EDITORIAL COMMENT
The Impact of Mechanical Circulatory Support on Post-Transplant SurvivalA Different View*
Leslie Miller, MD, FACC*
Department of Medicine, Division of Cardiology, Washington Hospital Center/Georgetown University, Washington, DC
* Reprint requests and correspondence: Dr. Leslie Miller, Department of Medicine, Division of Cardiology, Washington Hospital Center/Georgetown University, 110 Irving Street NW, 1E-7, Washington, DC 20010 (Email: Leslie.W.Miller{at}medstar.net).
Key Words: heart-assist devices • ventricular assist device • mortality • outcome • heart transplantation
An increasing percentage of patients who are listed for a heart transplant either present initially with such advanced heart failure or deteriorate after listing that they are essentially refractory to even intravenous inotrope and/or vasodilator therapy. These patients have been increasingly managed with mechanically circulatory support in the form of ventricular assist devices (VAD) until a donor heart is identified, also known as a "bridge to transplant." The Cardiac Transplant Research Database has shown that currently more than one-third of all patients undergoing heart transplantation are being supported with a VAD at the time of transplantation. The first-generation devices were effective in supporting the circulation, but were associated with significant complications such as infection, bleeding, and organ failure caused by the severity of the patient's condition (renal and hepatic dysfunction, malnutrition, and coagulation abnormalities) at the time of implant. That led physicians to keep the patients listed at the highest priority status for transplant and to use the first donor identified early after device implantation in hopes of minimizing complications of the devices. However, that strategy was found to be associated with significant morbidity and mortality after transplantation because patients often developed nosocomial infections caused by indwelling catheters, malnutrition, and muscle weakness, with up to one-third of patients not surviving to transplantation. Over time, improvements in the durability and design of the VADs, coupled with improved management of these patients, led to an extensive experience with successful hospital discharge and outpatient management for periods of months to years, and significant recovery of functional status. This experience has led to the current approach in most centers of delaying relisting the patient for transplantation until they have recovered physical condition and are stable, usually a period of 1 to 3 months. Mechanical support of the circulation allowed such progressive exercise and rehabilitation that VAD patients now are often the very best candidates for heart transplantation because they are the best conditioned.
The paper by Patlolla et al. (1) in this issue of the Journal is the largest review of the long-term impact on mortality associated with the use of VADs in patients awaiting heart transplantation, or "bridge to transplant." The investigators used the United Network for Organ Sharing (UNOS) database and included all patients who underwent transplantation over a 9-year period from 1995 to 2004. A total of 11,336 patients were included, with 1,887 of those, or 16.5%, having had pre-transplantation VAD support. The study wisely divided the patients with VAD support into those with the more recent intracorporeal design versus the older extracorporeal types of devices. Hazard ratios (HRs) for mortality were then calculated over a 5-year period post-transplantation for the 2 types of VADs, with outcomes compared with the 9,455 patients who were listed as status 1, but did not have mechanical circulatory support.
The investigators found a small but significant increase in risk (HR: 1.2) at 6 months post-transplantation for those receiving intracorporeal VADs, but this risk was reduced to only 1.1 (10%) over the next 4 years until the final period of observation at 5 years, when it again increased to an HR of 1.2. There was a significantly greater risk for those supported with the uncommonly used earlier generation of extracorporeal VADs at 6 months (HR: 1.9). It is of note that this increase in risk was also lost for the time between 6 months and 5 years, when the risk was shown to again be even higher (HR: 2.93).
The questions raised by these data include whether there is a direct cause-and-effect relationship between VAD use and the increased mortality seen 5 years after transplantation, and if there is such an association, what is the cause. It could be argued that the only direct correlation between pre-transplantation VAD use and mortality would be expected to be in the immediate perioperative period, and perhaps the first 6 months if the VAD patients were in fact sicker pre-transplantation and at higher risk for the transplantation procedure. This is in fact what the investigators found in their analysis. An alternative hypothesis to explain the increased risk is that VAD use, because of either required blood transfusion or the blood–device interface, leads to immune activation and allosensitization, which could be associated with an increased risk of rejection and the need for increased immunosuppression post-transplantation and mortality risk. However, the International Society for Heart and Lung Transplantation Registry report has shown that there is no correlation between VAD use and an increase in rejection episodes post-transplantation (2). The leading causes of death long-term in heart transplant recipients are primarily cardiac allograft vasculopathy and malignancy. To date, there has been no reported association between the use of VADs and either of these complications, and the most recent International Society for Heart and Lung Transplantation Registry has shown that VAD use pre-transplantation is not associated with a secondary increase in mortality at 5 years (2). The failure to show any significant difference in survival between 6 months and 4 years after transplant raises doubt about the basis and importance of the 2% difference noted at year 5. It seems that the difference is not clinically significant, as the difference was 0% and 1% in the 2 preceding years (3 and 4) and only 2% at 5 years.
The investigators interpret these data to suggest that the use of VADs in stable UNOS status 1 patients is not warranted because of the small (questionably clinically relevant) increased mortality risk at the 2 time points noted. Given the evolution in the management of the VAD patients over time, it may be of value to see the data broken out by era, rather than by duration of follow-up. The outcomes with medical therapy of status 1 patients with and without VAD support have improved over the past 5 years (2), and a more recent examination of the data would be helpful in determining whether the observations made are accurate in the current era.
The investigators acknowledge that the findings may not apply to the newest generation of continuous-flow devices, which have been shown to have significantly better survival and quality of life and significantly lower adverse events than the previous generation of pulsatile devices (3). The survival with the latest generation of continuous-flow devices may be as high as 75% at 1 year, with little decrease by year 2. These improved outcomes may lead to loss of the increased risk of VAD-supported patients compared with status 1 patients supported medically at 6 months and much later post-transplant by Patlolla et al. (1) The only way to objectively test this question is with a randomized trial, but many patients initially assigned to medical therapy may deteriorate and require cross-over to receive a VAD, and the time on the waiting list may vary considerably for patients in either assigned therapy, making direct comparison of outcomes and complications difficult. A large cohort would be required to adequately power the study.
The question of whether the data presented suggest that the risk for stable status 1 patients to undergo semielective VAD implant is too high is also open to debate. Some patients can be well supported with intravenous inotropes for a period of time, but there is an inherent risk of infection, proarrhythmia, and other complications, and there are several reports of increased mortality in patients supported with inotropes compared with VADs pre-transplantation (4,5). The UNOS database showed that 516 patients, or 20% of the 2,258 de novo patients listed as status 1A for a heart transplant between 1999 and 2006, died or were removed from the list for worsening condition in the absence of mechanical circulatory support (6,7). One interpretation of these data is that use of VADs in a good percentage of these patients may have prevented a number of those deaths or removals. There is also difficulty is assuming that the mortality risk of semistable status 1 patients would be the same as for those who have undergone typically urgent if not emergent VAD implantation as a bridge to transplant to date. Recently, a risk stratification system has been reported that identified patients at highest risk for in-hospital death with VAD implant when used as an alternative to transplantation or destination therapy (8). This risk score has not been validated for bridge to transplant patients, but the complications associated with VAD use are exactly the same for bridge to transplant and destination therapy, suggesting that the risk score would likely be valid for either indication. The score was based on pre-operative laboratory values and suggests that despite similar low ejection fraction and blood pressure, and other demographics, those with the lowest risk had a 90% survival to hospital discharge and 84% survival at 1 year. Equally important is that it was able to identify patients with a prohibitive risk at the time of planned implantation.
The study by Patlolla et al. (1) has raised some important questions about the impact of VAD use in patients awaiting transplantation. In this era of expanding health care costs, it is important to look closely at the therapies now being applied to patients with advanced heart failure and to ask critical questions about their impact on survival, adverse events, and quality of life, as well as the cost-effectiveness of a therapy. The new generation of continuous-flow devices has now been shown to provide much better outcomes than previous pulsatile design devices, and it will be important in the future to compare the outcomes with these devices to the current cost and mortality of those managed without mechanical circulatory support (9). These trials will likely be forthcoming in the near future.
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Footnotes
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Dr. Miller has received honoraria and research support from Thoratec Corp., and is on the advisory boards of Thoratec and Heartware.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. 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]2. Taylor DO, Hertz MA, Keck B. Twenty-first annual report of the Registry of the International Society of Heart and Lung Transplantation J Heart Lung Transplant 2007;26:769-781.[CrossRef][Web of Science][Medline] 3. 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.[CrossRef][Web of Science][Medline] 4. Jaski BE, Kim JC, Naftel DC, et al. Cardiac Transplant Research Database Research Group Cardiac transplant outcome of patients supported on left ventricular assist device vs. intravenous inotropic therapy J Heart Lung Transplant 2001;20:449-456.[CrossRef][Web of Science][Medline] 5. Aaronson KD, Eppinger MJ, Dyke DB, Wright S, Pagani FD. Left ventricular assist device therapy improves utilization of donor hearts. Evaluation studies. J Am Coll Cardiol 2002;39:1247-1254.[Abstract/Free Full Text] 6. Lietz K, Miller LW. Improved survival of patients with end-stage heart failure listed for heart transplantation: analysis of organ procurement and transplantation network/U.S. United Network of Organ Sharing data, 1990 to 2005 J Am Coll Cardiol 2007;50:1282-1290.[Abstract/Free Full Text] 7. Lietz K, Deng M, Morgan J, Naka Y, Mancini D. Selection of UNOS status 1A candidates for mechanical circulatory support as bridge-to-transplantation (BTT)?. Analysis of UNOS/OPTN 2000–2005. J Heart Lung Transplant 2008;27:S244. 8. 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.[Abstract/Free Full Text] 9. Russo M, Gelijns A, Stevenson LW, et al. The cost of medical management in advanced heart failure during the final two years of life J Card Fail 2008;14:651-658.[CrossRef][Web of Science][Medline]
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