Continuous flow left ventricular assist devices (LVAD) are the predominant devices used for advanced heart failure patients awaiting heart transplantation and nontransplant-eligible patients who are refractory to medical management (1). After completion of a prospective multicenter clinical trial, the HeartMate (HM) II Left Ventricular Assist System was approved by the U.S. Food and Drug Administration (FDA) for the bridge to transplant (BTT) indication in April 2008. Initial results of the trial were published on 133 patients that received implantation from March 2005 to May 2006 (2), followed by an updated report on 281 patients with enrollment extended through April 2008 with a continued access protocol (3). The clinical trial for destination therapy in nontransplant-eligible patients has also been completed, and results were published on the initial 200 patients (4). Post-approval studies were required by the FDA to determine whether results in both trials with the device in a commercial setting are comparable to other available devices for the same indication. In the current report we present the findings of the BTT post-approval study in comparison with other FDA-approved ventricular assist devices for BTT.

The purpose of the post-approval study was to assess whether the clinical use of the HM II Left Ventricular Assist System (Thoratec Corporation, Pleasanton, California) in a commercial setting is comparable to other available devices that are FDA-approved for the same indication for use, BTT.

The study was a prospective evaluation of the first 169 consecutive HM II patients after FDA approval of the device enrolled in the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) (5). All patients who were identified before implant in the INTERMACS registry as BTT—listed for transplant or BTT—likely to be eligible were enrolled in the study. Patients receiving the HM II (HM II group) were enrolled from April through August 2008 at 52 U.S. centers. A comparison group (COMP) included patients (n = 169 at 27 centers) reported to the INTERMACS registry with other types of LVADs approved for the same BTT indication (6). Because fewer COMP devices compared with HM II devices were being used, the protocol allowed up to 6 months additional prospective enrollment after completion of HM II enrollment and then allowed retrospective consecutive COMP patients previously enrolled in the INTERMACS registry to be included to make up the total 169 patients with the most recent consecutive patients. The final enrollment of 169 COMP patients occurred from September 2007 to February 2009 (7-month retrospective [n = 114] and 10-month prospective [n = 55]). There were a total of 77 centers that enrolled at least 1 patient into either group. The mean number of patients/center was 2.2 for both groups, and the median was 2 for both groups.

In the COMP group, 135 (80%) received the electric HeartMate XVE LVAD and 34 (20%) received the pneumatic Thoratec Implantable Ventricular Assist Device (Thoratec Corporation). An illustration of all 3 devices is shown in (Figure 1). Right ventricular assist support was used in 5 of the HM II patients (3%) with temporary right ventricular assist devices and in 21 of the COMP patients (12%), including 15 patients with biventricular Thoratec Implantable Ventricular Assist Devices and 6 patients with temporary right ventricular assist devices.

All patients were followed for at least 12 months after implant or until outcome. The primary endpoint was survival while waiting for transplantation. Secondary endpoints included adverse events reported upon occurrence and functional status with the 6-min walk test and quality of life (QoL) with the EuroQol EQ-5D visual analog scale determined at baseline and 3, 6, and 12 months after implant.

This was a registry-based study using the INTERMACS database. Self-reporting is provided by each center per the specified INTERMACS definitions and time points that facilitate the overlay of an FDA-stipulated post-market outcomes analysis. Information regarding INTERMACS variables, definitions, reporting time points, and data analysis is available at the INTERMACS website (7). This report represents the first FDA-required, post-market approval study using the INTERMACS registry.

Differences in continuous variables between the study group and COMP group were evaluated with the t test. For non-normal data, the Mann-Whitney U test was used. Differences in categorical variables were evaluated with the Fisher exact test. Survival analysis of patients receiving ventricular assist device support was performed with the Kaplan-Meier method, with patients censored for transplantation, recovery of the native heart function with device removal, or withdrawal from the study. Differences in survival were evaluated with the Mantel log-rank test. Competing outcomes were also determined by the cumulative proportion of patients reaching the outcomes of transplantation, recovery with device explant, and death. Adverse events were reported as percentages of patients with events and as event rates in events/patient year, which is calculated as the number of events divided by the cumulative support durations for all patients. All statistical comparisons were 2-sided, and the level of significance was set at p < 0.05. All biochemical and hemodynamic data are presented as mean ± SD or median and range when appropriate. Discrete variables are presented as percentages. Adverse events are presented as both percentages of all patients as well as events/patient year. Comparisons of adverse event rates between groups were performed with a Poisson Regression model. Quality of life comparisons over time were performed with linear mixed effects modeling. All statistical analyses were done with SAS software (SAS Institute, Inc., Cary, North Carolina).

The baseline characteristics for the 338 patients from both groups are shown in (Table 1). Demographic data were similar between groups, with the exceptions noted. There were no statistically significant differences in most laboratory values, but blood urea nitrogen and creatinine were lower in the HM II versus COMP groups (Table 1). A similar percentage of patients in each group were reported as listed for transplant at the time of implant (62% HM II vs. 65% COMP) or likely to be listed (38% vs. 35%). The distribution of patients reported to be in the 6 INTERMACS clinical profiles at baseline was different between groups (Table 1). Fewer HM II patients were in INTERMACS profile 1 (acute cardiogenic shock) compared with COMP (24% vs. 39%), and more in were in profiles 3 (stable while taking inotropes) and 4 (symptomatic while taking oral medications).

The average support duration for the HM II was 306 ± 173 days (median 386), which was significantly longer than for COMP, at 207 ± 188 days (median 152 days). The cumulative follow-up duration was 142.0 (HM II) and 96.2 (COMP) patient-years of support.

All 338 patients were followed for at least 12 months or until either transplantation or death. Operative 30-day mortality for HM II was 4% versus 11% for COMP, and in-hospital mortality for HM II was 6% versus 15% for COMP (p = 0.012). Of the HM II patients, 155 (92%) were discharged from the hospital, compared with 125 (75%) for COMP (p < 0.001). The median length of hospital stay for discharged patients for HM II was 23 days versus 31 days for COMP. Kaplan-Meier survival was significantly greater (p < 0.001 log-rank test) between HM II and COMP over 12 months, with estimated survival at 6 and 12 months being 90% and 85%, respectively, for HM II and 79% and 70% for COMP (Figure 2). After controlling for the significant baseline variables creatinine, blood urea nitrogen, WBC, HR, pump type, and AST with Cox regression analysis, the adjusted p value was p = 0.009. A greater percentage of patients in the HM II (90%, n = 152) versus the COMP (80%, n = 130) group reached the successful outcomes of survival to transplant, recovery of the heart, or ongoing support at 6 months (Figure 3) (p = 0.018). There were no statistically significant differences in survival rates for patients in different INTERMACS profiles within each device group, but survival for profile 1 patients was significantly better for HM II versus COMP (Table 2).

Event rates as reported to the INTERMACS registry were similar or lower for HM II versus COMP for all categories (Table 3). Bleeding was the most frequent adverse event for both groups, with event rates of 1.44 and 1.79 events/patient-year for HM II and COMP, respectively. Infection rates were lower for HM II versus COMP, as were event rates for renal and respiratory dysfunction, cardiac arrhythmias, and hypertension. There were no statistically significant differences between groups for hepatic failure or hemolysis. There was no difference in the incidence of stroke, with event rates of 0.08 and 0.11 events/patient-year for HM II versus COMP, respectively; but nonstroke neurologic dysfunction was less in HM II group.

Quality of life in HM II patients as measured with the EQ-5D visual analog scale was significantly improved at 3 months of support in both groups compared with baseline and was sustained through 12 months (Figure 4). In addition, the EQ-5D total score showed similar improvements for both devices from 9.3 ± 2.5 at baseline to 7.0 ± 1.9 at 12 months (HM II) (p < 0.0001) and from 9.6 ± 2.3 to 7.3 ± 1.7 (COMP) (p < 0.0001). Results were based on a total of 253 tests (50%) completed of 508 potential test sessions for HM II patients and 169 of 386 potential (44%) test sessions for COMP patients. Functional capacity is measured by the 6-min walk test in the INTERMACS registry; however, the frequency of collection in this voluntary registry is under 25%, and we elected to not report the results.

The results of this post-approval study support the original findings from the pivotal clinical trial regarding the efficacy and risk profile of the HM II LVAD in a post-market approval “real world” BTT population. The results also show encouraging improvement in outcomes with the device in commercial use since completion of the clinical trial. Finally, we are able to demonstrate that the percentage of patients who were transplanted, recovered ventricular function, or were receiving ongoing device support at 180 days has improved (Table 4). The 30-day operative mortality has decreased from 11% to 4% since the initial clinical trial cohort. Similarly, 1-year Kaplan-Meier survival has improved progressively from 68% to 74% and now to 85% in the current report. Several factors might contribute to the improving trends over time. As centers gained experience during the clinical trial and in commercial use, important variables were identified as contributing to survival, including patient selection, implantation techniques, postoperative patient management, and training. These observations have been summarized in a recent detailed review of management practices for continuous flow devices (8). Heart transplant patient outcomes are related to center volume, cardiologist experience, and dedicated transplant coordinators. Similar observations are emerging that have identified experienced and dedicated patient care teams as critical elements to LVAD patient outcomes. It is of interest that the percentage of HM II patients that are alive and receiving ongoing device support at 1 year has increased from 28% in the trial (3) to 52% in the current study and the percentage of transplants decreased from 50% to 34%, which would suggest that improved survival was not due to earlier transplantation.

The HM II survival is superior to the observed COMP group as shown in (Figures 2, 3). It should be emphasized that this is an observation that we will provide rationale to explain but does not indict the COMP group devices as inferior. Indeed, direct comparisons with the HM II and HM XVE have been completed in randomized clinical trials and concluded that the HM II yielded results superior to the HM XVE (4). The importance of this INTERMACS-based registry, post-market approval, observational study is that it has demonstrated further incremental improvements in outcomes with the HM II. However, it should be noted that 1 factor potentially explaining improving survival between HM II and COMP group might be differences in baseline severity of illness. The COMP group had a greater proportion of patients in the most severely ill INTERMACS profile 1 (cardiogenic shock) than the HM II group. Although it has previously been shown in the INTERMACS annual report (5) that patients in INTERMACS profile 1 have poorer outcomes than in profiles 2 and 3 (less-ill patients), we did not find statistically significant differences in either group in this study. Patients presenting in cardiogenic shock often have severe biventricular failure requiring biventricular circulatory support, explaining the more frequent use of biventricular assist devices in the COMP group. Analysis of right heart failure during the HM II BTT clinical trial shows reduced survival in patients who had severe right heart failure requiring right ventricular assist devices or extended inotropic support compared with patients without right heart failure (9). There was no attempt in this study to create a well-matched control group or to adjust groups for severity of illness, because the objective of the study was to track outcomes in a real-world registry using consecutive patients. The COMP group included 114 of 169 patients accrued from a 7-month retrospective period compared with the HM II cohort that was rapidly enrolled over 4 months. Most likely, there were fewer INTERMACS level 1 patients in the HM II cohort, because the data had emerged educating clinicians to the pitfalls of LVAD in INTERMACS 1 patients and triggered the growing trend to use acute short-term support as a “bridge to bridge” for critically ill cardiogenic shock patients. Nonetheless, almost one-quarter of patients receiving the HM II were still in the most severely ill patient profile level 1, and the survival rate at 1 year (87%) in that profile was superior to COMP (64%).

Bleeding was the most frequently reported adverse event for both groups, which is consistent with previous clinical trials and data reported from the overall INTERMACS registry with all devices (5). Comparison of results in the current study with other trials is problematic, due to different definitions as well as reporting differences in registries versus formal clinical trials. Further effort should be applied to management practices and device design for continual reduction of adverse events, including bleeding, stroke, and infection. Anticoagulation strategies are still being refined, and the target International Normalized Ratio levels on long-term warfarin therapy for the HM II has been reduced from 2.0 to 3.0 when the trial was started to 1.5 to 2.5 at the end of the trial, due to a low incidence of pump thrombosis and ischemic stroke compared with a higher rate of hemorrhagic events (10). Another analysis showed that intravenous heparin might not be needed in the transition to warfarin therapy in the early postoperative period, which was based on the observation of no increase in thrombotic events in patients who were managed without heparin, and they had less bleeding in the first 30 days (11). Additionally, the reported INTERMACS-defined adverse events in these real-world cohorts might be generalizable to serve as benchmarks for individual LVAD centers monitoring their bleeding outcomes and establishing quality metrics.

There was a marked improvement in QoL during LVAD support by 3 months that was sustained through 1 year on LVAD support. The EuroQol instrument was used in the current study and is used in the overall INTERMACS registry to provide a simple test to assess global QoL of patients during circulatory support. This test (EuroQol) is different from the heart failure QoL instruments used in the HM II clinical trial (Minnesota Living with Heart Failure and the Kansas City Cardiomyopathy Questionnaires), but the results mirror both the BTT and destination trial patients, who also showed significant improvements in QoL (12). Changes in neurocognitive function have also been evaluated for HM II patients, with improvements seen in visual memory, executive functions, visual spatial perception, and processing speed from Month 1 through 6, with stable function in other domains (13). Unfortunately there was insufficient completion of 6-min walk test data in this registry to be included in this report. Improvements in functional capacity and QoL have been demonstrated in HM II trial participants by Rogers et al. (12).

The results reported demonstrate consistency of outcomes with the HM II LVAD in a post-market approval BTT patient population compared with results from the pivotal clinical trial patient populations. Surprisingly, as the HM II device became available outside of the controlled context of a clinical trial, excellent results were maintained or perhaps surpassed. There is clearly a shift in earlier use of devices in less-ill patients, and currently approximately 35% of patients undergoing heart transplantation in the United States receive some type of mechanical support before transplant. These data suggest that dissemination of this technology has been associated with excellent results and further incremental improvement of outcomes. Importantly, this is the first example of the utility of the INTERMACS registry to conduct a post-market approval study with an LVAD and to demonstrate prospective outcomes with standardized definitions.