Moderate mitral regurgitation in patients undergoing CABG – the MoMIC trial

Abstract

Background. The presence of mild to moderate ischemic mitral regurgitation (IMR) marks a significantly reduced long-term survival and increased hospitalizations due to heart-failure. However, it is common practice in many institutions to refrain from repairing the mitral valve in these patients. There are no available conclusive data to support this practice, and thus there is a need for an adequately powered randomized trial. Study design. The Moderate Mitral Regurgitation In Patients Undergoing CABG (MoMIC) trial is the first international multi-center, large-scale study to clarify whether moderate IMR in CABG patients should be corrected. A total of 550 CABG patients with moderate IMR are to be randomized to treatment of either CABG alone or CABG plus mitral valve correction. The primary end point is a composite end point of mortality and rehospitalization for heart failure at five years. The inclusion and randomization of patients started in February 2008. Implication. If correction of moderate IMR in CABG patients proves to be the superior strategy, most patients should be treated accordingly.

Trial registration: ClinicalTrial.gov identifier: NCT00613548.

• Mitral
• surgery
• ischemia
• regurgitation
• trial

Ischemic mitral regurgitation (IMR) was observed in 19% of 11 748 patients during cardiac catheterisation for symptomatic coronary disease 1. In the majority of cases the regurgitation was mild, but 7.2% of the patients had at least grade 2 regurgitation. According to data from the MoMIC trial's pilot-phase 2, the current prevalence of IMR in Scandinavia in the contemporary percutaneous coronary intervention (PCI) era is 4%, defined by semiquantitative estimation of a grade 2+ valve regurgitation that corresponds to a calculated effective regurgitant orifice (ERO) of 5-30 mm². The treatment dilemma is currently in patients with an ERO interval between 15-30 mm². In this group, 50% of the patients had a concomitant mitral valve repair. Such patients, however, only accounted for 2.7% (95% CI, 1.5-4.7%) of the total population of non-emergency CABG patients. The presence of ischemic MR after acute myocardial infarction has been shown to have a prognostic implication3, where an “effective regurgitant orifice area” (ERO) above 20 mm² is a marker of significantly reduced long-term survival 4, 5. Additionally, the presence of IMR in patients undergoing isolated coronary artery bypass grafting (CABG) is also associate with an increased mortality 6–10.

The benefit of adding mitral valve surgery to CABG is well documented in the combination of coronary artery disease and severe MR 11–14. On the other hand, it is clinical practice to refrain from repairing the mitral valve in CABG cases where IMR is mild to moderate. However, there are no conclusive data available to support this principle. The existing studies are small, retrospective, and the results contradictive 7, 15–18. Moreover, some studies indicate that an uncorrected IMR after CABG is related to reduced long-term survival and increased frequency of hospitalization due to heart failure 9, 10, 18.

A prospective randomized trial has frequently been proposed and discussed, however, to the best of our knowledge, no such study is so far launched. Therefore, to evaluate which treatment strategy is superior, we present a large-scale, international multi-center trial.

The “Moderate Mitral Regurgitation In Patients Undergoing CABG (MoMIC) trial” is designed to elucidate, on an international multi-center basis, whether moderate IMR in CABG patients should be corrected or not. The study started to randomize patients in February 2008.

Methods

Overview

The planned randomization calls for a total of 550 CABG patients with moderate ischemic MR. The patients will be randomized either to receive CABG alone or to CABG with concomitant correction of the IMR. The trial is registered at “Clinicaltrial.gov” (MoMIC, 20040224). The protocol is designed according to the “Consort Statement” regarding randomized controlled trials.

Hypothesis

The hypothesis is that patients who undergo mitral valve repair with CABG will have improved late survival and freedom from hospitalization due to heart failure in comparison to patients treated with isolated CABG.

End-points

The primary end-point is a composite end-point of mortality and rehospitalization for heart failure. Hospitalization for heart failure is defined by the occurrence of increasing symptoms and the need for treatment with intravenous diuretics or a substantial increase in oral diuretics (an increase of at least 40 mg of furosemide per day, 1 mg of bumetanid per day, or 10 mg of torsemide per day) or the initiation of a combination of a thiazide and a loop diuretics. The inability to safely wean the patient from cardio-pulmonary by-pass due to severe IMR and hence necessitating a mitral valve procedure will also be considered as heart failure.

The secondary endpoints are disabling neurological deficit, new onset atrial fibrillation, need for pacemaker insertion, and endocarditis.

Number of patients

The size of the study population is determined to be 550 patients based on the assumption of 10% units improvement from 60% 9, 10 to 70% in the primary end-point (freedom from death and hospitalization due to heart failure) of either method (CABG alone or CABG with correction of IMR) after five years. Based on the number and size of the participating centers, the expected inclusion period is two years.

Inclusion criteria

Patients to be included will have with ischemic heart disease fulfilling the indications for CABG. Additionally, the patients should have a moderate IMR.IMR is defined as mitral regurgitation due to coronary artery disease and not fortuitously associate with it. It is caused either by a mitral annular dilatation (Carpentier type I), or a restrictive motion of the posterior mitral leaflet (Carpentier type IIIb) 19, or a combination. The mitral leaflets should be slender and without signs of intrinsic organic disease. The mitral annulus should be with no significant calcification responsible for valve insufficiency 2. The severity of mitral regurgitation is quantified by means of echoardiography using the Proximal Isovelocity Surface Area (PISA)-method 20. Moderate IMR is defined as a calculated ERO of 15 – 30 mm² at rest (2). Hence, patients referred for CABG with signs of mitral regurgitation on auscultation, by echocardiography, or by ventriculography will be further evaluated by a complete echocardiography (Transthoracic (TTE) in ambiguous cases supplemented with transesophageal echocardiography (TEE) before surgery, in order to determine whether the patient meets the inclusion criteria. In addition, ejection fraction (visually estimated), left atrial dimension, mitral annular and tricuspid annular size, as well as estimates of pulmonary hypertension will be recorded:

1. Age ≥ 18 yrs.

2. Inclusion is independent of the left ventricular function.

3. Inclusion is independent of the left atrial size.

4. It is mandatory that the patient is able to fully understand the written information, the purpose of the study, and is able to give an informed consent.

Exclusion criteria

1. Patients with previous cardiac surgery.

2. Emergency surgery.

3. Malignant disease with an expected survival of less than 5 years.

4. ST-elevation myocardial infarction within 16 days.

5. Significant aortic valve disease necessitating aortic valve replacement.

6. Calcification of the ascending aorta.

7. Significant mitral annular calcification.

8. Type II MR (ruptured papillary muscle, or infarcted elongated papillary muscle with prolapse).

9. Refusal to participate in the study.

Randomization

Internet based randomization is performed on the day before surgery. In each center randomization of the patients will be stratified according to sex, age (above and below 70 years) and according to ejection fraction (EF) (above and below 30%).

Surgery, anesthesia, and postoperative treatment

Surgery, anesthesia, and postoperative treatment will be performed according to standards at each participating department. In addition to the preoperative TTE performed in order to determine the etiology and degree of mitral regurgitation, ejection fraction and the above mentioned dimensions and estimate of pulmonary artery pressure. TEE will be performed after weaning from cardiopulmonary bypass and in the presence of a systolic blood pressure of at least 100 mmHg.

In patients randomized to receive mitral correction, a suitable valve repair will be performed according to the addendum. In the event of an expected non-satisfactory result or a residual ERO > 30 mm² according to per-operative TEE, a prosthesis will be inserted with preservation of the subvalvular apparatus.

All patients will be treated with low-dose aspirin, unless there are contraindications. In such cases clopidogrel may be considered. Anticoagulation treatment after mitral valve repair, insertion of a bioprosthesis, or atrial fibrillation is administered according to standards at each department. All patients with an ejection fraction < 40% should receive contemporary heart failure medication.

Follow-up assessment

All patients included in the trial should undergo follow-up including an out-patient visit for TTE (in ambiguous cases supplemented by TEE) three months after the operation, a telephone interview 12 months after the surgery, and subsequently every year for a period of five years.

Patients safety aspects

The study has been approved by the ethics committee (ref nr 20040224). The presence of an IMR in patients with ischemic heart disease carries an increased perioperative risk at CABG 6–10. In theory, an additional mitral repair carries a slightly increased risk for cerebral complications, bleeding, atrial fibrillation, need for pacemaker insertion, endocarditis and a future artificial valve replacement. On the other hand, a correction of a moderate mitral regurgitation is expected to reduce the peri- and postoperative morbidity and mortality related to heart failure. Moreover, there is evidence that an uncorrected IMR at the time of surgery results in a reduced long-term survival 9, 10, 18. All patients will be operated by experienced mitral valve surgeons and we do not anticipate that patients randomized to mitral repair are subject to an increased operative risk.

Statistical analysis

The main purpose of the statistical analysis is to evaluate possible differences in clinical outcome between CABG alone and CABG with correction of moderate IMR. Firstly, it will be tested whether the treatment groups are comparable with respect to established prognostic determinants at study entry. This will be done by applying a t test or the equivalent nonparametric test and a χ² test, respectively.

Secondly, the primary end-point will be analyzed using Kaplan-Meier plots for graphical comparison between the treatment groups and using log-rank tests for numerical comparisons.

Hazard ratios and associate 95% confidence intervals (CI) will be analyzed using Cox regression analysis. Furthermore, the primary outcome will be assessed for variation of the effect of the randomised treatment in subgroups.

All statistical analyses will be conducted according to the intention-to-treat principle.

Study organization

The steering committee will monitor all aspects of the MoMIC trial. The Aarhus University Trial Unit will administer the randomisation, data handling and analysis. The end point committee will independently and blinded decide whether the patients fulfil the end point criteria. An independent monitoring group was initially planned for, but the interim analysis has been omitted due to the sample size.

Conclusion

The MoMIC trial is an international, multicenter, randomized trial planned to include 550 CABG patients with moderate MR, in order to determine whether or not this patient group will benefit from mitral valve correction concomitantly with CABG treatment.

Acknowledgements

Declaration of interest: Patrick McCarthy is a co-inventor of the IMR ring and receives royalties from Edwards Lifescience.

Appendix 1

Committees

Steering committee

Per Wierup, consultant, PhD, associate professor (principal investigator)

Henrik Egeblad, consultant, DMSc, associate professor

Henning Mølgaard, consultant, DMSc, associate professor

Henrik Scherstén, consultant, PhD

Odd Bech-Hansen, consultant, PhD, associate professor

Folke Nilsson, consultant, PhD, professor

Sten Lyager Nielsen, consultant, DMSc

Per Ola Kimblad, consultant, PhD

Anders Roijer, consultant, PhD

Patrick M McCarthy, MD, professor

Denis Bouchard, MD, PhD, associate professor

End-point committee

Peter Kildeberg Paulsen, professor emeritus, cardiac surgeon, Aarhus, Denmark.

Ole Goetszche, MD, cardiologist, Amtsygehuset, Aarhus, Denmark.

Flemming Hald Steffensen, MD, cardiologist, Vejle Country Hospital, Vejle, Denmark.

Johan Holm, MD, cardiologist, Malmö University Hospital, Malmö, Sweden.

Appendix 2

The MoMIC Trial Investigators

Denmark

Skejby Hospital (principal investigation centre)

Department of Cardiothoracic Surgery

Per Wierup, consultant, PhD, associate professor (principal investigator)

Sten Lyager Nielsen, consultant, DMSc (project-coordinator SKH)

Kaj-Erik Klaaborg, Hans-Henrik Kure, consultant

Department of Cardiology

Henrik Egeblad, consultant, DMSc, associate professor

Henning Mølgaard, consultant, DMSc, associate professor

Sten Hvitfeldt Poulsen, consultant, MD, DMSc

Department of Cardiothoracic Anesthesia

Erik Sloth, consultant, DMSc

Rigshospitalet, Copenhagen University

Department of Cardiothoracic Surgery

Jens Lund, consultant

Jens Thies, consultant

Daniel Steinbrüchel, consultant, DMSc, professor

Department of Cardiology

Lars Køber, consultant, DMSc, professor

Christian Hasseager, consultant, DMSc, associate professor

Odense University Hospital

Department of Cardiothoracic Surgery

Bent Møller Jensen, consultant, PhD

Department of Cardiology

Sabine Gill, consultant, PhD

Henrik Nissen, consultant, PhD

Gentofte Hospital, Copenhagen University

Dep]artment of Cardiothoracic Surgery

John Brochorst Christensen, consultant, PhD

Susanne Holme, consultant, PhD

Department of Cardiology

Thomas Fritz Hansen, consultant, PhD

Aalborg Hospital, Aarhus University

Department of Cardiothoracic Surgery

Jan Jesper Andreasen, consultant

Department of Cardiology

Eva Korup, consultant, PhD

Geert Espersen, consultant, PhD

Varde Heart Center.

Per Wierup, consultant, PhD

Sten Oxelbark, consultant, PhD, associate professor

Lars Bengtsson, consultant, PhD, associate professor

Ricardo Sanchez, consultant, director

Sweden

Sahlgrenska University Hospital, Gothenburg

Department of Cardiothoracic Surgery

Henrik Scherstén, consultant, PhD (project-coordinator, SUH)

Folke Nilsson, consultant, PhD, professor

Vincenzo Lepore, consultant, PhD

Department of Cardiology

Nedim Selimovic, consultant

Department of Clinical Physiology

Odd Bech-Hansen, consultant, PhD, associate professor

University Hospital, Lund

Department of Cardiothoracic Surgery

Per Ola Kimblad, consultant, PhD

Department of Cardiology

Anders Roijer, consultant

Linköping University Hospital

Department of Cardiothoracic Surgery

Henrik Ahn, consultant, PhD, Professor

Ulf Hermansson, consultant, PhD

Gabriella Boano, consultant

Karlskrona Hospital.

Department of Cardiothoracic Surgery

Bengt Åberg, consultant, PhD

Finland

Meilahti University Hospital, Helsinki.

Department of Cardiothoracic Surgery

Kalervo Werkkala, consultant, PhD, associate professor

Antero Sahlman, consultant

Department of Cardiology

Markku Kupari, consultant, PhD, associate professor

Norway

Rikshospitalet, Oslo.

Department of Cardiothoracic Surgery

Odd Geiran, consultant, PhD, professor

Kjell-Arne Rein, consultant, PhD

Rune Lundblad, consultant, PhD

S:t ElisabethUniversity Hospital, Trondheim.

Department of Cardiothoracic Surgery

Alexander Wahba, consultant, PhD, professor

Asbjørn Karevold, consultant, PhD

Department of Cardiology

Arve Tromsdal, consultant, PhD

Haukeland University Hospital, Bergen.

Department of Cardiothoracic Surgery

Rune Haaverstad, consultant, PhD, professor

Knut Andersen, consultant, PhD

Department of Cardiology

Eva Gerdts, consultant, PhD, professor

Einar Skulstad Davidsen, consultant

Feiring Clinic.

Department of Cardiothoracic Surgery

Sven-Martin Almdahl, consultant, PhD

Stein Rynning, consultant, PhD

Department of Cardiology

Olaf Rødevand, consultant, PhD

Ullevaal University Hospital, Oslo

Department of Cardiothoracic Surgery

Theis Tønnessen, consultant, PhD, professor

Bjørn Braathen, consultant, PhD

Department of Cardiology

Gunnar Smith, consultant, PhD

University Hospital North Norway.

Department of Cardiothoracic and Vascular Surgery

Truls Myrmel, consultant, PhD, professor

Per Erling Dahl, consultant, PhD

Department of Cardiology

Børge Schive, consultant

US

Bluhm Cardiovascular Institute,Northwestern University, Chicago, Illinois

Department of Cardiothoracic Surgery

Patrick M McCarthy, Surgical Director, professor

Canada

Montreal Heart Institute.

Department of Cardiothoracic Surgery

Denis Bouchard, consultant, PhD

Appendix 3

Surgical principles – the MoMIC trial

General

All patients are referred for coronary artery by-pass surgery (CABG). They are randomized to either CABG alone or CABG with additional surgical correction of the mitral insufficiency. All patients are operated by experienced mitral valve repair surgeons. All patients are operated on cardiopulmonary by-pass, with cardioplegic arrest. Graft selection and strategy are at the surgeon's discretion.

Mitral valve correction

Mitral valve repair with a full, rigid annuloplasty (Edwards IMR^®, measured according to the height of the anterior leaflet). Mitral valve replacement is carried out with a bioprosthesis/mechanical valve according to each departments indication in case of unsatisfactory result (ERO > 30 mm²) in a patient randomized to mitral correction. Postpump TEE should be performed 15 minutes after weaning from by-pass, and at a systolic blood pressure > 100 and a heart rate of 80-115.

Atrial fibrillation

Atrial fibrillation should be treated according to standards at each department.

Tricuspid valve repair

Associate tricuspid regurgitation/ annular dilatation should be treated according to standards at each department.

Postoperative medical treatment

Low-dose aspirin is administered to all patients with no contraindication. Anticougulation treatment for mitral repairs, bioprosthesis, and atrial fibrillation are in accordance with standards at each department. All patients with an ejection fraction < 40% should receive optimal heart failure medication concurrently.