Early Versus Deferred Aortic Valve Replacement in Patients With Moderate Aortic Stenosis and Mitral Regurgitation (TIAMAR)

Early Versus Deferred Aortic Valve Replacement in Patients With Moderate Aortic Stenosis Combined With Mitral Regurgitation: a Randomized Clinical Trial

The aim of the present study is to investigate safety and efficacy of early versus deferred aortic valve replacement in patients with moderate aortic stenosis combined with moderate mitral regurgitation.

Study Overview

• Status: Recruiting
• Conditions: Aortic Valve Replacement in Patients With Moderate Aortic Stenosis Combined With Mitral Regurgitation
• Intervention / Treatment: Procedure: Transcatheter or surgical aortic valve replacement with or without transcatheter or surgical mitral valve repair/replacement; Procedure: Deferred treatment, with intervention once AVA is ≤1.0 cm2 or if concomitant mitral regurgitation meets an indication for intervention

Detailed Description

In more than one-half of all patients with valvular heart disease, more than a single valve is involved. Valvular aortic stenosis coexists with significant mitral valve disease in up to one-third of patients undergoing aortic valve replacement (AVR).

Guidelines for the management of valvular heart disease provide recommendations for isolated valvular lesions; data to guide timing of intervention in patients with multivalvular disease is however scarce. Currently, patients with moderate aortic stenosis (AS) in combination with mitral regurgitation have an indication for aortic valve replacement (AVR) only if the concomitant mitral regurgitation meets an indication for surgery. However, the hemodynamic stress of combined valvular lesions is greater than its individual components, and patients may benefit from early intervention.

Furthermore, the presence of multivalvular heart disease complicates the assessment of individual valvular lesions. In patients with combined AS and mitral regurgitation (MR), increased left ventricular pressure exacerbates the mitral regurgitant volume. Conversely, decreased forward flow across the aortic valve underestimates the severity of aortic stenosis when assessed by a pressure gradient.

Standard cut-off values inadequately reflect the hemodynamic stress in concomitant aortic and mitral valve disease, and recommendations for the timing of valvular replacement fail to account for the complex interplay of multiple valvular lesions.

Timing of intervention in patients with combined AS and MR is therefore challenging and evidence on the optimal timing of intervention is scarce.

Thus, the objective of the present study is to investigate safety and efficacy of early versus deferred aortic valve replacement in patients with moderate aortic stenosis combined with at least moderate mitral regurgitation.

Patients with combined aortic stenosis and mitral regurgitation will be screened for eligibility. If eligible and informed consent is provided, patients will be randomly allocated in a 1:1 ratio to early (within 3 months) or deferred aortic valve replacement (with or without mitral valve intervention).

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Thomas Pilgrim, Prof. Dr.; Phone Number: 0041316325000; Email: kardio.studien@insel.ch
• Study Contact Backup: Name: Bartowiak Joanna, Dr. med.; Phone Number: 0041316325000; Email: kardio.studien@insel.ch

Study Locations

• Switzerland
  • Bern, Switzerland, 3010
    • Recruiting
    • Insel Gruppe AG, Inselspital Bern
    • Contact: Thomas Pilgrim, Prof
  • Geneva, Switzerland
    • Recruiting
    • University Hospital Geneva (HUG)
    • Contact: Stephane Noble, Prof
  • Zürich, Switzerland
    • Recruiting
    • Heart Clinic Hirslanden
    • Contact: Peter Wenaweser, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥18 years
• Moderate native aortic stenosis defined by an aortic valve area (AVA) ≤1.5 cm2 and >1.0 cm2 and transvalvular mean gradient ≥20 mmHg and <40 mmHg.
• Primary or secondary mitral regurgitation (at least moderate) defined by effective regurgitant orifice area (EROA) ≥20 mm2 or regurgitant volume ≥30 ml
• New York Heart Association (NYHA) functional class ≥2

Exclusion Criteria:

• Life expectancy <1 year irrespective of valvular heart disease
• Left ventricular ejection fraction <30% or LVESD >70mm
• Echocardiographic evidence of severe right ventricular dysfunction
• Untreated clinically significant CAD requiring revascularisation
• Moderate or severe aortic regurgitation
• Severe tricuspid valve disease requiring intervention
• Symptomatic patients with severe primary MR who are operable and not high risk
• Patients with severe secondary MR who remain symptomatic despite optimal medical therapy and who are judged appropriate for transcatheter edge-to-edge repair or surgery by the Heart Team
• Transcatheter or surgical treatment of valvular and/or coronary artery disease within 90 days prior to randomization
• COPD with home oxygen therapy
• Estimated or measured systolic PAP >70 mmHg
• Stroke within 30 days prior to the randomization
• Inability to provide written informed consent
• Participation in another cardiovascular trial before reaching the primary endpoint.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Early transcatheter or surgical aortic valve replacement; Early transcatheter or surgical aortic valve replacement with or without transcatheter or surgical mitral valve repair/replacement.	Procedure: Transcatheter or surgical aortic valve replacement with or without transcatheter or surgical mitral valve repair/replacement; Early transcatheter or surgical aortic valve replacement with or without transcatheter or surgical mitral valve repair/replacement.
Other: Control Intervention; Deferred treatment, with intervention once AVA is ≤1.0 cm2 or if concomitant mitral regurgitation meets an indication for intervention.	Procedure: Deferred treatment, with intervention once AVA is ≤1.0 cm2 or if concomitant mitral regurgitation meets an indication for intervention; Deferred transcatheter or surgical aortic valve replacement with or without transcatheter or surgical mitral valve repair/replacement.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary outcome will be a composite of all-cause death, stroke, and unplanned hospitalization for heart failure related to valvular heart disease at 2 years.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause death	Number of all-cause death within study participation	5 years
Cardiovascular death	Number of patients with Cardiovascular death within study participation	5 years
Neurologic events	Number of patients with stroke, symptomatic hypoxic-ischaemic injury, TIA and evaluation	5 years
Hospitalization for heart failure	Number of patients who need hospitalization for heart failure within study participation and evaluation	5 years
New-onset atrial fibrillation	Number of patients with new-onset atrial fibrillation within study participation and evaluation	5 years
Implantation of a permanent pacemaker	Number of patients with atrioventricular conductance disturbance requiring the implantation of a permanent pacemaker	5 years
Aortic or mitral valve re-intervention	Number of patients with Aortic or mitral valve re-intervention within study participation and evaluation	5 years
NYHA functional class	Measurement of NYHA functional class within study participation	5 years
Days alive out of hospital (DAOH)	Calculation of days alive out of hospital (DAOH) within study participation	5 years
The evaluation Health-related quality of life assessment by means of the KCCQ 12 questionnaire	Record the health-related quality of life assessment by means of the KCCQ 12 questionnaire within study participation	5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Major vascular complications (VARC-3)	Number of patients with major vascular complications within the study population and evaluation	5 years
Cardiac structural complications (major, minor) (VARC-3)	Number of patients with cardiac structural complications within the study population and evaluation	5 years
Cerebrovascular events (disabling and non-disabling stroke, and TIA) (VARC-3)	Number of patients with Cerebrovascular events (disabling and non-disabling stroke, and TIA) (VARC-3) within the study population and evaluation	5 years
Myocardial infarction	Number of patients with Myocardial infarction within the study population and evaluation	5 years
Acute kidney injury (VARC-3)	Number of patients with acute kidney injury (VARC-3) within the study population and evaluation	5 years
Access-related non-vascular major complications (VARC-3)	Number of patients with access-related non-vascular major complications (VARC-3) within the study population and evaluation	5 years
Bleeding type 3-5 (VARC-3)	Record all bleeding type 3-5 (VARC-3) within the study population	5 years
Prosthetic valve endocarditis	Number of patients Prosthetic valve endocarditis within the study population	5 years
Prosthetic valve thrombosis	Number of patients prosthetic valve thrombosis within the study population	5 years
Valve-related dysfunction requiring reintervention	Number of patients valve-related dysfunction requiring reintervention within the study population	5 years

Collaborators and Investigators

• Sponsor: Insel Gruppe AG, University Hospital Bern
• Investigators: Principal Investigator: Thomas Pilgrim, Prof. Dr., Insel Gruppe AG

Publications and helpful links

General Publications

• Shah AM, Solomon SD. Valvular heart disease in older adults: seeking an ounce of prevention. Eur Heart J. 2016 Dec 14;37(47):3523-3524. doi: 10.1093/eurheartj/ehw354. Epub 2016 Sep 1. No abstract available.
• Khan F, Okuno T, Malebranche D, Lanz J, Praz F, Stortecky S, Windecker S, Pilgrim T. Transcatheter Aortic Valve Replacement in Patients With Multivalvular Heart Disease. JACC Cardiovasc Interv. 2020 Jul 13;13(13):1503-1514. doi: 10.1016/j.jcin.2020.03.052.
• Unger P, Pibarot P, Tribouilloy C, Lancellotti P, Maisano F, Iung B, Pierard L; European Society of Cardiology Council on Valvular Heart Disease. Multiple and Mixed Valvular Heart Diseases. Circ Cardiovasc Imaging. 2018 Aug;11(8):e007862. doi: 10.1161/CIRCIMAGING.118.007862. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2022
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): January 1, 2030

Study Registration Dates

• First Submitted: March 25, 2022
• First Submitted That Met QC Criteria: March 25, 2022
• First Posted (Actual): April 5, 2022

Study Record Updates

• Last Update Posted (Estimated): November 21, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Aortic Valve Stenosis; Mitral Valve Insufficiency; Constriction, Pathologic
• Other Study ID Numbers: TIAMAR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No