Brief Title
RHEIA (Randomized researcH in womEn All Comers With Aortic Stenosis)
Official Title
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
Brief Summary
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.
Detailed Description
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.
Study Type
Interventional
Primary Outcome
Mortality
Secondary Outcome
Length of Index hospitalization
Condition
Aortic Valve Stenosis
Intervention
Transcatheter aortic valve replacement
Study Arms / Comparison Groups
SAPIEN 3 or SAPIEN 3 Ultra
Description: 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.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Procedure
Estimated Enrollment
440
Start Date
November 29, 2019
Completion Date
April 2022
Primary Completion Date
February 2021
Eligibility Criteria
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/mL), anemia (Hgb < 9 g/dL), Thrombocytopenia (Plt < 50,000
cell/mL), 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
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Hélène Eltchaninoff, Prof., +49 89 800 650, [email protected]
Location Countries
Austria
Location Countries
Austria
Administrative Informations
NCT ID
NCT04160130
Organization ID
RHEIA
Secondary IDs
CIV-19-11-030544
Responsible Party
Sponsor
Study Sponsor
SSS International Clinical Research GmbH
Collaborators
Edwards Lifesciences
Study Sponsor
Hélène Eltchaninoff, Prof., Principal Investigator, CHU Rouen - Hopital Charles Nicolle
Verification Date
June 2020