Author + information
- Received April 29, 2008
- Revision received July 14, 2008
- Accepted August 18, 2008
- Published online January 20, 2009.
- Vishnu Patlolla, MD, MPH⁎,
- Richard D. Patten, MD†,
- David DeNofrio, MD†,
- Marvin A. Konstam, MD† and
- Rajan Krishnamani, MD†,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Rajan Krishnamani, Division of Cardiology, Tufts Medical Center, 800 Washington Street, Box 5931, Boston, Massachusetts 02111
Objectives This study sought to determine the relationship between pre-transplant ventricular assist device (VAD) support and mortality after heart transplantation.
Background Increasingly, VADs are being used to bridge patients to heart transplantation. The effect of these devices on post-transplant mortality is unclear.
Methods Patients 18 years or older who underwent first-time, single-organ heart transplantation in the U.S. between 1995 and 2004 were included in the analyses. This study compared 1,433 patients bridged with intracorporeal and 448 patients bridged with extracorporeal VADs with 9,455 United Network for Organ Sharing status 1 patients not bridged with a VAD with respect to post-transplant mortality. Because the proportional hazards assumption was not met, hazard ratios (HRs) for different time periods were estimated.
Results Intracorporeal VADs were associated with an HR of 1.20 (95% confidence interval [CI]: 1.02 to 1.43; p = 0.03) for mortality in the first 6 months after transplant and an HR of 1.99 (95% CI: 1.44 to 2.75; p < 0.0001) beyond 5 years. Between 6 months and 5 years, the HRs were not significantly different from 1. Extracorporeal VADs were associated with an HR of 1.91 (95% CI: 1.53 to 2.37; p < 0.0001) for mortality in the first 6 months and an HR of 2.93 (95% CI: 1.19 to 7.25; p = 0.02) beyond 5 years. The HRs were not significantly different from 1 between 6 months and 5 years, except for an HR of 0.23 (95% CI: 0.06 to 0.91; p = 0.04) between 24 and 36 months.
Conclusions Extracorporeal VADs are associated with higher mortality within 6 months and again beyond 5 years after transplantation. Intracorporeal VADs are associated with a small increase in mortality in the first 6 months and a clinically significant increase in mortality beyond 5 years. These data do not provide evidence supporting VAD implantation in stable United Network for Organ Sharing status I patients awaiting heart transplantation.
Ventricular assist devices (VADs) are increasingly used to successfully bridge patients to heart transplantation. Patients bridged with VADs typically show significant improvement in end-organ function after implantation (1,2). These observations have contributed to the notion that VAD therapy may therefore render patients more medically suitable to endure the rigors of cardiac transplantation. Despite the increase in use of VADs before transplantation, studies exploring the effect of VADs on post-transplant mortality have yielded conflicting results. Although some single-center studies analyzing outcomes from a limited number of patients have concluded that VAD therapy before heart transplantation is not related to post-transplant survival, others have shown that VAD therapy is associated with improved post-transplant survival (3–9). Furthermore, 1 study has observed diminished survival for patients bridged to transplant with a VAD (10).
We conducted a retrospective analysis in 11,336 patients entered into the United Network for Organ Sharing (UNOS) Thoracic Registry to examine the relationship between intracorporeal and extracorporeal VAD implantation and post-transplant mortality.
This analysis was based on Organ Procurement and Transplantation Network data as of May 25, 2006. We limited our analysis to patients in the UNOS Thoracic Registry who were 18 years or older and who underwent heart transplantation between January 1995 and December 2004. The analysis was limited to first-time, single-organ heart transplant recipients. Patients with a history of malignancy were excluded. Patients were divided into 3 groups based on the support at the time of transplant. The UNOS status 1 group included UNOS status 1 patients without VAD support at the time of transplant. The intracorporeal VAD group included patients on a HeartMate (Thoractec Corporation, Pleasanton, California) or Novacor (World Heart Inc., Oakland, California) intracorporeal VAD. The extracorporeal VAD group included patients with a Thoratec (Thoractec Corporation) or Abiomed (Abiomed Inc., Danvers, Massachusetts) extracorporeal VAD. Patients in either VAD group who were also on an intra-aortic balloon pump (IABP) were excluded. Patients with both an intracorporeal and an extracorporeal VAD were included in the extracorporeal VAD group. The primary outcome was all-cause mortality.
Baseline characteristics were compared among the 3 groups using analysis of variance, with the Tukey method for controlling for multiple comparisons, for continuous variables, and the chi-square test for categorical variables. Survival curves were estimated using the Kaplan-Meier method, and equality of survival curves was tested using a log-rank test. The Cox proportional hazards regression model was used to estimate hazard ratios (HRs) of death in the intracorporeal and extracorporeal VAD groups compared with the UNOS status 1 group, after adjustment for covariates: donor and recipient age, recipient sex, sex mismatch (female donor–male recipient), time on waiting list, ischemic etiology of heart failure, cytomegalovirus-positive donor/cytomegalovirus-negative recipient, recipient use of ventilator, inotropes and amiodarone before transplant, recipient history of diabetes, recipient's serum creatinine and bilirubin, cold ischemia time, most recent panel reactive antibodies (PRA), and year of transplant. Proportional hazards assumption for each of the variables was examined using an interaction term with time. Ventilator use before transplant, serum bilirubin, PRA, and year of transplant showed a significant interaction with time, and the interaction term with time for these variables was retained in the final model. The relationship between intracorporeal or extracorporeal VAD use and mortality, using UNOS status 1 patients as the reference group, was found to be time dependent. Therefore, HRs for different time periods were estimated with the use of indicator variables that represented interaction between these groups and the different time periods. Values of missing variables were replaced by their median value for continuous variables and their most common value for categorical variables.
Secondary analysis was performed, treating various causes of death as competing risks in the Cox proportional hazards model, in selected time periods in which the mortality between the groups was different, to identify the cause responsible for the difference in mortality (11). The causes of death were grouped into 6 categories for this analysis: rejection, infection, cardiovascular, pulmonary, malignant, and other (Online Appendix). A separate Cox proportional hazards model for each of these categories of death was built, with adjustment for all of the variables as in the main analysis. In addition, malignancy in the donor was included as a covariate in the model for death due to malignancy. Statistical analysis was performed using SAS version 9.1 (SAS Institute, Cary, North Carolina).
There were 9,455 patients in the UNOS status 1 group, 1,433 patients in the intracorporeal VAD group, and 448 patients in the extracorporeal VAD group.
The median follow-up time was 49 months in the UNOS status 1 group, 36.5 months in the intracorporeal VAD group and 24.4 months in the extracorporeal VAD group.
The baseline characteristics of the 3 groups are summarized in Table 1. The etiology of cardiomyopathy was similar between the groups. UNOS status 1 patients were older than intracorporeal VAD patients, who were older than the extracorporeal VAD patients. Time on the waiting list was shorter for the extracorporeal VAD patients compared with UNOS status 1 and intracorporeal VAD patients. Creatinine was lower in the intracorporeal VAD group than in the other 2 groups. Bilirubin was higher in the extracorporeal VAD group compared with the other 2 groups. The most recent PRA was highest in the extracorporeal VAD group, followed by the intracorporeal VAD group, followed by the UNOS status 1 group. Extracorporeal VAD patients were more likely to be on a ventilator compared with the other 2 groups. Inotropic support was more common in the UNOS status 1 group compared with the other 2 groups. Eight percent of patients in the UNOS status 1 group were supported with an IABP. The majority of patients in the extracorporeal and intracorporeal VAD groups were transplanted from 1999 to 2004, whereas patients in the UNOS status 1 group were more evenly derived from 1995 to 2004.
The effect of VAD therapy on post-transplant mortality
Figures 1 and 2⇓ and Table 2 summarize the unadjusted survival in each of the 3 groups after transplantation. Survival curves in the intracorporeal VAD group and UNOS status 1 group were similar up to 48 months, when they started to diverge with decreased survival in the intracorporeal VAD group compared with the UNOS status 1 group. The overall p value for equality of survival between the groups was 0.033 (Fig. 1). The rate of decline in survival was steeper in the extracorporeal VAD group compared with the UNOS status 1 group in the first post-transplant year (Fig. 2). The decline in survival in the extracorporeal VAD group was equal to or less than that in the UNOS status 1 group between 12 and 60 months. The smaller number of patients with follow-up >60 months in the extracorporeal VAD group makes survival estimates after this time point in this group unreliable. The overall p value for equality of survival between these groups was <0.0001.
Intracorporeal and extracorporeal VAD groups were associated with nonproportional time-dependent hazards for mortality compared with the UNOS status 1 group. Thus, HRs were obtained for different time periods and are shown in Table 3. After adjusting for covariates mentioned in the Methods section, the intracorporeal VAD group was associated with an HR of 1.20 (95% confidence interval [CI]: 1.02 to 1.43) for mortality in the first 6 months after transplant compared with the UNOS status 1 group. Between 6 and 60 months, the HRs were not significantly different from 1, after which the HR for the intracorporeal VAD group was 1.99 (95% CI: 1.44 to 2.75) compared with the UNOS status 1 group. The extracorporeal VAD group had an HR of 1.91 (95% CI: 1.53 to 2.37) for mortality compared with the UNOS status 1 group in the first 6 months after transplant. Thereafter, HRs in this group decreased to 0.23 (95% CI: 0.06 to 0.91) at 24 to 36 months and remained diminished until 60 months, after which the extracorporeal VAD group was associated with an HR of 2.9 (95% CI: 1.19 to 7.25) for mortality compared with the UNOS status 1 group.
Causes of increased mortality
The results of the competing risks analysis to identify causes of increased mortality in the VAD groups in selected time periods are shown in Tables 4 and 5.⇓⇓ In the first 12 months post-transplant, the intracorporeal VAD group showed a trend toward increased death caused by infection. During this period, the extracorporeal VAD group experienced increased risk of death caused by infections and due to other causes. Beyond 60 months post-transplant, the intracorporeal VAD group showed an increased risk of death caused by infection, malignancy, and other causes. The number at risk was small in the extracorporeal VAD group, yielding unreliable estimates in this time period.
Effect of VADs on post-transplant mortality by era of transplantation
We examined the effect of VADs on post-transplant mortality by era of transplantation (1995 to 1999 vs. 2000 to 2004) by introducing an interaction term of the VAD group and the period of transplantation into the model. No significant difference was noted in the effect of intracorporeal or extracorporeal VADs on post-transplant mortality between these time periods.
The treatment options for patients with advanced heart failure or those with deteriorating end-organ function on maximal medical management are limited to intravenous inotropes and mechanical assistance with IABP or VAD. Evidence from observational studies suggests that VADs are superior to IABP and inotropic support in successfully bridging patients to transplantation (8,9). VADs have been shown to improve cardiac output and end-organ function (1,2). A study by Deng et al. (12) compared mortality by the urgency of placement of a VAD including semielective, urgent, and emergent, and showed that the best outcomes were observed in patients who received VADs semielectively. Gronda et al. (13) showed that patients receiving intravenous inotropic support while awaiting transplantation for more than 21 days had a >50% mortality post-transplant. These observational data lend support to the hypothesis that transitioning patients who are on inotropic support to VAD support may improve post-transplant survival. This idea, combined with the scarcity of donor organs, has led to an increasing number of transplant recipients being bridged to transplant with a VAD (14).
Several studies exploring effect of VADs on post-transplant outcomes have reported conflicting results, showing improved, neutral, or even worse survival for patients supported with VADs pre-transplant (3–10,14–19). One study that used data from the Cardiac Transplant Research Database reported no significant difference in post-transplant survival between 502 patients treated with a left ventricular assist device (including 85 patients on an extracorporeal left ventricular assist device) and 2,514 patients on intravenous inotropes bridged to transplant between 1990 and 1997 (20). In contrast, however, 4 of the last 6 annual reports from the International Society for Heart and Lung Transplantation registry reported increased early post-transplant mortality in patients supported with VADs (14–19). These data are in agreement with our own findings. Indeed, the primary strength of the current analysis is that it is a study with the largest number of patients to date to help address this important issue in the care of patients before cardiac transplantation. We found that patients bridged to transplant with intracorporeal VADs had a 20% higher risk of mortality in the first 6 months after transplant and a nearly 2-fold higher risk of mortality beyond 5 years compared with UNOS status 1 patients. In absolute terms this translates to 2% excess mortality at 6 months, 1% excess mortality at 1 year, and 7% to 10% excess mortality at 6 to 8 years. The difference at 6 months and 1 year is small and of unclear clinical significance, but the 7% to 10% excess mortality at 6 to 8 years in the intracorporeal VAD group is of considerable concern.
Patients bridged with extracorporeal VADs showed a nearly 2-fold increase in mortality in the first 6 months after transplant compared with UNOS status 1 patients not bridged with a VAD. These findings are consistent with the results from the registry of the International Society for Heart and Lung Transplantation (14,18,19,21). Beyond 6 months, however, patients bridged with extracorporeal VADs had a lower mortality compared with UNOS status 1 patients. This is probably the result of self-selection of patients who were able to survive the initial post-transplant period. Similar to the finding in patients with intracorporeal VADs, patients bridged with extracorporeal VADs had a higher mortality beyond 5 years of transplant compared with UNOS status 1 patients not bridged with a VAD, although the number of patients for this analysis was small.
Infection seems to mediate part of the excess mortality in the early post-transplant period in the extracorporeal and possibly in the intracorporeal VAD group. Although we did not have the data to look at, it is known that extracorporeal VAD patients are more likely to have biventricular failure and therefore a number of contributors to increased mortality, including poor nutritional status and increased inotrope use, which could potentially explain the higher mortality in this group compared with the intracorporeal VAD group in the immediate post-transplant period. The increase in mortality in the intracorporeal VAD group attributable to infection, malignancy, and other causes 5 years beyond transplant is an intriguing finding. It has been shown that patients with VADs have impaired cellular immunity (22,23). Although this can explain the trend toward increased infections in patients bridged with VADs in the early post-transplant period, the reason for increased infections in these patients 5 years after transplant is not clear. Further study into this aspect of VADs is warranted. The reason for increased death caused by malignancy in intracorporeal VAD patients is unclear. Ventricular assist devices are associated with allosensitization (21). However, we did not see increased mortality associated with rejection in VAD patients in our study. Allosensitization may play a role in a longer waiting time to transplant with intracorporeal VADs (21). It is not known whether this results in end-organ damage, which manifests as late increased mortality.
Survival to transplant is an important component of the overall effect of any intervention in patients awaiting transplantation. We could not assess the effect of VADs on survival to transplant and could only assess their effect post-transplant. We therefore cannot estimate the overall benefit or harm with VADs. Although we adjusted for a variety of indicators of the patient's illness at the time of transplant, it is possible that there were unmeasured differences between the groups that could potentially bias the results. We did not have the indication for VAD in the database and resorted to combining all patients on VAD. It was therefore not possible to determine the effect of VADs on post-transplant mortality by the reason for VAD implantation (i.e., elective vs. clinical instability). Because the data used predate the appearance of continuous flow devices, the results of this study cannot be generalized to these newer devices, which are gaining popularity (24). Only a randomized controlled trial can establish the overall effect of VADs in stable status 1 patients awaiting transplantation.
Patients who are unstable or symptomatic despite maximal medical therapy require VAD support as a bridge to transplant. One question raised by studies that have shown improved end-organ function with VADs is whether VADs improve post-transplant survival. Our results do not confirm this conclusion, but rather show that VADs are associated with increased early and late post-transplant mortality. Based on our results, we cannot recommend VAD implantation with a view to improving post-transplant survival for patients who are stable on intravenous inotropic therapy.
For a classification of causes of death into categories, please see the online version of this article.
The data reported here have been supplied by the United Network for Organ Sharing as the contractor for the Organ Procurement and Transplantation Network. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the Organ Procurement and Transplantation Network or the U.S. Government.
- Abbreviations and Acronyms
- hazard ratio
- intra-aortic balloon pump
- panel reactive antibodies
- United Network for Organ Sharing
- ventricular assist device
- Received April 29, 2008.
- Revision received July 14, 2008.
- Accepted August 18, 2008.
- American College of Cardiology Foundation
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