Clinical trial NCT04160130: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Aortic Valve Stenosis
Heart Valve Diseases
Keywords: Research in woman
Transcatheter Aortic Valve Implantation (TAVI)
surgical aortic valve replacement (SAVR)
cardiovascular disease
heart disease
Sapien 3
Transcatheter Aortic Valve Replacement (TAVR)
Lead sponsor: Optimapharm
Sponsor class: INDUSTRY
Collaborators: name: Edwards Lifesciences
First posted: 2019-11-12
Enrollment: 432
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

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/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

Primary outcomes:
measure: Mortality
timeFrame: through study completion, an average of 1 year
measure: Stroke
timeFrame: through study completion, an average of 1 year
measure: Re-hospitalization
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Length of Index hospitalization
timeFrame: through day of procedure until day of discharge
measure: Prosthesis-patient mismatch
timeFrame: up to 30 days post-procedure
measure: New onset atrial fibrillation
timeFrame: through study completion, an average of 1 year
measure: Vascular complications
timeFrame: through study completion, an average of 1 year
measure: Bleeding complications
timeFrame: through study completion, an average of 1 year
measure: Myocardial infarction
timeFrame: through study completion, an average of 1 year
measure: Acute kidney injury
timeFrame: up to 30 days post-procedure
measure: Acute kidney injury
timeFrame: through study completion, an average of 1 year
measure: New permanent pacemaker implantation
timeFrame: through study completion, an average of 1 year
measure: Change in New York Heart Association (NYHA) classification
timeFrame: through study completion, an average of 1 year
measure: Change in hemodynamic valve performance
timeFrame: through study completion, an average of 1 year
measure: Change in impairment caused by a stroke
timeFrame: through study completion, an average of 1 year
measure: Change in cognitive function
timeFrame: through study completion, an average of 1 year
measure: Change in the degree of disability in the daily activities
timeFrame: through study completion, an average of 1 year
measure: Change in Frailty Index
timeFrame: through study completion, an average of 1 year
measure: Change in disease-specific health status
timeFrame: through study completion, an average of 1 year
measure: Change in health-related quality of life
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Graz
country: Austria
facility: LKH-Univ. Klinikum Graz
city: Innsbruck
country: Austria
facility: Universitätskliniken Innsbruck
city: St. Pölten
country: Austria
facility: Universitätsklinikum St. Pölten - Lilienfeld
city: Vienna
country: Austria
facility: Allgemeines Krankenhaus der Stadt Wien
city: Bouge
country: Belgium
facility: Clinique Saint-Luc
city: Charleroi
country: Belgium
facility: CHU De Charleroi
city: Leuven
country: Belgium
facility: UZ Leuven Campus Gasthuisberg
city: Nicosia
country: Cyprus
facility: Nicosia General Hospital
city: Hradec Králové
country: Czechia
facility: University hospital Hradec Králové
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Praha 5
country: Czechia
facility: Nemocnice Na Homolce
city: Praha
country: Czechia
facility: IKEM (Institut Klinické a Experimentální Medicíny)
city: Helsinki
country: Finland
facility: Helsinky University Hospital
city: Tampere
country: Finland
facility: Tampere University Hospital
city: Bordeaux
country: France
facility: CHU de Bordeaux - Hôpital cardiologique du Haut-Lévêqu
city: Brest
country: France
facility: CHRU de Brest
city: Bron
country: France
facility: GHE-Hôpital Cardiologique Louis Pradel
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand - Hôpital Gabriel Montpied
city: Dijon
country: France
facility: CHU Dijon
city: Lille
country: France
facility: CHU Lille - Institute Coeur Poumon
city: Montpellier
country: France
facility: CHU Montpellier
city: Nantes
country: France
facility: CHU de Nantes - Hôpital Guillaume et René Laënnec
city: Paris
country: France
facility: Hôpital Privé Jacques Cartier
city: Poitiers
country: France
facility: CHU et Université de Poitiers
city: Rennes
country: France
facility: CHU Rennes - Hopital de Pontchaillou
city: Rouen
country: France
facility: CHU Rouen - Hopital Charles Nicolle
city: Strasbourg
country: France
facility: Les Hopitaux Universitaires de Strasbourg - Nouvel Hôpital Civil
city: Toulouse
country: France
facility: Clinique Pasteur
city: Bad Oeynhausen
country: Germany
facility: Universitätsklinik der Ruhr-Universität Bochum
city: Berlin
country: Germany
facility: Deutsches Herzzentrum Berlin
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt Am Main
city: Mainz
country: Germany
facility: Universitätsmedizin der Johannes Gutenberg-Universität Mainz
city: Dublin
country: Ireland
facility: St. James´s Hospital
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco"
city: Firenze
country: Italy
facility: A.O.U. Careggi
city: Massa
country: Italy
facility: Ospedale del Cuore G. Pasquinucci
city: Padova
country: Italy
facility: Universita di Padova
city: Roma
country: Italy
facility: European Hospital
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Verona
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis Eindhoven
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Nieuwegein
country: Netherlands
facility: St Antonius Ziekenhuis Nieuwegein
city: Bern
country: Switzerland
facility: Inselspital Universitätsspital Bern
city: Zürich
country: Switzerland
facility: Hirslanden Klinik Im Park
city: Zürich
country: Switzerland
facility: Universitätsspital Zürich
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary of Edinburgh
city: Morriston
country: United Kingdom
facility: Morriston Hospital
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals - John Radcliffe hospital
Study officials:
affiliation: CHU Rouen - Hopital Charles Nicolle
name: Hélène Eltchaninoff, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Pasteur Toulouse
name: Didier Tchétché, Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eltchaninoff H, Bonaros N, Prendergast B, Nietlispach F, Vasa-Nicotera M, Chieffo A, Pibarot P, Bramlage P, Sykorova L, Kurucova J, Bax JJ, Windecker S, Dumonteil N, Tchetche D. Rationale and design of a prospective, randomized, controlled, multicenter study to evaluate the safety and efficacy of transcatheter heart valve replacement in female patients with severe symptomatic aortic stenosis requiring aortic valve intervention (Randomized researcH in womEn all comers wIth Aortic stenosis [RHEIA] trial). Am Heart J. 2020 Oct;228:27-35. doi: 10.1016/j.ahj.2020.06.016. Epub 2020 Jun 30.