RHEIA (Randomized researcH in womEn All Comers With Aortic Stenosis)

A Prospective, Randomized, Controlled, Multi-Center Study to Evaluate the Safety and Efficacy of Transcatheter Aortic Valve Implantation in Female Patients Who Have Severe Symptomatic Aortic Stenosis Requiring Aortic Valve Replacement

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