Eur J Cardiothorac Surg 2003;24:283-291
© 2003 Elsevier Science NL
Long-term survival (>10 years) of patients >60 years with induction therapy after cardiac transplantation
Andreas Zuckermann*,
Daniela Dunkler,
Elena Deviatko,
Arthur Bodhjalian,
Martin Czerny,
Jan Ankersmit,
Ernst Wolner,
Michael Grimm
Department of Cardiothoracic Surgery, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria
Received 26 September 2002;
received in revised form 13 March 2003;
accepted 17 March 2003.
* Corresponding author. Tel.: +43-1-40400-5643; fax: +43-1-40400-5642
e-mail: 101634.174{at}compuserve.com
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Abstract
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Objective: Cardiac transplantation has become an established method for end-stage heart disease. Short- and mid-term outcome has been known to be similar between younger and older (>60 years) recipients. So far, nothing is known about long-term outcome of old patients and the potential long-term effects of antibody induction therapy in these patients. The purpose of this study was to analyse long-term outcome of old cardiac transplant recipients who underwent antibody induction therapy. Methods: Since 1989, 203 patients (total n=882) above 60 years have been transplanted at our center. On these patients n=66 were above 65 years. Survival, incidences of rejection, infection, cancer, graft arteriosclerosis and the amount of renal insufficiency were compared with patients <60 years (n=679), transplanted during the same period of time. Freedom from specific event was computed by Kaplan–Meier analysis and compared by log–rank test. Results: Ten year survival was similar in all groups (<60 years: 53.7%; 60–64 years: 53.1% and >65 years: 60.2%; P=NS). Causes of death were similar in all patient groups. There were significant fewer rejection episodes in the older patient group (freedom from rejection: 74.9 vs. 83.5 vs. 90.6; P=0.03). Yet significantly more number of patients >65 years were without steroid maintenance therapy (43.1%) compared to other patient groups (8.2 vs. 9.3%; P<0.05). There was no difference in overall freedom from severe infection (74.1 vs. 67.7 vs. 85.3%; P=NS), whereas there was a trend towards more CMV disease in the oldest patient group (82.7 vs. 88.6 vs. 70.8%; P=0.06). The incidence of cancer was similar in all groups (freedom from cancer: 82.2 vs. 84.7 vs. 79.1%; P=NS), as well as there was no difference in severe graftsclerosis between all patients (79.2 vs. 93.7 vs. 93.3%; P=NS). There was no difference in development of chronic renal dysfunction (creatinine >2.0 mg/dl) between the three groups (10 vs. 14 vs. 16%; P=NS). Conclusions: Old recipients of cardiac transplants have a similar long-term outcome than younger recipients. They were less prone to rejections, had a similar incidence of severe infections and showed a trend towards more CMV disease. All patients had a very low rate of graft arteriosclerosis that was similar amongst the groups. Age-related decline of the immune system further enhanced by immunomodulation of antibody induction therapy might be accounted for the results as well as steroid-free immunosuppression.
Key Words: Cardiac transplantation • Age • Risk factors • Survival • Antibody induction therapy
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1. Introduction
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Cardiac transplantation has evolved to be the best treatment option for patients with advanced heart failure that remains refractory to medical therapy. The advances made in transplant candidate management, selection, surgical techniques, immunosuppression and post-transplant patient care have resulted in significant improvements in patient outcomes. The current survival rates with cardiac transplantation are around 80% at 1 year and approximately 70% at 5 years [1]. As a result of these advances and reports of improved survival, the number of patients referred and listed for transplantation has increased markedly. Advanced recipient age has long been considered a criterion for not performing cardiac transplantation, but the upper age limit has never been well defined [2]. Many transplant centers have liberalised recipient eligibility criteria and have gained additional experience in transplanting older patients. The average recipient age has been steadily moving upward, with the number of patients aged 65 and older being transplanted increasing from 5% in the time period 1989–1993 to 11% in the time period 1999–2001 at our center.
Registry data and early reports have indicated that there may be increased post-transplant mortality in older patients. A number of single-center reports have shown that survival of older patients may be similar to that of younger patients [3,4]. The limited supply of donor hearts makes it imperative that careful consideration be given to transplantation results in older recipients and the overall impact that expanding eligibility criteria for transplantation will have. Furthermore, nothing is known about long-term outcome of old patients and the potential effects of antibody induction therapy.
The purpose of this analysis was to analyse long-term outcome of cardiac transplant patients >60–64 and >65 years of age, who underwent antibody induction therapy.
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2. Patients and methods
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Between March 1984 and December 2001, 973 patients underwent orthotopic heart transplantation at Vienna University hospital. Clinical patient data were prospectively collected and recorded into a computerised database. Follow-up was complete for all patients. Since January 1989, patients above 60 years of age have been accepted for transplantation. All patients transplanted before 1989 as well as paediatric patients (<18 years) were excluded from analysis. The remaining 882 patients were divided into three study groups: group 1 included 679 patients between 18 and 60 years (48.3±9.1 years); group 2 included 137 patients between 60 and 65 years (61.8±1.2) and group 3 included 66 patients above 65 years (66.8±1.7).
The preoperative characteristics of all three patient groups are listed in Table 1. The older groups had a higher incidence of diabetes (P>0.001), a lower incidence of smoking history (P=0.0032). There was a trend towards a higher rate of previous sternotomies in both older groups (P=0.09). Group 2 showed a trend towards a higher incidence of ischemic cardiomyopathy (P=0.09), a lower incidence of other etiology of heart failure (P=0.075) and a lower incidence of overweight (P=0.09).
There was a significant difference (P<0.001) in waiting time between all three patient groups, with longest waiting time for group 3, followed by group 2. Death on the waiting list was also higher for groups 2 and 3 compared to group 1 (P=0.011).
Donor and peri-operative characteristics are listed on Table 2. Older patients received allografts from older donors (P=0.001) and had a significantly higher rate of older donors (>50 years) (P<0.001) and had significantly longer ischemic times (P<0.001).
2.1. Immunosuppressive therapy
All patients received antibody induction therapy with either polyclonlal ATG (thymoglobuline; SangStat, Fremont, CA, USA) 2 mg/kg for 7 days (n=651) or Fresenius-ATG (Fresenius AG, Bad Homburg, Germany) 5–10 mg/kg for 7–10 days (n=152) or ATGAM (Upjohn, Kalamazoo, MI, USA) 10 mg/kg for 10 days (n=20) or monoclonal murine antibodies (OKT 3; Ortho Biotech, USA) 5 mg/day for 14 days (n=32) or BT563 (Biotest Pharmazeutika, Dreireich, Germany), 10 mg/day for 7 days (n=26). Maintenance immunosuppression therapy consisted of cyclosporine A (CyA), azathioprine and steroids. In all patients >65 years routine weaning off steroids was performed during the first year if no rejection episodes were diagnosed. In the other two groups, steroid weaning was performed only if patients did not tolerate steroid side effects. Since the beginning of 1998 all patients were routinely switched from azathioprine to mycophenolate mofetil.
2.2. Infectious prophylaxis and assessment of infection
Patients in all groups received systemic antistaphylococcal antibiotics for 5 days, anti-CMV hyperimmunoglobulin (Cytotect, Biotest Pharmazeutika, Dreireich, Germany), weekly during the first month after transplantation and daily oral nystatin for 28 days.
Infections were defined as ‘clinically evident infectious disease that required treatment and that was documented by proven culture tests and/or histology’. CMV disease was characterized if CMV infection was associated with (1) fever (>38°C), (2) an influenza-like illness with or without pneumonitis, colitis, hepatitis or carditits, (3) leukopenia (leukocyte count <3.5x109 cells/l on two consecutive measurements after stopping azathioprine therapy) and (4) absence of any other probable explanation for the symptoms (infection or rejection).
2.3. Assessment of rejection and graft arteriosclerosis
The International Society for Heart and Lung Transplant (ISHLT) grading system was used to detect cardiac rejection from serial endomyocardial biopsies [5]. A rejection episode was defined as either ISHLT grade 
2 or grade <2 with hemodynamic compromise. Biopsies were performed weekly during the first month, monthly in the first six months and once at the end of the first year or as clinically indicated. Rejection episodes were treated with methylprednisolone, in pulses of 15 mg/kg intravenously daily for 3 days, with a control biopsy after 7 days. If steroid therapy failed, a 10-day course of OKT3 therapy was initiated.
All patients received coronary angiograms 12, 36, 60 and 120 months after transplantation. Angiograms were also performed, whenever the clinical situation suggested occurrence of graft arteriosclerosis. Graft sclerosis was defined as any coronary wall abnormalities; severe graft arteriosclerosis was defined as 1 vessels with 50% stenosis. Moreover, an autopsy was performed on all patients who died during follow-up. Any significant lesion in 1 coronary vessel was also defined as severe graft arteriosclerosis.
2.4. Statistical analysis
Patients were stratified on the basis of age (18–<60 or 60–<65 or >65 years of age). Data were presented as frequency distributions and simple percentages. Values of continuous variables were expressed as mean±standard deviation. Patient pre- and post-operative group characteristics were compared by the analysis of variance and Bonferroni t-test for continuous variables. Chi2 test was used for categoric variables. Actuarial survival and freedom from events (rejection, infection, cancer and graft sclerosis) in the three groups were examined using Kaplan–Meier procedures and compared by log–rank and Wilcoxon tests. A P value of <0.05 was considered to indicate statistical significance.
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3. Results
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3.1. Survival
The 30-day mortality was 11.3% in group 1 vs. 15.3% in group 2 vs. 15.2% in group 3 (P=0.4). Actuarial survival at 1, 5 and 10 years was similar for all three groups: group 1(82.2, 71.2 and 53.7%) group 2 (78.2, 60.7 and 53.1%) and group 3 (73.9, 68.5 and 60.2%) (P=0.3252; Fig. 1
). The causes of early as well as late death were not significantly different between the three groups (Table 2). The mean follow-up time was significantly longer for groups 1 and 3 compared to group 2 (Table 3).
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Fig. 1. Actuarial survival up to 10 years after cardiac transplantation comparing age group 1 (18–60 years) vs. group 2 (60–64 years) vs. group 3 (65 years).
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3.2. Initial hospitalisation and immunosuppression
The post-transplantation intubation time and intensive care unit stay were significantly longer in groups 2 and 3 (P<0.001), whereas total in hospital stay was similar between all groups. As shown in Table 2, CyA doses were similar in all groups, whereas blood levels were different, 1 month after transplantation. Prednisolone doses were lower for groups 2 and 3.
One year after transplantation, CyA doses were significantly lower in both older age groups, whereas CyA blood levels were similar in all groups. In group 3, 43.1% of patients were weaned off steroids completely compared to only 9.3 and 8.2% in groups 2 and 1, respectively (P<0.001). Nevertheless, those patients for group 3, who remained on steroids had similar doses as both the other groups.
3.3. Morbidity
Freedom from clinical rejection was significantly lower in both older patient groups at 1, 6 and 12 months: group 1 (88.7, 76.8 and 74.9%), group 2 (89.9, 85.3 and 83.5%) and group 3 (94.7, 90.6 and 90.6%) (P=0.0352; Fig. 2
). The average number of rejection episodes during the first 6 months post-transplantation were significantly lower in the oldest patient group (0.23±0.46 vs. 0.14±0.57 vs. 0.09±0.29; P<0.05).
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Fig. 2. Actuarial freedom from acute clinical rejection after cardiac transplantation is significantly higher in older patients vs. younger patients after 1 year.
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Freedom from severe infection at 1, 6 and 12 months showed a trend for lower infections in group 3: group 1 (87.1, 75.9 and 74.1%), group 2 (79.6, 67.6 and 67.7%) and group 3 (90.6, 85.3 and 85.3%) (P=0.0954; Fig. 3
).
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Fig. 3. Actuarial freedom from severe infection after cardiac transplantation comparing age group 1 (18–60 years) vs. group 2 (60–64 years) vs. group 3 (65 years).
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There was a clear trend towards a higher incidence of CMV disease in group 3: group 1 (3, 6, 12 months: 86.2, 83.2 and 82.7%), group 2 (91.3, 88.6 and 88.6%) and group 3 (81.1, 72.9 and 70.8%) (P=0.0688).
Creatinine levels were significantly lower in group 1, 1 month after transplantation (P<0.001), nevertheless they increased significantly over the first year and were similar in all groups thereafter (Table 3).
All groups showed similar incidence of angiographic documented graft arteriosclerosis 5 and 10 years after transplantation (71 vs. 61 vs. 68% and 54 vs. 53 vs. 60%; P=0.3252). Furthermore, no difference in incidence of severe graft arteriosclerosis (50% stenosis on 1 coronary vessel at 5 and 10 year follow-up (91 vs. 95 vs. 98% and 79 vs. 93 vs. 93%; P=0.1209; Fig. 4
) was documented.
Actuarial freedom from malignancy was 90 and 82% in group 1, compared to 87 and 84% in group 2 and 85 and 79% in group 3 (P=0.8132; Fig. 5
), 5 and 10 years after transplantation. All groups did not differ in the spectrum of tumors they developed: skin cancer, 5.7 vs. 5.1 vs. 12.1%, P=0.1; lymphoma, 2.1 vs. 0.7 vs. 3%, P=0.5; other, 4.6 vs. 8 vs. 4.5%, P=0.3.
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Fig. 5. Actuarial freedom from post-transplant malignant disease after cardiac transplantation comparing age group 1 (18–60 years) vs. group 2 (60–64 years) vs. group 3 (65 years) after 10 years.
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4. Discussion
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With the increasing number of elderly patients being referred for cardiac interventions, cardiologists and cardiac surgeons are faced with evaluating older patients with end-stage heart disease not amenable to further medical or conventional cardiovascular surgical therapy for heart transplantation. For a long time, advanced age by itself was considered by many programs to be an absolute contraindication to cardiac transplantation. As survival after cardiac transplantation improved, criteria including age, gradually, were relaxed. Cited in support of such a policy change were the results from several centers indicating that survivals were not significantly worse in patients older than 60 years [6–8]. Long-term survival and functional results become more relevant when the best use of a limited supply of cardiac donors is considered.
In our experience, the peri-operative mortality in patients 60 years of age or older has been the same as that in younger patients. In addition, the actuarial survival at 12 months has not differed from that in younger patients. Although older patients had longer intubation times combined with longer intensive care unit stay, their overall hospital stay did not differ from that of younger patients. Despite the fact that there was a higher incidence of diabetes mellitus, worse renal function, older donor age, a higher incidence of female donor to male recipients and a longer ischemic time in the older donors.
At this time point most centers that transplant older recipients agree that a strict recipient selection process results in good outcome [3,4]. Our center has adopted a policy towards older recipients: ‘biological age above real age’. With this policy, we propose that we do not support the use of mere chronologic age as a criterion for selecting potential heart-transplant candidates. Preoperative evaluations were similar to those performed in younger patients. However, more extensive evaluations for cancer, diverticular disease, carotid and peripheral vascular disease were performed. Moreover, examinations for osteoporosis and the impact of diabetes, if present, on end-organ function were carefully assessed. All patients were evaluated by our transplant-psychologist to verify compliance and clear understanding of the diverse implications. Acceptance rate was similar for older and younger patients (both 60%), that may have been influenced by pre-selection of transferring cardiologists.
Older patients had significant longer waiting time and higher rate of death on the waiting list. At status I, younger patients at the same size have priority. For status II patients we do not assign older patients a lower priority score, but we attempt to match older hearts to older recipients.
Our data show that older patients have comparable long-term survival rates with younger patients. Moreover, the average follow-up of our patients is longer than in all other studies, with almost 30% of our older patients having follow-up of more than 10 years. In the literature, outcome of long-term follow-up in old transplant patients is still controversial [3,4,9–13]. Moreover, the definition of advanced age for cardiac transplantation among those reports is poorly defined, having been reported as more than 55, 60, 65 years and even 70 years [3,4,6–12]. Opponents of transplantation in older patients are supported by data from the ISHLT that show significant decrease in survival at 1 and 5 years with increasing recipient age, especially in those above 65 years [6,10,12,13]. In a multicenter analysis, Bourge found that advanced age was, amongst others, pretransplantation risk factor for death after cardiac transplantation [14]. Contrary to this report, our group has shown before that in a multivariate analysis, recipient age above 60 years was no risk factor for early or late death after cardiac transplantation [15]. Differences in outcome may be influenced by the lack of standardisation of the diverse and varied methods of surgical and medical care of heart transplant patients at the various institutions.
Heart transplantation in older patients may have the advantage of an age-associated decrease in allograft rejection without a concomitant increase in opportunistic infections [16]. Aging is associated with a generalised decline in immunologic function, particularly T-effector cell-mediated immunity [17].
Because most cardiac allograft rejection episodes are T-cell mediated, we and others before us have observed a decreased incidence of rejection in older patients, particularly, when the dose of maintenance steroids is minimised in immunosuppression protocols [6,10,16]. We could successfully wean almost 50% of our patients above an age of 65 off steroids within the first year after transplantation. Thus, older patients may require less immunosuppression than younger patients. In the future, introduction of new immunosuppressive agents (e.g. rapamycin) in combination with weaning of steroid and/or calcineurin-inhibitor therapy might reduce the incidence of infection even more without endangering older patients. It is perhaps this intriguing aspect of cardiac transplantation that is indirectly responsible for the increased incidence of infection cited in some reports: Elderly patients maintained on the same immunosuppression protocol as younger patients may be more susceptible to opportunistic infections if the immunosuppression regimen is not tailored to accommodate their increased immune responsiveness [8,13]. This might have been the reason that there was a trend towards a higher incidence of CMV disease in patients above 65 years of age. New diagnostic (quantitative polymerase chain reaction (PCR)) and therapeutic (valganciclovir) tools may be good options for the future (especially in older patients) for early detection and therapy of CMV infection before potential damage of the graft can happen [18,19].
Older transplant patients may face increased risk of malignancies post-transplantation. Non-lymphoid cancers, especially skin cancer, occur more frequently in older than younger transplant recipients [4]. There are further concerns regarding the use of prophylactic antibody treatment that it may be associated with an increased risk for development of lymphoproliferative disease, especially in older patients [20,21]. Surprisingly, the incidence of malignant tumors has been no greater in older patients than in younger patients. Especially, lymphoma had a rather low incidence in all patient groups (0.7–3%). This is perhaps due to the proper tailoring of immunosuppressive protocols to accommodate the decreased immune responsiveness seen in elderly patients. The impact of an individualised approach of the immunsuppressive protocol in the final outcome of older transplant recipients cannot be overemphasised. However, continuous awareness for the development of malignant disease with the necessary surveillance for early detection is needed, as patients with cancer have a poor long-term outcome.
Another major concern for long-term morbidity and mortality is graft arteriosclerosis. The incidence of asymptomatic coronary artery disease (ACAD) in our study was significantly less compared to that of previous reports [22]. Yet the incidence of death related to graft arteriosclerosis did not differ from others [3,4,6,10–13]. The apparent similar number of deaths in our patients from this cause may, in part, be related to the observed difference in follow-up periods between our and other reports, i.e. patients in other studies were not followed long enough to develop life-threatening ACAD.
The rather low incidence of graft arteriosclerosis in our patients could be associated with low early rejection rates and the use of prophylactic antibody therapy. Our group and others have reported about the potential protective effect of induction therapy against graft arteriosclerosis before [23]. Of special interest is the fact that older patients in our analysis had an extremely low rate of severe graft arteriosclerosis, despite the fact that organ donors in this group of patients were significantly older than in the younger recipients. Moreover, the incidence of diabetes, CMV disease and ischemic times, all potential risk factors for development of graft arteriosclerosis, were higher in the older patients. One possible explanation could be that the protective effect of antibody induction treatment outweighs potential damaging factors [24,25].
In summary, our experience with cardiac transplantation in patients above 60 and 65 years of age is encouraging and indicates that advanced age per se is not a contraindication to cardiac transplantation. However, care must be taken not to interpret these data as endorsement to pursue this treatment modality in all older patients who may be candidates for cardiac transplantation. Instead, selective criteria should be applied identifying risks and benefits individually. Ultimately, advances in mechanical assist devices, such as destination therapy, organ bioengineering or stem cell therapy for regeneration will be required to address the needs of the growing population of older patients with advanced heart failure.
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Footnotes
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Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.
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Appendix A. Conference discussion
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Dr J. Svennevig (Oslo, Norway): Do you have an upper age limit in Vienna?
Dr Zuckermann: Yes. We have 70 years as the upper age limit for cardiac transplantation.
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References
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Invited commentary.
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Abstract
1. Introduction
