ATS
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Ann Thorac Surg 2009;88:1457-1461. doi:10.1016/j.athoracsur.2009.07.021
© 2009 The Society of Thoracic Surgeons
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Jay D. Pal
Mani A. Daneshmand
Andrew J. Lodge
Carmelo A. Milano
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pal, J. D.
Right arrow Articles by Milano, C. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pal, J. D.
Right arrow Articles by Milano, C. A.
Related Collections
Right arrow Valve disease

Original Articles: Adult Cardiac

Impact of Left Ventricular Assist Device Bridging on Posttransplant Outcomes

Jay D. Pal, MD, PhDa, Valentino Piacentino, MD, PhDa, Angela D. Cuevas, MSNb, Tim Depp, BSa, Mani A. Daneshmand, MDa, Adrian F. Hernandez, MD, MHSc, G. Michael Felker, MDc, Andrew J. Lodge, MDa, Joseph G. Rogers, MDc, Carmelo A. Milano, MDa,*

a Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina
b School of Nursing, Duke University Medical Center, Durham, North Carolina
c Department of Medicine, Duke University Medical Center, Durham, North Carolina

Accepted for publication July 10, 2009.

* Address correspondence to Dr Milano, Duke University Medical Center, Duke University Medical Center 3043, Durham, NC 27705 (Email: milan002{at}mc.duke.edu).

Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26–28, 2009.


Drs Rogers and Milano disclose that they have financial relationships with Thoratec.

 

   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 
Background: Bridge to heart transplantation with a left ventricular assist device (LVAD) can be a promising therapy for patients who are not effectively stabilized with conservative measures. However, referral for LVAD therapy may be limited secondary to reports of poor outcomes when mechanical circulatory support is required before transplantation.

Methods: A retrospective review was undertaken to evaluate outcomes in United Network of Organ Sharing (UNOS) status 1 heart transplant recipients who were bridged to transplant with an implantable LVAD or with intravenous inotropes only from 1994 to 2007. Preoperative characteristics, posttransplant survival, and postoperative complications were compared between 86 patients with an implantable LVAD and 173 patients bridged with intravenous inotropes only.

Results: The patients had similar baseline characteristics and pretransplant hemodynamics. Hemodynamics in the LVAD group, as measured by cardiac index, pulmonary vascular resistance, central venous pressure, and pulmonary capillary wedge pressure, significantly improved during mechanical support. Short-term and long-term posttransplant survival and the incidence of posttransplant infectious complications and rejection episodes during the first year was similar. The incidence of posttransplant renal dysfunction was higher in patients bridged with inotropes.

Conclusions: Patients bridged to transplant with a LVAD represent a subset of UNOS status 1 patients who deteriorated on intravenous inotropic therapy. Bridging to heart transplantation with an implantable LVAD provides comparable outcomes to similar status 1 patients who were stabilized on inotropic infusions only. In contrast with International Society of Heart and Lung Transplantation data, no increase in posttransplant morbidity or mortality occurred in LVAD-bridged patients.

Orthotopic heart transplantation is the best treatment option for patients with end-stage heart failure; however, the demand for donor hearts is far greater than the supply. Two options to bridge patients to heart transplantation are intravenous inotropes and left ventricular assist devices (LVADs). In current practice, the inotrope bridge is initially preferred due to the morbidity and mortality associated with LVAD support [1]. Furthermore, current data from the International Society of Heart and Lung Transplantation (ISHLT) suggest significantly decreased survival at 1 and 10 years when a patient is bridged to transplant with an LVAD [2]. Another recent report analyzed United Network of Organ Sharing (UNOS) data to assess the effect of LVAD bridging and found similar short-term survival but a 7% to 10% increase in late mortality with LVAD support [3].

In recent years, however, implantable LVADs have become smaller and more reliable, and have been approved by the United States Food and Drug Administration for destination therapy and bridge to transplantation. Given these advances, centers have become more experienced with implantable LVADs as a strategy to bridge patients to transplantation [4, 5].

Contrary to the ISHLT report, several reports from experienced LVAD centers have demonstrated equal or improved survival for patients bridged to transplant with an LVAD compared with inotropes [1, 4, 6, 7]. In this article, we report our retrospective review of transplant outcomes at our institution of UNOS status 1 patients bridged to heart transplantation with inotropes only or with an implantable LVAD. Preoperative characteristics are compared as well as outcomes, including survival and important complications such as rejection and infection episodes.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 References
 
This study was approved by the Duke University Institutional Review Board, and the requirement for individual patient consent was waived.

We retrospectively reviewed 259 consecutive patients who underwent orthotopic heart transplantation at Duke University Medical Center as UNOS status 1 recipients from 1994 to 2007 (Table 1). Of these, 173 were bridged with continuous intravenous inotropes and 86 with an implantable LVAD. Patients referred for orthotopic heart transplantation in whom oral medical therapy was not successful were initially treated with continuous inotropic infusions. Patients who were stabilized on intravenous inotropes, as defined by hemodynamics, end-organ function, and pulmonary vascular resistance, were maintained on inotropes until transplantation.


View this table:
[in this window]
[in a new window]

  		Table 1 Total Transplants by Year and Bridging Strategy
 
Worsening hemodynamics or end-organ function was an indication for bridging with an implantable LVAD. We excluded patients who decompensated acutely and required emergency mechanical circulatory support with an extracorporeal LVAD or extracorporeal membrane oxygenation. A first-generation pulsatile-flow device was used in 73 patients, and a second-generation continuous-flow device was used in 13. All patients bridged with an implantable LVAD received an initial period of support with intravenous inotropes. No LVADs were used in the inotrope group, but 21 patients were supported with an intraaortic balloon pump at the time of transplantation.

All patients in both groups received a maintenance immunosuppressive regimen consisting of corticosteroids, a calcineurin inhibitor (cyclosporine A or tacrolimus), and an antiproliferative agent (azathioprine or mycophenolate mofetil). The dosing adjustment of calcineurin inhibitors was determined by the number of rejection episodes and posttransplant renal function. Induction immunosuppressive therapy was used selectively according to an institutional protocol for both groups of patients.

Differences in biochemical and hemodynamic data between patient groups were evaluated with an independent-samples t test. Kaplan-Meier survival estimates were compared using the log-rank test. The primary end point was posttransplant survival. Additional end points were length of stay, postoperative hemorrhage requiring reoperation, cerebrovascular accidents, renal failure, number of rejection episodes exceeding ISHLT grade 3A, and hospitalizations for infectious complications. Antihuman leukocyte antigen (HLA) antibodies were measured with a cytotoxic assay from 1994 to 2001, and a flow-cytometric assay was used from 2001 to 2007.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 References
 
Pretransplant characteristics were similar between inotrope- and LVAD-bridged groups (Table 2); specifically, age, gender, diabetes mellitus, etiology of heart failure, serum creatinine, and international normalized ratio were similar. Of the patients bridged with inotropes, 27% had undergone a previous cardiac operation. By necessity, all of the LVAD patients were reoperations at the time of transplant; 31% were reoperations at the time of LVAD implantation. A small but statistically significant difference was found in the incidence of mechanical ventilation at the time of transplantation (6.7% LVAD vs 4.6% inotrope, p = 0.02). The two groups had similar median waitlist times of 153 days for the LVAD group and 184 days for the inotrope group.


View this table:
[in this window]
[in a new window]

  		Table 2 Pretransplant Characteristics
 
Hemodynamic measurements and laboratory assessment of end-organ function were obtained before LVAD implantation or initiation of intravenous inotropes (Table 3). Central venous pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance were significantly elevated and cardiac index was significantly decreased in the patients who were bridged with a LVAD vs those patients who were bridged with inotropes. These hemodynamic values illustrate the institutional practice of initially supporting patients with inotropes and offering LVAD bridging only when intravenous inotropes fail.


View this table:
[in this window]
[in a new window]

  		Table 3 Hemodynamics and Other Variables Before Left Ventricular Assist Device Support or Inotrope Initiation
 
At the time of transplantation, a significant improvement was measured in the hemodynamic status of the LVAD-bridged group (Table 4). Central venous pressure, cardiac index, and pulmonary vascular resistance were now similar to the inotrope- bridged group. Pulmonary capillary wedge pressure was significantly decreased relative to inotrope-bridged patients.


View this table:
[in this window]
[in a new window]

  		Table 4 Pretransplant Hemodynamics and Other Variables
 
The median ± SEM duration of LVAD support was 59 ± 32 days. During the study period, 11 additional patients underwent LVAD implantation but did not undergo heart transplantation. Eight patients died before transplant (4 within 30 days of the LVAD procedure). Three patients were deemed unsuitable for transplantation and were delisted. The 30-day mortality rate of LVAD implantation as a bridge to transplantation was 4.1%.

Short-term and long-term survival after transplantation was similar between the groups (Fig 1). The survival rate at 30 days was 98.3% for the inotrope group and 96.7% for the LVAD group. Survival rates were 88.1% inotrope vs 84.9% LVAD at 1 year, 77.1% inotrope vs 79.1% LVAD at 3 years, and 76.1% inotrope vs 72.7% LVAD at 5 years. The two groups had a similar intensive care unit and total length of stay (Table 5).


Figure 1
View larger version (7K):
[in this window]
[in a new window]

  		Fig 1. Kaplan-Meier curve shows survival of patients bridged to transplantation with an implantable left ventricular assist device (LVAD; dotted line) compared with intravenous inotropes (solid line).

 

View this table:
[in this window]
[in a new window]

  		Table 5 Length of Stay
 
The likelihood of reoperation for postoperative hemorrhage and cerebrovascular accidents was similar between patients bridged with intravenous inotropes or LVADs (Table 6). All radiographic evidence of cerebrovascular events was considered, including events that occurred during LVAD support before transplantation. A significantly greater proportion of patients bridged with inotropes had at least a 50% decrease in creatinine clearance, but the incidence of posttransplant hemodialysis was similar for the two groups. The two groups had a similar likelihood of a rejection episode greater than ISHLT grade 3A in the first year and a similar incidence of hospitalization for infectious causes. Posttransplant pneumonia was the most common infection in the LVAD group, and urinary tract infection was the most common in patients bridged with intravenous inotropes.


View this table:
[in this window]
[in a new window]

  		Table 6 Postoperative Complications
 
Allosensitization was assessed by measuring anti-HLA panel reactive antibodies (PRA) before LVAD implantation and before transplantation (Table 7). A significant number of inotrope- and LVAD-bridged patients had elevations in the PRA. Anti-HLA antibodies developed in 13% of LVAD patients during LVAD support; however, the pretransplant mean PRA was similar between the two groups.


View this table:
[in this window]
[in a new window]

  		Table 7 Panel Reactive Antibody
 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 References
 
The effect of LVAD bridging on posttransplant outcomes remains controversial. Experienced centers have shown outstanding posttransplant results with LVAD bridging [1, 4–9]. Conversely, large registries continue to identify LVAD bridging as a predictor of reduced survival after transplantation [2, 3, 10–12]. Other reports suggest LVAD bridging may lead to clinically important immunosensitization and greater rejection. Understanding the impact of LVAD bridging on transplant outcomes is important and influences the timing of patient referral for VAD support.

Our study found that LVAD support led to a significant improvement in hemodynamics and end-organ function. The study also demonstrates excellent posttransplant survival in patients who were bridged with an implantable LVAD. Both short-term and long-term survival was similar to those patients who were bridged with intravenous inotropes. These findings are remarkable given that the LVAD group had significantly worse presenting hemodynamics and represented a subset of patients in whom inotrope therapy failed.

Morbidity after transplantation was also similar between patients who underwent LVAD bridging and inotrope bridging. Although the two groups had a similar overall incidence of renal failure requiring dialysis, a larger proportion of patients sustained a 50% reduction in creatinine clearance in the inotrope-bridged group. VAD support may have better optimized pretransplant renal function, resulting in less postoperative renal insufficiency. This may ultimately affect survival by requiring fewer modifications in immunosuppressive intensity due to renal insufficiency.

Previous reports have suggested that LVAD implantation leads to allosensitization that could increase the likelihood of posttransplant rejection [13, 14]. Despite these reports, we did not observe an increased incidence of rejection episodes in the first year after transplantation. Furthermore, measured levels anti-HLA antibodies were similar in the LVAD group compared with the intravenous inotrope group. This may be due to the significant proportion of patients in the inotrope group who had previously undergone heart operations or required transfusions during admissions for heart failure, or both. Large increases in the PRA did develop in a small number of patients supported with a LVAD, but the group as a whole was not significantly different from the inotrope group.

A limitation of this report is that only posttransplant outcomes are reported. The current analysis did not include patients who died, who presented with complications on the waitlist, or who were delisted. An additional 11 patients underwent LVAD implantation as a bridge to transplantation during the study period but never received an allograft. Eight of these patients died during VAD support, before transplantation. Given our treatment algorithm of performing LVAD implantation when a patient's clinical condition worsens on intravenous inotropic support, these 8 deaths represent failures of both inotropic support and LVAD treatment. Earlier referral of such patients for LVAD implantation might have reduced their procedural risk.

Similarly, patients who died while receiving intravenous inotrope therapy without attempted LVAD implantation were also not included in the current study. Further retrospective review indicates that 20 patients were supported on intravenous inotropes, but ultimately did not receive an allograft. These patients either died or were delisted. In general, these patients experienced rapid decompensation, including cardiac arrest, and 9 sustained neurologic injury with cardiac arrest and therefore were deemed ineligible for transplantation or LVAD bridging to transplantation. Eleven patients succumbed to infection, again, making them ineligible for cardiac transplantation and inappropriate for LVAD bridging as well. It has been difficult to fully characterize this failure group because in some instances patients were delisted but then ultimately stabilized. The focus of this report, however, is to examine the outcomes of patients who received cardiac transplantation rather than those in whom the inotrope support or the LVAD bridging strategy failed.

In conclusion, bridging to heart transplantation with an implantable LVAD is a beneficial strategy for patients who are not stabilized with conservative measures. LVAD bridging is not a predictor of negative outcomes after heart transplantation. Short-term and long-term survival and morbidity after transplantation is similar with LVAD bridging compared with inotrope bridging.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
References
 
DR JOSEPH C. CLEVELAND JR (Denver, CO): This is really a very timely paper. There is still a lot of controversy that remains about device implantation and its long-term effects. A couple of questions for the authors. You decided to compare status 1A patients who received a VAD [ventricular assist device] vs those that did not. Did you go back and look at your whole cohort of transplant patients or was it just that so few status 2s received VADs that you didn't include them? So how does this compare if you just looked at your overall survival as a group of VAD versus no VAD? And then secondarily, for the posttransplant renal—at least better renal function seen by the VAD patients—did you at least examine that the two groups received the same induction strategy? Did one group receive more cyclosporine or things that might have been more difficult on kidneys and cause renal problems or not?

DR PAL: Going back to the first question, there were very few status 2 VAD patients who received a transplant, so we chose not to include that patient group. As far as the renal function, the patients' immunosuppression was managed according to an established institutional protocol. The amount of calcineurin inhibitors used was comparable between the two groups.

DR PETER McKEOWN (Pikeville, KY): I want to particularly thank the Duke group for these excellent results, and I want to ask you a little bit about what seems to be a change in the trend for bridge to transplant. It does seem to be that the results are actually improving. So some of those older results might not reflect current outcomes. Particularly, I wanted to ask you about the subgroup that has pulmonary hypertension. It seems to be that from now on, some of these patients that would not normally be suitable candidates may become so if you bridge them long enough. In fact, the pulmonary hypertension seems to have a reversible component, and they become acceptable candidates. I wondered if you would comment on that, please. Thanks again for a great paper.

DR PAL: Pulmonary hypertension poses a unique challenge for heart transplantation, and there is a definable benefit when patients are treated with an LVAD for some period time. We included many patients who initially demonstrated elevated pulmonary vasculature resistance [PVR] and would have been excluded from transplantation. However, we found significant reductions in PVR during the period of LVAD support and these patients ultimately received transplants and did well. Unloading of the left ventricle during the period of mechanical support has allowed significant reversal of pulmonary hypertension.

Your question about the older results I think is an important one. Some of the improvement we have reported is undoubtedly due to the newer generation of LVADs which is easier to implant, more durable, and associated with fewer complications. The ISHLT [International Society of Heart and Lung Transplantation] data identify an implantable LVAD as a negative predictor at 1-year and at 10-year follow-up and not at 5 years. That is, an LVAD is not a negative predictor at 5 years. No clear reason is given, but if you look at the devices that are available, at 10 years they are all the earlier generation pusher-plate design, and we know that those have higher complication rates and poorer outcomes. At 1 year, the effect of a second cardiac procedure has an important impact on total risk. At 5 years, there is increasing use of the newer generation devices that we believe to be safer, and I think that is why we don't see a detriment to bridging with an LVAD.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 

  1. Aaronson K, Eppinger M, Wright S, Pagani FD. LVAD therapy improves utilization of donor hearts: implications for prolonged inotropic therapy J Heart Lung Transplant 2001;20:241.[Medline]
  2. Taylor DO, Edwards LB, Aurora P, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-fifth official adult heart transplant report—2008 J Heart Lung Transplant 2008;27:943-956.[Medline]
  3. 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.[Abstract/Free Full Text]
  4. Frazier OH, Rose EA, McCarthy P, et al. Improved mortality and rehabilitation of transplant candidates treated with a long-term implantable left ventricular assist system Ann Surg 1995;222:327-336discussion 336–8.[Medline]
  5. Miller LW, Pagani FD, Russell SD, et al. Use of a continuous-flow device in patients awaiting heart transplantation N Engl J Med 2007;357:885-896.[Medline]
  6. Drakos SG, Kfoury AG, Long JW, et al. Effect of mechanical circulatory support on outcomes after heart transplantation J Heart Lung Transplant 2006;25:22-28.[Medline]
  7. Cleveland Jr JC, Grover FL, Fullerton DA, et al. Left ventricular assist device as bridge to transplantation does not adversely affect one-year heart transplantation survival J Thorac Cardiovasc Surg 2008;136:774-777.[Abstract/Free Full Text]
  8. Aaronson KD, Eppinger MJ, Dyke DB, Wright S, Pagani FD. Left ventricular assist device therapy improves utilization of donor hearts J Am Coll Cardiol 2002;39:1247-1254.[Abstract/Free Full Text]
  9. Morgan JA, John R, Rao V, et al. Bridging to transplant with the HeartMate left ventricular assist device: The Columbia Presbyterian 12-year experience J Thorac Cardiovasc Surg 2004;127:1309-1316.[Abstract/Free Full Text]
  10. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report—2006 J Heart Lung Transplant 2006;25:869-879.[Medline]
  11. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report—2005 J Heart Lung Transplant 2005;24:945-955.[Medline]
  12. 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.[Medline]
  13. Pagani FD, Dyke DB, Wright S, Cody R, Aaronson KD. Development of anti-major histocompatibility complex class I or II antibodies following left ventricular assist device implantation: effects on subsequent allograft rejection and survival J Heart Lung Transplant 2001;20:646-653.[Medline]
  14. Drakos SG, Stringham JC, Long JW, et al. Prevalence and risks of allosensitization in HeartMate left ventricular assist device recipients: the impact of leukofiltered cellular blood product transfusions J Thorac Cardiovasc Surg 2007;133:1612-1619.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Circ Heart FailHome page
J. Suarez, C. B. Patel, G. M. Felker, R. Becker, A. F. Hernandez, and J. G. Rogers
Mechanisms of Bleeding and Approach to Patients With Axial-Flow Left Ventricular Assist Devices
Circ Heart Fail, November 1, 2011; 4(6): 779 - 784.
[Full Text] [PDF]

Home page
 Interact CardioVasc Thorac SurgHome page
M. Urban, J. Pirk, Z. Dorazilova, and I. Netuka
How does successful bridging with ventricular assist device affect cardiac transplantation outcome?
Interact CardioVasc Thorac Surg, October 1, 2011; 13(4): 405 - 409.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
A. C. Alba, M. McDonald, V. Rao, H. J. Ross, and D. H. Delgado
The effect of ventricular assist devices on long-term post-transplant outcomes: a systematic review of observational studies
Eur J Heart Fail, July 1, 2011; 13(7): 785 - 795.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
N. Uriel, S.-W. Pak, U. P. Jorde, B. Jude, S. Susen, A. Vincentelli, P.-V. Ennezat, S. Cappleman, Y. Naka, and D. Mancini
Acquired von Willebrand Syndrome After Continuous-Flow Mechanical Device Support Contributes to a High Prevalence of Bleeding During Long-Term Support and at the Time of Transplantation
J. Am. Coll. Cardiol., October 5, 2010; 56(15): 1207 - 1213.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to Personal Folders
Right arrow Download to citation manager
Right arrow Author home page(s):
Jay D. Pal
Mani A. Daneshmand
Andrew J. Lodge
Carmelo A. Milano
Right arrow Permission Requests
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pal, J. D.
Right arrow Articles by Milano, C. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pal, J. D.
Right arrow Articles by Milano, C. A.
Related Collections
Right arrow Valve disease

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
ANN THORAC SURG ASIAN CARDIOVASC THORAC ANN EUR J CARDIOTHORAC SURG
J THORAC CARDIOVASC SURG ICVTS ALL CTSNet JOURNALS