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

Aortic Valve Stenosis Clinical Trial

— RHEIA  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04160130
• Other study ID #: RHEIA
• Secondary ID: CIV-19-11-030544
• Status: Active, not recruiting
• Phase: N/A
• Start date: November 29, 2019
• Est. completion date: June 2024

Study information

• Verified date: May 2023
• Source: Optimapharm
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 432
• Est. completion date: June 2024
• Est. primary completion date: February 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aortic Valve Stenosis
• Constriction, Pathologic
• Heart Valve Diseases

Intervention

Procedure:
• Transcatheter aortic valve replacement
Patients will be randomized 1:1 to receive either transcatheter aortic valve replacement (TAVI) or aortic valve replacement with a commercially available surgical bioprosthetic valve.

Locations

Country	Name	City	State
Austria	LKH-Univ. Klinikum Graz	Graz
Austria	Universitätskliniken Innsbruck	Innsbruck
Austria	Universitätsklinikum St. Pölten - Lilienfeld	St. Pölten
Austria	Allgemeines Krankenhaus der Stadt Wien	Vienna
Belgium	Clinique Saint-Luc	Bouge
Belgium	CHU De Charleroi	Charleroi
Belgium	UZ Leuven Campus Gasthuisberg	Leuven
Cyprus	Nicosia General Hospital	Nicosia
Czechia	University hospital Hradec Králové	Hradec Králové
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	IKEM (Institut Klinické a Experimentální Medicíny)	Praha
Czechia	Nemocnice Na Homolce	Praha 5
Finland	Helsinky University Hospital	Helsinki
Finland	Tampere University Hospital	Tampere
France	CHU de Bordeaux - Hôpital cardiologique du Haut-Lévêqu	Bordeaux
France	CHRU de Brest	Brest
France	GHE-Hôpital Cardiologique Louis Pradel	Bron
France	CHU Clermont-Ferrand - Hôpital Gabriel Montpied	Clermont-Ferrand
France	CHU Dijon	Dijon
France	CHU Lille - Institute Coeur Poumon	Lille
France	CHU Montpellier	Montpellier
France	CHU de Nantes - Hôpital Guillaume et René Laënnec	Nantes
France	Hôpital Privé Jacques Cartier	Paris
France	CHU et Université de Poitiers	Poitiers
France	CHU Rennes - Hopital de Pontchaillou	Rennes
France	CHU Rouen - Hopital Charles Nicolle	Rouen
France	Les Hopitaux Universitaires de Strasbourg - Nouvel Hôpital Civil	Strasbourg
France	Clinique Pasteur	Toulouse
Germany	Universitätsklinik der Ruhr-Universität Bochum	Bad Oeynhausen
Germany	Deutsches Herzzentrum Berlin	Berlin
Germany	Universitätsklinikum Frankfurt Am Main	Frankfurt
Germany	Universitätsmedizin der Johannes Gutenberg-Universität Mainz	Mainz
Ireland	St. James´s Hospital	Dublin
Italy	Azienda Ospedaliero Universitaria Policlinico "G.Rodolico - San Marco"	Catania
Italy	A.O.U. Careggi	Firenze
Italy	Ospedale del Cuore G. Pasquinucci	Massa
Italy	Universita di Padova	Padova
Italy	European Hospital	Roma
Italy	Azienda Ospedaliera Universitaria Integrata Verona	Verona
Netherlands	Catharina Ziekenhuis Eindhoven	Eindhoven
Netherlands	Leids Universitair Medisch Centrum	Leiden
Netherlands	St Antonius Ziekenhuis Nieuwegein	Nieuwegein
Switzerland	Inselspital Universitätsspital Bern	Bern
Switzerland	Hirslanden Klinik Im Park	Zürich
Switzerland	Universitätsspital Zürich	Zürich
United Kingdom	Royal Infirmary of Edinburgh	Edinburgh
United Kingdom	Morriston Hospital	Morriston
United Kingdom	Oxford University Hospitals - John Radcliffe hospital	Oxford

Sponsors (2)

Lead Sponsor	Collaborator
Optimapharm	Edwards Lifesciences

Countries where clinical trial is conducted

Austria,  Belgium,  Cyprus,  Czechia,  Finland,  France,  Germany,  Ireland,  Italy,  Netherlands,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mortality	Number of patients with death of any cause (death due to proximate cardiac cause, death caused by non-coronary vascular conditions, procedure-related deaths, valve-related deaths, sudden or unwitnessed death, non-cardiovascular mortality, death of unknown cause)	through study completion, an average of 1 year
Primary	Stroke	Number of patients with stroke (disabling and non-disabling).	through study completion, an average of 1 year
Primary	Re-hospitalization	Number of patients with re-hospitalization (valve-related or procedure-related or worsening of congestive heart failure).	through study completion, an average of 1 year
Secondary	Length of Index hospitalization	Number of days per patient for index hospitalization.	through day of procedure until day of discharge
Secondary	Prosthesis-patient mismatch	Number of patients with a prosthesis mismatch.	up to 30 days post-procedure
Secondary	New onset atrial fibrillation	Number of patients with a new onset of atrial fibrillation.	through study completion, an average of 1 year
Secondary	Vascular complications	Number of patients with major vascular complications.	through study completion, an average of 1 year
Secondary	Bleeding complications	Number of patients with life-threatening, disabling, or major bleeding complications.	through study completion, an average of 1 year
Secondary	Myocardial infarction	Number of patients with new myocardial infarction.	through study completion, an average of 1 year
Secondary	Acute kidney injury	Number of patients with new onset of acute kidney injury stage II/III (AKIN classification).	up to 30 days post-procedure
Secondary	Acute kidney injury	Number of patients with the need of renal replacement therapy.	through study completion, an average of 1 year
Secondary	New permanent pacemaker implantation	Number of patients with new permanent pacemaker implantation caused by new or worsened conduction disturbances.	through study completion, an average of 1 year
Secondary	Change in New York Heart Association (NYHA) classification	Severity of cardiac disease based on functional capacity will be described using the NYHA classification. Classification ranges from I - IV, with the lowest (I) as no limitations and the highest (IV) unable to carry on any physical activity.	through study completion, an average of 1 year
Secondary	Change in hemodynamic valve performance	Hemodynamic valve performance will be evaluated by echocardiography for aortic valve stenosis and aortic valve regurgitation (paravalvular & central).	through study completion, an average of 1 year
Secondary	Change in impairment caused by a stroke	Impairment caused by a stroke will be assessed using the the National Institutes of Health Stroke Scale (NIHSS)	through study completion, an average of 1 year
Secondary	Change in cognitive function	Cognitive function will be assessed using the Mini-mental state Examination-2 (MMSE-2) questionnaire	through study completion, an average of 1 year
Secondary	Change in the degree of disability in the daily activities	Degree of disability in the daily activities will be assessed using the modified Rankin Scale (mRS).	through study completion, an average of 1 year
Secondary	Change in Frailty Index	Frailty index will be assessed by the 5 Meter Walk Test, grip strength, Instrumental Activities of Daily Living and serum Albumin	through study completion, an average of 1 year
Secondary	Change in disease-specific health status	The health status in regards to congestive heart failure will be assessed by the patient using the Kansas City Cardiomyopathy Questionnaire (KCCQ).	through study completion, an average of 1 year
Secondary	Change in health-related quality of life	The health-related Quality of Life will be assessed by the patient using The Medical Outcomes Study Short-Form 12 (SF-12) questionnaire.	through study completion, an average of 1 year