Asian Cardiovasc Thorac Ann 2003;11:33-36
© 2003 Asia Publishing EXchange Ltd
Risk Factor Analysis of Orthotopic Heart Transplantation
Tadashi Omoto, MD,
Kazutomo Minami, MD,
Dietmar Böthig, MD,
Ulrich Schütt, MD,
Gero Tenderich, MD,
Stephan Wlost, MD,
Reiner Körfer, MD
Department of Thoracic and Cardiovascular Surgery, Heart Center North-Rhine-Westphalia, Ruhr-University of Bochum, Bad Oeynhausen, Germany
For reprint information contact: Tadashi Omoto, MD Tel: 49 5731 97 0 Fax: 49 5731 2300 email: omoto{at}kddnet.de Department of Thoracic and Cardiovascular Surgery, Heart Center North-Rhine-Westphalia, Ruhr-University of Bochum, Georgstrasse 11, Bad Oeynhausen D-32545, Germany.
 |
ABSTRACT
|
|---|
From March 1989 to December 1999, 1,013 heart transplantations were carried out in this center. Univariate analysis of potential risk factors for early death was followed by stepwise logistic regression to determine independent risk factors. Long-term results were assessed by the Kaplan-Meier method. Multivariate comparisons of long-term results were performed using Cox’s proportional hazards model. Early mortality was 8.6%. Actuarial survival was 78.1%, 69.4%, and 53.1% at 1, 5, and 10 years, respectively. Mean total ischemic time was 194 minutes. Independent risk factors of early mortality were female recipient, donor age over 50 years, and ischemic heart disease in the recipient. The precise mechanism of the increased early mortality in female recipients should be studied in the future. Although older donor age was a predictor of early mortality, because of the donor shortage, older hearts should not be excluded from the donor pool. Survival was better in patients with dilative cardiomyopathy than in those with ischemic heart disease.
|
INTRODUCTION
|
|---|
Two large multicenter studies reported by the Cardiac Transplant Research Database Group1,2 indicated that older donor and longer ischemic time are both independent risk factors for increased mortality following heart transplantation. Previously, the ideal criteria for donors included age less than 35 years, ischemic time less than 4 hours, and the absence of coronary artery disease.3 However, the increasing demand for donor organs in the face of a fixed donor population has led to acceptance of less ideal conditions such as advanced donor age or ischemic time longer than 4 hours. The heart transplant program in our institution started in March 1989. Since then, perioperative strategy has been the same: Lower-Shumway anastomosis, Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) solution, and double-drug therapy for long-term immunosuppression. The purpose of this study was to analyze risk factors for early mortality after orthotopic heart transplantation in a single center.
|
PATIENTS AND METHODS
|
|---|
The patient population consisted of 1,013 consecutive heart transplant recipients, the mean age was 49.8 years (range, 1–77 years), and 74 were under 18 years old. There were 842 males (83%) and 171 females (17%). Orthotopic heart transplantation was performed between March 1989 and December 1999. Retransplantation was carried out in 19 patients. The preoperative diagnoses of the recipients are listed in Table 1
. The eligibility criteria for a cardiac transplant were: New York Heart Association class III or IV, irreversible endstage heart failure incurable by surgical treatment other than heart replacement, limited life expectancy with survival prognosis estimated to be less than 6 months, physiologic age less than 65 years, and no systemic illness other than abnormalities related to heart failure. Exclusion criteria included: severe pulmonary hypertension (fixed pulmonary vascular resistance > 6 Wood units), severe irreversible hepatic, renal, or pulmonary disease, systemic infection, acute pulmonary infarction, active peptic ulcer disease, and history of drug or alcohol abuse.
Donor age ranged from 3 months to 72 years (mean, 33.2 years); there were 488 (48%) males and 525 females (52%). Causes of death in the donors were: trauma (420), intracranial bleeding (395), hypoxia (74), cerebral ischemia (32), cerebral tumor (30), intoxication (14) and others (48). Donor heart procurement was performed using HTK solution in all cases. At the time of explantation, a minimum of 50 mL per kg body weight of HTK solution was used for flushing, and the heart was stored in 1 L HTK solution. Following crossclamping of the ascending aorta, the cardioplegia perfusion pressure was maintained at 60 mm Hg initially, and at 40 mm Hg after cardiac arrest. The mean perfusion time was 10 ± 1.5 min. During transport, the temperature was maintained between 4°C and 5°C.
The recipient’s heart was explanted through a median sternotomy after institution of cardiopulmonary bypass. Atrial anastomosis was carried out by the Lower-Shumway technique.4 In patients with complex cardiac malformations, bicaval anastomosis was used as an alternative method. Our immunosuppression protocol after heart transplantation has been documented previously.5 Briefly, immunosuppression was based on initial triple-drug therapy and subsequent long-term double-drug therapy consisting of cyclosporine A (6 mg•kg-1 per day) and azathioprine (2 mg•kg-1 per day). Surveillance endomyocardial biopsies were performed postoperatively before discharge and annually thereafter. If rejection was suspected on clinical grounds in the interim, supplementary biopsies were conducted accordingly. Whenever possible, steroid maintenance (10 mg per day) was avoided. Antiplatelet agents including aspirin (50 mg) and dipyridamole (300 mg) were administered prophylactically to prevent coronary artery vasculopathy after heart transplantation.
Data from all donors and recipients were registered ad hoc and analyzed with SPSS version 9.0 (SPSS Inc., Chicago, IL, USA). Continuous numerical variables are expressed as mean ± standard deviation of the mean. In redo transplant patients, data from the second transplantation were analyzed. The Kaplan-Meier method was used to estimate long-term event-free rates.6 Survival between groups was compared by the univariate log-rank test. Univariate analysis of potential risk factors for early death (defined as death within 30 days postoperatively) was carried out by the chi-squared test (Pearson) and followed by stepwise logistic regression to determine independent risk factors. To evaluate the influence of ischemic time on early survival, a discriminant analysis was performed. Values of p < 0.05 were considered statistically significant.
|
RESULTS
|
|---|
The actuarial survival curve after orthotopic heart transplantation is shown in Figure 1. Overall survival was 91.4% at 30 days, 83.0% at 90 days, 78.1% at 1 year, 69.4% at 5 years, and 53.1% at 10 years (44 patients reached the 10-year follow-up). A ventricular assist device (VAD) was implanted preoperatively in 174 patients as a bridge to transplantation. The percentage of bridged heart recipients rose from 7.8% in 1990 to 36.8% in 1995 and 34% in 1999. The mean total ischemic time was 191.9 ± 42.3 min (range, 68–328 min). In 19 cases (1.8%), the total ischemic time was longer than 300 min.
Significant risk factors for early mortality were donor age > 50 years, total ischemic time > 5 hours, and female sex of the recipient, by univariate analysis. Factors of no significant influence were: female sex of the donor, preoperative need for inotropics in the donor, total ischemic time > 4 hours, recipient age > 50 years, pulmonary vascular resistance > 5 Wood units, and in-hospital status of the recipient. There was no significant difference in early mortality between patients with VAD implantation prior to transplantation (7.7%) and those without a VAD (8.8%). Patients with ischemic heart disease showed a higher tendency towards early mortality than those with dilative cardiomyopathy (p = 0.06).
By multivariate analysis, female sex of the recipient (p = 0.009), donor age > 50 years (p = 0.011), and ischemic heart disease (p = 0.043) were significant risk factors for early death. Total ischemic time > 5 hours did not reach statistical significance as a risk factor (p = 0.06). Total-ischemic-time-related early mortality is shown in Figure 2 and Table 2. There was a higher mortality in patients with total ischemic time > 300 min (26.3%). Discriminant analysis including total ischemic time confirmed its small influence on early death with only 50.6% of correctly predicted deaths and 57.8% of correctly predicted survivors. Donor-age-related early mortality is shown in Figure 3 and Table 3. Recipient-age-related early mortality is shown in Figure 4 and Table 4.
|
DISCUSSION
|
|---|
Analysis of risk factors is important in making informed judgments in any particular donor-recipient situation. Data from multicenter registries have formed the basis of our risk stratification knowledge.1,2,7 Although data from multicenter registries have been helpful, the information was obtained from centers with various preoperative management protocols. More than 17% of transplanted patients had undergone pretransplant VAD bridging in our review. Our results demonstrate that the presence of an implanted VAD in bridged patients was not a risk factor for early death after transplantation, in contrast to multicenter registry data.7 High pulmonary vascular resistance was not a risk factor, as we have previously demonstrated.8 Due to the large variability in each center’s institutional protocols and results, risk stratification may not translate to a particular center’s experience.
Female sex of the recipient was shown to be a risk factor in our study. Female recipients have also been found to be at higher risk of rejection with severe hemodynamic compromise, and of recurrent rejection, particularly if multiparous.9,10 This suggests that preformed antibodies may cross-react with the allograft, producing a more frequent and potentially more severe rejection response.
Donor age > 50 years was found to be a negative predictor of early mortality in our study, which is consistent with previous findings.1,2,7 Although older donor age increases the likelihood of posttransplant coronary artery disease, the rate was shown to be 3% in 2 years and 6% in 5 years when the recipient received a heart from a 50-year-old rather than a 20-year-old donor.11 This finding should not discourage the acceptance of older hearts, and taking donor shortage into consideration, we cannot support the exclusion of older subjects from the donor pool.
Ischemic heart disease (IHD) and cardiomyopathy are the most common indications for heart transplantation. Early mortality of patients with IHD and cardiomyopathy was 9.7% and 6.3%, respectively. A pretransplant diagnosis of IHD was found to confer a risk factor of early death after transplantation by multivariable analysis. Patients with IHD may have a greater inherent propensity to atheroma formation, leading to coronary artery disease with resultant graft dysfunction.12 Recipients with IHD have a higher incidence of acute rejection at long-term follow-up.12 The presence of IHD may add an additional element of physiological aging beyond a patient’s chronological years.13 It has been demonstrated that revascularization in cases of severe IHD improves symptoms and outcome. In those with severe IHD, quantification of viable myocardium is central to the decision on whether myocardial vascularization or transplantation is most favorable for the patient.
Because of the limited availability of donor organs, criteria for donor acceptance have broadened, particularly with respect to donor age and ischemic time. The improved survival in recent years has the added benefit of allowing expansion of the donor pool. In our series of 1,013 patients, we demonstrated the growing number of recipients with bridged transplants. It is important to base decisions regarding donor and recipient acceptance criteria on a given center’s experience.
|
REFERENCES
|
|---|
- Young JB, Naftel DC, Bourge RC, Kirklin JK, Clemson BS, Porter CB, et al. Matching the heart donor and heart transplant recipient. Clues for successful expansion of the donor pool: a multivariable multiinstitutional report. The Cardiac Transplant Research Database Group. J Heart Lung Transplant
1994;13:353–65.[Medline]
- Bourge RC, Naftel DC, Costanzo-Nordin MR, Kirklin JK, Young JB, Kubo SH, et al. Pretransplantation risk factors for death after heart transplantation: a multiinstitutional study. The Cardiac Transplant Research Database Group. J Heart Lung Transplant
1993;12:549–62.[Medline]
- Boehmer JP. Expanding the donor pool: how far is too far? J Heart Lung Transplant
1993;12:816–8.[Medline]
- Shumway NE, Lower RR, Stofer RC. Transplantation of the heart. Adv Surg
1966;2:265–84.[Medline]
- Körner MM, Posival H, Minami K, El-Banayosy A, Körtke H, Gromzik H, et al. Heart transplantation at the Heart Center North-Rhine-Westphalia. In: Terasaki PI, Cecka JM, editors. Clinical transplants. Los Angeles: UCLA Tissue Typing Laboratory 1992:137–47.
- Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc
1957;53:457–81.
- Hosenopud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: seventh official report — 2000. J Heart Lung Transplant
2000;19:909–30.[Medline]
- Tenderich G, Körner MM, Stüttgen B, Mirow N, Arsoglu L, Morshuis M, et al. Preexisting elevated pulmonary vascular resistance: long-term hemodynamic follow-up and outcome of recipients after orthotopic heart transplantation. J Cardiovasc Surg
2000;41:215–9.[Medline]
- Mills RM, Naftel DC, Kirklin JK, van Bakel AB, Jaski BE Massin EK, et al. Heart transplant rejection with hemodynamic compromise: multiinstitutional study of the role of endomyocardial cellular infiltrate. Cardiac Transplant Research Database. J Heart Lung Transplant
1997;16:813–21.[Medline]
- Kubo SH, Naftel DC, Mills RM Jr, O’Donnell J, Rodeheffer RJ, Cintron GB, et al. Risk factor for late recurrent rejection after cardiac transplantation: a multiinstitutional, multivariable analysis. Cardiac Transplant Research Database. J Heart Lung Transplant
1995;14:409–18.[Medline]
- Costanzo MR, Naftel DC, Pritzker MR, Heilman JK III, Boehmer JP, Brozena SC, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. Heart Lung Transplant
1998;17:744–53.[Medline]
- Aziz T, Hasleton P, Hann AW, Yonan N, Deiraniya A, Hutchinson IV. Transforming growth factor beta in relation to cardiac allograft vasculopathy after heart transplantation. J Thorac Cardiovasc Surg
2000;119:700–8.[Abstract/Free Full Text]
- Borkon AM, Muehlebach GF, Jones PG, Bresnahan DR Jr, Genton RE, Gorton ME, et al. An analysis of the effect of age on survival after heart transplantation. J Heart Lung Transplant
1999;18:668–74.[Medline]
This article has been cited by other articles:
|
|
|
|
 
Y. S. Tjang, G. J.M.G. van der Heijden, G. Tenderich, R. Korfer, and D. E. Grobbee
Impact of Recipient's Age on Heart Transplantation Outcome
Ann. Thorac. Surg.,
June 1, 2008;
85(6):
2051 - 2055.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. S. Tjang, G. J.M.G. van der Heijden, G. Tenderich, D. E. Grobbee, and R. Korfer
Survival analysis in heart transplantation: results from an analysis of 1290 cases in a single center
Eur. J. Cardiothorac. Surg.,
May 1, 2008;
33(5):
856 - 861.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
