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Patients Awaiting Heart Transplantation on HVAD Support for Greater Than 2 Years

Aaronson, Keith D.; Silvestry, Scott C.; Maltais, Simon; Mallidi, Hari R.; Frazier, O. H.; Boyce, Steven W.; Leadley, Katrin; Najarian, Kevin B.; Slaughter, Mark S.; Pagani, Francis D.

doi: 10.1097/MAT.0000000000000380
Adult Circulatory Support

Advanced heart failure patients who are classified as bridge to transplant (BTT) often remain on mechanical circulatory support (MCS) for long durations because of the limited supply of donor organs. Here, we present the outcomes of patients who have been supported by the HeartWare ventricular assist device system for more than 2 years. In the HeartWare BTT and continued access protocol trial, 74 of the 382 total patients (19.4%) had more than 2 years of MCS with a mean time of 1,045 days on device. The long-term group was more frequently female, was nonwhite, and had Interagency Registry for Mechanically Assisted Circulatory Support profiles 4–7. Postimplant adverse event rates including bleeding, cardiac arrhythmia, infection, stroke, renal dysfunction, and right heart failure were less frequent in the long-term cohort. In addition, the long-term cohort displayed significant improvements in Kansas City Cardiomyopathy Questionnaire Overall Summary Score, EuroQOL-5D Overall Health State Score, and 6 minute walk scores from baseline values. The rate of heart transplantation was lower for the long-term cohort, which may have been a result of their sex and blood type. However, most of these patients are still listed for cardiac transplantation and maintained their quality of life profiles through 3 years of support.

From the *Division of Cardiovascular Medicine, Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan; Department of Thoracic and Cardiovascular Surgery, Florida Hospital, Orlando, Florida; Department of Cardiac Surgery, Mayo Clinic Rochester, Rochester, Minnesota; §Heart and Lung Transplant Center, Texas Heart Institute, St. Luke’s Episcopal Hospital, Houston, Texas; Departments of Internal Medicine and Cardiac Surgery, MedStar Heart Institute, Washington, DC; HeartWare Inc., Framingham, Massachusetts; and #Division of Cardiothoracic Surgery, University of Louisville, Louisville, Kentucky.

Submitted for consideration September 2015; accepted for publication in revised form March 2016.

Disclosures: K.D.A. received contracted research support from HeartWare Inc. and Thoratec Corp., which is managed by the University of Michigan. S.C.S. is on the advisory board for HeartWare Inc. and Thoratec Corp. S.M. is on the advisory board for HeartWare Inc. O.H.F. received minimal travel reimbursement from HeartWare Inc. S.W.B. has ownership interest in HeartWare Inc. and Thoratec Corp. D.R.H. and K.B.N. are employees of HeartWare Inc. F.D.P. received contracted research support from HeartWare Inc. and Thoratec Corp., which is managed by the University of Michigan. None of the other authors have a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

Correspondence: Keith D. Aaronson, MD, Division of Cardiovascular Medicine, University of Michigan, 1500 E Medical Center Dr. SPC 5644, Ann Arbor, MI 48109. Email: keith@med.umich.edu.

Advanced chronic heart failure (HF) is a debilitating condition characterized by severely reduced quality of life (QoL) and repeated hospitalizations despite intense management. Of the approximately 5.1 million Americans with HF, heart transplantation is available to only approximately 2,400 each year.1 Because of the lack of suitable donors, mechanical circulatory support (MCS) devices are implanted as a bridge to transplant (BTT) for an increasing proportion of those on the heart waiting list.2 As survival and QoL with ventricular assist device (VAD) therapy have improved across indications, the number of patients receiving a VAD as destination therapy (DT) or bridge to candidacy has increased and now outnumber those receiving a VAD as BTT.3,4 Thus, the population of patients who will require longer periods of support on a VAD is increasing and will very likely continue to do so.

Heart transplantation is still considered the optimal treatment for advanced HF, with a 2 year post-transplant survival rate slightly greater than 80%.5 Although there are potential risks and complications associated with continuous flow VADs, end-organ function is usually well maintained with long-term support and post-transplant outcomes are not adversely impacted.6,7 Numerous studies have investigated the short-term outcomes of continuous flow MCS patients. In both the HeartWare (HeartWare Inc., Framingham, MA) Conformité Européene Mark trial and the U.S. BTT + continued access protocol (CAP) trial, survival was 84% at 1 year of support.8,9 However, reports of longer-term outcomes of continuous flow MCS are limited to single-center experiences and case studies. Given the expanded use of continuous flow pumps, it is necessary to analyze device performance and patient outcomes after extended periods of MCS. In this study, we report the outcomes of patients from the ADVANCE BTT + CAP trials with a focus on those with over 2 years of HeartWare ventricular assist device (HVAD) support.

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Methods

The study designs of the ADVANCE BTT + CAP trials are described in detail previously.9 The HeartWare VAD system was evaluated as a BTT therapy in the United States with a prospective multicenter trial that enrolled 140 patients. The CAP protocol followed the same enrollment criteria as the BTT trial and the Food and Drug Administration (FDA) granted allotments for an additional 242 patients. Of the 382 patients in the BTT + CAP trials, there were 74 patients (long-term group) who were supported for greater than 2 years. There were 252 patients (near-term group) who potentially could have reached 2 years of support but did not because of transplant, explant for recovery, or death. Two patients voluntarily withdrew from the study before 2 years of support, and the remaining patients did not have the opportunity to exceed 2 years on device because of their implant date and the June 11, 2013, database lock. Device implants occurred between August 2008 and November 2012, and all patients received smooth inflow, nonsintered pumps. If a pump exchange occurred, the total time of support for this analysis included the combined time on the initial and replacement HVAD devices. Adverse events were defined using Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definitions,10 and patients were followed to transplant, death, or alive at last follow-up. The studies were conducted in compliance with FDA regulations for Good Clinical Practices and approved by the Institutional Review Board designated by each participating study site. All patients or their authorized representatives provided written informed consent.

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Statistical Analysis

Descriptive statistics were used to evaluate baseline clinical and demographic characteristics of the long-term patients (n = 74), near-term patients (n = 252), and the entire BTT + CAP cohort (n = 382). Results were reported as mean ± standard deviation for continuous variables and as percentage (count × 100/sample size) for binary variables. Comparisons between the long-term and near-term patients were made with a two-sample t-test for continuous variables and the Fisher exact test for categoric variables. Statistical comparisons between the long-term group and overall BTT + CAP cohort were not performed because the long-term patients were a subset of the entire cohort.

Quality of life was evaluated with the Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ) and the EuroQOL-5D Overall Health State Score (EQ-5D), and functional capacity was tested by 6 minute walk (6MW). Within-group comparisons were made with a paired sample t-test. Adverse events are reported as events per patient year (EPPY) (number of events) and were compared between the near- and long-term groups by the Poisson regression. The Kaplan–Meier methodology was used to generate survival estimates for the entire cohort, survival for the long-term group, and competing outcomes for the long-term group. The survival curve for the long-term cohort was constructed to begin at 2 years because all long-term patients, by definition, survived for 2 years. All statistical analyses were performed with SAS v. 9.2 software (SAS Institute, Cary, NC).

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Results

At the time of this extended analysis, the 74 patients with over 2 years of MCS had a mean support time of 1,045 days (range 735–1,569 days). The 252 patients who were transplanted, recovered, or died before 2 years had a mean support time of 248 days (range 11–728 days), and the overall BTT + CAP cohort had a mean support time of 424 days (range 11–1,569 days). Most baseline clinical and demographic characteristics of the long-term and near-term groups were not different (Table 1). The long-term group had a significantly higher percentage of African Americans, had higher body mass index, and were less likely to have an ischemic HF etiology. In the long-term group, there were also statistically nonsignificant trends (0.05 < p < 0.10): more women, less severe HF (as assessed by INTERMACS Patient Profile [IPP]) and lower mean arterial pressures at baseline. A type O blood group was predominant in the 53 long-term patients with available blood group data (Figure 1).

Table 1

Table 1

Figure 1

Figure 1

Assessments of the KCCQ overall summary score, EuroQoL EQ-5D overall health status score, and 6MW test are presented in Table 2. The long-term patients had sustained improvements in functional capacity with significantly higher scores at all follow-up visits compared with their baseline measurements. The large improvements in QoL at all time points compared with baseline for long-term patients were similar to those for the entire BTT + CAP cohort. Differences between the -long and near-term patient groups did not achieve statistical significance at baseline, 6 months, or 12 months. The adverse event profile of the entire 382 BTT + CAP patients is consistent with the results reported for the 332 patients analyzed by Slaughter et al.9 Compared with the near-term group, the long-term group had significantly lower rates of the majority of adverse events, including gastrointestinal bleeding, cardiac arrhythmia, infection, neurologic events, and right HF (Table 3).

Table 2

Table 2

Table 3

Table 3

After 3 and 4 years, 63% and 54% of the 382 patients in the BTT + CAP study patients were alive on original device, transplanted, or explanted for recovery, respectively (Figure 2). However, the number of patients remaining in the Kaplan–Meier survival analysis at 4 years is very small. In the competing risk outcomes of the entire cohort, 79.4% of the patients were transplanted or alive on HVAD support after 2 years (Figure 3). In addition, there were 31 patients (8.1% of the entire cohort) that had a pump replacement with a mean time to first pump replacement of 261 ± 296 days.

Figure 2

Figure 2

Figure 3

Figure 3

The long-term cohort had 89% and 77% survival at 3 and 4 years post-HVAD implant according to the Kaplan–Meier analysis (Figure 4). By nature of examining patients who were on support for greater than 2 years, there were no deaths before the 2 year time point in that cohort. Of the 74 long-term patients who had survived 2 years on device, 74.7% were transplanted or alive on device 3 years after implant (Figure 5). At the 3 year time point, 15% of the long-term patients had a device exchange. Of the 12 long-term patients who received a pump exchange, one has received a transplant and the others have a mean postexchange support time of 803 days (range 72–1,418 days).

Figure 4

Figure 4

Figure 5

Figure 5

Although the long-term group showed a trend of having a lower prevalence of ischemic HF, the survival rates of patients with and without a history of ischemic HF were very similar at 3 years (87.3% vs. 90.3%). Similarly, despite trends for more women and nonwhite patients in the long-term cohort, the survival at 3 years was not different when patients were divided by sex (90.4% vs. 88.9% for men vs. women) and race (90.3% vs. 89.0% for whites vs. nonwhites).

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Discussion

This retrospective multicenter analysis of the BTT + CAP data set examines the pump performance and patient outcomes associated with over 2 years of HVAD support. The results of the entire BTT + CAP cohort (N = 382) were also presented as a representative BTT population and 79.4% of the patients were alive on HVAD support or transplanted after 2 years. The full patient cohort showed improvements in QoL in the first year similar to what was previously published by Slaughter et al.9

The long-term cohort of 74 patients had an average of 1,045 ± 229 days of support, which is greater than the average time on device in previous HVAD studies.9,11 Only 10 (13.5%) of the long-term patients had a pump exchange within the first 2 years after HVAD implant with an additional two patients having a pump exchange after the 2 year time point. The rate of driveline infections in this cohort was 0.18 EPPY, which is similar to the rates reported for the other commercially available LVAD in the BTT or DT settings.12,13 The long-term group also demonstrated significant and sustained improvements in QoL through the 3 year time point (Table 2).

Although the 74 patients with over 2 years of support had promising outcomes, the authors acknowledge the inherent bias in the long-term cohort, as inclusion in this group was conditional on having already survived 2 years of HVAD support. In general, their baseline characteristics appeared similar to the general BTT patient population. The trend for higher IPP categorization in the long-term patients suggests that they may have had less severe HF at baseline, which could have contributed to their improved outcomes.14 However, their lower mean blood pressure at baseline would be a bias in the opposite direction. The long-term group also had lower rates of severe adverse events that negatively affect LVAD survival.4,15–18 Finally, the significant differences in event profiles between the near- and long-term groups may be exaggerated as the incidence of events is generally higher in the period soon after implantation.19

With consideration of the bias in the long-term group, there was a large discrepancy in the rates of transplants for the patients who remained on long-term HVAD support. In the entire 382 patient group, 182 (48%) received a heart transplant within the first 2 years. Of the 74 patients in the long-term group, only 10 (13.5%) received a transplant while 47 (64%) are still on the transplant wait list and 27 patients are no longer listed. The most frequent reasons for delisting were BMI/weight contraindications (N = 7) and patient decision/refusal (N = 6). The majority of the long-term patients had blood type O, reflecting the known lower heart transplant rate of individuals with that blood type.20 There was also a larger fraction of women in the long-term cohort, and previous reports show women are less likely to be listed for heart transplantation.21,22 Fortunately, 73.4% of the women in the long-term group were either alive on original device or after exchange 3 years post-HVAD implant, which was no different from the men (77.5%). In a previous report, there were also no significant differences in post-LVAD mortality between men and women.23 Taken together, this suggests that the HVAD system is a viable solution for long-term support of women with advanced HF.

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Limitations

As mentioned in the discussion, the analysis of a subset of the BTT + CAP patients who had over 2 years of support may have introduced an inherent selection bias resulting in the favorable adverse event and survival outcomes. The near-term group had a large number of patients supported for shorter durations, whereas the long-term group had fewer patients each with a sustained period of support. Although the overall patient years of support are similar, the increased risk of adverse events immediately postimplantation could have contributed to the superior adverse event profile of the long-term group.19 Although we present potential reasons why patients remained on HVAD support after 2 years, other factors such as listing status over time, socioeconomic factors, and geographic variations could have played a role as well. No comparison were made with patients treated with the other commercially available continuous flow device. The ENDURANCE Supplemental trial, a prospective randomized trial comparing outcomes of patients receiving the HVAD versus the HeartMate II (Thoratec Corp., Pleasanton, CA) for DT (https://clinicaltrials.gov/ct2/show/NCT01966458) will allow for a more complete analysis of the long-term performance of both pumps.

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Conclusions

Seventy-four of the 382 patients from the HeartWare BTT + CAP trial have exceeded 2 years of HVAD support with nine patients currently supported for at least 5 years. In addition, in the complete BTT + CAP cohort, nearly 80% of the 382 patients were transplanted or alive on device after 2 years. The long-term group generally had low incidences of adverse events and sustained improvements in QoL profiles. Women comprised a larger than normal fraction of the long-term patient population, and their outcomes were positive with no significant difference in mortality compared with the men. In conclusion, the favorable outcomes and stable QoL of patients with over 2 years of support suggest that the HVAD system deserves consideration when extended MCS may be required.

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Acknowledgments

The authors acknowledge Mary V. Jacoski and Ming-Jay Chow, HeartWare Inc., for their assistance in the analysis and preparation of the manuscript.

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Keywords:

long-term support; mechanical circulatory support; patient outcomes; HVAD

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