Trial Design and Oversight

The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) was a nonblinded randomized trial that compared the centrifugal-flow pump HeartMate 3 with the axial-flow pump HeartMate II in patients with advanced heart failure.10 The trial was sponsored by St. Jude Medical, which provided the trial devices. The trial protocol, which is available with the full text of this article at NEJM.org, was designed by the sponsor in consultation with clinical advisors and the study oversight committee (a list of members is provided in the Supplementary Appendix, available at NEJM.org).

The trial was conducted at 69 centers in the United States at which there were surgeons who had experience in the implantation of left ventricular assist systems; the protocol was approved by the institutional review board at each participating center. Data were collected by trial coordinators at the participating centers, verified by principal investigators at each site, and analyzed and audited by the sponsor. An independent data and safety monitoring board (see the Supplementary Appendix) monitored the trial and reviewed adherence to the protocol, device malfunction, and outcomes. All the authors had access to the data and vouch for the completeness and accuracy of the data and analyses and for the fidelity of the study to the trial protocol. An independent statistician confirmed all analyses. The manuscript was written by the first author, and all the authors had input into its drafting and content; the trial publication committee (see the Supplementary Appendix) made the decision to submit the article for publication.

Patients

Patients with advanced heart failure that was refractory to standard medical therapy were enrolled. Patients were eligible irrespective of whether the intended goal of pump support was a bridge to transplantation or destination therapy (i.e., permanent therapy for a patient who is not a candidate for heart transplantation). Main exclusion criteria were planned biventricular support, irreversible end-organ dysfunction, and active infection. A detailed list of inclusion and exclusion criteria is provided in the Supplementary Appendix. All patients or their authorized representatives provided written informed consent.

Randomization and Data Collection

Patients were randomly assigned, in a 1:1 ratio, to receive the centrifugal-flow pump or the axial-flow pump. Randomization was performed with the use of permuted blocks and with stratification according to trial center and was implemented through an electronic data-capture system (eClinicalOS, Merge Healthcare). The investigators and patients were aware of the treatment assignments. Data were collected at baseline, 1 day after implantation, 1 week after implantation, at discharge, and 1, 3, and 6 months after implantation. Outcome events and adverse events were recorded throughout the trial.10

Left Ventricular Assist Systems

Figure 1. Figure 1. Diagrams of the Axial-Flow Pump and the Centrifugal-Flow Pump. Panel A shows a diagram of the axial-flow pump; blood enters at one end of the rotor and is driven along the axis of the rotor to the outflow of the pump. Panel B shows a diagram of the fully magnetically levitated centrifugal-flow pump; blood enters at the central axis of the rotor and is driven outward centrifugally to the outflow of the pump. Both pumps are considered to be continuous-flow pumps (rather than pulsatile-flow pumps) because blood flow is continuous and not interrupted, although the centrifugal-flow pump incorporates rapid changes in rotor speed to create an intrinsic artificial pulse. Panel A is adapted from Slaughter et al.1 LVAS denotes left ventricular assist system.

The two circulatory pumps used in the trial were the fully magnetically levitated centrifugal continuous-flow pump HeartMate 3 and the mechanical-bearing axial continuous-flow pump HeartMate II (both manufactured by St. Jude Medical) (Figure 1). Details about the circulatory pumps and their differences and similarities are provided in the Pump Characteristics section, Fig. S1, and Table S1 in the Supplementary Appendix. All investigators underwent surgical training before performing their first implantation of a centrifugal-flow pump. Recommended antithrombotic management in both groups included aspirin (at a dose of 81 to 100 mg daily for all patients) and warfarin (with dose adjustment to achieve a target international normalized ratio [INR] of 2.0 to 3.0).

Outcomes

The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove the device (for reasons other than recovery) at 6 months after implantation. Patients who underwent urgent heart transplantation for pump malfunction were considered to have had treatment failure with respect to the primary end point, whereas patients who underwent transplantation for other reasons were considered to have had treatment success. Secondary end points included the frequency of adverse events; actuarial survival; functional status, as assessed with the New York Heart Association (NYHA) classification and with the 6-minute walk test performed by a trained technician; and quality of life, as assessed with the European Quality of Life–5 Dimensions (EQ-5D) questionnaire (EQ-5D-5L), the EQ-5D visual-analogue scale (EQ-5D VAS), and the Kansas City Cardiomyopathy Questionnaire (KCCQ). An independent clinical events committee, whose members were unaware of the treatment assignments, adjudicated the causes of death and all adverse events; definitions of events and a list of the committee members are provided in the Supplementary Appendix.

Statistical Analysis

The primary objective of the trial was to show the noninferiority of the centrifugal-flow pump to the axial-flow pump with respect to the primary end-point measure at 6 months after implantation. We estimated that 138 patients in each group would be required for the study to have 80% power to show the noninferiority of the centrifugal-flow pump to the axial-flow pump. We determined that noninferiority would be demonstrated if the 95% lower confidence boundary for the difference between treatment groups (centrifugal-flow pump group minus axial-flow pump group) in the occurrence of the primary end point would be greater than −10 percentage points, at a one-sided alpha level of 0.025 or a two-tailed P value of less than 0.05. To account for transplantation or explantation for recovery before 6 months, 9 additional patients were included in each group. A total of 294 patients was required for analysis.

Enrollment in the trial continued after the proposed sample of 294 patients was reached, to provide sufficient power for two prespecified subsequent analyses. These include the occurrence of the primary end-point measure at 24 months after implantation (366 patients) and the occurrence of the prespecified secondary end-point measure of pump replacement at 24 months after implantation (1028 patients). These additional populations and analyses are not discussed in this report.

The primary end-point analysis was based on data from the intention-to-treat population, which included all patients who underwent randomization. For patients who had more than one event during follow-up that resulted in failure to reach the primary end point, the event that occurred first is the one included in the analysis. Patients who underwent randomization but not implantation were considered to have treatment failure at the time of randomization. If noninferiority was proved, the primary end point was then analyzed for superiority with the use of a z test of proportions, performed according to the normal approximation of the binomial distribution. Cox proportional-hazards analyses, with data stratification according to treatment, were used to calculate hazard ratios and 95% confidence intervals for the primary end point and its individual component events.

All secondary end-point analyses were based on data from the per-protocol population, which included only patients who underwent implantation of the assigned device. Longitudinal changes in functional status and quality of life were analyzed by means of linear mixed-effects modeling. Adverse events were compared between the two treatment groups with the use of Fisher’s exact test. Analysis of actuarial survival was performed by means of the Kaplan–Meier method, and the results were compared between groups with the use of log-rank analysis. All reported P values are two-tailed, and P values of less than 0.05 were considered to indicate statistical significance. Statistical analysis was performed with the use of SAS software, version 9.3 (SAS Institute).