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

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ClinicalTrials.gov Identifier: NCT04160130
Recruitment Status : Recruiting
First Posted : November 12, 2019
Last Update Posted : November 9, 2020
Sponsor:
Collaborator:
Edwards Lifesciences
Information provided by (Responsible Party):
SSS International Clinical Research GmbH

Study Description
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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.

Condition or disease Intervention/treatment Phase
Aortic Valve Stenosis Heart Valve Diseases Procedure: Transcatheter aortic valve replacement Not Applicable

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 440 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
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
Actual Study Start Date : November 29, 2019
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: SAPIEN 3 or SAPIEN 3 Ultra
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.
 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.
Other Name: Surgical aortic valve replacement
Active Comparator: any surgical bioprosthetic aortic valve
Any commercially available surgical bioprosthetic valve
 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.
Other Name: Surgical aortic valve replacement


Outcome Measures
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Primary Outcome Measures :
  1. Mortality [ Time Frame: through study completion, an average of 1 year ]
    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)

  2. Stroke [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with stroke (disabling and non-disabling).

  3. Re-hospitalization [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with re-hospitalization (valve-related or procedure-related or worsening of congestive heart failure).


Secondary Outcome Measures :
  1. Length of Index hospitalization [ Time Frame: through day of procedure until day of discharge ]
    Number of days per patient for index hospitalization.

  2. Prosthesis-patient mismatch [ Time Frame: up to 30 days post-procedure ]
    Number of patients with a prosthesis mismatch.

  3. New onset atrial fibrillation [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with a new onset of atrial fibrillation.

  4. Vascular complications [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with major vascular complications.

  5. Bleeding complications [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with life-threatening, disabling, or major bleeding complications.

  6. Myocardial infarction [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with new myocardial infarction.

  7. Acute kidney injury [ Time Frame: up to 30 days post-procedure ]
    Number of patients with new onset of acute kidney injury stage II/III (AKIN classification).

  8. Acute kidney injury [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with the need of renal replacement therapy.

  9. New permanent pacemaker implantation [ Time Frame: through study completion, an average of 1 year ]
    Number of patients with new permanent pacemaker implantation caused by new or worsened conduction disturbances.

  10. Change in New York Heart Association (NYHA) classification [ Time Frame: through study completion, an average of 1 year ]
    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.

  11. Change in hemodynamic valve performance [ Time Frame: through study completion, an average of 1 year ]
    Hemodynamic valve performance will be evaluated by echocardiography for aortic valve stenosis and aortic valve regurgitation (paravalvular & central).

  12. Change in impairment caused by a stroke [ Time Frame: through study completion, an average of 1 year ]
    Impairment caused by a stroke will be assessed using the the National Institutes of Health Stroke Scale (NIHSS)

  13. Change in cognitive function [ Time Frame: through study completion, an average of 1 year ]
    Cognitive function will be assessed using the Mini-mental state Examination-2 (MMSE-2) questionnaire

  14. Change in the degree of disability in the daily activities [ Time Frame: through study completion, an average of 1 year ]
    Degree of disability in the daily activities will be assessed using the modified Rankin Scale (mRS).

  15. Change in Frailty Index [ Time Frame: through study completion, an average of 1 year ]
    Frailty index will be assessed by the 5 Meter Walk Test, grip strength, Instrumental Activities of Daily Living and serum Albumin

  16. Change in disease-specific health status [ Time Frame: through study completion, an average of 1 year ]
    The health status in regards to congestive heart failure will be assessed by the patient using the Kansas City Cardiomyopathy Questionnaire (KCCQ).

  17. Change in health-related quality of life [ Time Frame: through study completion, an average of 1 year ]
    The health-related Quality of Life will be assessed by the patient using The Medical Outcomes Study Short-Form 12 (SF-12) questionnaire.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04160130


Contacts
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Contact: Michael Sigmund, Dr. +49 89 800 650 ext 0 michael.sigmund@cro-sss.de
Contact: Christine Schubert, Dr. +49 89 800 650 ext 0 christine.schubert@cro-sss.de

Locations
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Sponsors and Collaborators
SSS International Clinical Research GmbH
Edwards Lifesciences
Investigators
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Principal Investigator: Hélène Eltchaninoff, Prof. CHU Rouen - Hopital Charles Nicolle
Principal Investigator: Didier Tchétché, Dr. Clinique Pasteur Toulouse
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: SSS International Clinical Research GmbH
ClinicalTrials.gov Identifier: NCT04160130    
Other Study ID Numbers: RHEIA
CIV-19-11-030544 ( Other Identifier: DIMDI )
First Posted: November 12, 2019    Key Record Dates
Last Update Posted: November 9, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by SSS International Clinical Research GmbH:
Research in woman
Transcatheter Aortic Valve Implantation (TAVI)
surgical aortic valve replacement (SAVR)
cardiovascular disease
 heart disease
Sapien 3
Transcatheter Aortic Valve Replacement (TAVR)
Additional relevant MeSH terms:
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Aortic Valve Stenosis
Heart Valve Diseases
Constriction, Pathologic
Pathological Conditions, Anatomical
 Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction