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Ann Thorac Surg 2007;84:1226-1235
© 2007 The Society of Thoracic Surgeons
a Baylor College of Medicine, Houston, Texas
b University of Pennsylvania, Philadelphia, Pennsylvania
c Henry Ford Health Care System, Detroit, Michigan
d The Cleveland Clinic Foundation, Cleveland, Ohio
e Acorn Cardiovascular Inc, St. Paul, Minnesota
Accepted for publication March 19, 2007.
* Address correspondence to Dr Mann, Winters Center for Heart Failure Research, MS F524, 6565 Fannin, Houston, TX 77030 (Email: dmann{at}bcm.tmc.edu).
| All authors disclose that they have a financial relationship with Acorn Cardiovascular Inc.
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Abstract |
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 Top Abstract IntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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Methods: The Acorn trial assessed the safety and efficacy of the CSD in 300 heart failure patients. Patients needing mitral surgery (n = 193) were randomized to mitral surgery alone or mitral surgery plus CSD. Patients who did not need mitral surgery (n = 107) were randomized to medical therapy or medical therapy plus CSD. The primary endpoint was a clinical composite based on changes in patient vital status, the need for major cardiac procedures for worsening heart failure, and a change in New York Heart Association (NYHA) class.
Results: The proportional odds ratio for the primary endpoint favored treatment with the CSD (1.73 confidence interval [CI]: 1.07 to 2.79; p = 0.024). The CSD-treated patients received significantly (p = 0.01) fewer cardiac procedures indicative of worsening heart failure and had an improvement in New York Heart Association class (p = 0.049). There was no significant difference in survival between groups (p = 0.85). Treatment with the CSD led to a decrease in LV end-diastolic (p = 0.009) and end-systolic volumes (p = 0.017), an increase in the LV sphericity index (p = 0.026), an improvement in the Minnesota Living with Heart Failure score (p = 0.04), and the Short Form-36 Questionnaire (p = 0.015). There was no evidence for a significant difference (p = 0.43) in serious adverse events between the treatment and control groups.
Conclusions: The results of the Acorn trial support the hypothesis that preventing LV remodeling with a CSD favorably impacts the untoward natural history of heart failure.
Left ventricular (LV) remodeling, with an attendant change in the shape of the ventricle from a prolate ellipse to a more spherically shaped ventricle, is directly related to deterioration in LV performance and poor prognosis in patients with heart failure [1–3]. Left ventricular remodeling contributes to the progression of heart failure because of mechanical and energetic burdens created by the physiologically unfavorable changes in the remodeled ventricle [4]. Further, despite optimal medical therapy and BiV pacemakers [5, 6], heart failure advances in a significant number of patients. However, there are no device therapies that directly address the clinical problem of progressive LV remodeling.
The CorCap Cardiac Support Device (CSD; Acorn Cardiovascular Inc, St. Paul, MN) is a fabric mesh device that is surgically implanted around the heart. It is designed to provide circumferential diastolic support and reduce LV wall stress. In animal models of heart failure the CSD resulted in beneficial changes in LV structure and function consistent with reverse remodeling [7, 8]. Early safety studies have shown that the CSD was safe and was associated with long-term improvements in ventricular structure and function [9]. Here we report the results of the first randomized, prospective, controlled trial that evaluates the safety and efficacy of the CorCap CSD (Acorn Cardiovascular) in patients with dilated cardiomyopathy.
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Material and Methods |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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Patients
Eligible patients had New York Heart Association (NYHA) class III-IV heart failure, were between the ages of 18 and 80 years, and had heart failure of ischemic or nonischemic etiology. All patients had an LV ejection fraction 35% or less, LV end diastolic dimension 60 mm or greater or an LV end-diastolic dimension index 30 mm/m2 or greater, a six-minute walk test less than 450 meters, and acceptable laboratory and pulmonary function tests. All patents received an optimal medication regimen that included a diuretic (as needed), angiotensin-converting enzyme (ACE) inhibitors (or angiotensin receptor blockers if ACE intolerant) and a beta-blocker (for at least three months) prior to randomization. The doses of these background medications were stable for at least one month prior to enrollment. Patients in the MVR stratum could also be enrolled with NYHA class II symptoms and an ejection fraction 45% or less. Exclusion criteria have been described previously [11]. The Institutional Review Board of each center approved the study protocol and all patients gave written informed consent.
Enrollment, Baseline Surgery, and Follow-Up
Baseline testing included chest X-ray, blood tests, transthoracic echocardiogram, electrocardiogram, maximal cardiopulmonary exercise test, six-minute walk test and quality of life evaluation with the Minnesota Living with Heart Failure Questionnaire (MLHF), and the Short Form-36 (SF-36) Questionnaire. In addition, patients had an assessment of NYHA class made by the site physician and by a blinded core laboratory, using a validated instrument [12]. Randomization was stratified by site and stratum using random permuted blocks. The control group of the no-MVR stratum did not undergo any surgery; crossover from control to treatment was not permitted.
Surgical implants were performed under general anesthesia using standard sternotomy approach (as described in reference 9). Transesophageal echocardiograms were monitored to ensure that the LV end-diastolic dimension (LVEDD) was not reduced by more than 10%, to minimize the potential for any adverse events related to the fit of the device. Patients were seen at three months, six months, and then every six months thereafter. Blood tests, echocardiograms, six-minute walk tests, and quality of life surveys were completed at all visits. Cardiopulmonary exercise tests were completed at the six and 12 month visits. Data on events (ie, survival status, hospitalizations, adverse events, major cardiac procedures) were collected on all patients until the common closing date, which was prespecified to be after the last enrolled patient had been followed for one year.
Core laboratories, blinded to treatment, assessed NYHA status, echocardiograms, and cardiopulmonary exercise tests. The Clinical Events Review Committee (CERC) adjudicated all deaths, serious adverse events, and any adverse events considered device-related. The CERC also adjudicated major cardiac procedures (biventricular [BiV] pacing, coronary artery bypass grafting, repeat mitral valve and tricuspid valve surgery) blinded to treatment status, to determine whether the procedure was associated with clear evidence of progressive heart failure. The Data and Safety Monitoring Board (DSMB) convened on a regular basis to review aggregate data summarized by treatment group.
Statistical Analysis
The data analysis plan specified that both MVR and non-MVR treatment strata would be analyzed together. The primary endpoint was a change in a composite ordinal endpoint that was based on three components: vital status (alive or dead), the occurrence of a major cardiac procedure indicative of or worsening of heart failure, and a change in NYHA status. Patients were considered "improved" if they were alive, had not experienced a major cardiac procedure indicative of worsening heart failure, and had improved by at least one NYHA class compared with baseline. Patients were considered "unchanged" if they were alive, had not experienced a major cardiac procedure, and NYHA was unchanged from baseline. Patients were considered "worsened" if they had died, had experienced a major cardiac procedure, or they had deteriorated by at least one NYHA class compared with baseline. To qualify for the primary endpoint, deaths (all cause) and major cardiac procedures could have occurred any time from enrollment to the common closing date (July 4, 2004). Major cardiac procedures were adjudicated by the CERC, who were blinded to treatment status; only those procedures adjudicated to be associated with worsening heart failure were counted in the primary endpoint. The change in NYHA class in the primary data analysis was determined as the difference between the core lab NYHA class determined at baseline and the Core lab NYHA class determined at last available follow-up. Because the Core lab NYHA instrument was implemented after the trial was initiated, multiple imputation was used in the analysis of the primary endpoint. The model followed the approach developed by Rubin [13], creating a set of 100 imputations from Markov chain Monte Carlo simulations using four predictor variables measured at baseline: site NYHA, MLHF score, six-minute walk distance, and SF-36 physical functioning score. The resulting imputed NYHA values were rounded off to the nearest whole number as recommended by Schafer [14]. To confirm the results of the imputation model we analyzed the elements of the primary endpoint by examining patient status at the final follow-up visit. The distribution of outcomes was compared using proportional odds model, with the clinical site and stratum as stratifying factors. Data on events (ie, survival status, hospitalizations, adverse events, major cardiac procedures) were collected on all patients until the common closing date, which was prespecified to be after the last enrolled patient had been followed for one year.
Secondary endpoints included all-cause mortality or rehospitalization, total number of all-cause hospitalizations; hospital days and intensive care unit days for cardiac reasons; change in NYHA functional class; change in six-minute walk distance, change in quality of life as determined by the MLHF and SF-36 questionnaires; change in LVEDD, LV end-systolic dimension, ejection fraction, LV volumes, mitral regurgitation and LV sphericity, change in peak oxygen consumption, anaerobic threshold, and exercise time; and the incidence of major cardiac procedures. Safety endpoints included the incidence of deaths, serious adverse events, and cause specific adverse events. All efficacy and safety endpoints were analyzed according to the intention-to-treat principle.
Cumulative survival curves for the risk of death, adverse events, and major cardiac procedures were constructed according to the Kaplan-Meier method and significance assessed by the log-rank statistic. Cox proportional hazards regression models were used to estimate hazard ratios. For continuous variables, comparisons of changes from baseline to 6 to 24 months were evaluated with longitudinal regression analysis, a mixed-effects model in which follow-up visit was the repeated measure and the baseline value of the response was included as a covariate. All differences were considered significant at the p less than 0.05 level (two-sided).
Within each stratum patients were randomized in a 1:1 allocation between treatment and control. The sample size of 300 patients was estimated to provide 90% power for a proportional odds ratio of 2.15 at the p less than 0.05 (2-sided) level.
Clinical decisions involving device therapies and surgical implants typically require optimizing patient selection criteria so that patients who receive a device will have best clinical outcomes when compared with patients who did not receive the device [15]. To this end, we performed a cumulative trends analysis (see Focused Cohort Analysis in Appendix 2) that was used to identify the baseline characteristics of patients with the largest and most consistent treatment versus control effect. Similar analyses of the primary endpoint were comparable in this patient subset.
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Results |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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Effect on the Primary Endpoint by Treatment Stratum
Although this study was not powered to detect significant differences in the individual strata, we separately examined patients undergoing concomitant MV surgery (MVR stratum) and in whom the only surgical intervention was CorCap implantation (no-MVR stratum). This analysis (Table 4) showed that the proportional odds analysis of the no-MVR treatment stratum favored CSD treatment with a proportional odds ratio of 2.57 (CI: 1.09 to 6.08; p = 0.032) indicating that treatment patients had 257% better odds of being in a better category than the control group. Similarly, in the MVR treatment stratum there was a trend toward improvement with the CSD, with a proportional odds ratio of 1.51 (CI: 0.84 to 2.72; p = 0.17). An interaction test examining potential differences between MVR and no-MVR was not significant.
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Device safety was maintained in the focused cohort. There were no significant differences between the treatment and control groups in terms of the number of patients with a serious adverse event (SAE) (p = 0.88) or the Kaplan-Meier time to either death or SAE (p = 0.79).
Analysis of the two strata revealed consistent evidence of safety and efficacy (Table 5). In the no-MVR stratum of the focused cohort, the primary composite endpoint demonstrated an odds ratio of 8.33 (CI: 1.85 to 37.6, p = 0.006). In the MVR stratum of the focused cohort, the primary composite endpoint also favored treatment with a CSD with an odds ratio of 1.81 (CI: 0.78 to 4.19; p = 0.160).
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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In the present study, we also observed a progressive decrease in LV end-diastolic and end-systolic volumes, as well as an increase in the LV sphericity index, consistent with the preclinical [7, 8] and early clinical studies [9]. Moreover, there was a significant increase in LVEF from baseline to 12 months in the CSD-treated patients, whereas there was no significant change in control patients. Taken together, these observations suggest that the use of the CSD leads to energetically favorable changes in the size and shape of the ventricle that are accompanied by improvements in patient functional status.
One potential concern with any therapy that requires an invasive surgical intervention is whether the device can be implanted with acceptable morbidity and mortality. The present results show that the CSD was safe and did not result in a significant increase in morbidity or mortality. There was no difference in the number and types of AEs between treatment and control groups. Moreover, there were no AEs that were related to cardiac constriction. Overall survival and hospitalization were not different between the groups.
Although the study was not powered to detect significant differences in the individual treatment strata, the results demonstrated a consistency of risk to benefit considerations. In the no-MVR stratum, patients experienced greater risk with the CSD implant than control patients, (no implant in the control group) but they also had a greater benefit (odds ratio = 2.57). In the MVR stratum, the benefit was less (odds ratio = 1.51) but there was minimal risk in the CorCap CSD implant treatment group when compared with control patients, because all patients were already undergoing mitral valve surgery.
Because of the invasive nature of device implantation, it has been suggested that patient selection criteria should be individualized and optimized so that devices are implanted in those patients who are the most likely to receive a maximal benefit from the device when compared with subjects who do not receive a device [15]. To this end we utilized a cumulative trends analysis (see Appendix 2) to identify a "focused cohort of 159 patients" who had the largest and most consistent treatment effect. This analysis showed that patients with an LVEDDi that was 30 mm/m2 or greater and 40 mm/m2 or less were the most likely to benefit from the CSD treatment, based on analysis of the primary composite endpoint (OR = 2.45; p = 0.011), freedom from major cardiac procedures (p = 0.013), and mortality (34% decrease; p = 0.17). Moreover, the treatment effects were consistent in the no-MVR and MVR strata, with the largest benefit in the no-MVR stratum. These more selective patient criteria should prove useful in selecting those patients who will be most likely to benefit from CSD implantation.
One limitation of the Acorn trial is that it was unblinded. Several measures were employed to minimize bias, including the use of a composite primary endpoint that incorporated an objective endpoint, namely all cause mortality. Second, the use of major cardiac procedures for worsening heart failure involved cardiac transplantation and LVAD implantation, which are reserved for patients with clear evidence of refractory heart failure. The assessment of other major cardiac procedures indicative of worsening heart failure (repeat valve surgery and implantation of BiV pacemakers) was adjudicated by an independent CERC that was blinded to treatment allocation. Finally, Core labs for the determination of NYHA echocardiograms and maximal exercise tests were performed by a central assessor who was blinded to treatment allocation. However, because the NYHA core lab was implemented after trial enrollment was initiated, 174 patients had to have baseline NYHA status imputed. Nonetheless, it bears emphasis that only the baseline value (prior to randomization) was missing from the data set. Two additional issues maybe important for the potential clinical application of the CorCap Cardiac Support Device. First, the implantation of the mesh support will result in adhesions, similar to those observed in all cardiac implant procedures. These adhesions may complicate subsequent cardiac surgery. Second, while there has been no clinical evidence of pericardial constriction in routine surveillance six-month echocardiograms thus far, we cannot formally exclude this eventuality as a rare to late complication. Accordingly, long-term surveillance is planned for these patients.
In conclusion, results of the Acorn trial support the hypothesis that preventing LV remodeling with a CSD favorably impacts the untoward natural history of heart failure. Insofar as there are no therapies that are specifically designed to address the problem of cardiac remodeling, and many patients will have progressive heart failure in spite of intensive medical regimes and BiV pacemakers, the CorCap CSD fits an unmet clinical need for patients with advanced heart failure and LV dilation. Accordingly, the results of the present study show that the CorCap CSD represents a novel adjunctive therapy for stabilizing the progression of heart failure in patients who remain symptomatic despite optimal medical therapy.
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Appendix 1 |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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Appendix 2 |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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To accomplish this, 19 different baseline characteristics, such as various measures of heart size, clinical history metrics, and other physiologic characteristics were identified as being of potential value in predicting patient outcomes. Also, several outcome measures of safety and efficacy were chosen as being of greatest interest in identifying "responding" patients. These screening outcomes measures included death, HF related hospitalizations, changes in LV size, and change in quality of life.
Then, cumulative trends analysis was applied to each combination of outcome and potential predictor, with the objective being to find a patient subgroup of reasonable size in which a single predictor showed consistent enhancement of multiple signals of safety and efficacy. Consistent improvement among many outcome measures would provide assurance that the identified efficacy in the patient subgroup is a real measure of clinical improvement, as opposed to a purely probabilistic outcome.
The analysis begins with the choice of a particular outcome measure (eg, death), indexed against a potential baseline predictor (eg, left ventricular end diastolic dimension indexed to body surface area, abbreviated LVEDDi). Using the entire 300-patient cohort, a scatterplot can be created with LVEDDi on the x axis and treatment-control difference in death on the y axis as follows:
The value of this technique is that, by using cumulative treatment versus control difference as the variable on the y axis, one can immediately see the patient groups experiencing the greatest response to CorCap therapy in a simple visual fashion (see Appendix Fig. 1,). Patient groups in which the CorCap shows no or little efficacy will be flat (horizontal), while groups in which the CorCap treatment group displays high efficacy will have a steep positive slope. (Conversely, groups in which the treatment displays negative efficacy will have a negative slope.)
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The example provided in Appendix Fig. 5 illustrates that the patients with LVEDDi between 30 and 40 mm/m2 show a strong positive slope, while patients outside of this group display a flat graph. This indicates that patients between 30 and 40 mm/m2 in LVEDDi in the treatment group are experiencing positive outcomes relative to the control group; ie, these are the patients in whom the efficacy of the CorCap CSD is concentrated.
This same graphic method was applied to all 19 baseline characteristics. Baseline LVEDDi was clearly the best patient characteristic that demonstrated a consistent pattern for all the key safety and efficacy outcomes.
Formal statistical analyses were then performed to validate that patient subgroups based on LVEDDi were indeed demonstrating different responses. For the analysis, patients were divided into three subgroups, including the less than 30 mm/m2 group, the greater than 30 mm/m2 and less than 40 mm/m2 group, and the greater than 40 mm/m2 group. These analyses confirmed that the greater than 30 mm/m2 and less than 40 mm/m2 group had a consistent benefit across all the endpoints and this benefit was greater than the responses in the two other subgroups. Neaton, D. Homans, C. O’Connor, W. Curtis. Clinical Events Review Committee: S. Goldstein (Chair), F. Spinale, J. Lindenfeld.
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Acknowledgments |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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Footnotes |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionMaterial and MethodsResultsCommentAppendix 1Appendix 2FootnotesAcknowledgmentsReferences |
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