Patients and Device Implantation. From September 2014 through November 2015, a total of 366 patients underwent randomization (190 patients to the centrifugal-flow pump group and 176 patients to the axial-flow pump group).
The baseline characteristics of the patients in the two treatment groups are presented in Table 1, and in Tables S1 and S2 in the Supplementary Appendix.
One patient who had been assigned to receive the centrifugal-flow pump and 4 who had been assigned to receive the axial-flow pump did not undergo implantation per protocol (Fig. S1 in the Supplementary Appendix).
The remaining patients (per-protocol population) included 189 who underwent implantation of a centrifugal-flow pump and 172 who underwent implantation of an axial-flow pump. A total of 78 surgeons performed 361 implantations at 52 sites.
A total of 177 of 189 patients (93.7%) in the centrifugal-flow pump group and 160 of 172 (93.0%) in the axial-flow pump group were discharged from the hospital with the device in place. The median length of stay during the hospitalization for implantation was 20 days in the centrifugal-flow pump group and 18 days in the axial-flow pump group (P=0.12 by the Wilcoxon rank-sum test). The percentage of time spent out of the hospital after device implantation did not differ significantly between groups (91.4% in the centrifugal-flow pump group and 90.3% in the axial-flow pump group). The number of rehospitalization days after discharge was nonsignificantly lower in the centrifugal-flow pump group than in the axial-flow pump group (median, 11 and 17 days per discharged patient, respectively; P=0.07).
Primary End Point
All the patients were followed for 2 years or until death, and no end-point data were missing. The primary end point occurred in more patients assigned to receive the centrifugal-flow pump than in those assigned to receive the axial-flow pump (79.5% vs. 60.2%). The noninferiority criterion was met (absolute difference, 19.2 percentage points; 95% lower confidence boundary, 9.8 percentage points; P<0.001 for noninferiority), as was superiority (hazard ratio, 0.46; 95% confidence interval CI, 0.31 to 0.69; two-tailed P<0.001 for superiority) (Table 2).
Table 2. Noninferiority and Superiority Analyses in the Intention-to-Treat Population.*
The difference between groups was primarily driven by reoperation or device removal for pump malfunction, the rates of which were significantly lower in the centrifugal-flow pump group than in the axial-flow pump group. Among the patients who had been assigned to the centrifugal-flow pump group, 3 (1.6%) underwent pump replacement (1 for a drive-line communication fault causing electrical failure, 1 because of a drive-line infection, and 1 because of persistent low pump flow that was due to an obstructive outflow-graft twist), whereas 30 patients (17.0%) who had been assigned to the axial-flow pump group underwent either a device exchange or device explantation, most often (in 67% of the patients) for pump thrombosis or severe hemolysis (hazard ratio, 0.08; 95% CI, 0.03 to 0.27; P<0.001) (Fig. S2 and Table S3 in the Supplementary Appendix). There were no significant between-group differences in the rates of death or disabling stroke.
The intention-to-treat population included all the patients who underwent randomization. The primary end point was a composite of survival free of disabling stroke (with disabling stroke indicated by a modified Rankin score of >3; scores range from 0 to 6, with higher scores indicating more severe disability) or survival free of reoperation to replace or remove a malfunctioning device at 24 months after implantation. Rates of the primary end point at 6, 12, and 24 months are shown.
Figure 1. Kaplan–Meier Estimates of the Primary End Point in the Intention-to-Treat Population.
The Kaplan–Meier estimate of actuarial event-free survival (primary end point) in the intention-to-treat population was significantly higher among patients assigned to the centrifugal-flow pump group than among those assigned to the axial-flow pump group (77.9% vs. 56.4%, P<0.001 by the log-rank test) (Figure 1). Individual components of the primary end point, including overall survival, freedom from disabling strokes, and freedom from pump reoperations or removal, are shown in Figures S3 through S5 in the Supplementary Appendix.
In a worst-case sensitivity analysis, patients who had undergone randomization but had not received an implant were considered to have had treatment failure for the centrifugal-flow pump and treatment success for the axial-flow pump. In this analysis, the centrifugal-flow pump was again superior to the axial-flow pump with regard to the primary end point (hazard ratio, 0.51; 95% CI, 0.34 to 0.75; P<0.001) (Table S4 in the Supplementary Appendix). We also reanalyzed urgent heart transplantations that had been performed for the indication of device malfunction as a treatment success (rather than treatment failure), and the result was similar to what was observed in the primary end-point analysis (hazard ratio, 0.53; 95% CI, 0.35 to 0.78; P=0.002).
Suspected events of pump thrombosis occurred in 2 patients (1.1%) in the centrifugal-flow pump group, as compared with 27 patients (15.7%) who had 33 such events in the axial-flow pump group (hazard ratio, 0.06; 95% CI, 0.01 to 0.26; P<0.001). Individual case narratives for each case of suspected pump thrombosis are presented in the Supplementary Appendix, and the events are tabulated in Table S5 in the Supplementary Appendix. The Kaplan–Meier estimates of actuarial event-free survival for suspected pump thrombosis are shown in Figure S6 in the Supplementary Appendix.
The per-protocol population included only patients who received the assigned device implant. Rates of freedom from stroke at 6, 12, and 24 months are shown.
Figure 2. Actuarial Freedom from Stroke of Any Severity in the Per-Protocol Population.
In the centrifugal-flow pump group, 22 strokes occurred in 19 patients (10.1%), as compared with 43 strokes that occurred in 33 patients (19.2%) in the axial-flow pump group (hazard ratio, 0.47; 95% CI, 0.27 to 0.84; P=0.02). The actuarial freedom from stroke of any severity is shown in Figure 2. The between-group differences in the rates of stroke according to severity (on the basis of the modified Rankin score) are shown in Figure S7 in the Supplementary Appendix. The incidence of ischemic stroke and of hemorrhagic stroke was lower in the centrifugal-flow pump group than in the axial-flow pump group (to a similar extent), although the difference in the incidence of hemorrhagic stroke did not reach significance.
No significant differences were noted between the two groups with respect to blood-pressure control, antiplatelet therapy, anticoagulation regimens, preexisting or new atrial fibrillation, or history of stroke (Table 1, and Table S6 and Fig. S8 in the Supplementary Appendix). The rates of other adverse events, including right heart failure, surgical and nonsurgical bleeding (gastrointestinal bleeding), and infection, including drive-line infection, did not differ significantly between the two groups (Table 3, and Table S7 in the Supplementary Appendix).
Table 3. Major Adverse Events in the Per-Protocol Population.*
At 1 month, the lactate dehydrogenase levels had decreased below baseline values in the centrifugal-flow pump group, whereas they had increased in the axial-flow pump group (P<0.001). The use of aspirin (or another antiplatelet agent) and anticoagulation levels did not differ significantly between groups, with similar percentages of international normalized ratio values in the therapeutic range2,3 at all time points. Details of these analyses and data regarding hepatic and renal function are provided in Figures S9 and S10 and in Tables S8 through S10 in the Supplementary Appendix.
There were 30 total deaths in the centrifugal-flow pump group and 36 in the axial-flow pump group. The most common causes of death among the patients with either device were right heart failure, stroke, and infection (Table S11 in the Supplementary Appendix). Competing-risk analyses are shown in Figure S11 in the Supplementary Appendix.
No significant interaction between groups with regard to the primary end point was observed for the prespecified subgroups of age, sex, race or ethnic group, intended goal of pump support (bridge to transplantation or destination therapy), or Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile. Details are provided in Figure S12 in the Supplementary Appendix.
Functional Status and Quality of Life
Performance on the 6-minute walk test and NYHA functional class improved to a similar extent in the two groups. Scores on the KCCQ, the EQ-5D-5L, and the EQ-5D VAS improved, as compared with baseline scores, in each group at the 3-month and 6-month time points. No significant differences in improvement were observed between the treatment groups. Sensitivity analyses to account for missing values favored the centrifugal-flow pump group over the axial-flow pump group with regard to the EQ-5D-5L and the EQ-5D VAS (Fig. S13 in the Supplementary Appendix).