RHEIA (Randomized researcH in womEn All Comers With Aortic Stenosis)
RHEIA (Randomized researcH in womEn All Comers With Aortic Stenosis)
Purpose of this prospective, randomized, controlled, multi-center study is to evaluate the
 safety and efficacy of Transcatheter Aortic Valve Implantation (TAVI) as compared to surgical
 aortic valve replacement (SAVR) in female patients with severe symptomatic aortic stenosis.
 Patients will be randomized 1:1 to receive either TAVI or SAVR aortic valve replacement. For
 TAVI procedure, Edwards SAPIEN 3 THV system Model 9600 TFX (20, 23, 26 and 29 mm) or SAPIEN 3
 Ultra THV system Model 9750 TFX (20, 23, 26) with the associated transfemoral delivery
 systems will be sued, for SAVR any commercially available surgical bioprosthetic valve.
 Patients will undergo the following visits: Screening, Procedure, Post Procedure, Discharge,
 30 day, 6 months (telephone contact) and 1 year.
Recent large meta-analyses and a large retrospective study from the STS/ACC TVT Registry
 demonstrated improved survival in female versus male aortic sclerosis patients undergoing
 TAVI despite their advanced age and increased rates of major peri-procedural vascular
 complications, bleeding events and strokes. These gender-related patient profile differences
 have also been present in multicentre cohorts across the world. A recent meta-analysis by
 Siontis et al. showed that TAVI, when compared with SAVR, was associated with a significant
 13% relative risk reduction in 2-year mortality, a benefit more pronounced amongst females
 and patients undergoing transfemoral TAVI.

 In a recent meta-analysis, the female-specific survival advantage from TAVI over SAVR was
 explored. Amongst females, TAVI recipients had a significantly lower mortality than SAVR
 recipients, at 1 year (OR 0.68; 95%CI 0.50 to 0.94). Amongst males there was no difference in
 mortality between TAVI and SAVR at 1 year (OR 1.09; 95%CI 0.86 to 1.39). There was
 statistically significant evidence of a difference in treatment effect between genders at 1
 year (p interaction = 0.02). In an attempt to explore the mechanisms for an increased
 mortality rate in women undergoing SAVR, different endpoints were explored in female patients
 exclusively. It was shown that women, undergoing SAVR, having both a higher periprocedural
 mortality, higher rates of bleeding and acute kidney injury, worse patient prosthesis match
 and worse long term recovery of left ventricular function.In the recent PARTNER 3 the
 composite of death from any cause, stroke, or rehospitalization had occurred in 42 patients
 (8.5%) in the TAVI group as compared with 68 patients (15.1%) in the surgery group at 1 year.
 The difference was 6.6% (95%CI -10.8% to -2.3%) and thus exceeded the pre-defined
 non-inferiority margin of 6%.

 Subgroup analyses of the primary end point at 1 year showed no heterogeneity of treatment
 effect in any of the subgroups that were examined including gender (p=0.27). There were 292
 women included with an endpoint rate of 18.5% for SAVR (men 13.8%) and 8.1% for TAVI (men
 8.7%), showing a clear trend for an increased benefit of women undergoing TAVI instead of
 SAVR (rate difference -10.4%; 95%CI -18.3% to -2.5%). Nonetheless, the benefits of TAVI were
 preserved in both men and women.Earlier observational and clinical studies indicated an
 increased risk for women undergoing SAVR compared to men while being at a comparable risk for
 TAVI. In a recent meta-analysis of TAVI vs. SAVR in men and women the risk of dying from the
 intervention was reduced by a relative 32% in women (OR 0.38; 95%CI 0.50-0.94) while there
 was no such difference in men (OR 1.09; 95%CI 0.86-1.39). This was mostly documented as being
 the effect of a reduced periprocedural mortality with TAVI (-54%; OR 0.46; 95%CI 0.22-0.96)
 and major bleeding (-57%; OR 0.43; 95%CI 0.25-0.73) while the difference in strokes and acute
 kidney injury did not reach statistical significance. Taken all available scientific data on
 the comparison of TAVI versus open surgery in patients with indication for AVR together it
 remains probable, that independently of the individual surgical risk female patients in
 particular seem to benefit from a non-surgical aortic valve replacement strategy.

 As the indirect comparisons of the intermediate to low risk outcomes in PARTNER 2/3 suggest a
 favorable risk reduction in women compared to men as described, the investigators believe it
 is timely for a dedicated trial to demonstrate the non-inferiority of TAVI in women compared
 to SAVR and, in case of this being true, whether TAVI is actually superior to performing
 SAVR.
Inclusion Criteria:

 1. Female patients with severe aortic stenosis as follows:

 • High gradient severe AS (Class I Indication for aortic valve replacement [AVR]): Jet
 velocity ≥ 4.0 m/s or mean gradient ≥ 40 mmHg with Aortic Valve Area (AVA) ≤ 1.0 cm^2
 or AVA index ≤ 0.6 cm^2/m^2 OR

 • Low gradient severe aortic stenosis (Class I/IIa indication of AVR) Jet velocity <
 4.0 m/s and mean gradient < 40 mmHg and AVA ≤ 1.0 cm^2 and AVA index ≤ 0.6 cm^2/m^2
 with confirmation of severe AS by: mean gradient ≥40 mmHg on dobutamine stress
 echocardiography and/or aortic valve calcium score ≥ 1200 AU on non-contrast CT.

 AND

 -  NYHA Functional Class ≥ II OR

 -  Exercise test that demonstrates a limited exercise capacity, abnormal BP
 response, or arrhythmia

 2. Age ≥ 18 years

 3. The study patient has been informed of the nature of the study, agrees to its
 provisions and has provided written informed consent as approved by the Institutional
 Review Board (IRB)/Ethics Committee (EC) of the respective clinical site.

 Exclusion Criteria:

 1. Patient is not a candidate for both surgical and transcatheter aortic valve
 replacement.

 2. Native aortic annulus size unsuitable for sizes 20, 23, 26, or 29 mm THV based on 3D
 imaging analysis

 3. Iliofemoral vessel characteristics that would preclude safe placement of the
 introducer sheath.

 4. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before randomization

 5. Aortic valve is unicuspid, bicuspid, or is non-calcified

 6. Severe aortic regurgitation (>3+)

 7. Any concomitant valve disease that requires an intervention

 8. Pre-existing mechanical or bioprosthetic valve in any position (mitral ring is not an
 exclusion).

 9. Complex coronary artery disease:

 -  Unprotected left main coronary artery stenosis

 -  Syntax score > 32 (in the absence of prior revascularization)

 -  Heart Team assessment that optimal revascularization cannot be performed.

 10. Symptomatic carotid or vertebral artery disease or successful treatment of carotid
 stenosis within 30 days before randomization

 11. Leukopenia (WBC < 3000 cell/mcL), anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt <
 50,000 cell/mcL), history of bleeding diathesis or coagulopathy, or hypercoagulable
 states

 12. Hemodynamic or respiratory instability requiring inotropic support, mechanical
 ventilation or mechanical heart assistance within 30 days before randomization

 13. Hypertrophic cardiomyopathy with obstruction

 14. Ventricular dysfunction with lleft ventricular ejection fraction < 30%

 15. Cardiac imaging (echo, CT, and/or MRI) evidence of intracardiac mass, thrombus or
 vegetation

 16. Inability to tolerate or condition precluding treatment with anti-
 thrombotic/anticoagulation therapy during or after the valve implant procedure

 17. Stroke or transient ischemic attack within 90 days before randomization

 18. Renal insufficiency (eGFR < 30 ml/min per the Cockcroft-Gault formula) and/or renal
 replacement therapy

 19. Active bacterial endocarditis within 180 days of randomization

 20. Severe lung disease (FEV1 < 50%) or currently on home oxygen

 21. Severe pulmonary hypertension (e.g., pulmonary arterial systolic pressure ≥ 2/3
 systemic pressure)

 22. History of cirrhosis or any active liver disease

 23. Significant abdominal or thoracic aortic disease (such as porcelain aorta, aneurysm,
 severe calcification, aortic coarctation, etc.) that would preclude safe passage of
 the delivery system or cannulation and aortotomy for surgical AVR.

 24. Hostile chest or conditions or complications from prior surgery that preclude safe
 reoperation (e.g., mediastinitis, radiation damage, abnormal chest wall, adhesion of
 aorta or internal mammary artery to sternum, etc.)

 25. Patient refuses blood products

 26. BMI > 50 kg/m^2

 27. Estimated life expectancy < 24 months

 28. Absolute contraindications or allergy to iodinated contrast agent that cannot be
 adequately treated with pre-medication

 29. Immobility that would prevent completion of study procedures

 30. Currently participating in an investigational drug or another device study.

 31. Pregnancy or lactation