Heart failure remains to be a global problem with approximately 5.7 million individuals suffering from heart failure in the United States alone.1 Heart transplantation is currently the gold standard and is the best means of improving quality of life and survival with a 1 year survival average almost 90%. However, the shortage of donors has limited its applicability, and the number of annual heart transplantations (approximately 2,000 cases) has remained stagnant in the United States in the last decade.2,3 With the limited amounts of donor organs and the increasing number of patients with heart failure whose condition deteriorates while waiting on the waiting list, the use of left ventricular assist device (LVAD), especially with the current generation of continuous-flow devices, as bridge-to-transplant (BTT) has increased significantly in major transplant centers.4 Pulsatile LVADs, for example, HeartMate XVE, have been shown to improve survival and quality of life of patients with advanced heart failure for both BTT and destination therapy.5,6 But their applicability has been limited by device size, durability, device malfunction, and complications.
The current-generation continuous-flow LVAD, that is, HeartMate II (HMII), has been shown to be more durable and is associated with fewer adverse events and improved patient survival, functional capacity, and quality of life when compared with the first-generation pulsatile-flow LVADs.7–9 There are conflicting reports in the past (including studies on the first-generation pulsatile LVAD) on the effects of pretransplant LVAD placement on posttransplant survival.10–13 Patlolla et al. 10 used the United Network for Organ Sharing (UNOS) database and reported the use of pulsatile ventricular assist devices (VADs) before heart transplantation to be associated with a higher posttransplant mortality after heart transplantation. Hence, concern has been raised on the effect of LVAD on transplantation outcome. With the improvement in device technology and increased experiences on patient selection, intraoperative management, and postoperative care, recent data have demonstrated excellent survival after heart transplantation in patients with continuous-flow LVAD device as BTT.11,12 However, the data are limited by small numbers, single-center experience, short-term outcomes, being nonrisk adjusted, or having no control group. The objective of this study is to directly compare both the short- and long-term posttransplant all-cause mortality in a large cohort of patients with and without pretransplant HMII placement using the UNOS database.
Data from the UNOS registry of heart transplant recipients between the 2004 and 2010 were used for this analysis. De-identified data from the Standard Transplant Analysis and Registry and the follow-up files were merged to create a cohort of patients with heart failure who received heart transplantation. A retrospective cohort analysis was conducted to determine the posttransplant survival in patients associated with and without pretransplant HMII placement.
The study sample was limited to adult patients (>18 years old) with heart failure listed for heart transplantation after April 2004. By the year of 2005, HMII LVAD had been implanted at some major transplant center in the United States before its 2008 US Food and Drug Administration approval for BTT.8 Only HMII continuous-flow device was included in this analysis. Data from UNOS status 1A and 1B patients were used in this study.
Outcome and Covariates
The primary outcome of this study is postheart transplant mortality from any causes. All-cause mortality was based on the last follow-up status of a recipient after heart transplantation. Death was confirmed by the use of the National Death Index database. Other important pretransplant data such as total duration on waiting list and waiting list status, an indicator of priority on the basis of medical urgency, were assessed and included in the analysis. Age, sex, race, and educational level of transplant recipients at the time of transplant were the demographic variables assessed. Clinical outcomes at the time of transplantation known to be associated with posttransplant survival, that is, renal insufficiency (serum creatinine >1.8 mg/dl), ischemic time, infection status, and implantable cardioversion defibrillator were also evaluated. Heart failure comorbidity factors before transplantation assessed were diabetes mellitus and obesity (body mass index [BMI] ≥30 kg/m3). Other known critical factors for posttransplant survival including donor characteristics such as age, race, sex, and BMI category were analyzed.
All statistical analysis was completed with SAS 9.3 (SAS, Cary, NC). χ2 test and paired t-test were used to evaluate the distribution of participants’ characteristics at the time of transplant by the status of HMII LVAD implantation. The majority of these characteristics were not balanced between recipients and nonrecipients of HMII LVAD (Table 1). This suggests that the use of the HMII LVAD was biased by these factors which could then confound the association between HMII use and posttransplant mortality. To minimize this selection bias, HMII LVAD recipients and nonrecipients were matched through propensity score matching. A multivariable-adjusted logistic regression model was used to generate propensity scores. HMII LVAD recipients and nonrecipients were matched in a 1:2 ratio based on the generated propensity scores using the so-called “Greedy-matching” SAS (9.3) macro.
Cox proportional hazard regression models were used to estimate the hazard ratio (HR) of posttransplant mortality associated with the use of HMII LVAD before heart transplantation. Graphical (Schoenfeld residual plots and Kaplan–Meier cumulative incidence plots) and numerical (time-dependent covariates) methods were used to evaluate whether the major predictor or other covariates violated the proportionality assumption. HMII LVAD and other covariates (such as BMI, age, sex, acute graft rejection, and age of heart donor) violated the proportionality assumption. Hence, a time-dependent Cox regression model was used to model time-to-death after heart transplantation. Time after transplantation was stratified into less than 30 days, 30 days to 1 year, and more than 1 year to allow estimation of conditional survival associated with pretransplant HMII placement. Statistical significance was based on two-sided tests of p value less than 0.05. All HRs were also reported along with their 95% confidence intervals (CIs).
There were 48,090 adult recipients listed in UNOS after April 2004. With all the exclusion criteria, the final sample for analysis consisted of 17,814 recipients of heart transplantation; 1,435 (8.1%) of whom received a HMII LVAD before heart transplantation whereas 16,379 (91.9%) did not (Figure 1). All status 2 patients were purposefully excluded for same status comparison between groups. Seven hundred fifty-eight (33.6%) HMII LVAD recipients and 1,507 (66.4%) nonrecipients had similar baseline characteristics at the time of transplantation after matching on propensity scores (Table 1). There were 281 (73 HMII LVAD and 208 no HMII LVAD) deaths during a median follow-up period of 1.91 (interquartile range: 1.01–3.00) years after heart transplantation. The crude baseline annual hazard rate was slightly higher among those who were implanted with the HMII compared with that among those without (89.1 vs. 68.7 per 10,000 person-years). However, the cumulative incidence of mortality curves crossed over at approximately 1.6 years postheart transplantation and the incidence of death in nonrecipients of HMII LVAD became higher than that in recipients (Figure 2). However, the cumulative incidence of death between recipients and nonrecipients of HMII LVAD was not significantly different (log-rank test, p = 0.99). Overall, the study sample consisted of middle-aged persons (51.9 years, standard deviation: 12.3 years). There were approximately five times more males (83.9%) than females (16.1%).
The time-dependent Cox proportional hazard regression models fitted the data better than the traditional Cox models based on the Akaike information criterion model test of fitness criterion, 3,996.3 vs. 4,003.6. Table 2 reports conditional HRs for the association between HMII LVAD and time-to-death after heart transplantation estimated from a time-dependent Cox proportional hazard regression models. Within the first 30 days after heart transplant, HMII LVAD was associated with a trend to a increased risk of death in both unadjusted and multivariable-adjusted analysis (HR = 1.23, 95% CI: 0.79–1.95, p = 0.36), but this was not statistically significant. This risk of mortality among those who survived beyond the first 30 days up to 1 year after heart transplantation remained slightly increased (HR = 1.31, 95% CI: 0.86–2.01, p = 0.22) with preheart transplant HMII LVAD placement, but this was not significant. However, among those who survived beyond the first 1 year after transplantation, HMII LVAD pretransplant placement was associated with a statistically significant 64% lower risk of mortality (HR = 0.36, 95% CI: 0.16–0.77, p = 0.01).
Multiple studies have shown that pulsatile-flow LVAD as BTT, for example, HeartMate XVE, provides excellent hemodynamic support and improves patient survivals.5,6 But its use has been limited by its durability and device complications. The current generation of continuous-flow rotary LVADs has been proven to have enhanced durability and provides improved quality of life for extended periods of support.14,15 The most recent Interagency Registry for mechanically assisted circulatory support Annual Report9 highlighted the paradigm shift of the LVAD use from pulsatile-flow device to continuous-flow device. By the first half of 2011, more than 99% of LVADs implanted were continuous-flow devices. Conflicting reports, including analysis on pulsatile-flow LVAD, have been published on the effect of LVADs on posttransplant survival.10–13 Patlolla et al.,10 using the UNOS database, with patients who underwent heart transplantation between January 1995 and December 2004, showed that the use of pulsatile VADs before heart transplantation was associated with a higher posttransplant mortality. Pulsatile LVADs were associated with an HR of 1.2 (95% CI: 1.02–1.43; p = 0.03) for mortality in the first 6 months after transplant and an HR of 1.99 (95% CI: 1.44–2.75; p < 0.0001) beyond 5 years. This raised the concern on the effect of LVADs on the heart transplantation outcomes. But recent data evaluating the effect of continuous-flow LVAD (HMII) on posttransplant survival have demonstrated excellent results.11,12 John et al. 11 reported a multi-center study (n = 468) and demonstrated that the 30 days and 1 year posttransplant survivals were 97% and 87% in patients with pretransplant HMII placement as BTT. In a single-center retrospective study (n = 167), Kamdar et al. 12 demonstrated that the survival after transplantation at 30 days, 1 year, 3 years, and 5 years were 97%, 93%, 91.1%, and 88%, and there is no survival difference between those patients supported with an LVAD for less than 180 days or more than 180 days before transplantation. In our current study, using the UNOS database, with a larger sample size, we directly compared both the short- and long-term posttransplant mortality in patients with and without pretransplant HMII placement. The objective was to examine whether pretransplant HMII placement affected the risk of all-cause mortality after heart transplantation and whether there is a differential effect between short- and long-term postheart transplant mortality associated with pretransplant HMII support as BTT.
The major strengths of this study include a larger sample size and the use of propensity score–matched analysis to create two similar groups of patients who were and were not implanted with HeartMate II before heart transplantation. The finding of this study described that the risk of postheart transplant mortality with HMII pretransplant placement seems to decrease over time. Pretransplant HMII placement was associated with only a mild and nonstatistically significant increase of mortality risk at 30 days and 1 year (nonstatistically significant: p = 0.36 and p = 0.22) but an improved survival after 1 year (p = 0.01). The mild short-term increased risk of postheart transplant mortality could be because of a higher risk of complications after a longer and more complicated second operation for the heart transplantation after LVAD placement. But further analysis will be needed. The improved long-term (i.e., >1 year) survival could be a result of improved overall health and multi-organ function with HMII placement before heart transplantation. A few previous reports have shown that patients bridged with VADs typically have improvement in end-organ function after implantation, have lower pulmonary artery pressures, and may be medically more suitable to endure the rigors of the heart transplantation.16,17 The survival results from this larger patient group seem to be very comparable to the survival results from the most recent studies on continuous-flow device mentioned before.11,12 When compared with the previous UNOS analysis on pulsatile LVAD,10 the data have demonstrated a better posttransplantation outcome. We found that patients with continuous-flow LVADs as BTT had a 31% higher risk of mortality in the first year after transplantation and a 64% less risk of mortality in more than 1 year after transplantation. The long-term lower risk of posttransplant mortality associated with HeartMate II observed in this study was independent of UNOS listing status.
The findings of this study along with the previous reports11,12 may implicate and encourage the use of earlier continuous-flow LVAD placement for patient waiting on intravenous inotrope support, if it is an option, to improve posttransplant survival. This may allow more time for improved donor selection while the patient is stably supported by the LVAD. Gronda et al. 18 showed that the patients receiving intravenous inotrope support while awaiting transplantation for more than 21 days had a greater than 50% posttransplant mortality. The remarkable durability of the HeartMate II LVAD can allow improved donor selection in contrast to the pulsatile pump era in which decreasing durability beyond the 1 year mark increased the urgency for transplantation and the subsequent potential for suboptimal donor selection.
With the limited donor organ supply and the increasing heart failure patient population, the finding of this current study along with the excellent clinical outcome from recent studies on continuous-flow LVAD might suggest that stable patients with the continuous-flow LVAD and without device-related complication may not need to be listed as UNOS status 1. The current UNOS status codes were developed at the time of the previous generation of pulsatile LVAD. Now this has created a disproportionate advantage to patients on LVADs support despite their stability. As the device technology improves, with extended device durability and a lower rate of device-related complications, LVAD patients are now more stable and can be supported for a much longer period of time with better survival when compare with the patients supported with the previous generation of LVADs. The most current 1 year survival rate for BTT therapy with a continuous-flow LVAD is 86% and is associated with improved functional capacity and quality of life,14,15 and the 1 year transplantation survival is approximately 89%.10 This may indicated that there may not be a need to rush BTT patients to transplantation. Slaughter et al. have described the need for the UNOS status criteria to be reconsidered secondary to the improved functionality and durability of the current-generation LVADs.
The main limitation of the study is that the survival impact of the duration of the LVAD (or inotrope) could not be assessed. Previous study11 has reported that the duration of LVAD support has no influence on the posttransplant survival. The other limitation of the current study is that it did not included posttransplant morbidity or the causes of mortality, for example, infection, bleeding, length of stay, rejection, and etc. This study also did not include breakdown of the LVAD patients with device-related complications who were upgraded to UNOS status 1A. Moreover, this study described only the use of HMII LVAD. The use of the newer-generation continuous-flow device as BTT, for example, HeartWare HVAD, was not included in this study.
Patients with continuous-flow LVAD as BTT seemed to have a comparable short-term posttransplant survival when compared with patients without HMII placement before heart transplantation. Continuous-flow LVAD as BTT is associated with improved long-term survival (>1 year) after heart transplantation
1. Lloyd-Jones D, Adams RJ, Brown TM, et al. Heart disease and stroke statistics—2010 update: A report from the American Heart Association. Circulation. 2010;121:e46–e215
2. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: Twenty-fourth official adult heart transplant report—2007. J Heart Lung Transplant. 2007;26:769–781
3. O’Connell JB, Bourge RC, Costanzo-Nordin MR, et al. Cardiac transplantation: Recipient selection, donor procurement, and medical follow-up. A statement for health professionals from the Committee on Cardiac Transplantation of the Council on Clinical Cardiology, American Heart Association. Circulation. 1992;86:1061–1079
4. Uriel N, Jorde UP, Woo Pak S, et al. Impact of long term left ventricular assist device
therapy on donor allocation in cardiac transplantation. J Heart Lung Transplant. 2013;32:188–195
5. Rose EA, Gelijns AC, Moskowitz AJ, et al.Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist device
for end-stage heart failure. N Engl J Med. 2001;345:1435–1443
6. Lietz K, Long JW, Kfoury AG, et al. Outcomes of left ventricular assist device
implantation as destination therapy in the post-REMATCH era: Implications for patient selection. Circulation. 2007;116:497–505
7. Slaughter MS, Pagani FD, Rogers JG, et al.HeartMate
II Clinical Investigators. Clinical management of continuous-flow left ventricular assist devices in advanced heart failure. J Heart Lung Transplant. 2010;29(4 suppl):S1–S39
8. Pagani FD, Miller LW, Russell SD, et al.HeartMate
II Investigators. Extended mechanical circulatory support with a continuous-flow rotary left ventricular assist device
. J Am Coll Cardiol. 2009;54:312–321
9. Kirklin JK, Naftel DC, Kormos RL, et al. Fifth INTERMACS annual report: Risk factor analysis from more than 6,000 mechanical circulatory support patients. J Heart Lung Transplant. 2013;32:141–156
10. Patlolla V, Patten RD, Denofrio D, Konstam MA, Krishnamani R. The effect of ventricular assist devices on post-transplant mortality
an analysis of the United Network for Organ Sharing thoracic registry. J Am Coll Cardiol. 2009;53:264–271
11. John R, Pagani FD, Naka Y, et al. Post-cardiac transplant survival after support with a continuous-flow left ventricular assist device
: Impact of duration of left ventricular assist device
support and other variables. J Thorac Cardiovasc Surg. 2010;140:174–181
12. Kamdar F, John R, Eckman P, Colvin-Adams M, Shumway SJ, Liao K. Postcardiac transplant survival in the current era in patients receiving continuous-flow left ventricular assist devices. J Thorac Cardiovasc Surg. 2013;145:575–581
13. Urban M, Pirk J, Dorazilova Z, Netuka I. How does successful bridging with ventricular assist device affect cardiac transplantation outcome? Interact Cardiovasc Thorac Surg. 2011;13:405–409
14. Miller LW, Pagani FD, Russell SD, et al.HeartMate
II Clinical Investigators. Use of a continuous-flow device in patients awaiting heart transplantation
. N Engl J Med. 2007;357:885–896
15. Slaughter MS, Rogers JG, Milano CA, et al.HeartMate
II Investigators. Advanced heart failure treated with continuous-flow left ventricular assist device
. N Engl J Med. 2009;361:2241–2251
16. Farrar DJ, Hill JD. Recovery of major organ function in patients awaiting heart transplantation
with Thoratec ventricular assist devices. Thoratec Ventricular Assist Device Principal Investigators. J Heart Lung Transplant. 1994;13:1125–1132
17. Friedel N, Viazis P, Schiessler A, et al. Recovery of end-organ failure during mechanical circulatory support. Eur J Cardiothorac Surg. 1992;6:519–522; discussion 523
18. Gronda EG, Barbieri P, Frigerio M, et al. Prognostic indices in heart transplant candidates after the first hospitalization triggered by the need for intravenous pharmacologic circulatory support. J Heart Lung Transplant. 1999;18:654–663
Keywords:Copyright © 2014 by the American Society for Artificial Internal Organs
heart transplantation; HeartMate; left ventricular assist device; mortality