Author + information
- Received October 5, 2009
- Revision received April 15, 2010
- Accepted June 16, 2010
- Published online December 7, 2010.
- Eugene A. Grossi, MD*,* (, )
- Nirav Patel, MD†,
- Y. Joseph Woo, MD‡,
- Judith D. Goldberg, ScD*,
- Charles F. Schwartz, MD*,
- Valavanur Subramanian, MD†,
- Ted Feldman, MD§,
- Robert Bourge, MD∥,
- Norbert Baumgartner, MD¶,
- Christopher Genco, MD¶,
- Scott Goldman, MD#,
- Marco Zenati, MD**,
- J. Alan Wolfe, MD††,
- Yugal K. Mishra, MD‡‡,
- Naresh Trehan, MD§§,
- Sanjay Mittal, MD§§,
- Shulian Shang, MA, MPhil*,
- Todd J. Mortier, BS∥∥,
- Cyril J. Schweich Jr, MD∥∥,
- RESTOR-MV Study Group
- ↵*Reprint requests and correspondence:
Dr. Eugene A. Grossi, Thoracic Surgery, NY Harbor Healthcare System, New York University School of Medicine, Suite 9-V, 530 First Avenue, New York, New York 10028
Objectives We sought to determine whether patients with functional mitral regurgitation (FMR) would benefit from ventricular reshaping by the Coapsys device (Myocor, Inc., Maple Grove, Minnesota).
Background FMR occurs when ventricular remodeling impairs valve function. Coapsys is a ventricular shape change device placed without cardiopulmonary bypass to reduce FMR. It compresses the mitral annulus and reshapes the ventricle. We hypothesized that Coapsys for FMR would improve clinical outcomes compared with standard therapies.
Methods RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) was a randomized, prospective, multicenter study of patients with FMR and coronary disease with core laboratory analysis. After enrollment, patients were stratified to the standard indicated surgery: either coronary artery bypass graft alone or coronary artery bypass graft with mitral valve repair. In each stratum, randomization was to either control (indicated surgery) or treatment (coronary artery bypass graft with Coapsys ventricular reshaping).
Results The study was terminated when the sponsor failed to secure ongoing funding; 165 patients were randomized. Control and Coapsys both produced decreases in left ventricular (LV) end-diastolic dimension and MR at 2 years (p < 0.001); Coapsys provided a greater decrease in LV end-diastolic dimension (p = 0.021). Control had lower MR grades during follow-up (p = 0.01). Coapsys showed a survival advantage compared with control at 2 years (87% vs. 77%) (hazard ratio: 0.421; 95% confidence interval: 0.200 to 0.886; stratified log-rank test; p = 0.038). Complication-free survival (including death, stroke, myocardial infarction, and valve reoperation) was significantly greater with Coapsys at 2 years (85% vs. 71%) (hazard ratio: 0.372; 95% confidence interval: 0.185 to 0.749; adjusted log-rank test; p = 0.019).
Conclusions Analysis of RESTOR-MV indicates that patients with FMR requiring revascularization treated with ventricular reshaping rather than standard surgery had improved survival and a significant decrease in major adverse outcomes. This trial validates the concept of the ventricular reshaping strategy in this subset of patients with heart failure. (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve [RESTOR-MV]; NCT00120276)
Left ventricular (LV) dysfunction often develops in patients with coronary artery disease, which leads to negative remodeling with increased LV chamber size. As ventricular dimensions increase, the mitral annulus dilates and papillary muscle displacement tethers leaflets, causing functional mitral regurgitation (FMR). Increasing LV dimensions and wall stress in combination with FMR increase the cardiac workload, which further degrades function with progression of LV remodeling (1–3).
Current treatments for LV dysfunction with FMR include medical therapy and surgery. Medical therapy includes unloading the ventricle and down-regulating the metabolic pathways that cause progression of ventricular failure; this unfortunately has limited effects on the progression of FMR (4). For patients with viable ischemic myocardium, revascularization is a first step, with the objectives of preventing further damage, relieving the ischemia that may contribute to FMR, and perhaps arresting or reversing the remodeling process. The effect of correcting ischemia on mitral valve (MV) function has been unpredictable and often transient, leaving the majority of patients with residual, recurrent, or progressive MR (5). Alternatively, FMR is treated by MV surgery, consisting of either MV repair or prosthetic replacement. MV repair involves placing an undersized annuloplasty device to increase the coaptive leaflet margin, eliminate regurgitation, and achieve a durable repair (6). Although MV repair is generally superior to replacement, replacement is sometimes recommended in patients with significant leaflet tethering who are considered at high risk of recurrence (7). Current operations have significant procedural risk in the FMR population, and late outcomes remain guarded (8). Due to the risk associated with current therapies, the vast majority of FMR patients are not treated (9). With whichever treatment, percutaneous coronary intervention, coronary artery bypass graft (CABG) alone, or CABG plus MV repair, the 1-year mortality rate is unfortunately approximately 20% (1,8,10–13).
As previously reported (14), Coapsys (Myocor, Inc., Maple Grove, Minnesota) was developed to treat FMR. Coapsys reshapes the ventricle, compressing the mitral annulus and subvalvular apparatus to decrease FMR. This decreases LV wall stress and induces positive ventricular remodeling (15). Coapsys consists of posterior and anterior extracardiac epicardial pads connected by a flexible, transventricular subvalvular chord (Fig. 1).The posterior pad compresses both the mitral annular and papillary muscle levels (Fig. 2).The device is sized intraoperatively by shortening the chordal length of the device, thus drawing the pads together. Echocardiography simultaneously assesses MR reduction. Implantation is performed without cardiotomy or cardiopulmonary bypass.
An initial feasibility study indicated that Coapsys significantly decreased FMR and improved follow-up New York Heart Association (NYHA) functional class (14). On the basis of these findings, prospective evaluation of Coapsys was initiated under U.S. Food and Drug Administration supervision.
RESTOR-MV (Randomized Evaluation of a Surgical Treatment for Off-Pump Repair of the Mitral Valve) was a prospective, randomized, multicenter trial (Online Appendix A) comparing Coapsys with a standard of care control in patients with FMR undergoing CABG. Patients were allocated by the surgeon per protocol to a standard of care stratum, either CABG with MV repair (CABG + MV repair) or CABG alone. In the CABG + MV repair stratum, subjects were randomized 1:1 to undergo CABG with mitral ring annuloplasty (control) or undergo CABG + Coapsys (treatment). In the CABG alone stratum, subjects were randomized 1:1 to CABG alone (control) or CABG + Coapsys (treatment) (Fig. 3).
This study had the approval of each center's institutional review board. MR was evaluated by a core laboratory (Mayo Clinic) by 1 of 2 observers. MR was graded as 1 (mild), 2 (moderate), 3 (moderate to severe), or 4 (severe).
Selection of patients and randomization
Patients referred for CABG were screened for FMR. Enrollment criteria included moderate or worse MR assessed with 2-dimensional echocardiography, the need for concomitant CABG, and LV ejection fraction ≥25%. Patients were excluded if they had a structural abnormality of the MV, asymptomatic moderate MR, transmural myocardial infarction (MI) within 30 days, or NYHA functional class IV. Complete study criteria are provided in Online Appendix B. Patient comorbidities and the degree of MR were used by the surgeon to decide stratum assignment (CABG + MV repair vs. CABG alone); the significant majority of the patients were assigned to the CABG + MV repair stratum. Surgeons had the option of placing patients with significant MR and specific contraindications to cardiopulmonary bypass in the CABG alone stratum. After stratum assignment and confirmation of FMR with intraoperative transesophageal echocardiography, randomization was performed.
All patients receiving Coapsys were part of the study; no patients were excluded from this analysis. All surgeons were required to follow the randomized assignment unless a safety concern was documented. This protocol did not restrict subsequent alternative treatments using standard therapies. Conversions from the treatment arm to the control arm were permitted for safety reasons and tracked.
Primary and secondary outcomes
Patients were evaluated at baseline; intraoperatively; before hospital discharge; at 3, 6, 12, 18, and 24 post-operative months; and annually thereafter. All-cause mortality, primary adverse events (PAEs), and MR decrease were the primary outcomes. PAEs were defined as death (cardiac and noncardiac), stroke, MI, reoperation (for bleeding, valvular dysfunction or life-threatening arrhythmias), and mechanical device failure. Adverse event types are summarized in Online Appendix C. Secondary outcomes included NYHA functional class.
The study was designed to test noninferiority of Coapsys therapy at 12 months as measured by the change in MR (efficacy hypothesis) and freedom from PAEs (safety hypothesis) in the CABG + MV repair stratum. The original design (based on Bayesian simulations) had planned interim analyses with 75 patients in each arm of the CABG + MV repair stratum, and again at 100 and 125 patients. RESTOR-MV was terminated approximately at the first planned interim analysis with 150 patients in the primary stratum. Because the primary focus was patient survival randomized to control versus Coapsys, we considered a Pocock boundary based on a 3-look interim design to provide a measure of statistical significance based on an overall 2-sided p value of 0.05 (power = 90%) to interpret the reported analyses. At first look, with 60% of all planned patients entered, we can detect a hazard ratio (HR) for Coapsys versus control of ≤0.49 or ≥2.02 (α ≤ 0.035; computations EAST version 5.2, Cytel, Inc., Boston, Massachusetts).
Baseline characteristics that differed between the 2 treatments (p ≤ 0.05) were included in the survival analyses. All patients are included as randomized (intention-to-treat). Survival time was measured from the date of treatment until death or censored at the date of last follow-up for survivors. A stratified log-rank test evaluated differences in survival probabilities for the 2 treatment arms. Cox proportional hazards models (with and without covariates) were fitted to estimate the stratified hazard ratio for patient survival in Coapsys compared with control. Unstratified log-rank tests and HRs were estimated for each stratum separately (Online Appendix D). Similar analyses were conducted for PAEs and by actual treatment rendered (as treated).
MR reduction at 12 months was analyzed using a 2-sided ttest for the CABG + MV repair and CABG alone strata separately. To compare the effects of treatment over time on MR, random-effects linear regression models were fitted that included as independent variables treatment, time, and interaction between treatment and time. NYHA functional class change was analyzed using generalized estimating equation models. The probabilities of NYHA functional classes having lowervalues were modeled; the effects of treatment, time, and their interaction were tested.
Between April 2003 and September 2008, 165 patients were randomized: 149 in the CABG + MV repair stratum and 16 in the CABG alone stratum. (Fig. 3). The study population was 77% male and the mean age was 65.3 years; a list of demographic data by stratum and randomized treatment is shown in Table 1.
Conversions/Operative Protocol Deviations
Intraoperative conversions from the randomized therapy to an alternative occurred where clinically indicated for patient safety. There were 2 (2.67%) control patients who converted to CABG + MV replacement and 7 (9.45%) treatment patients converted to an alternative (4 to CABG + annuloplasty, 1 to CABG + MV replace, 2 to CABG only) after randomization occurred (Online Appendix E).
Alternative Treatment Following Study Procedure
Three patients in follow-up (1 in control and 2 in treatment, all in the CABG + MV repair stratum) underwent reoperation for severe MR. Patients who received subsequent alternative treatment remained in the study and were followed per the study protocol to allow intention-to-treat analyses. The reoperated-on control patient received an MV replacement. Of the 2 treatment patients who underwent reoperation, 1 underwent mitral annuloplasty and 1 underwent MV replacement. In both cases, the Coapsys device was left implanted.
The study was prematurely terminated after the sponsor failed to secure ongoing funding in October 2008 with 165 patients randomized. An intention-to-treat analysis of all patients showed a survival advantage for the Coapsys treatment with a 2-year survival rate of 87% compared with 77% for the control patients (HR: 0.421; 95% confidence interval [CI]: 0.200 to 0.866, stratified log-rank test; p = 0. 038) (Fig. 4);at 2 years, 18 deaths had occurred in the control arm and 10 in the treatment arm. The mean follow-up interval was 28.3 months, with a median of 27.2 months. As-treated analysis of all patients confirmed the advantage in overall survival at 2 years for the Coapsys group (treatment, 89%; control, 76%) (HR: 0.378; 95% CI: 0.174 to 0.824; log-rank test; p = 0.020).
Intention-to-treat analysis of complication-free survival from any PAE was significantly greater with Coapsys (control, 63% vs. treatment, 76%) (HR: 0.461; 95% CI: 0.258 to 0.825; adjusted log-rank test; p = 0.022) (Fig. 5).MV-related complication-free survival (including death, stroke, MI, and MV reoperation) was significantly greater with Coapsys at 2 years (85% vs. 71%) (HR: 0.372; 95% CI: 0.185 to 0.749, adjusted log-rank test; p = 0.019). The Cox proportional hazard model with both treatment and sex as predictor variables was also fitted, and the hazard of MV-related complications was also significantly greater for female patients (HR: 2.34; 95% CI: 1.16 to 4.71). As-treated analysis of complication-free survival showed a similar advantage to Coapsys treatment. PAE occurrences are shown in Online Appendix F.
In the CABG + MV repair stratum, MR at 1 and 2 years was 0.52 ± 0.66 and 0.35 ± 0.63 and 1.4 ± 1.00 and 1.2 ± 0.97 for control and treatment, respectively (Table 2).MR decrease from baseline to 12 months in the control arm was significantly greater than in the treatment arm (p < 0.0001). Based on the random-effects model, the time effect and the treatment × time interaction were both statistically significant (each p < 0.0001); the effect of treatment alone was not. In the CABG + MV repair stratum, MR at 2 years was decreased at least 2 grades or was grade 1 or less in 92.0% of the control arm compared with 66.7% in the treatment arm (p = 0.02).
As-treated analysis revealed an initial decrease in LV end-diastolic dimension with both CABG + MV repair (5.9 ± 0.7 cm to 5.6 ± 0.9 cm) and CABG + Coapsys therapies (6.0 ± 0.8 cm to 5.4 ± 0.8 cm) (p < 0.001, repeated-measures analysis of variance) with a significantly greater decrease with the CABG + Coapsys treatment (p = 0.02). Coapsys started with an average resting transventricular chordal length of 8.6 ± 1.5 cm and was shortened to 6.4 ± 1.1 cm (25.3%) (directly measured from a sizing instrument).
Percentages of patients in the CABG + MV repair stratum with NYHA functional class improvement of ≥1 at 1 and 2 years from baseline are 65.9% and 72.0%, respectively, for the control arm and 70.6% and 79.4%, respectively, for the treatment arm (Online Appendix G). Although the effect of time was significant (p < 0.0001, generalized estimating equation), the effect of group was not (p = 0.86). In each group, 73% of deaths were truly cardiac in origin.
We compared the survival outcomes of standard of care controls with that of the Coapsys device in patients undergoing CABG with moderate or worse MR. Results demonstrate that patients undergoing a strategy of ventricular shape change with the Coapsys device in combination with CABG had improved survival at 2 years. In the surviving patients of the CABG + MV repair stratum, both the control and Coapsys arms had significant and similar improvements in NYHA functional class. Superior safety of the procedure was also documented, with fewer PAEs in the Coapsys treatment group. Because a significant portion of PAEs occurred in the early perioperative time frame, Coapsys may confer an advantage from its off-pump, less invasive placement. The ability to conduct a higher-risk operation, such as combined MV repair and CABG without the need for cardiopulmonary bypass, may convey the previously reported benefits of isolated off-pump coronary revascularization, such as decreased inotrope dependence, decreased bleeding and transfusion, faster intensive care unit recovery, and shorter length of hospital stay (16).
The survival benefit in the Coapsys group may result from several factors, including the lower PAE rate and the possible benefit of the combined MR treatment in conjunction with LV wall stress reduction. Although the control annuloplasty stratum did show a greater decrease in MR, this did not translate into improved survival or better symptom reduction. It is most likely that the survival benefit was related to the ventricular shape change effected by the device. The Coapsys has an acute positive reshaping effect on the entire ventricle, whereas the effect of traditional annuloplasty is limited to the base of the ventricle (17). This effect was demonstrated again in the current trial with twice the initial decrease in LV end-diastolic dimension in patients receiving CABG + Coapsys compared with those receiving CABG + MV repair. It is additionally possible that the long-term survival benefit seen with the device is due to a global and progressive reversal of LV remodeling, which was seen in the earlier TRACE (Treatment of Functional Mitral Regurgitation without Atriotomy or CPB Clinical Evaluation) study (15).
Contrasting “negative” results of ventricular volume reduction in the recent STICH (Surgical Treatment for Ischemic Heart Failure) trial (18) deserve comment. The Coapsys method decreases wall stress by changing the chamber shape rather than decreasing chamber size by excluding a dyskinetic wall. The STICH study postulated that the failure to demonstrate clinical benefit was related to decreased diastolic distensibility. In contrast, the Coapsys device does not create the same diastolic impairment for the same level of LV radius/wall stress reduction (19,20). Additionally, the effect of inflow restriction is not well understood when restrictive annuloplasty is used to treat FMR; one study demonstrated dynamic mitral stenosis after such treatment (21). This has not been seen with the Coapsys device. It has been speculated that lack of clinical equipoise in patient recruitment and the failure to achieve the targeted 30% ventricular volume decrease led to the STICH trial results, which contradict earlier experience (22). Finally, the greater invasiveness of the STICH approach compared with Coapsys may contribute to the difference in outcome for these LV remodeling approaches.
Two questions arise when looking at these data: Are the control outcomes representative of previous reports? Would an alternative strategy of not performing MV repair result in better survival? Recent publications on CABG and MV repair for FMR indicate that mortality rates are very similar to those in the RESTOR-MV CABG + MV repair stratum, with a weighted perioperative mortality rate of 8% and 1-year mortality rate of 19% (1,8,10–13,23–27). For ischemic FMR patients, medical management has poorer survival than with revascularization or repair strategies (1,28). Additionally, no survival advantage has been demonstrated when comparing FMR patients undergoing PCI, CABG alone, or CABG + MV repair (1,28,29). The RESTOR-MV study suggests that decreasing the MR and reshaping the ventricle with a less invasive therapy have a survival benefit that was not noted in previous studies of “standard” surgical therapy for FMR. In this high-risk patient cohort, the observed survival benefit may be due to a combination of a less invasive procedure, fewer periprocedural complications, and direct ventricular wall stress reduction.
The main limitation was that the study was terminated early, which was beyond the control of the investigators. However, recruitment was very near the U.S. Food and Drug Administration pre-specified “first look.” The significant outcomes of the intention-to-treat analysis were reinforced by similar, stronger outcomes in the as-treated analysis. Additionally, this series did not include patients with an ejection fraction <25%; this restriction was set in place to limit the perceived high early mortality in such patients, which would limit the discriminatory power of the device trial. This trial did not perform myocardial viability testing, and it was not always possible to distinguish symptoms of coronary disease from symptoms of MR. Although this may have an impact on overall survival for all patients, this could not explain the differential outcomes between randomized treatments in such a large patient population, particularly when all patients were being revascularized. The echocardiography laboratory was not blinded to therapy; interobserver and intraobserver variability is not reported in this study.
We have described a novel off-pump surgical therapy, Coapsys, which simultaneously reshapes both the left ventricle and the mitral annulus with the intent of treating FMR. On the basis of intention-to-treat analyses, the RESTOR-MV trial found that patients with FMR who required revascularization and were treated with ventricular reshaping rather than the standard surgical approach had HRs of less than one-half for both mortality and major adverse outcomes. This unique approach to reshaping the left ventricle and treating the valve has effected a meaningful impact on the clinical outcomes of patients with FMR.
The authors thank George Gogoladze, MD, Julia Price, RN, and Steven Sedlis, MD, for their assistance.
For a list of trial participants and additional trial details, please see the online version of this article.
This study was sponsored by Myocor, Inc.Dr. Bourge is a consultant to the research study for Myocor. Dr. Goldman is a consultant to Edwards, St. Jude, and ATS. Mr. Mortier and Dr. Schweich are former employees of Myocor. All other authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- coronary artery bypass graft
- confidence interval
- functional mitral regurgitation
- hazard ratio
- left ventricular
- myocardial infarction
- mitral regurgitation
- mitral valve
- New York Heart Association
- primary adverse event
- Received October 5, 2009.
- Revision received April 15, 2010.
- Accepted June 16, 2010.
- American College of Cardiology Foundation
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