TAVR vs SAVR in Severe Bicuspid Aortic Stenosis

Bicuspid aortic valve is a congenital heart condition characterized by the presence of two, rather than the typical three, cusps in the aortic valve.

The condition can lead to various complications, including aortic stenosis (AS; narrowing of the valve opening), aortic regurgitation (leaking of the valve), and an increased risk of aortic aneurysm.

The BELIEVERS trial builds on this foundation, integrating imaging-guided methodologies to create a robust framework for randomization with contemporary technologies and thus provide definitive evidence for treatment of this complex population.

Since the congenital severe bicuspid aortic valve stenosis was considered in most of the cases an exclusion from all large TAVR vs SAVR trials, there is no clear evidence on which procedure would be more efficient for such anatomical condition.

The suitable consented subjects will be randomized 1:1 on either TAVR or SAVR arm. These patients will be followed through clinic visits at 30 days, one year and annually up to 10 years.

• Transcatheter Aortic Valve Replacement (Procedure): This is a transcatheter, percutaneous approach using the commercially approved bioprosthetic valve device to replace the diseased aortic valve
• the open chest surgery to replace the aortic valve (Procedure): This is the open chest surgical approach using the commercially approved bioprosthetic valve device to replace the diseased aortic valve

Primary outcomes

• To compare the safety and effectiveness of TAVR vs SAVR for the treatment of severe AS in patients with BAV [2 years post end of enrollment]: A hierarchical composite (assessed by Win ratio at latest available follow-up) of: 1. death, 2. disabling stroke, 3. non-disabling stroke, 4. valve reintervention, 5. rehospitalization†, 6. unfavorable KCCQ (VARC-3*)

Secondary outcomes

• Time-averaged KCCQ [3 years post end of enrollment]: time-weighted mean of KCCQ overall summary score across at follow-up timepoints
• KCCQ status (serial) [at 2 years post end of enrollment]: overall summary score at discharge and specified follow-up visits
• SF-12 questionnaire [at 2 years post end of enrollment]: physical and mental component summary scores at prespecified visits.
• NYHA class [at 2 years post end of enrollment]: NYHA I-IV at prespecified visits
• 6-minute walk test [at 2 years post end of enrollment]: distance (meters) at prespecified visits.
• PHQ-9 questionnaire [at 2 years post end of enrollment]: depression score (0-27) at prespecified visits
• Time-to-recovery to baseline (QOR-15) [at 2 years post end of enrolment]: time from index procedure to first follow-up at which QOR-15 returns to (or exceeds) the participant's pre-procedure baseline (operational rules and handling of missingness specified in SAP).
• Additional clinical time-to event endpoints [at 2 years post end of enrollment]: death (time-to-first event) and cardiovascular death (time-to-fist event),•All stroke, disabling stroke (time-to-first event). • Rehospitalization (time-to-first event), • Composite of death/stroke/rehospitalization: time to first occurrence of any of death, any stroke, or qualifying rehospitalization. • Aortic dissection: imaging-, operative-, or autopsy-confirmed aortic dissection after randomization. • Need for surgery of the aorta: • CV rehospitalization days
• Secondary Imaging Endpoints [at 2 years post end of enrollment]: Echocardiography Core Lab• Bioprosthetic valve failure (BVF): • Paravalvular leak (PVL) severity:
• Secondary Imaging Endpoints CT [at 2 years post end of enrollment]: Ascending aorta dimension >50 mm: maximum ascending aorta diameter measured by CT Core Lab; endpoint met if >50 mm at any follow-up CT• Change in ascending aorta dimension (cm/year): annualized change in maximum ascending aorta diameter from baseline to follow-up CT by CT Core Lab.

Sex: All, ages: 50 Years to any

Inclusion Criteria:

1. 50 years of age or older at time of consent
2. Severe AS deemed suitable for a bioprosthesis by a local heart team (unsuitable or patient declined a mechanical valve or Ross procedure, following demonstration of evidence-based shared decision making with a validated decision-aid(1)
3. Gated contrast CT available and suitable for core laboratory analysis;
4. BAV anatomy confirmed by CT core laboratory analysis

Exclusion Criteria:

1. Recent cardiovascular intervention within 30 days prior to randomization.
2. Presence of an existing TAVR or SAVR device
3. Pregnancy or lactation
4. Extreme or prohibitive TAVR or SAVR risk, adjudicated by Patient Selection Committee (PSC) Review
5. Active enrollment in another investigational study
6. Disproportionate TAVR vs SAVR risk, as adjudicated by the patient selection committee
7. Associated aortopathy (AA≥45mm by maximal cross-sectional dimension, as confirmed by CT core laboratory analysis, or AA<45mm but site plan for surgery of the aorta in the event of randomization to surgery
8. Site plan for treatment of concomitant non-coronary cardiovascular disease in the event of randomization to surgery (for instance, concomitant valve surgery, septal defect or coarctation repair, aorta or root replacement or repair)
9. In the presence of coronary artery disease deemed necessary for revascularization in the event of randomization to SAVR or TAVR, Syntax score ≥ 32 or deemed unsuitable for PCI, or deemed unsuitable for coronary artery bypass grafting (CABG)
10. Plan to use any device other than commercially approved Edwards balloon expandable or Medtronic self-expanding TAVR
11. Leukopenia (WBC < 3000 cells/µL), anemia (Hgb < 8 g/dL), Thrombocytopenia (Plt < 50,000 cells/µL) on latest available labs within 30 days prior to randomization
12. Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation, or mechanical heart assistance within 30 days prior to randomization
13. LVEF < 25% within 90 days prior to randomization
14. Stroke or transient ischemic attack (TIA) within 90 days prior to randomization
15. Renal insufficiency (eGFR < 30 ml/min per the Cockcroft-Gault formula)
16. Severe lung disease (FEV1 < 50% predicted), unresolved prior to randomization
17. History of liver disease defined as MELD Score ≥ 10 or Child-Pugh Class B or C
18. Unable to complete the KCCQ due cognitive impairment or other medical condition

• Study Protocol (PDF, 2026-03-31)

• Raj Makkar, MD, Principal investigator, Cedars-Sinai Medical Center
• Marcio Diniz, PhD, Principal investigator, Icahn School of Medicine at Mount Sinai
• Vinod Thourani, MD, Principal investigator, Emory University