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Ann Thorac Surg 1996;62:1442-1446
© 1996 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Heart Transplantation in Patients 65 Years of Age and Older: A Comparative Analysis of 40 Patients

Department of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, California

Accepted for publication June 19, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Advanced age has traditionally been considered a relative contraindication to heart transplantation because of the potential for increased morbidity and decreased long-term survival.

Methods. We analyzed the results in 40 patients 65 years of age and older who underwent heart transplantation and compared them with those in 138 patients younger than 65 years.

Results. The older age group had a higher incidence of diabetes mellitus (p = 0.01), donor-recipient weight mismatch (<0.80) (p = 0.004), lower donor-recipient weight ratio (p = 0.02), and longer allograft ischemic time (p = 0.008), among other differences. However, the 30-day operative mortality was similar in both groups (2.5% in older versus 2.2% in younger patients). Actuarial survival at 12, 24, and 36 months was not statistically different between the older and younger patients (86% ± 6% versus 93% ± 2%, 78% ± 8% versus 89% ± 3%, and 72% ± 9% versus 81% ± 4%, respectively; p = 0.26). The posttransplantation intensive care unit stay, total hospital stay, and associated hospital costs were also similar. The incidence of rejection during the first posttransplantation year was similar in both groups.

Conclusions. Heart transplantation in selected patients 65 years of age and older can be performed successfully, with a morbidity and mortality comparable with those seen in younger patients. Advanced age should not be an exclusion criterion for heart transplantation, but selective criteria should be applied that identify risks and benefits individually.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
See also page 1447.

Despite many advances in heart transplantation over the past two decades, most transplant centers still consider advanced age a relative contraindication to cardiac transplantation. This is based on data showing that advanced age is a strong factor influencing short- and long-term survival [1].

As the elderly are becoming the fastest growing and largest segment of the United States population, the patterns of cardiac surgery practice are evolving. As evidence of this, more elderly people have been undergoing highly sophisticated open heart interventions at our institution, with an acceptable morbidity and mortality and improved quality of life [2]. Encouraged by this experience, and because of our success with heart transplantation in younger patients, we have extended the age criteria in selected patients with end-stage cardiomyopathy not amenable to further medical or surgical intervention. To analyze the impact of age as a risk factor after heart transplantation, we retrospectively reviewed our experience in patients 65 years of age and older who underwent cardiac transplantation and compared it with our experience in a younger cohort of patients.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Between December 1988 and December 1995, 178 patients underwent orthotopic heart transplantation at Cedars-Sinai Medical Center. The hospital records for 40 patients 65 years of age and older were compared with the records for 138 patients younger than 65 years.

The preoperative characteristics of both patient age groups are listed in Table 1. A higher incidence of diabetes mellitus (p = 0.01) and a greater preoperative left ventricular ejection fraction (p = 0.0002) in the older age group were the only statistically significant differences between the groups. Donor characteristics are given in Table 2. Patients 65 years and older had a greater incidence of donor-recipient weight mismatch (<0.80) (p = 0.004) and a lower donor-recipient weight ratio (p = 0.02). Intraoperative and postoperative characteristics are listed in Table 3. Older patients had a longer allograft ischemic time (p = 0.008), a higher incidence of the use of an alternative surgical transplantation technique (p = 0.0003), and shorter duration (7 days) of OKT3 induction therapy (p = 0.0002).

Surgical Technique
Three techniques for orthotopic heart transplantation have been used. In the initial 64 patients, including 58 patients in the younger group and 6 patients in the older group, the standard biatrial technique originally described by Shumway and colleagues [3] was used. An alternative surgical approach consisting of total excision of the recipient's atria with cardiac allograft implantation performed using bicaval and pulmonary venous anastomoses [4] has been used in most patients since October 1991 and is currently our routine technique. A third surgical approach consisting of left atrial and bicaval anastomoses [5] has been used, although infrequently (see Table 3).

Immunosuppressive Therapy
Immunosuppressive therapy consisted of OKT3 induction therapy (5 mg intravenously daily) maintained for 7, 10, or 14 days (see Table 3). Currently, the 7-day protocol is used. Maintenance immunosuppressive therapy consists of cyclosporine (5 mg • kg^-1 • day^-1, for a level of 200 to 400 ng/mL, as shown by monoclonal fluorescence polarization immunoassay, within the first 12 weeks after transplantation, and for a level of 120 to 200 ng/mL thereafter, started postoperatively once the serum creatinine level is <2.0 mg/dL); azathioprine (4 mg/kg preoperatively and 2 mg • kg^-1 • day^-1 postoperatively, adjusted to the patient's white blood cell count); and steroids (methylprednisolone sodium succinate, 1 g at removal of the aortic cross-clamp intraoperatively, and then 125 mg intravenously every 8 hours for three doses postoperatively, followed by prednisone, 0.25 mg • kg^-1 • day^-1 during OKT3 therapy, increased to 0.5 mg • kg^-1 • day^-1, and then tapered in the subsequent 3 to 8 months).

Although the same immunosuppression protocol is used for older and younger patients, the levels of cyclosporine in older patients are generally in the lower end of the intended range. In addition, older patients are tapered off steroids faster than younger patients, so by and large most of them are off prednisone by the end of the sixth month after transplantation.

Statistical Methods
Patient preoperative group characteristics were compared using either the two-sample t test for continuous variables or the Fisher's exact text for categoric data. Age differences with regard to body surface area were tested using a two-way analysis of variance, with sex and age group as factors. A log-rank test was used to compare the survival curves of the two age groups. A Cox multivariate survival model was used to compare survival in the two age groups, while controlling for preoperative and treatment differences.

All testing was two-sided, using an alpha level of 0.05. When distributions were heavily skewed, data transformations were used to normalize data. The Statistical Analysis System (SAS Institute, Cary, NC) and BMDP statistical packages were used in all data analysis.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The 30-day operative mortality was 2.5% (1/40 patients) in the older group and 2.2% (3/138 patients) in the younger group (p = not significant). Actuarial survival at 12, 24, and 36 months was not statistically different between the older and younger patients (86% ± 6% versus 93% ± 2%, 78% ± 8% versus 89% ± 3%, and 72% ± 9% versus 81% ± 4%, respectively; p = 0.26; mean ± standard error). The posttransplantation intensive care unit stay and total hospital stay were similar in both groups, which translated into similar total hospital costs. Follow-up is shorter in the older group, because the older patients underwent heart transplantation later in the study period (see Table 3). The incidence of rejection during the first posttransplantation year was similar in both groups, with a mean number of rejection episodes of 0.8 per patient for the older group and 0.9 per patient for the younger group (p = 0.45) (Table 4). The causes of death in both patient populations are shown in Table 5. There were no statistically significant differences between the groups in the time interval from transplantation until death (p = 0.26). In a Cox stepwise regression model, preoperative and treatment factors, which differed between the two age groups, were allowed to compete for selection into the regression model. These included history of diabetes, left ventricular ejection fraction, donor-recipient weight mismatch, bicaval transplantation technique, and use of OKT3 therapy for 7 days. The factor most predictive of patient survival was the type of transplantation surgical technique (p-to-enter = 0.03). After this factor went into the model, age 65 years or older was the next most predictive factor (p-to-enter = 0.09). No additional factors entered the model (p > 0.20 all). The Cox regression model, including p-to-remove values, is summarized in Table 6. At the present time, no conclusions can be drawn regarding morbidity related to infection episodes or the incidence of transplant atherosclerosis as assessed by coronary angiography.

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

On the basis of these findings, it is easy to understand why the results of heart transplantation in the elderly can vary between transplant centers. In one multicenter study involving 911 patients, Bourge and colleagues [9] found that very young age (<5 years) and advanced age were, among others, pretransplantation risk factors for death after heart transplantation. Their multivariate analysis showed that the expected mortality in patients older than 50 years progressively increases [9]. These results are supported by data from the Registry of the International Society for Heart and Lung Transplantation (ISHLT). In addition, data from the ISHLT Registry show a significant decrease in survival in patients older than 65 years at 12, 24, and 36 months after heart transplantation [1]. Other studies have also shown decreased survival, increased morbidity and incidence of infection, and decreased functional capacity in older patients after heart transplantation [7, 8, 10]. In addition, Bull and colleagues [7] found that patients older than 60 years were more likely to die of malignant and infectious complications after transplantation. However, these studies do not agree in terms of the definition of older age for cardiac transplantation, as they define it as more than 50 years, 60 years, 54 years, and 65 years of age, respectively [7–10].

In contrast, other studies comparing the results in elderly patients with those in younger patients have shown good results with respect to morbidity and mortality. The investigators in these studies have concluded that advanced age should not be considered a major contraindication to cardiac transplantation, provided physiologic age is not advanced by disease of other organ systems, which could limit survival [6, 11–15]. However, as noted, the definition of older age is not uniform.

Notwithstanding the lack of a clear definition of "advanced age" in heart transplantation, we adopted the ISHLT guideline of 65 years of age to analyze the impact of age as a pretransplantation risk factor. We have even extended our recipients' upper age limit because of the good results obtained in our entire transplant population over the past 4 years. This includes a 30-day or to-discharge operative survival of 100% in the last 141 consecutive patients and a 1-year and 2-year actuarial survival of 97% ± 1.7% and 93% ± 2.9%, respectively.

Patients 65 years of age and older represent 22% of our heart transplant population. The donor criteria used for transplant patients between 65 and 69.9 years of age were similar to those used for younger patients. Although it can be argued that older patients are utilizing a limited resource of donor hearts at a time when there is an increased demand for organs, we believe that the indications for heart transplantation are constantly evolving, particularly the recipients' upper age limit. Further, to deny these patients the benefits of transplantation solely on the basis of age seems very controversial. However, patients 70 years of age and older are placed on an "alternative" list to avoid taking the scarce donor organs away from younger patients. This involves the use of organs deemed unsuitable by other transplant centers because of the donor's weight, lack of an available recipient for their blood type, or high-risk donors with potentially compromised organs. To date, 6 carefully selected patients aged 70 to 77 years have undergone heart transplantation, with a morbidity comparable with that in younger patients and excellent short-term survival and quality of life.

In our experience, the operative mortality in patients 65 years of age and older has been the same as that in younger patients. In addition, the actuarial survival at 12, 24, and 36 months has not differed from that in younger patients. Further, both patient groups had a similar incidence of rejection, posttransplantation intensive care unit stay, total hospital stay, and total hospital costs, despite the fact that there was a higher incidence of diabetes mellitus, a higher incidence of donor-recipient weight mismatch (<0.80), a lower donor-recipient weight ratio, and a longer allograft ischemic time in the older patients. An aggressive approach regarding the use of potentially compromised allografts, particularly a high degree of donor-recipient undersizing (0.50 to 0.80), has been used in this group of patients, with excellent clinical results, as previously documented [16]. Although the sample size is small for statistical validation, mortality resulting from infection in the older group did not differ from that in younger patients.

Our current practice is to use mechanical support or assist devices as a bridge to transplantation in patients up to the age of 69.9 years if they suffer hemodynamic deterioration. However, patients 70 years of age and older are listed for transplantation only as status II, as defined by the United Network for Organ Sharing (ie, awaiting transplantation at home), to minimize perioperative morbidity; the use of mechanical support in this subgroup of patients is probably not warranted because they may not be able to tolerate related complications.

Extending the age limit of potential candidates for cardiac transplantation would certainly increase the demand for donor organs. As the number of heart transplants performed is limited by a relatively fixed donor pool, this increased demand could increase the waiting time for and perhaps the mortality in younger patients waiting for a donor heart. These are complex medical, ethical, and socioeconomic issues that would have to be addressed by the respective professional and governmental organizations at the national level.

In summary, the improved longevity of the American population has resulted in more elderly patients in need of complex cardiac interventions. These demographic changes will bring pressure on the medical community in the future to evaluate older patients with end-stage heart disease not amenable to further surgical therapy for heart transplantation, in light of the efficacy of this mode of therapy in younger patients. As the field of cardiac transplantation continues to evolve, the criteria for the selection of potential recipients, as well as donors, continues to expand, particularly the recipients' upper age limit. The definition of older age in heart transplantation is purely arbitrary and not clearly defined; in our experience, heart transplantation in selected elderly people (65 years and older) can be performed successfully, with a morbidity and mortality and associated hospital costs comparable to those in younger patients. These encouraging results indicate that advanced age should not be considered a contraindication to heart transplantation, but selective criteria should be applied when screening potential older patients. A rigid criterion regarding recipients' upper age limit would deprive some older patients with end-stage cardiomyopathy of the benefits of heart transplantation. Immunosuppression regimens should be tailored to accommodate the decreased immune responsiveness and T-cell function seen in the elderly, to minimize the incidence of infectious and malignant complications. Finally, our criteria have evolved so that we now evaluate all potential transplant candidates in a selective fashion, identifying the risks and benefits individually. Further studies and continuing follow-up are needed to validate these results.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
We thank Kathleen Farrington for her secretarial assistance and Marilyn Sanders from Ortho-Biotech, Inc., for her technical expertise in the preparation of the manuscript.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Blanche, Department of Cardiothoracic Surgery, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Rm 6215, Los Angeles, CA 90048.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

1. Hosenpud JD, Novick RJ, Breen TJ, Keck B, Daily P. The Registry of the International Society for Heart and Lung Transplantation: twelfth official report-1995. J Heart Lung Transplant 1995;14:805–15.[Medline]
2. Tsai TP, Chaux A, Matloff J, et al. Ten-year experience of cardiac surgery in patients aged 80 years and over. Ann Thorac Surg 1994;58:445–51.[Abstract]
3. Shumway NE, Lower RR, Stofer RC. Transplantation of the heart. Adv Surg 1966;2:265–84.[Medline]
4. Blanche C, Valenza M, Aleksic I, Czer LSC, Trento A. Technical considerations of a new technique for orthotopic heart transplantation: total excision of recipient's atria with bicaval and pulmonary venous anastomoses. J Cardiovasc Surg 1994;35:283–7.[Medline]
5. Blanche C, Czer LSC, Valenza M, Trento A. Alternative technique for orthotopic heart transplantation. Ann Thorac Surg 1994;57:765–7.[Abstract]
6. Renlund DG, Gilbert EM, O'Connell JB, et al. Age-associated decline in cardiac allograft rejection. Am J Med 1987;83:391–8.[Medline]
7. Bull DA, Karwande SU, Hawkins JA, et al. Long-term results of cardiac transplantation in patients older than sixty years. J Thorac Cardiovasc Surg 1996;111:423–8.[Abstract/Free Full Text]
8. Heroux AL, Costanzo-Nordin MR, O'Sullivan JE, et al. Heart transplantation as a treatment option for end-stage heart disease in patients older than 65 years of age. J Heart Lung Transplant 1993;12:573–9.[Medline]
9. Bourge RC, Naftel DC, Costanzo-Nordin MR, et al. Pretransplantation risk factors for death after heart transplantation: a multiinstitutional study. J Heart Lung Transplant 1993;12:549–62.[Medline]
10. Fabbri A, Sharples LD, Mullins P, Caine N, Large S, Wallwork J. Heart transplantation in patients over 54 years of age with triple-drug therapy immunosuppression. J Heart Lung Transplant 1992;11:929–32.[Medline]
11. Frazier OH, Macris MP, Duncan JM, Van Buren CT, Cooley DA. Cardiac transplantation in patients over 60 years of age. Ann Thorac Surg 1988;45:129–32.[Abstract]
12. Carrier M, Emery RW, Riley JE, Levinson MM, Copeland JG. Cardiac transplantation in patients over 50 years of age. J Am Coll Cardiol 1986;8:285–8.[Abstract]
13. Aravot DJ, Banner NR, Khaghani A, et al. Cardiac transplantation in the seventh decade of life. Am J Cardiol 1989;63:90–3.[Medline]
14. Miller LW, Vitale-Noedel N, Pennington DG, McBride L, Kanter KR. Heart transplantation in patients over age fifty-five years. J Heart Transplant 1988;7:254–7.[Medline]
15. Olivari MT, Antolick A, Kaye MP, Jamieson SW, Ring WS. Heart transplantation in elderly patients. J Heart Transplant 1988;7:258–64.[Medline]
16. Ott GY, Herschberger RE, Ratkovec RR, Norman D, Hosenpud JD, Cobanoglu A. Cardiac allografts from high-risk donors: excellent clinical results. Ann Thorac Surg 1994;57:76–82.[Abstract]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Jack M. Matloff Alfredo Trento Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Blanche, C. Articles by Trento, A. Search for Related Content PubMed PubMed Citation Articles by Blanche, C. Articles by Trento, A. Related Collections Related Article