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Original Article
A BS T R AC T
BACKGROUND
Ischemic mitral regurgitation is associated with a substantial risk of death. Practice The authors affiliations are listed in the
Appendix. Address reprint requests to
guidelines recommend surgery for patients with a severe form of this condition but Dr. Gelijns at the Department of Health
acknowledge that the supporting evidence for repair or replacement is limited. Evidence and Policy, Icahn School of
Medicine at Mount Sinai, 1 Gustave L.
METHODS Levy Pl., Box 1077, New York, NY 10029,
We randomly assigned 251 patients with severe ischemic mitral regurgitation to un- or at annetine.gelijns@mssm.edu.
dergo either mitral-valve repair or chordal-sparing replacement in order to evaluate *A list of members of the Cardiothoracic
efficacy and safety. The primary end point was the left ventricular end-systolic volume Surgical Trials Network (CTSN) is pro-
vided in the Supplementary Appendix,
index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in available at NEJM.org.
which deaths were categorized below the lowest LVESVI rank.
This article was published on November
RESULTS 18, 2013, at NEJM.org.
At 12 months, the mean LVESVI among surviving patients was 54.625.0 ml per square N Engl J Med 2014;370:23-32.
DOI: 10.1056/NEJMoa1312808
meter of body-surface area in the repair group and 60.731.5 ml per square meter in
Copyright 2013 Massachusetts Medical Society.
the replacement group (mean change from baseline, 6.6 and 6.8 ml per square
meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the
replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to
1.47; P=0.45 by the log-rank test). There was no significant between-group difference
in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or
severe recurrence of mitral regurgitation at 12 months was higher in the repair group
than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant
between-group differences in the rate of a composite of major adverse cardiac or cere-
brovascular events, in functional status, or in quality of life at 12 months.
CONCLUSIONS
We observed no significant difference in left ventricular reverse remodeling or sur-
vival at 12 months between patients who underwent mitral-valve repair and those who
underwent mitral-valve replacement. Replacement provided a more durable correction
of mitral regurgitation, but there was no significant between-group difference in
clinical outcomes. (Funded by the National Institutes of Health and the Canadian In-
stitutes of Health; ClinicalTrials.gov number, NCT00807040.)
F
unctional ischemic mitral regur- Me thods
gitation affects 1.6 million to 2.8 million
patients in the United States and is associ- Study Design and Oversight
ated with a doubling in mortality among patients We randomly assigned patients with chronic,
with mild or greater degrees of mitral regurgita- severe ischemic mitral regurgitation, in a 1:1
tion after myocardial infarction.1-3 Ischemic mi- ratio, to undergo either mitral-valve repair or
tral regurgitation is a consequence of adverse chordal-sparing replacement. The randomiza-
left ventricular remodeling after myocardial in- tion was stratified according to center and
jury with enlargement of the left ventricular cham- blocked to ensure ongoing equivalence of group
ber and mitral annulus, apical and lateral migra- size. The trial was designed to enroll 250 pa-
tion of the papillary muscles, leaflet tethering, tients; 1 additional patient underwent random-
and reduced closing forces. These processes lead ization before the completion of enrollment.
to malcoaptation of the leaflets and variable de- Investigators were unaware of overall outcome
grees of mitral regurgitation that can fluctuate data. End points were measured at 30 days and
dynamically as a function of volume status, after at 6, 12, and 24 months; the 24-month follow-up
load, heart rhythm, and residual ischemia. The is ongoing.
leaflets themselves are normal, and the disease The trial was conducted at 22 clinical centers,
occurs in the myocardium rather than in the with a coordinating center, an independent com-
valve itself. As such, the treatment of functional mittee that adjudicated causes of death and ad-
ischemic mitral regurgitation differs consider- verse events, and a data and safety monitoring
ably from that of primary, degenerative mitral board, appointed by the National Institutes of
regurgitation.4 Health, that oversaw trial progress. The institu-
Practice guidelines recommend consideration tional review board at each study center ap-
of mitral-valve repair or chordal-sparing replace- proved the protocol, which is available with the
ment for patients with severe ischemic mitral full text of this article at NEJM.org. All patients
regurgitation that is causing limiting symptoms provided written informed consent.
despite the best available medical therapy and,
possibly, cardiac resynchronization.5,6 These Patients
guidelines, however, do not specify whether to The target population was adults with severe
repair or replace the mitral valve, because con- ischemic mitral regurgitation and coronary ar-
clusive evidence is lacking to indicate which of tery disease who were eligible for surgical repair
these interventions is superior. Clinical studies or replacement of their mitral valves, with or
have suggested that repair is associated with without coronary-artery bypass grafting (CABG).
lower perioperative mortality,7-10 whereas re- Severe ischemic mitral regurgitation was as-
placement provides better long-term correction sessed by means of resting transthoracic echo-
with a lower risk of recurrence (an important cardiography on the basis of integrative crite-
consideration, since recurrence of mitral regur- ria11 that were verified by an independent core
gitation confers a predisposition to heart failure, laboratory. Severe mitral regurgitation was de-
atrial fibrillation, and readmission). This per- fined as an effective regurgitant orifice area of
ceived tradeoff between reduced operative mor- 0.4 cm2 or more. If the effective regurgitant ori-
bidity and mortality with repair and better long- fice area was less than 0.4 cm2, the assessment
term correction of ischemic mitral regurgitation of the severity of mitral regurgitation was guid-
with replacement has generated substantial ed by associated findings, including the ratio of
variation in surgical practice for this high-prev- the jet area to the left atrial area, the width of
alence condition.4 the vena contracta, the density of the continu-
The Cardiothoracic Surgical Trials Network ous-wave Doppler profile of mitral systolic func-
(CTSN) conducted a multicenter, randomized tion, the pulmonary-vein systolic flow pattern,
trial to evaluate the relative benefits and risks of and left-sided chamber dimensions.
repair versus replacement, with or without coro- Exclusion criteria included any echocardio-
nary revascularization, in patients with severe graphic evidence of structural (chordal or leaf-
ischemic mitral regurgitation. let) mitral-valve disease or ruptured papillary
muscle. Complete eligibility criteria have been months. We tested this hypothesis in an inten-
reported previously.12 tion-to-treat analysis using a two-tailed Wilcox-
on rank-sum test, at a 0.05 alpha level. This
Interventions analysis accommodated nonignorable missing
Mitral-valve replacement included complete pres- LVESVI outcomes owing to the death of patients
ervation of the subvalvular apparatus. The tech- by assigning deceased patients the worst ranks
nique of preservation, type of prosthetic valve, in order on the basis of the time of death. We
and technique of suture placement were chosen used multiple imputation for data that were
according to the preference of the surgeon, as missing for reasons other than death to calcu-
was the type of annuloplasty ring in the repair late the 12-month LVESVI on the assumption
group. The protocol mandated the use of an ap- that the data were missing at random. We used
proved rigid or semirigid complete annuloplasty the HodgesLehmann estimator to quantify be-
ring, which was downsized for the annulus di- tween-group differences in the reduction of the
ameter. All patients were to receive guideline- LVESVI from baseline. Sensitivity analyses as-
directed medical therapy by their treating cardi- sessed the robustness of findings to protocol
ologist, including aspirin, lipid-lowering agents, deviations, missing data, and mortality (for ad-
beta-blockers, and angiotensin-convertingenzyme justment to the LVESVI).
inhibitors, as well as cardiac-resynchronization We used the log-rank test to compare rates of
therapy. major adverse cardiac or cerebrovascular events
and death from any cause and used hazard ra-
End Points tios from Cox regression models to quantify
The primary end point of the trial was the de- relative risks. Poisson regression was used to
gree of left ventricular reverse remodeling, as test between-group differences in rates of ad-
assessed by means of the left ventricular end- verse events. We used chi-square tests to com-
systolic volume index (LVESVI) on the basis of pare between-group differences in functional
transthoracic echocardiography performed 12 status (NYHA and Canadian Cardiovascular So-
months after randomization. The LVESVI was ciety classifications). We used the Minnesota
verified by the echocardiography core laboratory. Living with Heart Failure questionnaire and the
Secondary end points included mortality, a com- physical and mental subscales of the Medical
posite of major adverse cardiac or cerebrovascular Outcomes Study 12-Item Short Form Health Sur-
events (rate of death, stroke, subsequent mitral- vey (SF-12) to assess quality of life. We used t-tests
valve surgery, hospitalization for heart failure, or to compare differences in mean quality-of-life
an increase in New York Heart Association scores among surviving patients at 12 months.
[NYHA] class of 1), serious adverse events, re-
current mitral regurgitation, quality of life, and R e sult s
rehospitalization.
Patients
Statistical Analysis From 2009 through 2012, we screened 3458 pa-
The trial was designed with a power of 90% to tients; 447 of these patients were eligible to
detect a between-group difference of 15 ml per participate in the study, and 251 underwent
square meter in the LVESVI from baseline to 12 randomization (126 to mitral-valve repair and
months. We assumed a baseline LVESVI of 100 125 to mitral-valve replacement) (Fig. S1 in the
ml per square meter, improvements of 20 ml per Supplementary Appendix, available at NEJM.
square meter in the repair group and 35 ml per org). The two groups had similar baseline char-
square meter in the replacement group, and acteristics (Table1). The mean (SD) LVESVI was
equal 1-year mortality of 10 to 20% in the two 61.126.2 ml per square meter in the repair
groups.13-15 We planned one interim analysis us- group and 65.727.4 ml per square meter in the
ing a group-sequential monitoring procedure replacement group (P=0.17). The echocardiogra-
with a LanDeMets stopping boundary and phy core laboratory confirmed the diagnosis of
OBrienFleming spending function.16,17 The pri- severe mitral regurgitation in 96% of the pa-
mary null hypothesis was that there would be no tients; the remaining 4% of the patients had
between-group difference in the LVESVI at 12 moderate mitral regurgitation. The use of anti-
* Plusminus values are means SD. CABG denotes coronary-artery bypass grafting, and PCI percutaneous coronary in-
tervention.
Race or ethnic group was self-reported.
Grades III or IV for the Canadian Cardiovascular Society (CCS) classification of angina are as follows: grade III, marked
limitation of ordinary physical activity, with walking one or two blocks on the level and climbing one flight of stairs in
normal conditions and at normal pace; grade IV, inability to carry on any physical activity without discomfort, and angi-
nal syndrome may be present at rest.
New York Heart Association (NYHA) classes range from I to IV, with higher classes indicating worse condition.
Scores on the Minnesota Living with Heart Failure questionnaire range from 0 to 105, with higher scores indicating
worse condition.
Death (%)
log-rank test). The rank-based assessment of
LVESVI at 12 months after adjustment for death
MV repair
showed no significant between-group difference 10
Table 2. Clinical End Points, Serious Adverse Events, and Hospitalizations at 30 Days and 1 Year.
30 Days 1 Year
* The composite major adverse event was death, stroke, hospitalization for heart failure, worsening heart failure, or mi-
tral-valve reintervention.
r
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Baseline 6 Mo 12 Mo
assumed, so too was its variability, with the sta-
Figure 2. Rates of New York Heart Association Class and Death at Baseline, tistical power for the study remaining at 90%.
6 Months, and 12 Months. The mitral regurgitation in patients enrolled in
this trial was entirely ischemic in nature and
was severe (in 96% of the patients) according to
for differences when particular risk factors are integrative echocardiographic criteria, and the
unknown or unmeasured, which may explain baseline ejection fraction was similar to that
why some studies have shown no differences in reported previously.33 The mean effective regur-
short-term or long-term rates of survival be- gitant orifice area among patients in our study
tween repair and replacement groups,28 whereas was 0.4 cm2, which qualifies as severe mitral
a majority of studies have favored repair. The regurgitation according to the recent guidelines
evolution of valve replacement with chordal of the European Society of Cardiology, which
sparing may account for the improved results we provide a threshold of 0.2 cm2. The patients in
observed, as compared with previous studies, our study had a relatively long length of stay dur-
since the retention of the internal architectural ing the index hospitalization, with the majority
support of the left ventricle may preserve con- of the stay occurring after surgery. This duration
tractile efficiency and reduce left ventricular may reflect the patients relatively high rates of
dilatation and dysfunction. respiratory failure, bleeding, and supraventricu-
Our trial confirmed an excess incidence of lar arrhythmia in the first 30 days, complica-
recurrence of mitral regurgitation at 1 year tions that provide targets for quality-improve-
among patients undergoing mitral-valve repair. ment measures.
Among survivors, the rate of moderate or severe Our trial has several limitations. First, al-
recurrent mitral regurgitation at 1 year was 30 though it assesses surgical approaches to the
percentage points higher among patients who mitral valve, it does not evaluate the strategy of
underwent repair than among those who under- revascularization alone. Given current guide-
went replacement. Our findings are similar to lines, there was lack of equipoise to randomly
those reported in previous studies, in which the assign patients with severe mitral regurgitation
6-month prevalence of mitral regurgitation of 2+ to a CABG-only group. However, there is equi-
or more after repair was 15 to 25% and increased poise for the randomization of patients with
substantially over time.29,30 The patients with moderate ischemic mitral regurgitation to revas-
recurrence in the repair group showed no reverse cularization alone, and such a CTSN trial is on-
remodeling, as compared with those without going (ClinicalTrials.gov number, NCT00806988).
recurrence (LVESVI of 64.123.9 and 47.323.0, Second, the primary end point was an echocar-
diographic measure of left ventricular remodel- used a repair approach.41 However, our com-
ing, not a clinical outcome such as survival. parison between chordal-sparing mitral-valve
However, a randomized trial with a 1-year mor- replacement and repair in patients with severe
tality end point would have required more than ischemic mitral regurgitation did not show sig-
4000 patients, exceeding our capacity for timely nificant differences. This conclusion is based on
enrollment. Our choice of the LVESVI as the the absence of a significant difference in left
primary end point was driven by strong evidence ventricular reverse remodeling and in the rate of
correlating the LVESVI with clinical outcomes, major adverse cardiac or cerebrovascular events
including the NYHA class and rates of hospital- at 12 months. Mitral-valve replacement provides
ization and survival.34-40 Third, the use of trans- a considerably more durable correction of mitral
thoracic echocardiography for measuring recur- regurgitation, which may have an important ef-
rent mitral regurgitation may underestimate the fect on long-term outcomes. However, this fac-
degree of mitral regurgitation in patients with tor must be weighed against any potential ad-
prosthetic valves. However, the transmitral gra- verse consequences of a prosthetic valve. Further
dient, and thus the inflow velocity, that were patient follow-up is needed to confirm the find-
observed in these patients were within normal ings of this trial; such follow-up may lead to the
ranges, which suggests no substantial mitral identification of predictors of recurrence of mi-
regurgitation. Finally, we report here on a rela- tral regurgitation to allow for a more appropri-
tively short follow-up period of 12 months, al- ate selection of patients.
though follow-up will continue for 24 months.
Supported by a cooperative agreement (U01 HL088942) with
Recently, the field has embraced mitral-valve the National Heart, Lung, and Blood Institute and the National
repair over replacement, without a strong evi- Institute of Neurological Diseases and Stroke, National Insti-
dence base. According to 20082012 data from tutes of Health, and by the Canadian Institutes of Health Re-
search.
the Society of Thoracic Surgeons, 66% of mitral- Disclosure forms provided by the authors are available with
valve surgeries in patients undergoing CABG the full text of this article at NEJM.org.
Appendix
The authors affiliations are as follows: the Department of Surgery, Division of Cardiovascular Surgery, University of Pennsylvania
School of Medicine, Philadelphia (M.A.A., Y.J.W.); the International Center for Health Outcomes and Innovation Research (InCHOIR),
Department of Health Evidence and Policy, Mount Sinai School of Medicine (M.K.P., A.J.M., A.C.G., D.D.A., E.B., E.G.M.), Division of
Cardiothoracic Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University (M.A.), and the Department
of Cardiothoracic Surgery, Montefiore Medical Center and Albert Einstein College of Medicine (D.A.D., R.E.M.) all in New York;
Montreal Heart Institute, University of Montreal, Montreal (L.P.P.); Institut Universitaire de Cardiologie de Qubec, Hpital Laval, Que-
bec, QC, Canada (P.V., F.D.); the Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical
Center, Durham (P.K.S.), and the Department of Cardiovascular Sciences, East Carolina Heart Institute at East Carolina University,
Greenville (T.B.F.) both in North Carolina; Echocardiography Core Lab, Massachusetts General Hospital (J.W.H.), and Cardiovascu-
lar Division, Brigham and Womens Hospital (P.T.O.) both in Boston; the Department of Thoracic and Cardiovascular Surgery,
Cleveland Clinic Foundation, Cleveland (E.H.B.); Clinical Research Unit, Division of Cardiothoracic Surgery, Emory University School
of Medicine, Atlanta (J.D.P.); Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore (J.S.G.); Baylor Re-
search Institute, Dallas (M.M.); National Institutes of Health (NIH) Heart Center at Suburban Hospital (K.A.H.), and the Office of
Biostatistics Research (N.L.G.) and the Division of Cardiovascular Sciences (M.A.M.), NIH all in Bethesda, MD; the Division of
Thoracic and Cardiovascular Surgery, University of Virginia School of Medicine, Charlottesville (G.A., I.L.K.); and the Center for Heart
and Vascular Health, Christiana Care Health System, Newark, DE (T.J.G.).
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