Eur J Cardiothorac Surg 2008;34:301-306. doi:10.1016/j.ejcts.2008.03.007
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Destiny of candidates for heart transplantation in the Eurotransplant heart allocation system
Takeshi Komoda*,
Roland Hetzer,
Hans B. Lehmkuhl
Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Received 24 August 2007;
received in revised form 29 February 2008;
accepted 6 March 2008.
* Corresponding author. Tel.: +49 30 4593 2031; fax: +49 30 4593 2047. (Email: komoda{at}dhzb.de).
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Abstract
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Objective: We analyzed the prognosis of candidates for heart transplantation (HTx) after being listed with ‘urgent status’ for donor heart allocation or after ventricular assist device (VAD) implantation without application for urgent status. Methods: Urgent status as used in this study refers to both the high urgency (HU) status awarded by Eurotransplant until August 31, 2005 and the urgent (U) status that replaced it from then on. Patients who underwent primary VAD implantation between January 2001 and December 2006 and who were listed as transplantable (T) (group VAD-prim, n
= 159), and patients listed primarily in urgent status before VAD implantation and/or HTx during the same period (group U-prim, n
= 168) were enrolled in the study. Group U-prim consists of subgroups: group U-HTx (n
= 123), who underwent primarily HTx in urgent status; group U-VAD (n
= 25), who underwent primarily VAD implantation in urgent status; patients who died in urgent status before HTx or VAD implantation (n
= 6); and patients in urgent status without HTx or VAD implantation (n
= 14). The survival rate in each group was studied. Results: Survival rates after VAD implantation in group VAD-prim were comparable to those after urgent status listing in group U-prim (67.0% vs 68.5% for 1-year survival, 56.6% vs 65.8% for 2-year survival, respectively). Actuarial survival after listing for urgent status in group U-HTx was significantly better than that in group U-VAD (73.7% vs 46.0% for 1-year survival, p
< 0.05, log-rank test). Actuarial survival during mechanical circulatory support after the VAD implantation (censored at HTx or weaning from the device) in group VAD-prim was significantly better than that in group U-VAD (80.7% vs 56.2% for 3-month survival, p
< 0.001, log-rank test). Conclusions: In order to receive urgent HTx, HTx candidates may choose urgency listing without primary VAD implantation at the risk of failed donor heart allocation in urgent status. However, the prognosis of the patients in the latter situation is poor.
Key Words: Heart failure • Heart failure operations • Heart transplantation • Circulatory assist devices • Left ventricular assist device
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1. Introduction
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Prioritization of the allocation of donor hearts to heart transplant (HTx) candidates with medical urgency was applied over the past 10 years in the USA and in Germany [1–3]. It is known that HTx candidates with longer waiting time, i.e., over 6 months on the waiting list [4,5], or who are not critically ill such as those listed in the United Network for Organ Sharing (UNOS) status 2 [6,7] have little or no survival benefit from HTx. However, there have been enough donor hearts in the USA to allocate some even to the patients listed in UNOS status 2 [8]. In Germany, the German Physicians’ Association introduced guidelines for the allocation of organs [9] following the enactment of the German Transplantation Law in 1997 [10], and finally Eurotransplant changed the allocation system in accordance with these German guidelines in 2000 [11]. The purpose of the new heart allocation system was to give the highest priority to all patients with the highest risk of dying from heart failure [12]. This allocation policy was based on the results obtained from the COCPIT study performed in German cohort in 1997 [12]. As a consequence, HTx in patients with urgent status accounts for an increasingly large proportion of the total number of HTx patients [13], and now almost all patients undergo HTx in urgent status. The circumstances of HTx candidates have changed since 1997, and a new problem has emerged, that of failed donor heart allocation in urgent status. In this paper we discuss the prognosis of patients with urgent status for HTx by studying patient cohort at our institution between 2001 and 2006.
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2. Patients and methods
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In 2000, Eurotransplant implemented a new allocation algorithm. A donor heart is allocated with the highest priority to the critically ill patients who are listed with high urgency (HU) status. Following a further modification of the algorithm, the new urgent (U) status has been equivalent to the previous HU status since September 1, 2005. Both of these are grouped as urgent status in this study. The study cohort consisted of candidates for HTx at our center and was divided into two groups: group VAD-prim (n
= 159), patients who underwent VAD implantation primarily between January 1, 2001 and December 31, 2006 and who were listed as transplantable (T); group U-prim (n
= 168), patients who were listed primarily in urgent status before VAD implantation and/or HTx during the same period. Group U-prim consisted of four subgroups: group U-HTx (n
= 123) patients, who underwent primarily HTx in urgent status; group U-VAD (n
= 25) patients, who underwent primarily VAD implantation in urgent status; patients (n
= 6) who died in urgent status before HTx or VAD implantation; and patients (n
= 14) who were in urgent status without HTx or VAD implantation on December 31, 2006. From the clinical records of these patients, data were obtained. The follow-up study was performed in March 2007 and the survival rate in each group was studied.
2.1 Indications for Eurotransplant urgency listing (Version September 1, 2005)
In order to obtain U status for Eurotransplant listing, the patient must fulfill one of the following criteria: (1) continuous intravenous inotropic therapy; (2) assist device complications; (3) documented intractable recurrent ventricular rhythm disorders; (4) end-stage transplant vasculopathy; and (5) persisting angina pectoris.
Patients with end-stage cardiac allograft vasculopathy (CAV) following HTx and heart failure qualify for evaluation for repeat HTx. When patients with end-stage CAV present to the transplant center, left ventricular ejection fraction (LVEF) is usually depressed and some may need inotropic support. End-stage CAV with heart failure and significantly reduced LVEF with inotropic support qualifies the patient to be listed for repeat HTx in urgent status according to Eurotransplant regulations. If the patient is on inotropic support with >7.5 µg/kg/min dobutamine and/or 0.5 µg/kg/min milrinone and/or levosimendan and has mean pulmonary capillary wedge pressure (PCWP) >10 mmHg, cardiac index (CI) <2.0 and mixed venous oxygen saturation (SvO2) <55%, he or she qualifies for high urgency listing according to Eurotransplant regulations.
2.2 Indications for VAD implantation
The indications for VAD implantation in elective HTx listed patients, who are listed as ‘transplantable’, are as follows:
- (1) Clinical deterioration despite intensification of heart failure medication.
- (2) Increase of pulmonary vascular resistance (PVR) > 250 dyne s cm–5 or transpulmonary gradient >15 (because of increased risk of right heart failure after HTx).
- (3) Intractable ventricular tachycardias.
- (4) Cardiac deterioration with threatening or beginning secondary organ failure (pulmonary/hepatic/kidney).
- (5) Cardiac deterioration with controllable infection, which is contraindication to current HTx.
- (6) Any serious clinical condition with vital threat due to cardiac deterioration and where it can be foreseen that waiting time for HTx cannot be managed other than with an assist device (best example: for pediatric dilated cardiomyopathy with cardiac deterioration waiting list, mortality is >50% without assist device options; extra-corporeal membrane oxygenation (ECMO) is only a short-term device and an assist device may be used for long-term bridging to HTx, lowering waiting list mortality to <10%).
2.3 Statistical analysis
Data are given as mean ± standard deviation unless otherwise stated. Comparisons of patient characteristics among the groups were made using the Mann–Whitney U-test or Fisher's exact test. Survival analysis was performed with the Kaplan–Meier method and survival curves were compared by the log-rank test or Gehan test [14]. All comparisons were considered statistically significant when p-value was less than 0.05.
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3. Results
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The characteristics of patients in each group are listed in Tables 1 and 2
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The outcome of the patients in group VAD-prim and group U-prim is shown in Figs. 1–3
. Survival rates after VAD implantation in group VAD-prim were comparable to those of patients after the listing for urgent status in group U-prim (67.0% vs 68.5% for 1-year survival, 56.6% vs 65.8% for 2-year survival, respectively, p
= 0.19, Gehan test) (Fig. 4a). Survival rates after HTx for patients who underwent HTx in group U-prim were comparable to those in group VAD-prim (75.2% vs 79.4% for 1-year survival, 73.0% vs 76.1% for 2-year survival, respectively, p
= 0.54, Gehan test) (Fig. 4b). Actuarial survival after listing for urgent status in group U-HTx was significantly better than in group U-VAD (73.7% vs 46.0% for 1-year survival, p
< 0.05, log-rank test) (Fig. 5
). Actuarial survival during mechanical circulatory support after VAD implantation (censored at HTx or weaning from the device) in group VAD-prim was significantly better than that in group U-VAD (80.7% vs 56.2% for 3-month survival, p
< 0.001, log-rank test) (Fig. 6
).
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Fig. 1. Summary of the patient cohort, showing the flow of patients to heart transplantation in group VAD-prim and group U-prim. VAD: ventricular assist device, U: urgent status, HTx: heart transplantation.
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Fig. 2. Flow of patients in group VAD-prim after ventricular assist device implantation between January 1, 2001 and December 31, 2006.
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Fig. 3. Flow of patients in group U-prim after listing in urgent status between January 1, 2001 and December 31, 2006.
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Fig. 4. (a) Actuarial survival after listing in urgent status in group U-prim and that after ventricular assist device implantation in group VAD-prim. (b) Actuarial survival after heart transplantation for patients who underwent heart transplantation in group U-prim and for group VAD-prim.
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Fig. 6. Actuarial survival during mechanical circulatory support after ventricular assist device implantation (censored at heart transplantation or weaning from the device) in group VAD-prim and group U-VAD.
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4. Discussion
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The essence of the change in Eurotransplant heart allocation policy in 2000 is that the ceiling for the number of donor heart allocations with highest priority in each heart transplant center was abolished. Until then very sick patients were awarded ‘special urgency’ (SU) status, which was permitted in a certain number (up to 15% of HTx) per transplant center [12]. Others were electively transplanted in whom the waiting time was strongly weighted (80%) as an allocation factor [3]. After the renewal of the allocation algorithm, the donor heart is allocated with priority to the patient with medical urgency, as long as the patient meets the ‘high urgency (HU)’ criteria as decided by the Eurotransplant audit group. As a result, HTx in patients with HU status represents an increasingly large proportion of the total number of HTx [13].
Another feature of the change in heart allocation policy made in 2000 is that the patient loses HU status when he or she receives a VAD, and will not regain HU status unless and until serious complications on the VAD occur. Therefore, a patient suffering from end-stage heart failure with acute hemodynamic decompensation, is forced to choose between two options: VAD implantation without applying for urgency listing, or continuation of further intensive medical therapy without VAD implantation accompanied by application for urgency listing. So far it has not been extensively discussed which option is better for the patient. Concerning overall survival rate and survival after HTx, both paths seem to be similar (Fig. 4a and b). However, patients with primary VAD implantation may have disadvantages in long-term survival rates, because the initial drop in survival rate arising from HTx is postponed during mechanical circulatory support (Fig. 4a).
As the final goal for the HTx candidates is, of course, HTx itself, the patients receiving primary VAD seem to make a long detour to HTx, shown by the time to HTx and the ratio of HTx patients (Table 1). However, if patients choose primary urgency listing without VAD implantation, the problem of failed donor heart allocation after urgency listing may be in store. The survival rate in the group who received the VAD after urgency listing is decreased (Fig. 5). This is due to the high mortality rate during mechanical circulatory support in this group (Fig. 6), because no patients in this group died after HTx (Fig. 3).
As the donor organ shortage in Germany is significant according to the Deutsche Stiftung Organ transplantation, the number of patients who undergo VAD implantation after failed urgent heart allocation will increase in the future. Currently, almost all HTx are performed in patients listed in urgent status. In order to prioritize the sickest patients among the increasing number of patients with urgency listing, Eurotransplant configured a higher class of urgency above the conventional HU on September 1, 2005 with the new ‘U’ status being equivalent to the previous HU status and the new HU status representing the new class of urgency. This change met the principle that heart transplantation listing in Germany should be limited to the sickest patients [12], which was drawn from the results of the COCKPIT study of a German cohort performed in 1997. However, in this study, the 3-month mortality rate was 23% on the waiting list in the high-risk group, for which a survival benefit with HTx was found, and much lower than in our patients who underwent VAD implantation after failed urgent heart allocation (43.8%). How to rescue these patients or prevent this situation arising is a pressing issue.
4.1 Limitation of the study
This is a retrospective, observational study and therefore has the inherent bias of a retrospective study.
In conclusion, in order to receive urgent HTx, HTx candidates may choose urgency listing without primary VAD implantation. However, they risk failed donor heart allocation in urgent status and the prognosis of patients in the latter situation is poor.
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Appendix A
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Conference discussion
Dr D. Tixier (Paris, France): I’m actually responsible for the national thoracic transplant coordination in France and the national program. We have used the high urgency status that was started in July 2004, and we are going in the same direction as you are. If I understood well your presentation, you have a better survival when you go directly to urgent transplantation compared to VAD implantation then transplantation; is that right?
Are your results better with urgent transplant compared to VAD transplant, is that right, in the U-prim group?
Dr Komoda: After heart transplantation or overall survival, you’re asking?
Dr Tixier: So what I understood is that it's better to go directly to a transplant even in an emergent situation compared to a VAD then transplant, if I understood well. And this is what we are getting, the impressions we are having now with our experience in France for the national database.
Dr Komoda: Our data shows that there is no difference between the VAD group and the urgency group.
Dr G. Laufer (Innsbruck, Austria): As far as I understood your presentation, the survival rate was better if an urgent patient went directly to heart transplantation instead of having a VAD implanted before. I think that was the essence of the question.
Dr Tixier: Yes, it is.
Dr Laufer: I think that your data showed this message. It demonstrated that U-prim is a better survival than the VAD-prim.
Dr Laufer: Yes.
Dr Komoda: This is after urgent listing, U-prim and VAD implantation, VAD-prim survival rate. But we cannot find statistical difference in the two groups.
Dr Laufer: Was this your question?
Dr Tixier: Yes. I’m disappointed.
Dr Laufer: I think there are a lot of other things to be concerned about. I mean, you showed that the patients who underwent urgency primary transplantation, which is actually, at the moment, the status high urgency in your transplants.
Dr Komoda: But this group included transplant patients and not transplanted, died before heart transplantation.
Dr Laufer: I understand. This is the curve after listing in the urgent status.
Dr Komoda: Yes, after urgent status.
Dr Laufer: After listing after transplantation, you’re right. But my question is you showed that the median waiting time for a heart on high urgency status was about 27 days.
Dr Komoda: Median.
Dr Laufer: The median waiting time, median or mean, I don’t remember correctly, was 27 days from the listing to the transplantation, in case the patient was transplanted, it was 27 days. So my question is, if a lot of these patients survived 20 days, 27 days, which is nearly a month to heart transplantation, their condition could not be as severe as maybe the patients who received the VAD.
Dr Komoda: You’re asking this ...
Dr Laufer: I think we should go on with this discussion in the intermission or thereafter.
Dr Komoda: Of the patients that are studied, the median waiting time is 27 days. But when the patient rapidly, progressively heart function was deteriorated, then VAD implanted. This is only median value waiting time in urgent status.
Dr Laufer: Okay. I think maybe we can continue with the discussion later on. Because then I can explain to you my question a little bit better. It's a very complex matter nevertheless.
Maybe I have a final question to you. Are you in your institution at the moment satisfied with the allocation algorithm in heart transplantation you have in Germany? Are you satisfied, yes or no?
Dr Komoda: Yes, we are satisfied, but we can change. We can change better way.
Dr Laufer: Maybe I have to explain. Those of you who are not from the Eurotransplant. The Eurotransplant comprises of seven different countries and the organ allocation in heart as well as in lung is very contraspecific. So the characteristics that you see here are a not a Eurotransplant allocation system, but it's more a German-tailored allocation system. So as opposed to liver transplantation and kidney transplantation, the thoracic organs are highly individualized in the separate countries. So it's completely different in Austria and in Germany. Nevertheless there is a common umbrella under which there is some exchange of superfluous organs, or organs that cannot be used in one or the other country, so this has to be considered. So it's actually not a Eurotransplant as it states or suggests in the title, it's basically a German allocation algorithm, because the German law demands something separately from the Eurotransplant community.
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Acknowledgments
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We are indebted to Mrs Julia Stein, M.S., of the Deutsches Herzzentrum Berlin for her valuable advice in the statistical analysis of this study. We also thank Mrs. Anne M. Gale, Editor in the Life Sciences, of the Deutsches Herzzentrum Berlin for her editorial assistance, and Mr Detlef Goesmann and Mrs. Tanja Nienkarken for support with data acquisition.
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Footnotes
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Presented at the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16–19, 2007.
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Abstract
1. Introduction
