A Tale of Two Studies: Are We Closing in on Rational Therapy for Secondary MR?

Editor's Note: This Expert Analysis is part of a series presenting perspectives on major ESC Congress 2019 trials. Please follow this link for the companion articles.

The 2-year follow-up data from the MITRA-FR (Percutaneous Repair With the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation) trial was presented at the European Society of Cardiology Congress 2019 (ESC Congress 2019) and is the subject of this opinion piece. Mitral regurgitation (MR) is categorized as primary or secondary to inform therapeutic planning. Primary MR is due to an abnormality of the valve leaflets and will benefit from early surgery. Secondary MR occurs in patients with normal mitral valvar apparatus but who lack leaflet coaptation secondary to changes in left ventricular (LV) geometry. We know that MR in a patient with ventricular dysfunction confers a significant survival disadvantage. What remains undefined is whether the MR or the LV dysfunction is the primary factor for a given patient. For example, MR may lead to volume overload with resultant LV dysfunction, or a dysfunctional LV will cause leaflet tethering and resultant MR. Emerging from the recent trials utilizing MitraClip (Abbott; Abbott Park, IL) is evidence that these may be two different disease processes, a concept that may help explain some of the disparate findings between the MITRA-FR and COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trials.

Over the last 30 years, the philosophy behind therapy for MR and the accompanying LV dysfunction has undergone 3 distinct changes. In the 1970s and early 1980s, it was thought that if you render the mitral valve competent in a patient with LV dysfunction and MR, you would compromise the patient's survival by eliminating the "pop off" valve into the lower pressure pulmonary circulation. We were taught that the poorly functioning LV would be unable to work against a higher afterload. In the early 1990s, through research championed by Steven Bolling at the University of Michigan, a new concept was put forward with encouraging early surgical results. Bolling's group and others repaired the mitral valve using a reduction annuloplasty technique in patients with severe LV dysfunction. They hypothesized that a decrease in preload from elimination of the MR will benefit the impaired LV, allowing it to perform better. Early, nonrandomized, often single center series supported this hypothesis. However, as longitudinal data accumulated, our current concept of "it is the ventricle not the valve" emerged. The disappointing finding was a lack of long-term survival benefit in patients undergoing successful reduction annuloplasty. Absent a prospective trial looking at the role of surgery on secondary MR, the hypothesis that the less invasive MitraClip deployed in patients with severe MR and LV dysfunction will result in a therapeutic benefit was tested.

The MITRA-FR trial was reported contemporaneously with the COAPT trial in the New England Journal of Medicine. Both studies sought to understand the role of MitraClip in patients with LV dysfunction and significant MR. The 2-year follow-up data from MITRA-FR was presented in September at ESC Congress 2019. The trials differed in several ways and reported contradictory outcomes. The MITRA-FR 2-year follow-up found no significant difference in death or hospitalization at 24 months in patients randomized to medical therapy or MitraClip. The COAPT trial did demonstrate a survival benefit at 2 years for MitraClip. The trials did study somewhat different populations. There was more MR in smaller LVs in the COAPT trial (mean effective regurgitant orifice area of 41 mm2 with generally smaller ventricles) than the MITRA-FR trial (mean effective regurgitant orifice area of 31 mm2 in generally larger ventricles). We now have the interesting concept of proportionate MR.

The idea of proportionate or disproportionate MR was eloquently clarified in the discussion by Rebecca Hahn following the presentation at ESC Congress 2019. Basically, they are proposing a continuum where patients with more MR and less dilated LVs (disproportionate MR) are at one end, and patients with less MR but more dilated ventricles are at the other. The MitraClip may benefit patients with disproportionate MR. This observation is consistent with my current approach to secondary MR. Secondary MR patients with primarily annular dilatation, or those without severe valvar tethering who have relatively well-preserved LV systolic function (ejection fraction ≥35%), seem to enjoy a durable and reproducible benefit with surgical reduction annuloplasty. An added benefit of surgical reduction annuloplasty is our ability to more completely eliminate residual MR compared with MitraClip.

In summary, I believe the data coming out of these MitraClip trials for secondary MR should lead to further study of disproportionate MR coupled with the advantage of surgical reduction annuloplasty to render almost all valves fully competent. Perhaps a trial comparing this population with best medical therapy and/or MitraClip is warranted. Absent such data, I think many surgeons will continue to offer reduction annuloplasty to patients on the disproportionate MR continuum who have moderately impaired ventricles and severe secondary MR. Every effort should be made to reduce the MR to zero to trace intraoperatively, including the use of complete rings, papillary muscle repositioning if needed, and significant downsizing.

References

  1. Obadia JF. MITRA-FR - 2 years follow-Up of the MITRA-FR study a randomized controlled trial evaluating the effectiveness of percutaneous mitral valve repair in secondary mitral regurgitation. European Society of Cardiology Congress 2019; Paris, France: September 2, 2019.
  2. Bolling SF, Pagani FD, Deeb GM, Bach DS. Intermediate-term outcome of mitral reconstruction in cardiomyopathy. J Thorac Cardiovasc Surg 1998;115:381-6.
  3. Obadia JF, Messika-Zeitoun D, Leurent G, et al. Percutaneous Repair or Medical Treatment for Secondary Mitral Regurgitation. N Engl J Med 2018;379:2297-2306.

Clinical Topics: Acute Coronary Syndromes, Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Interventions and Structural Heart Disease, Echocardiography/Ultrasound, Diet, Hypertension, Sleep Apnea, Mitral Regurgitation

Keywords: ESC Congress, esc 2019, ESC 19, Cardiac Surgical Procedures, Adrenergic beta-Antagonists, Acute Coronary Syndrome, American Heart Association, Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, Aortic Valve, Aortic Valve Stenosis, Aspirin, Atrial Fibrillation, Australia, Cohort Studies, Cardiac Rehabilitation, Comorbidity, Confidence Intervals, Coronary Artery Bypass, Coronary Artery Disease, Diabetes Mellitus, Dilatation, Dyslipidemias, Drug Prescriptions, Echocardiography, Electronic Health Records, Diet, Follow-Up Studies, Heart Failure, Heart Diseases, Heart Valve Prosthesis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Heart Ventricles, Hospitalization, Hypertension, Hypotension, Incidence, Life Style, Long-Term Care, Mitral Valve, Mitral Valve Insufficiency, Myocardial Infarction, Nutritionists, Odds Ratio, Office Visits, Outcome Assessment (Health Care), Papillary Muscles, Percutaneous Coronary Intervention, Pharmacists, Physical Therapists, Physicians, Primary Care, Platelet Aggregation Inhibitors, Primary Health Care, Prospective Studies, Pulmonary Circulation, Referral and Consultation, Prognosis, Registries, Renal Insufficiency, Research, Renin-Angiotensin System, Risk, Secondary Prevention, Sleep Apnea Syndromes, Stroke, Stroke Volume, Smoking Cessation, Surgeons, Systole, Taxus, Thoracic Surgery, Transcatheter Aortic Valve Replacement, Ventricular Dysfunction, Ticlopidine, Ventricular Function, Left


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