The Dutch Asymptomatic Mitral Regurgitation Trial (Dutch AMR)

Dutch AMR; Early Mitral Valve Repair Versus Watchful Waiting in Asymptomatic Patients With Severe Organic Mitral Regurgitation; a Multicenter, Randomised Trial.

The purpose of this study is to compare early mitral valve repair versus a watchful waiting strategy in asymptomatic patients with severe organic mitral valve regurgitation and preserved left ventricular function.

Study Overview

• Status: Terminated
• Conditions: Mitral Valve Insufficiency; Diseases of Mitral Valve; Heart; Disease, Mitral(Valve)
• Intervention / Treatment: Procedure: Early mitral valve repair; Other: Watchful waiting

Detailed Description

Severe asymptomatic organic mitral valve (MV) regurgitation with preserved left ventricular (LV) function is a challenging clinical entity as data on the recommended treatment strategy for these patients are scarce and conflicting, which is reflected in current guidelines. European guidelines advocate a more conservative strategy i.e. watchful waiting, with yearly echocardiography, whilst American guidelines are more in favour of early surgery to reconstruct the MV, i.e. MV repair (in contrast to MV replacement) in order to prevent future LV dysfunction and complaints.

A number of non-randomised trials show a favourable outcome of early surgery and the early surgery strategy has shown to be associated with improved long-term survival, decreased cardiac mortality and decreased morbidity compared with the conservative management [citations 1-3]. On the other hand, non-randomised trials describe also that a conservative strategy (i.e. watchful waiting) can be safely accomplished. If facilitated surgery is performed in this population it has proven to be eventually associated with good perioperative and postoperative outcome in 50% of the patients at 10 years when careful follow-up is being carried out [citation 4]. Non-randomised trials inherently have a number of drawbacks. A randomised trial comparing both strategies and objectivising the best treatment strategy has never been performed.

The Dutch AMR (Asymptomatic Mitral Regurgitation) trial is a multicenter, prospective, randomised trial comparing early MV repair versus watchful waiting in asymptomatic patients with severe organic MV regurgitation and preserved LV function [citation 5, 6].

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Amsterdam Medisch Centrum
  • Breda, Netherlands
    • Amphia Hospital
  • Utrecht, Netherlands, 3584 CX
    • University Medical Center Utrecht (UMC Utrecht)
  • South Holland
    • Leiden, South Holland, Netherlands, 2333 ZA
      • Leiden University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Asymptomatic
• Severe organic mitral valve regurgitation.
• Preserved left ventricular function (left ventricular ejection fraction >60% and left ventricular end-systolic dimension ≤45 mm)
• The likelihood of MV repair should be more than 90% determined by the local heart team with a cardiologist and cardiothoracic surgeon

Exclusion Criteria:

• Pulmonary hypertension (>50 mmHg at rest)
• Atrial fibrillation
• Physical inability as determined by the heart team to undergo surgery
• Other life-threatening morbidity
• Higher expected surgical risks in advance, according to the dedicated heart team
• Moderate to severe kidney disease (eGFR less than 30 mL/min)
• Flail leaflet together with a left ventricular end systolic diameter (LVESD) >40 mm

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
Active Comparator: Early mitral valve repair	Procedure: Early mitral valve repair; Patients in the group of early mitral valve repair will be operated by way of routine mitral valve repair procedures in specialized centres.
Active Comparator: Watchful waiting	Other: Watchful waiting; In case of watchful waiting a conservative treatment is performed, based on close monitoring of the patient for clear signs of deterioration that triggers facilitated surgery before left ventricular dysfunction is present.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite endpoint: cardiovascular mortality, congestive heart failure and hospitalization for nonfatal cardiovascular events	The primary outcome is defined as 'time to first event'. It concerns time to first event of the composite endpoint of cardiovascular mortality, congestive heart failure, non-fatal cardiovascular events requiring hospitalization, defined as: stroke/cerebrovascular accident (CVA), atrial fibrillation (permanent or requiring hospitalization) and/or reoperation after elective MV surgery.	Min. 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cardiovascular mortality	Secondary outcome measures are the separate components of the composite primary endpoint: cardiovascular mortality, congestive heart failure, hospitalization for nonfatal cardiovascular events (stroke/cerebrovascular accident (CVA), AF (permanent or requiring hospitalization) and reoperation after elective MV surgery).	Min. 5 years
Congestive heart failure	Secondary outcome measures are the separate components of the composite primary endpoint: cardiovascular mortality, congestive heart failure, hospitalization for nonfatal cardiovascular events (stroke/cerebrovascular accident (CVA), AF (permanent or requiring hospitalization) and reoperation after elective MV surgery).	Min. 5 years
Hospitalization for nonfatal cardiovascular events	Secondary outcome measures are the separate components of the composite primary endpoint: cardiovascular mortality, congestive heart failure, hospitalization for nonfatal cardiovascular events (stroke/cerebrovascular accident (CVA), AF (permanent or requiring hospitalization) and reoperation after elective MV surgery).	Min. 5 years
All-cause mortality	Secondary outcome measures the incidence of all-cause mortality at a minimum of 5 years.	Min. 5 years
Costs and effectiveness	Secondary outcome measures total direct and indirect costs and cost-effectiveness at a minimum of 5 years.	Min. 5 years
Health-related quality of life	Secondary outcome measures health-related quality of life at a minimum of 5 years.	Min. 5 years
Echocardiographic parameters	Secondary outcome measures echocardiographic parameters at a minimum of 5 years.	Min. 5 years
CMR parameters	Secondary outcome measures Cardiovascular Magnetic Resonance imaging (CMR) parameters at a minimum of 5 years.	Min. 5 years.
Paroxysmal atrial fibrillation	Secondary outcome measures the incidence of paroxysmal atrial fibrillation at a minimum of 5 years.	Min. 5 years
Exercise test parameters	Secondary outcome measures exercise test parameters at a minimum of 5 years.	Min. 5 years.
BNP	Secondary outcome measures brain natriuretic peptide (BNP) plasma levels at a minimum of 5 years.	Min. 5 years
Myocardial infarction	Secondary outcome measures the incidence of myocardial infarction at a minimum of 5 years.	Min. 5 years
Pacemaker implantation	Secondary outcome measures the incidence of pacemaker implantation at a minimum of 5 years.	Min. 5 years
Transient ischemic attack	Secondary outcome measures the incidence of transient ischemic attack (TIA) at a minimum of 5 years.	Min. 5 years
Pulmonary embolism	Secondary outcome measures the incidence of pulmonary embolism at a minimum of 5 years.	Min. 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Surgery complication rate	The complication rate in the mitral valve surgery group (e.g. re-operation for bleeding, pneumonia, residual or recurrent mitral valve regurgitation) will be determined at a minimum of 5 years.	Min. 5 years
Rate for the need of facilitated surgery	Rate for the need of facilitated surgery in the watchful waiting group will be determined at a minimum of 5 years.	Min. 5 years

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: Leiden University Medical Center; The Interuniversity Cardiology Institute of the Netherlands; WCN, Dutch Network for Cardiovascular Research
• Investigators: Principal Investigator: Steven AJ Chamuleau, MD, PhD, University Medical Center Utrecht (UMC Utrecht); Principal Investigator: Jolanda Kluin, MD, PhD, University Medical Center Utrecht (UMC Utrecht); Principal Investigator: Robert JM Klautz, Prof. MD PhD, Leiden University Medical Center (LUMC Leiden)

Publications and helpful links

General Publications

• Enriquez-Sarano M, Avierinos JF, Messika-Zeitoun D, Detaint D, Capps M, Nkomo V, Scott C, Schaff HV, Tajik AJ. Quantitative determinants of the outcome of asymptomatic mitral regurgitation. N Engl J Med. 2005 Mar 3;352(9):875-83. doi: 10.1056/NEJMoa041451.
• Ling LH, Enriquez-Sarano M, Seward JB, Orszulak TA, Schaff HV, Bailey KR, Tajik AJ, Frye RL. Early surgery in patients with mitral regurgitation due to flail leaflets: a long-term outcome study. Circulation. 1997 Sep 16;96(6):1819-25. doi: 10.1161/01.cir.96.6.1819.
• Rosenhek R, Rader F, Klaar U, Gabriel H, Krejc M, Kalbeck D, Schemper M, Maurer G, Baumgartner H. Outcome of watchful waiting in asymptomatic severe mitral regurgitation. Circulation. 2006 May 9;113(18):2238-44. doi: 10.1161/CIRCULATIONAHA.105.599175. Epub 2006 May 1.
• Chenot F, Montant P, Vancraeynest D, Pasquet A, Gerber B, Noirhomme PH, El Khoury G, Vanoverschelde JL. Long-term clinical outcome of mitral valve repair in asymptomatic severe mitral regurgitation. Eur J Cardiothorac Surg. 2009 Sep;36(3):539-45. doi: 10.1016/j.ejcts.2009.02.063. Epub 2009 Jul 25.
• Tietge WJ, de Heer LM, van Hessen MW, Jansen R, Bots ML, van Gilst W, Schalij M, Klautz RJ, Van den Brink RB, Van Herwerden LA, Doevendans PA, Chamuleau SA, Kluin J. Early mitral valve repair versus watchful waiting in patients with severe asymptomatic organic mitral regurgitation; rationale and design of the Dutch AMR trial, a multicenter, randomised trial. Neth Heart J. 2012 Mar;20(3):94-101. doi: 10.1007/s12471-012-0249-y.
• Jansen R, Kluin J, Chamuleau SA. Research versus clinical practice in asymptomatic patients with severe organic mitral regurgitation and preserved LV function. J Am Coll Cardiol. 2014 Oct 14;64(15):1639-40. doi: 10.1016/j.jacc.2014.07.964. No abstract available.

Helpful Links

• Dutch AMR study homepage

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Anticipated): February 1, 2021
• Study Completion (Anticipated): February 1, 2021

Study Registration Dates

• First Submitted: October 11, 2012
• First Submitted That Met QC Criteria: October 15, 2012
• First Posted (Estimate): October 16, 2012

Study Record Updates

• Last Update Posted (Estimate): November 23, 2016
• Last Update Submitted That Met QC Criteria: November 22, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Mitral Valve Insufficiency; Mitral Valve Regurgitation; Watchful Waiting; Mitral Valve Repair; Asymptomatic Mitral Valve Regurgitation; Asymptomatic Mitral Valve Insufficiency
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Valve Diseases; Mitral Valve Insufficiency
• Other Study ID Numbers: NL39851.041.12.