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Eur J Cardiothorac Surg 2008;34:1129-1133. doi:10.1016/j.ejcts.2008.05.059
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Right arrow Transplantation - heart

Who needs ‘bridge’ to transplantation in the presence of the Eurotransplant high-urgency heart transplantation program?

Hiroyuki Kamiyaa,*, Achim Kocha, Falk-Udo Sacka, Payam Akhyaria, Andrew Remppisb, Thomas J. Denglerb, Matthias Karcka, Artur Lichtenberga

a Department of Cardiac Surgery, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg 69120, Germany
b Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 110, Heidelberg 69120, Germany

Received 18 February 2008; received in revised form 25 May 2008; accepted 27 May 2008.

* Corresponding author. Tel.: +49 6211 56 6278; fax: +49 6221 56 5585. (Email: hiroyuki.kamiya{at}med.uni-heidelberg.de).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 
Introduction: The purposes of this study are to identify a patient cohort that would benefit from the use of mechanical circulatory support (MCS) in the presence of the Eurotransplant high-urgency (HU) program. Methods: Sixty-five patients (heart transplantation (HTx) group, 77%) underwent heart transplantation and 17 patients (D group, 20%) died while on the HU waiting list. These 82 patients were included in this retrospective study. Results: The mean waiting time on HU list was 18.3 ± 17.7 days in HTx group and 12.5 ± 9.4 days in D group (p = 0.075). The average weekly allocation rate from the active HU list was 27.7%, and the mean weekly waiting-list mortality was 12.1%. The use of intra-aortic balloon pumping (p = 0.005), mechanical ventilation (p = 0.007), higher dose of dobutamine (0.005), lower serum level of sodium (p = 0.046), and higher serum level of C reactive protein (CRP) (0.040) at the registration of HU listing were associated with waiting-time mortality, and the serum creatinine level more than 1.5 mg/dl (p = 0.007, odds ratio; 14.5, 95% CI; 2.1–102.0) and the serum CRP level more than 10 mg/l (p = 0.026, odds ratio; 6.3, 95%CI; 1.2–31.4) were identified as significant predictors. Conclusion: It would be appropriate that a patient who would not be able to tolerate one or two weeks waiting time to be considered as a candidate for MCS implantation in the presence of the HU program. The patient selection criteria for MCS implantation should include not only hemodynamic parameters, but also the aspect of a beginning multi-organ failure.

Key Words: Heart transplantation • Eurotransplant • Mechanical circulatory support


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 References
 
Mechanical circulatory support (MCS) has been widely used as a bridge to transplantation by keeping candidates alive who otherwise would not have survived to transplantation [1]. However, short-term survival (up to 1 month) of patients with MCS is reported as similar to those with medical therapy (approximately 80%) as recently reported [2], and prognosis after implantation of MCS has not yet been satisfying when compared to heart transplantation despite the recent improvement in technology [1,3]. Therefore, heart transplantation may be a better therapy than MCS also in such critically ill patients with end-stage heart failure, if a donor heart would timely be available.

The Eurotransplant high-urgency (HU) heart transplantation program allows urgent heart transplantations to be carried out in rapidly deteriorating patients with acute-on-chronic heart failure on the elective waiting list, and the short-term outcome of heart transplantation in HU patients at our institution is excellent with 88% survival at 30 days [4]. In our previous study, the mean waiting time on the HU list was 13 days, and 7 of 39 patients died before heart transplantation. Under such circumstances, the use of MCS should be limited only to patients who would not survive until transplantation despite HU-listing; hence, to critical patients with expected survival of a few days.

The purposes of this study are to compare characteristics between patients who died despite HU listing and patients who received heart transplantation, as well as to identify a patient cohort that would benefit from the use of MCS.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 References
 
2.1 Criteria for HU listing
The Eurotransplant region consists of six western European countries with approximately 120 million inhabitants: Austria (6%), Belgium (8%), Germany (69%), Luxembourg (0.3%), Slovenia (2%), and The Netherlands (14%). According to the annual report of the Eurotransplant Foundation [5], 531 patients underwent heart transplantation and 864 patients were on the active waiting list in 2005. The waiting time for the 531 patients who underwent heart transplantation was 0–5 months in 323 (60.8%), 6–11 months in 93 (17.5%), 12–23 months in 76 (14.3%), and 24–59 months in 39 (7.3%).

The Eurotransplant Foundation offers the high-urgency heart transplantation program for critically ill patients who have very limited life expectancy if they do not receive heart transplantation. According to the Eurotransplant guidelines (Eurotransplant International Foundation annual report 2005, www.eurotransplant.nl), to become HU candidates, patients have to fulfill strict criteria as shown in Table 1 and are evaluated by three different external auditors. Briefly stated, the basic criteria for HU listing are a documented deterioration of myocardial function and progressive heart failure. HU candidates must be hospitalized in an intensive care unit. Furthermore, an NYHA functional status of IV and hemodynamic compromise proved by pulmonary catheter under high-dose inotropic therapy are recommended as another criterion.


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  		Table 1 Criteria for HU listing [5]
 
2.2 Patients
Between January 2000 and April 2007, 84 of our patients were listed on the HU heart transplantation program because of end-stage heart failure. Of those, 65 patients (77%) underwent heart transplantation and 17 patients (20%) died while on the HU waiting list. One patient was removed from HU status to the elective waiting list due to clinical recovery and another patient received MCS while on the HU waiting list. These two patients were excluded from the present study. These 82 patients were included in the present study and medical records were retrospectively reviewed.

2.3 Evaluated parameters
At the time of registration for HU waiting list, the patient data, including the following, were sent to the Eurotransplant foundation; age, sex, primary heart disease, use of MCS/intra-aortic balloon pump/extracorporeal membrane oxygenation, serum levels of creatinine/bilirubin/alanine transaminase (ALT), sodium, C-reactive protein (CRP), blood count of leukocytes, current inotropic therapy and hemodynamic parameters including arterial blood pressure, heart rate, systolic/diastolic/mean pulmonary artery pressure, pulmonary wedge pressure, central venous blood saturation, cardiac index, and central venous pressure. These parameters were evaluated in the present study.

2.4 Statistical analysis
Results are expressed as mean ± standard deviation. Statistical analysis was performed using Student's t-test for continuous variables after validation of normal distribution of data or {chi} 2 tests (Fisher's exact tests if n < 5) for categorical variables. Logistic regression was also used for the multivariate analysis of risk factors for mortality while waiting on the HU list. A p value less than 0.05 was considered significant. All statistical analyses were performed using SPSS 10.0 software (SPSS Inc., Chicago, IL).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 References
 
3.1 Patient characteristics
The patient characteristics of those who underwent heart transplantation (HTx group) and of those who died on the HU list while waiting (D group) are shown in Table 2 . There were no significant differences in patient characteristics between the two groups.


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  		Table 2 Patient characteristics
 
3.2 Waiting time, weekly allocation rate, and waiting-list mortality
The mean waiting time on HU list was 18.3 ± 17.7 days in HTx group and 12.5 ± 9.4 days in D group (p = 0.075). The distribution of waiting time in each group is demonstrated in Fig. 1 . Furthermore, the percentage of patients on active HU waiting list that underwent heart transplantation in each week was calculated as the weekly allocation and the results of the first four weeks are shown in Fig. 2 . The average weekly allocation rate of heart transplantation for those on the active HU list was 27.7%. In other words, 27.7% of patients on the active HU list were able to receive a donor heart each week in our study cohort. On the other hand, the waiting list mortality was 13.3% in the first week, 5.0% in the second week, 8.3% in the third week, and 29.4% in the fourth week. The mean weekly waiting-list mortality was 12.1%, corresponding with an approximate 40% mortality per month.


Figure 1
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  		Fig. 1. Waiting time on the active HU listing.

 

Figure 2
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  		Fig. 2. Weekly allocation rate on the active HU listing.

 
3.3 Patient condition at the HU registration
The patient condition, including current therapy, laboratory data, and hemodynamic data at the first HU registration, is summarized in Table 3 . In short, the use of intra-aortic balloon pumping, mechanical ventilation, dose of dobutamine, serum level of sodium, and serum level of CRP were statistically significant parameters, and the use of additional inotropic drugs (norepinephrine or epinephrine), count of white blood cells, and systolic body blood pressure fell short of being significant.


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  		Table 3 Patient condition at the HU registration
 
To identify the significant risk predictors of waiting time mortality, logistic regression analysis was performed, and all variables including patient characteristics and condition at the HU registration were entered into the model as categorical variables. In this analysis, a serum creatinine level more than 1.5 mg/dl (p = 0.007, odds ratio; 14.5, 95% CI; 2.1–102.0) and a serum CRP level more than 10 mg/l (p = 0.026, odds ratio; 6.3, 95% CI; 1.2–31.4) were identified as significant predictors.

3.4 Subanalysis: survival less than a week versus survival beyond a week
To identify risk factors for ultra-early mortality on the HU waiting list, patients who died within a week from the registration on HU (early D group) were analysed in comparison with patients who survived beyond a week while waiting (one-week survivor group). The one-week survivor group included nine patients who survived the first week and thereafter died while waiting for heart transplantation.

Mean survival in the early D group was 4.3 ± 2.1 days and mean duration on HU list in the one-week survivor group was 24.7 ± 16.5. The results of this analysis are shown in Tables 4 and 5 . The only difference in patient characteristics was the percentage of having an ICD. All the patients in the early D group had an ICD, whereas 61.5% of patients in the one-week survivor group had an ICD. With respect to patient condition at the HU registration, the patients in the early D group had higher dose of dobutamine (p = 0.007), higher level of serum creatinine (p = 0.027), lower systolic arterial pressure (p = 0.015), and a tendency to tachycardia (p = 0.085). Because of the small patient cohort, a multivariate analysis was not performed in this sub analysis.


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  		Table 4 Patient characteristics demonstrated for the sub-analysis
 

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  		Table 5 Patient condition at the HU registration demonstrated for the sub-analysis
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
References
 
The crucial findings of the present study were: (1) the average weekly allocation rate from the active HU list was 27.7%, whereas the weekly mortality was 12.1%, corresponding with an approximate 40% mortality per month in our study cohort; (2) patients with the need for intra-aortic balloon pumping, mechanical ventilation, high dose of dobutamine, low serum level of sodium, and high serum level of CRP had poor prognosis despite HU listing; (3) serum creatinine >1.5 mg/dl and serum CRP >10 mg/l were detected as positive predictors for waiting time mortality on the HU list; and (4) patients who died early after HU registration had higher dose of dobutamine, higher level of serum creatinine, and lower systolic arterial pressure than the patients who survived beyond a week.

The concept of ‘bridge to transplantation’ sets forth the shortage of donor hearts as a premise [5,6], and stresses that a patient who cannot timely receive a donor heart in a critical situation should be a candidate for MCS therapy. However, in the presence of the Eurotransplant HU program, one can expect a donor heart ‘relatively’ timely for a critically ill patient [4,7]. In the present study, the average weekly allocation rate was 27.7%. Assuming that no patient would die while waiting, the expectancy of receiving a donor heart on the HU waiting list in 4 weeks is calculated as (1–0.2774) x 100 = 72.7%; corresponding approximately with the expectancy of one donor heart per month. This allocation rate is quite higher than those in patients in UNOS (United Network for Organ Sharing) 1A or 1B status [8]. Besides this high allocation rate in patients on HU listing, it is also important to consider that prognosis after implantation of MCS has not yet been satisfied in contrast to heart transplantation despite the recent improvement in technology [1,3]. Therefore, it has been our policy, since the introduction of this program, to prefer urgent heart transplantation and to limit the implantation of MCS to the small cohort of patients who would otherwise inevitably develop cardiogenic shock and multiorgan failure.

However, all the patients on the HU list were critically ill with end-stage heart failure, and the weekly waiting list mortality was 12.1% in this study. Assuming that no patient would receive a donor heart while waiting, the expected mortality per month is calculated as (1–0.1214) x 100 = 59.7%. Considering the fact that the mean waiting time on HU list was 18.3 ± 17.7 days in the HTx group and 12.5 ± 9.4 days in the D group in the present study, it would be appropriate that a patient who would not be able to tolerate 1 week or 2 weeks waiting time be considered as a candidate for MCS implantation.

There have been some attempts to identify risk factors or predictors for waiting time mortality [9,10]. For example, Smits et al. reported that the urgency and the left ventricular subscore were found to be significantly associated with waiting list mortality in their large study with 889 patients transplanted in 1997 as a derivation set and 897 patients transplanted in 1998 as a validation set [10]. However, all the patients on the HU list require a donor heart urgently and have deteriorated ventricular function without exception, and therefore those previous findings cannot be applied to patients on the HU list. Copeland et al. implanted a total artificial heart (The CardioWest Total Artificial Heart, SynCardia Systems, Tucson, Ariz.) in 81 patients and they described inclusion criteria as follows: hemodynamic insufficiency according to either of the following definitions: (1) cardiac index ≤2.0 l/min/m2 and one of the following: systolic arterial pressure ≤90 mmHg or central venous pressure ≥18 mmHg; and (2) two of the following: dopamine at a dose of ≥10 µg/kg/min, dobutamine at a dose of ≥10 µg/kg/min, epinephrine at a dose of ≥2 µg/kg/min, other cardioactive drugs at maximal doses, use of an intra-aortic balloon pump, or use of cardiopulmonary bypass [6]. In our study cohort, 41 patients met their criteria and 26 of those patients underwent HTx and 15 patients died while waiting. Considering that the rate of survival to transplantation with the above mentioned artificial heart was 79% [6], approximately 12 patients of our study cohort would have been saved by implantation of MCS, but 26 patients would have been forced on unnecessary MCS implantation and approximately 6 patients would not have survived to transplantation according to their inclusion criteria. Their inclusion criteria in the cited study appear to be too broad and fails to include the aspect of a beginning multi-organ failure in the presence of the HU program.

In our present study, the use of intra-aortic balloon pumping, mechanical ventilation, high dose of dobutamine, low serum level of sodium, high serum level of CRP, high level of serum creatinine, and low systolic arterial pressure at the HU registration were associated with waiting list mortality. Especially, as signs of a beginning multi-organ failure, serum level of creatinine >1.5 mg/dl and serum level of CRP >10 were detected as significant predictors for waiting time mortality on the HU list by the multivariate analysis. In our study cohort, patients who met the following criteria at the HU registration had an 80% waiting list mortality (n = 4/5): (1) use of an intra-aortic balloon pump or mechanical ventilation; or (2) dobutamine at a dose of ≥10 µg/kg/min and serum level of creatinine >2.0 mg/dl. Those criteria may be justified for implantation of MCS in patients on HU list. However, the criteria should be validated by further large studies.

In conclusion, the Eurotransplant HU program is a promising allocation system for critically ill patients with end-stage heart failure resulting in 27.7% weekly allocation in our study cohort; but on the other hand, the weekly mortality was also as high as 12.1% corresponding with an approximately 40% mortality per month. Considering the fact that the mean waiting time on HU list was 18.3 ± 17.7 days in HTx group and 12.5 ± 9.4 days in D group in the present study, it would be appropriate that a patient who would not be able to tolerate one week or 2 weeks waiting time should be considered as a candidate for MCS implantation. The patient selection criteria for MCS implantation should include not only hemodynamic parameters, but also the aspect of a beginning multi-organ failure.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 References
 

  1. Deng MC, Edwards LB, Hertz MI, Rowe AW, Keck BM, Kormos R, Naftel DC, Kirklin JK, Taylor DO, International Society for Heart and Lung Transplantation Mechanical circulatory support device database of the International Society for Heart and Lung Transplantation: third annual report – 2005. J Heart Lung Transplant 2005;24(9):1182-1187.[CrossRef][Medline]
  2. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, Long JW, Ascheim DD, Tierney AR, Levitan RG, Watson JT, Meier P, Ronan NS, Shapiro PA, Lazar RM, Miller LW, Gupta L, Frazier OH, Desvigne-Nickens P, Oz MC, Poirier VL, Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group Long-term mechanical left ventricular assistance for end-stage heart failure. N Engl J Med 2001;345(20):1435-1443.[Abstract/Free Full Text]
  3. Taylor DO, Edwards LB, Boucek MM, Trulock EP, Waltz DA, Keck BM, Hertz MI, International Society for Heart and Lung Transplantation Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report – 2006. J Heart Lung Transplant 2006;25(8):869-879.[CrossRef][Medline]
  4. Koch A, Tochtermann U, Remppis A, Dengler TJ, Schnabel PA, Hagl S, Sack FU. The Eurotransplant high-urgency heart transplantation program: an option for patients in acute heart failure?. Thorac Cardiovasc Surg 2006;54(6):414-417.[CrossRef][Medline]
  5. Frazier OH, Rose EA, Oz MC, Dembitsky W, McCarthy P, Radovancevic B, Poirier VL, Dasse KA, HeartMate LVAS Investigators Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg 2001;122:1186-1195.[Abstract/Free Full Text]
  6. Copeland JG, Smith RG, Arabia FA, Nolan PE, Sethi GK, Tsau PH, McClellan D, Slepian MJ. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med 2004;351:859–67.
  7. Smits JM, Vanhaecke J, Haverich A, de Vries E, Roels L, Persijn G, Laufer G. Waiting for a thoracic transplant in Eurotransplant. Transpl Int 2006;19:54-66.[CrossRef][Medline]
  8. Smedira NG. Allocating hearts. J Thorac Cardiovasc Surg 2006;131:775-776.[Free Full Text]
  9. Aaronson KD, Schwartz JS, Chen TM, Wong KL, Goin JE, Mancini DM. Development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation. Circulation 1997;95:2660-2667.[Abstract/Free Full Text]
  10. Smits JM, Deng MC, Hummel M, De Meester J, Schoendube F, Scheld HH, Persijn GG, Laufer G, Van Houwelingen HC. Comparative outcome and clinical profiles in transplantation (COCPIT) Study Group. Transplantation 2003;76:1185-1189.[CrossRef][Medline]



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