The Role of cardIac magNeTic rEsonance in surGical Decision Making in Patients With Severe pRimAry miTral rEgurgitation (INTEGRATE)

Centro Cardiologico Monzino

Status: Active, not recruiting

Conditions: Mitral Regurgitation; Mitral Valve Prolapse

Treatments: Procedure: mitral valve surgery; Other: Clinical Follow up

Study type: Interventional

Funder types: Other

Identifiers

NCT07366723

L2-495

Details and patient eligibility

About

Mitral regurgitation (MR) is the second most frequent valvular heart disease and the second most frequent indication for valve surgery in Europe.

The management of patients with MV prolapse (MVP) and severe MR is mainly guided by symptoms, left ventricular (LV) dimensions and ejection fraction (EF), pulmonary artery systolic pressure (PASP) and atrial fibrillation (AF) occurrence.

According to the ESC/EACTS guidelines, surgical treatment of severe primary MR is indicated (recommendation Class I, Level B) in case of:

• symptomatic patients considered operable by the Heart Team;

• asymptomatic patients with LV dysfunction, intended as a LVEF ≤ 60% and/or LV end-systolic diameter (LVESD) ≥ 40 mm or LVESD indexed for body mass area (LVESDi) ≥ 20 mm/m2;

• low-risk asymptomatic patients without LV dysfunction (LVEF > 60%, LVESD < 40 mm, LVESDi < 20 mm/m2) when a durable result is likely, if at least 3 of the following criteria are fulfilled:

  • AF secondary to MR;
  • PASP value at rest > 50 mmHg;
  • significant left atrium (LA) dilation, intended as LA volume index ≥ 60 mL/m2 or diameter ≥ 55 mm
  • concomitant secondary tricuspid regurgitation ≥ moderate.

Surgery should be considered (recommendation Class IIa, Level B) in asymptomatic patients with preserved LV function (LVEF > 60%, LVESD < 40 mm, LVESDi < 20 mm/m2), when one of the following findings is present1:

• AF secondary to MR;
• PASP value at rest > 50 mmHg;
• LA volume index ≥ 60 mL/m2 or diameter ≥ 55 mm, provided surgical risk is low, surgery is performed in a Heart Valve Center and a durable MV repair is likely.

Preliminary data suggest that in patients with MVP, especially with Barlow's disease phenotype, left-sided chambers' enlargement and functional impairment may be disproportionate related to MR grade. Indeed, patients with BD and ≤ mild-to-moderate MR show larger LA and LV dimensions as compared to controls matched for age, gender and cardiovascular risk factors. These findings challenge the assumption that LA and LV remodeling is a direct effect of volume overload, with possible implications regarding the indication for MV intervention.

On the other hand, low mortality and good durability of valve repair has led some experienced centers to perform also early surgery, namely in any asymptomatic patient with severe MR, normal LV size and function, regular sinus rhythm, normal PASP and normal LA size, as long as surgical risk is very low and likelihood of successful valve repair is high. However, some studies have demonstrated that asymptomatic patients with severe degenerative MR can be safely followed up in experienced hands and remain free of indications for surgery for extensive periods of time. A watchful waiting strategy resulted in timely referral to surgery, excellent long-term survival, and good surgical outcomes, though requiring careful and active surveillance. Several authors agree that prospective randomized trials comparing active surveillance and early elective surgery are needed. There are also data suggesting that MR quantification by CMR has better discriminative power in identifying asymptomatic patients with degenerative MR and adverse outcomes as compared to the echocardiographic-derived integrative approach. Further prospective studies are necessary to validate these preliminary findings.

Full description

The present study is a multicenter, prospective, interventional, open randomized controlled trial. Patients will be screened for study eligibility by the clinical research staff of each investigational site. Patients meeting all inclusion criteria will be asked to sign an informed consent document prior to any trial-specific examinations and/or procedures, provided they do not have any of the exclusion criteria. After signing the informed consent, a structured interview will be performed and a clinical history obtained, assessing the presence of common cardiac risk factors, symptoms, and drug therapy (with a specific focus on anti-remodeling drugs, such as angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and mineralocorticoid receptor blockers). A Quality of Life (QoL) questionnaire will be administered13. Physical examination, rest ECG, CMR and a cardiopulmonary exercise test (CPET) will be also performed.

Subjects will be assigned a subject number upon enrolment. Afterwards, they will be randomized in a 1:1 ratio to a CMR-based strategy (unblinded CMR) or usual care1 (blinded CMR).

A randomization list will be generated using SAS statistical software (version 9.4, SAS Institute, Cary, NC, USA) and will be created by the Biostatistics Unit of Centro Cardiologico Monzino IRCCS, without direct contact with trial participants or involvement in the assessment of study eligibility.

After randomization, patients will be classified as follows (Figure 1 and 2):

• group A: patients with severe MR, as assessed by TTE, with less than severe MR documented by CMR, undergoing clinical follow-up;
• group B: patients with severe MR, as quantified by both TTE and CMR, undergoing surgery;
• group C: patients with severe MR, as assessed by TTE, undergoing surgery as per clinical practice.

After patients of group B and C have undergone surgery, baseline CMR of Group C will be unblinded. Then, patients of group C will be furtherly divided into two subgroups: those having less than severe MR as assessed by CMR (subgroup C1) and those having severe MR (subgroup C2).

At 1-year and 2-year follow-up after enrolment (group A) and after surgery (groups B and C), all patients will undergo a complete evaluation including a clinical interview and physical examination, administration of QoL questionnaires, performance of TTE, CMR and CPET.

Enrollment: 260 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• age ≥ 18 years;
• patients agree to all provisions of the protocol;
• patient can give informed consent;
• TTE diagnosis of MVP (defined as a systolic displacement of one or both mitral leaflets ≥ 2 mm above the plane of the MV annulus in long-axis views), and chronic severe MR;
• no symptoms;
• LVEF > 60%, LVESD < 40 mm and LVESDi < 20 mm/m2;
• sinus rhythm;
• PASP value at rest < 50 mmHg;
• LA volume index ≥ 60 mL/m2 or diameter ≥ 55 mm or normal LA size if likelihood of a successful and durable repair without residual MR is >95% and expected mortality rate is <1%
• ongoing adequate treatment per applicable standards;
• patient referred for isolated MV repair or replacement;
• willingness to undergo TTE, CMR and CPET at different timepoints

Exclusion criteria

• inability to provide informed consent;
• pregnancy or planned pregnancy within next 2 years;
• poor TTE image quality;
• usual contraindications to CMR and/or to gadolinium administration;
• inability to sustain a breath hold;
• known intracardiac shunts;
• coexistence of other cardiomyopathies or other > mild valve diseases;
• untreated clinically significant coronary artery disease requiring revascularization;
• planned concomitant cardiac surgical procedures (e.g. other valve procedures, or coronary artery bypass);
• need for an emergent/urgent surgery for any reason or any planned cardiac surgery within the next months;
• hemodynamic instability requiring inotropic support or mechanical heart assistance;
• sustained cardiac arrhythmias;
• active endocarditis;
• like expectancy < 12 months due to non-cardiac conditions.

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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260 participants in 4 patient groups

Blinded CMR - Group C1

Active Comparator group

Description:

Patients undergoing sugery based on TTE, showing less than severe MR by CMR

Treatment:

Procedure: mitral valve surgery

Unblinded CMR - Group A

Other group

Description:

Patients with severe MR, as assessed by TTE, with less than severe MR documented by CMR (Group A), undergo clinical follow-up.

Treatment:

Other: Clinical Follow up

Unblinded CMR - Group B

Active Comparator group

Description:

Patients with severe MR, as quantified by both TTE and CMR, undergo surgery.

Treatment:

Procedure: mitral valve surgery

Blinded CMR - Group C2

Active Comparator group

Description:

Patients undergoing surgery based on TTE, showing severe MR by CMR

Treatment:

Procedure: mitral valve surgery