years, as evaluated by the echocardiography core laboratory.

Readmissions, and clinical and paraclinical findings:

1.
Pacemaker implantation at 30 days before TAVI; during admission; and 30 days, and 3, 5, and 10 years after TAVI.
2.
Readmission for congestive heart failure at 30 days, and 1, 3, 5, and 10 years, according to VARC-3 criteria.
3.
AMI at 30 days, and 1, 3, 5, and 10 years, according to VARC-3 criteria.
4.
Revascularization with percutaneous coronary intervention (not scheduled before TAVI) or coronary artery bypass grafting (not scheduled before TAVI) at 30 days, and 1, 3, 5, and 10 years, according to VARC-3 criteria.
5.
Newly diagnosed atrial fibrillation/flutter at 30 days, and 1, 3, 5, and 10 years, according to VARC-3 criteria.
6.
Increase in renal creatinine level to ≥200% (AKIN stage 2-3, VARC-3 criteria) or resulting in dialysis (AKIN stage 4), according to VARC-3 criteria, during admission and at 30 days.

CT substudy, N = 850:

1.
Coprimary endpoint: Hypoattenuated leaflet thickening (HALT) or reduced leaflet motion or thrombus, assessed by HCT at 1 month and 1 year.
2.
Secondary endpoint: Commissural and coronary alignment, and THV implantation depth.

CMR substudy, N = 166

1.
Coprimary endpoint: Aortic regurgitation fraction (ARF) and aortic regurgitation volume, measured by CMR at 1 month.
2.
Secondary endpoint: EOA.

Follow-up with clinical assessment and echocardiography will be scheduled before discharge; after 30 days; and after 1, 3, 5, and 10 years. A standardized protocol for echocardiography established by the echocardiography core laboratory will be used, and all echocardiographies are evaluated by the echocardiography core laboratory (Echo protocol, Supplementary material). Endpoints will be assessed in relation to clinical and echocardiographic follow-up, and from registries.

In the CT substudy, CT will be performed at 30-day and 1-year follow-up. A standardized protocol for CT, established by the CT core laboratory, will be used, and all CT scans will be evaluated by the CT core laboratory.

In the CMR substudy, CMR will be performed at the 30-day follow-up. A standardized protocol for CMR, established by the CMR core laboratory, will be used, and all CMR scans will be evaluated by the CMR core laboratory.

Allocation and blinding

Patients are randomized through an online portal for medical research enabling both randomization and data registration. Randomization is stratified by sex and center. Center and sex are potential confounders, and while other potential confounders may exist, we did apply further stratification to minimize the risk of over-stratification.

Because blinding will not be achievable, the trial should be considered open label. The patient records indicate the implanted valve, and, although the core laboratories evaluate images without information on the implanted valve, the valves have different appearances on imaging, thus making blinding impossible.

Data collection, management, and monitoring

The electronic case report form (eCRF) will contain all patient and procedure characteristics and imaging analyses, as well as follow-up data and events. Data in the eCRF are encrypted, and all access events or attempts to access data are logged and monitored. The system has been approved by the Danish Data Protection Agency.

Monitoring of the study will involve a combination of on-site monitoring and remote monitoring, including through the eCRF. The monitors will follow a specific monitoring plan (Monitoring and event adjudication plan, Supplementary material). Sites will be continually provided with updates on data completeness.

The following serious adverse events will be filed with the ethical committee on occurrence: (1) structural THV deterioration resulting in repeated TAVI or surgical aortic valve replacement within 3 years, (2) death within 3 years, (3) endocarditis within 30 days, (4) stroke within 30 days, (5) vascular surgery associated with the access site within 30 days, and (6) device failures (embolization or use of more than 1 valve during index treatment). As of July 1, 2025, ethical regulations were changed in Denmark, such that only serious adverse events associated with the device must be reported to the ethical committee expedited, whereas remaining events will be reported once yearly. Same approach has since been adapted in Finland and will be proposed for Ireland.

The ethical committee can choose to undertake auditing at any time. In this event, the committee will be granted access to all data. The sponsor may perform on-site audit, in which event access to source data is needed.

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Tags: American Heart Journal Volume 297

Jun 27, 2026 | Posted by drzezo in CARDIOLOGY | Comments Off

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