A Stitch in Time
ABSTRACT & COMMENTARY
By Barbara A. Phillips, MD, MSPH
Professor of Medicine, University of Kentucky; Director, Sleep Disorder Center, Samaritan Hospital, Lexington
Dr. Phillips serves on the speakers bureau for PotomaCME.
This article originally appeared in the August 29, 2013, issue of Internal Medicine Alert. It was edited by Stephen Brunton, MD, and peer reviewed by Gerald Roberts, MD. Dr. Brunton is Adjunct Clinical Professor, University of North Carolina, Chapel Hill, and Dr. Roberts is Senior Attending Physician, Long Island Jewish Medical Center, NS/LIJ Health Care System, New Hyde Park, NY. Dr. Brunton serves on the advisory board for Abbott, Amarin, Boehringer Ingelheim, Duchesnay, Janssen, Lilly, Novo Nordisk, Sunovion, and Teva; he serves on the speakers bureau of Boehringer Ingelheim, Janssen, Lilly, Novo Nordisk, and Teva. Dr. Roberts reports no financial relationship to this field of study.
SYNOPSIS: In a large, international observational study, patients who had repair of flail mitral valve leaflets within 3 months of diagnosis had better long-term survival and a lower risk of heart failure than those managed with watchful waiting.
SOURCE: Suri RM, et al. Association between early surgical intervention vs watchful waiting and outcomes for mitral regurgitation due to flail mitral valve leaflets. JAMA 2013;310:609-616.
This study is a report from the Mitral Regurgitation International Database (MIDA) registry, which includes 2097 consecutive patients with flail mitral valve regurgitation in six tertiary centers (in France, Italy, Belgium, and the United States). Patients were enrolled in the MIDA registry if they had degenerative mitral regurgitation with a flail leaflet detected by a 2-dimensional transthoracic echocardiography (2D ECHO) diagnosed between 1980 and 2004. To be eligible for this study, they could not have heart failure symptoms, left ventricular ejection fraction < 60%, or left ventricular end-systolic diameter ≥ 40 mm. They also were excluded if they had ischemic mitral regurgitation, significant concomitant aortic valve disease, congenital heart disease, mitral stenosis with previous valve surgery, or a contraindication to surgery due to comorbidity. Each patient’s personal cardiologist was responsible for clinical decisions regarding medical management and referral for surgery. Diagnosis of flail leaflet was based on 2D ECHO. "Early surgery" was defined as being performed within 3 months from the ECHO diagnosis. "Initial medical management" was defined as medical management during the first 3 months of follow-up, then either medical or surgical treatment thereafter as deemed appropriate by the patient’s physician. The primary endpoint was all-cause mortality, and secondary endpoints were heart failure and new-onset atrial fibrillation.
Of the 2097 patients enrolled in the MIDA registry, 1021 were eligible for this study: 575 of these had medical management and 446 underwent early surgery. The group who had medical management were older (mean 67 vs 62 years), but were less symptomatic, less likely to have pulmonary hypertension, had lower left ventricular end diastolic and systolic diameters, and smaller left atrial diameters. Almost all (93%) of the early surgery patients were able to undergo mitral valve repair (as opposed to replacement). Significantly, during the follow-up period, 339 of 575 patients in the initial medical management group had surgery at a median time of 1.65 years after diagnosis. Of these, only 87% were able to have a valve repair; the others had replacement.
Within 3 months of initial diagnosis, there were no differences in rates of death or heart failure. However, 30 patients developed new-onset atrial fibrillation, 6.2% after early surgery vs 1.2% during initial medical management (P < 0.001), highlighting the predisposition to early atrial fibrillation after surgery.
Ninety-eight percent of patients were followed until death or at least 5 years. Overall, the 10-year survival rate was 76% and the 20-year survival rate was 48%. Survival among the early surgery group was 95% at 5 years, 86% at 10 years, and 63% at 20 years compared to 84% at 5 years, 69% at 10 years, and 41% at 20 years for the initial medical management group (P < 0.001, favoring early surgery). This finding did not change much after adjusting for confounders. Mortality rate (per 100 person-years) was lower in patients with early surgery during all periods after diagnosis.
In fact, survival at all points in follow-up was better among the early surgery group regardless of comorbidities, including atrial fibrillation, pulmonary hypertension, or mild symptoms. When analysis was restricted to patients surviving 3 months after diagnosis, long-term survival was again higher after early surgery.
Heart failure developed in 16% at 10 years and 27% at 20 years, but was less frequent after early surgery than after initial medical management at all time points and for all subgroups, even after adjustment for confounders.
Atrial fibrillation occurred in 25% at 10 years and 41% at 20 years. Although there was an increased rate of atrial fibrillation in the postoperative period in the early surgery group, the long-term incidence was not different between cohorts, even after adjusting for confounders and for subgroups.
Commentary
The most common cause of primary mitral regurgitation is mitral valve prolapse, which affects about 2% of the overall population.1 This is a prevalent condition! Mitral valve prolapse results in thickening of the mitral valve leaflets, redundant tissue, and laxity of the chordae tendonae. During ventricular systole, the mitral valve leaflet sags into the left atrium preventing closure of the valve leaflets, which results in regurgitation. Fortunately, in most patients with mitral valve prolapse, regurgitation is mild and the regurgitant volume increases gradually over many years. Because of this, even patients who develop severe regurgitation can be asymptomatic (this adaptive response is not infinite, however, and once the limits of this response are reached, patients develop symptoms and heart failure). Some patients with mitral valve prolapse experience chordal rupture, which allows that untethered leaflet segment to fall into the left atrium in systole. This is termed a flail leaflet. Although mitral valve prolapse is common, flail leaflet is much less so. In this study, Suri and colleagues found an average of only seven patients per year at each tertiary referral center over a 25-year period. In a 5-year, community-based, observational study of more than 800 people with mitral valve prolapse, Avierinos and colleagues observed development of flail leaflet in only 2.4%.2
Thus, the current report deals with a very select and specific subset of patients with mitral valve prolapse: those with flail leaflet who did not have classic indications for immediate surgery. This report is relevant to our patients with mitral valve prolapse who are identified when a systolic murmur is heard during a physical examination and/or who have an ECHO for some other reason. This turns out to be a very small subset of those with mitral valve prolapse.
What the current study adds to the literature is the largest, most carefully done prospective observational study of early surgical intervention vs watchful waiting in patients who have mitral regurgitation with a flail leaflet but who do not yet have classic indications for surgical intervention (which are left ventricular dysfunction and significant symptoms). There is controversy in the literature about the appropriateness of early intervention in these patients, which is partly due to the uncertain consequences of uncorrected severe mitral regurgitation.3 This controversy is reflected in current international consensus statements, in which North American guidelines favor the procedure,4 but the European guidelines do not.5 Surgical intervention is risky, and carries both the risk of the procedure and the risk of receiving a mechanical valve (requiring lifelong anticoagulation) or a bioprosthesis (with limited durability and a possible need for repeat future intervention). Compared with valve replacement, mitral valve repair has a much better prognosis, improved survival, excellent long-term durability, and no need for long-term anticoagulation. The difference in repair vs replacement of the valves (93 vs 87% in the early surgery vs initial medical management groups, respectively) is significant in that regard. In addition, it is notable that a majority of those in the watchful waiting group (339 [59%]) underwent subsequent mitral valve surgery anyway, at a median of 1.65 years after the initial diagnosis of a flail leaflet.
Besides having results that seem to favor early surgery, this observational study is notable because it truly is a comparative effectiveness study, as endorsed by the National Heart, Lung, and Blood Institute.6 Large clinical registries, such as MIDA, are essential in delivering the evidence necessary to evaluate some clinical questions in the absence of or due to the limited feasibility of randomized clinical trials.
References
1. Adams DH, et al. Degenerative mitral valve regurgitation: Best practice revolution. Eur Heart J 2010; 31:1958-1966.
2. Avierinos JF, et al. Natural history of asymptomatic mitral valve prolapse in the community. Circulation 2002;106:1355-1361.
3. Otto CM. Surgery for mitral regurgitation. Sooner or later? JAMA 2013;310:587-588.
4. Bonow RO, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006;114: 84-231.
5. Vahanian A, et al. Guidelines on the management of valvular heart disease: The Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology. Eur Heart J 2007;28:230-268.
6. Concato J, et al. Comparative effectiveness research: What kind of studies do we need? J Investig Med 2010; 58:764-776.
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