Trial Design

Details about the design of the Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) trial have been published previously.10 In brief, the COAPT trial was a multicenter, randomized, controlled, parallel-group, open-label trial of transcatheter mitral-valve repair with the MitraClip device in symptomatic patients with heart failure and moderate-to-severe or severe mitral regurgitation. Details about the organization of the trial and a list of participating centers are provided in the Supplementary Appendix, available with the full text of this article at NEJM.org.

The trial was sponsored by Abbott. The protocol, available at NEJM.org, was designed by the principal investigators and the sponsor in accordance with the principles delineated by the Mitral Valve Academic Research Consortium.4,11 The protocol was approved by the investigational review board at each participating center, and all the patients provided written informed consent. The sponsor participated in site selection and management and in data analysis. The principal investigators had unrestricted access to the data, wrote the manuscript, and vouch for the accuracy and completeness of the data and analyses and for the fidelity of the trial to the protocol.

Enrollment, Randomization, and Follow-up

Eligible patients had ischemic or nonischemic cardiomyopathy with a left ventricular ejection fraction of 20 to 50%, had moderate-to-severe (grade 3+) or severe (grade 4+) secondary mitral regurgitation that was confirmed at an echocardiographic core laboratory before enrollment, and remained symptomatic (New York Heart Association [NYHA] functional class II, III, or IVa [ambulatory]) despite the use of stable maximal doses of guideline-directed medical therapy and cardiac resynchronization therapy (if appropriate), which were administered in accordance with guidelines of professional societies. A complete list of enrollment criteria is provided in Table S1 in the Supplementary Appendix.5,6,12 At each site, patients were assessed by a heart team that consisted of a heart-failure specialist, an interventional cardiologist, and a cardiothoracic surgeon with expertise in mitral-valve disease. The interventional cardiologist confirmed that the patient was anatomically eligible for device implantation, and the cardiothoracic surgeon determined that mitral-valve surgery was not appropriate. A central eligibility committee confirmed that the patient met all the enrollment criteria (including use of maximal doses of guideline-directed medical therapy), confirmed that mitral-valve surgery would not be performed, and categorized the patient’s risk of surgery-related complications or death, with high risk defined as a Society of Thoracic Surgeons (STS) score for the risk of death within 30 days after mitral-valve replacement of 8% or higher (on a scale of 0.4 to 98.1%, with higher percentages indicating greater risk) or the presence of features that portend an extremely high risk of operative stroke or death.

Enrolled patients were randomly assigned, in a 1:1 ratio, to undergo transcatheter mitral-valve repair, to be performed within 14 days after randomization, and receive guideline-directed medical therapy (device group) or to receive guideline-directed medical therapy alone (control group). Randomization was stratified according to trial site and cause of cardiomyopathy (ischemic or nonischemic) and was performed with random block sizes of 2, 4, or 6. Details about the trial device and implantation procedure have been published previously and are provided in the Supplementary Appendix.8-10 Details about the trial assessments are shown in Table S2 in the Supplementary Appendix. Clinical follow-up, which is ongoing, was to be performed at 1 week and at 1, 6, 12, 18, and 24 months after the implantation procedure in the device group and after a visit with the site heart-failure specialist in the control group (either of which would occur within 14 days after randomization) and then annually through 5 years. Follow-up assessments include periodic echocardiography, 6-minute walk tests (with longer distances indicating more preserved functional capacity and a 10% relative change from the baseline value indicating a minimally significant difference), and assessments of quality-of-life measures, including the NYHA functional class and the Kansas City Cardiomyopathy Questionnaire (KCCQ) score (on a scale of 0 to 100, with higher scores indicating better quality of life and a difference of 5 points indicating a minimally significant difference). Assessment for the primary effectiveness end point was to be performed through 2 years, with a minimum of 1 year of follow-up in all patients. Crossover was not to be permitted before 2 years of follow-up.

End Points

The definitions of the primary and secondary end points for hypothesis testing are provided in Tables S3 and S4 in the Supplementary Appendix. The primary effectiveness end point was all hospitalizations for heart failure within 24 months of follow-up, including recurrent events in patients with more than one event. The primary safety end point was freedom from device-related complications at 12 months. A device-related complication was defined as any occurrence of single-leaflet device attachment, embolization of the device, endocarditis that led to surgery, mitral stenosis (as confirmed by the echocardiographic core laboratory) that led to mitral-valve surgery, implantation of a left ventricular assist device, heart transplantation, or any other device-related event that led to nonelective cardiovascular surgery. Adverse events were adjudicated by an independent events committee with the use of source documents. Ventricular volumes and function, the severity of stenosis, and the severity of mitral regurgitation (with grade 0 indicating none, 1+ mild, 2+ moderate, 3+ moderate-to-severe, and 4+ severe) were assessed at the independent echocardiographic core laboratory.13,14

Statistical Analysis

Details about the event-rate assumptions and power analyses have been published previously.10 Analysis of the primary effectiveness end point of all hospitalizations for heart failure was performed with a joint frailty model to account for correlated events and the competing risk of death.15 Assuming an annualized rate of all hospitalizations for heart failure of 42.0% per patient-year in the device group and 60.0% per patient-year in the control group, a 12-month mortality of 22.0% and 27.0%, respectively, and a 12-month attrition rate of 7.5%, we calculated that a sample of 610 patients would provide the trial with 80% power, at a one-sided alpha level of 0.05, to show the superiority of device-based treatment over medical therapy alone with regard to the annualized rate of all hospitalizations for heart failure within 24 months. Hazard ratios and two-sided 95% confidence intervals were also calculated with the joint frailty model. Analysis of the primary safety end point of freedom from device-related complications was performed with the asymptotic z test; the event-free rate was estimated with the Kaplan–Meier method and the standard error was estimated with the Greenwood method.16 We calculated that a sample of 305 patients in the device group would provide the trial with more than 95% power, at a one-sided alpha level of 0.05, to show that the rate of freedom from device-related complications at 12 months was higher than a prespecified objective performance goal of 88.0% (see the Supplementary Appendix). If the hypotheses for both primary end points were met, then analyses of 10 secondary end points that the trial was powered to assess were to be performed in a prespecified hierarchical order to control for multiple comparisons (Table S3 in the Supplementary Appendix).10

All effectiveness analyses were performed from the time of randomization in the intention-to-treat population. The primary safety analysis was performed in the safety population, which consisted of all patients in the device group in whom device implantation was attempted. Sensitivity analyses were performed in the per-protocol and as-treated populations. Detailed descriptions of these populations are provided in the Supplementary Appendix.

For analyses of time to first event, event rates were compared with a Cox regression model. Categorical variables were compared with Fisher’s exact test. Continuous variables were compared with t tests or the Wilcoxon rank–sum test for nonnormally distributed data. An analysis of covariance model was used to compare mean changes in continuous variables from baseline to follow-up between groups. A sensitivity analysis with multiple imputation was performed to account for missing data.17 For the analysis of superiority, a two-sided P value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were performed with SAS software, version 9.4 (SAS Institute).