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Ann Thorac Surg 2008;85:2051-2055. doi:10.1016/j.athoracsur.2008.02.015
© 2008 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Impact of Recipient's Age on Heart Transplantation Outcome

Yanto Sandy Tjang, MD, DSca,b,c,*, Geert J.M.G. van der Heijden, PhDa, Gero Tenderich, MD, PhDb, Reiner Körfer, MD, PhDb, Diederick E. Grobbee, MD, PhDa,c

a Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
b Department of Thoracic & Cardiovascular Surgery, Heart & Diabetes Center NRW, Bad Oeynhausen, Germany
c Netherlands Institutes for Health Sciences, Rotterdam, the Netherlands

Accepted for publication February 5, 2008.

* Address correspondence to Dr Tjang, c/o Dr Geert van der Heijden, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands (Email: ystjang{at}hotmail.com).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 References
 
Background: The shortage of donor hearts stimulates the debate whether heart transplantation is justified for older recipients. We studied the effect of recipient's age on heart transplantation outcome in a large cohort of recipients.

Methods: Between March 1989 and December 2004, 1262 adult recipients underwent heart transplantation. Recipients were divided into two groups: 540 recipients aged younger than 55 years and 722 aged 55 years or older.

Results: The overall 30-day mortality risk was 9%, at 6% for recipients younger than 55, and 10% for recipients 55 years or older (p = 0.005). Rejection, multiorgan failure, infection, and right heart failure dominated the causes of early death in both groups. The 1-, 5-, 10-, and 15-year survival was 84%, 75%, 60%, and 50%, respectively, for recipients younger than 55 years, and 73%, 63%, 48%, and 35%, respectively, for recipients aged 55 years and older (p < 0.001). The mortality rate for those who survived the first month was 58/1000 patient-years. The main causes for late mortality were cardiac allograft vasculopathy, rejection, and infection for recipients younger than 55 years; and infection, malignancies, and rejection for recipients aged 55 years or older. Both the crude and adjusted hazard ratio increased with increasing recipient's age.

Conclusions: The outcome of heart transplantation in older recipients is less favorable than in younger recipients. The decision to offer heart transplantation to recipients older than 55 years should be considered cautiously.


   Introduction
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 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 References
 
Initially, heart transplantation was restricted to recipients aged younger than 50 years [1]. As outcomes of heart transplantation improved, the number of patients waiting for heart transplantation has markedly increased. Subsequently, the upper limit of recipient's age has been liberalized, from 55 years to currently older than 70 years [2–5]. Owing to a shortage of donor hearts, the debate remains whether heart transplantation is justified for older recipients [6]. To date, solid data on the outcome of heart transplants, in particular on the effect of increasing recipient's age on survival, are limited and controversial. Some studies have reported equivalent survival and lower rejection rates in older recipients [4, 5, 7–11], but others have reported older recipients have reduced survival after heart transplantation [2, 3, 12]. We set out to study the effect of the recipient's age on heart transplantation outcome in a large cohort of patients who underwent transplantation in our center.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 References
 
Study Population
Our study comprised 1262 adult recipients undergoing heart transplantation at the Department of Thoracic & Cardiovascular Surgery, Heart & Diabetes Center North Rhine Westphalia in Bad Oeynhausen, Germany, between March 1989 and December 2004. Heart transplantations in recipients younger than 18 years and heart retransplantations were excluded from the analysis. Our Ethics Committee approved the study, and the need for individual informed consent was waived. The cohort consisted of 1065 men (84%) and 197 women (16%), and their average age was 54 years (standard deviation, 11; range, 18 to 77 years). Dilated cardiomyopathy (631 of 1262) and ischemic cardiomyopathy (543 of 1262) were the most frequent indications for adult heart transplantation.

Recipients were divided into two groups: 540 recipients aged younger than 55 years and 722 aged 55 years or older. All heart transplant recipients met the same eligibility criteria [13]. Recipient's evaluation involved assessment of clinical conditions that commonly related to advanced age, such as malignancies and diabetes mellitus, with associated carotid and peripheral vascular disease, and end-organ dysfunction. The absolute and relative contraindications for donor hearts in our center have been previously published [14]. Donor and recipient were matched on ABO blood type compatibility and body weight.

Surgical Techniques
Donor hearts were harvested from beating-heart brain-dead persons. Graft procurement and preservation was achieved by combination of cold cardioplegic arrest, mainly using Histidine-buffered tryptophane-ketoglutarate cardioplegia solution (Bretschneider-Custodiol, Kohler Chemie, Alsbach-Hahnlein, Germany) and topical hypothermia. All orthotopic heart transplantations were performed according to the biatrial technique [15].

Immunosuppression Therapy
All recipients received comparable immunosuppressive regimens, based on initial triple-drug therapy with cyclosporine A, azathioprine, and steroids. Long-term immunosuppressive therapy consisted of cyclosporine A and azathioprine. Steroid maintenance was preferably avoided. Rejection was diagnosed by routine endomyocardial biopsy. In case of significant rejection, defined as International Society of Heart and Lung Transplantation (ISHLT) grade 3A or higher rejection [16], pulsed steroids with methylprednisolone were given for 3 days. If more than three episodes of ongoing rejection occurred, prednisone was given orally and then tapered slowly.

Outcomes Measures
Primary posttransplant outcome included early death and long-term survival. Death within 30 days after transplantation was defined as early mortality. Death occurring after 30 days of heart transplantation was considered as late mortality.

Follow-Up and Data Collection
All recipients have been monitored closely by their family physicians as well as by periodical medical evaluations in our outpatient's clinic. Generally, recipients were referred to our center for further diagnostic and medical management if major complications developed. All data on donors and recipients were collected prospectively and maintained on a computerized database. Follow-up was 100% complete.

Data Analysis
Statistical evaluations were performed with SPSS 13.0 software (SPSS Inc, Chicago, IL). Categoric variables are reported as number and percentage. Continuous variables are expressed as mean and standard deviation or median and interquartile range (IQR). For comparative evaluations, the Pearson {chi}2 test (categoric variables) and the unpaired two-tailed t test (continuous variables) were used. To avoid any possible confounding effect by baseline characteristics apart from recipient's age on outcomes, a Cox proportional hazard model adjusted for significant differences in baseline characteristics between groups was used. Survival rates were calculated with the Kaplan-Meier product-limit estimator. The log-rank test was used to compare groups. A value of p ≤ 0.05 (two-tailed test) was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 References
 
Baseline Characteristics
The recipient, donor, and operative characteristics were compared across both groups and some differences were found (Table 1). Recipients aged 55 years and older were more likely to have ischemic cardiomyopathy as an indication for heart transplantation (p < 0.001). Fewer of these recipients were in high urgency status at transplantation (p < 0.001), and fewer required a ventricular assist device (p < 0.001). Still, a higher proportion of recipients in this group had prior cardiac operations (p < 0.001). The average age of donors was significantly higher in recipients aged 55 and older (p < 0.001). Younger recipients were more likely to receive a male donor's heart (p = 0.001). A cerebrovascular accident as the cause of death in the donor was more common in recipients aged 55 and older (p < 0.001), and sex mismatch was more frequent (p < 0.001). All other factors were distributed similarly across both age groups (no significant differences).


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  		Table 1 Comparison of Baseline Characteristics by Recipient's Age
 
Early Outcomes
There were 107 deaths within 30 days after transplantation, for an overall 30-day postoperative mortality risk of 9%: 6% for recipients younger than 55, and 10% for recipients 55 years and older (p = 0.005). The main causes of early death for recipients younger than 55 were acute rejection in 7 (22%), multi-organ failure in 6 (19%), infection in 5 (16%), and right heart failure in 4 (13%). A similar distribution of causes of early death was seen in recipients aged 55 years and older (Table 2).


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  		Table 2 Distribution of Causes of Early and Late Mortality by Recipient's Age a
 
Long-Term Outcomes
The total follow-up time was 7173 person-years (median, 5.7; IQR, 1.8 to 10.1 years). During the follow-up period, 521 recipients died, resulting in a mortality rate of 73/1000 patient-years. The mortality rate for the 414 patients who survived the first month was 58/1000 patient-years. In recipients younger than 55 years, the main causes of late death were cardiac allograft vasculopathy in 38 (25%), rejection in 37 (24%), and infection in 26 (17%); and in recipients aged ≥55 years, infection in 68 (26%), malignancies in 50 (19%), and rejection in 44 (17%; Table 2).

Table 3 reports the hazard ratios for late death according to increasing age. Because of the relatively large number in this category, the recipient age category of 46 to 55 years was used as the reference for outcome comparison among the five categories. The overall mortality risk progressively increased from lowest to highest age category. This trend remained after adjustment for differences in baseline characteristics.


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  		Table 3 Hazard Ratios by Recipient's Age Categories
 
The 1-, 5-, 10-, and 15-year survival was 84%, 75%, 60%, and 50%, respectively, for recipients younger than 55; and 73%, 63%, 48%, and 35%, respectively, for recipients aged 55 years and older (p < 0.001; Fig 1).


Figure 1
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  		Fig 1. Survival comparison by recipient's age younger than 55 years (black line) vs 55 years or older (gray line).

 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
References
 
This large cohort study of 1262 heart transplant recipients found that advanced recipient age (≥55 years) was associated with increased early death and reduced long-term survival. Our data show a clear trend for recipient's age on the outcomes of heart transplantation; that is, older recipients have less favorable outcomes than younger recipients. The hazard ratios increased with increasing recipient's age; that is, relative risk increases 25% for recipient's age category of 55 to 65 years and 58% for recipient's age older than 66 years. Decline of physical condition and physiologic organ function by decay of life may contribute to the adverse outcomes.

Initially, recipient's age between 50 and 55 years was considered as an important criterion to assure a better survival [17]. However, despite significant decreased posttransplant survival for older recipients [2, 3, 12], the upper age limit for heart transplant candidates has significantly increased in recent decades, leading to continued debate about the role of the recipient's age in making decisions about heart transplantation [18]. Expanding the recipient's upper age limit beyond 55 years may cause a further growth of the waiting list in heart transplant centers, and the more frequent use of marginal donor hearts for high-risk recipients may contribute to an increase in posttransplant death [6].

However, the advances in heart transplantation during the recent decades have considerably changed the heart transplant practice in most centers; thus, heart transplant outcomes for older recipients have been reported to improve. Richenbacher and colleagues [19], for example, showed similar survival risk for recipients older and younger than age 54 years, with a 1-year survival of 78% and 81%, respectively, and 5-year survival of 52% and 66%, respectively. This finding was confirmed by several comparable single-center studies [17, 20, 21]. The conflicting results between single-center studies may be related to problems in design and conduct of studies, notably limited follow-up time or small number of patients [22]. However, recent ISHLT registry data revealed higher mortality in older transplant recipients [23].

Despite significant older donor hearts and a more common pretransplant diagnosis of ischemic cardiomyopathy, we find that late mortality due to cardiac allograft vasculopathy is less frequent in older transplant recipient, a similar finding to other studies [2]. We believe that avoiding the use of steroids in our long-term immunosuppression protocol and prophylactic and aggressive treatment of hypertension and hypercholesterolemia may attribute to the lower incidence of cardiac allograft vasculopathy. The lower risk of late mortality due to rejection in older heart transplant recipients in our study is similar to previous studies [19, 24]. An age-related decrease of immune responsiveness and T-cell function may be responsible for this effect [24].

At the same time, we found a higher risk of infectious complications and malignancies after heart transplantation. This may also be explained by a decreased immune reactivity in the older recipients and their increased susceptibility to the effects of the immunosuppressive regimen [3, 4]. Reduction of immunosuppression levels in older recipients may perhaps decrease their risk of infection and malignancies without changing the rate of rejection [2].

In conclusion, our data support the view that the outcome of heart transplantation in older recipients is less favorable than in younger recipients. The decision to offer heart transplantation to recipients older than 55 years should be considered cautiously in view of the scarcity of donor hearts.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 References
 

  1. Copeland JG, Stinson EB. Human heart transplantation Curr Probl Cardiol 1979;4:1-5.[Medline]
  2. Borkon AM, Muehlebach GF, Jones PG, et al. An analysis of the effect of age on survival after heart transplant J Heart Lung Transplant 1999;18:668-674.[Medline]
  3. Bull DA, Karwande SV, Hawkins JA, et al. Long-term results of cardiac transplantation in patients older than sixty years. UTAH Cardiac Transplant Program. J Thorac Cardiovasc Surg 1996;111:423-427.[Abstract/Free Full Text]
  4. 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;12:573-578.[Medline]
  5. Morgan JA, John R, Mancini DM, Edwards NM. Should heart transplantation be considered as a treatment option for patients aged 70 years and older? J Thorac Cardiovasc Surg 2004;127:1817-1819.[Free Full Text]
  6. Robbins RC. Ethical implications of heart transplantation in elderly patients J Thorac Cardiovasc Surg 2001;121:434-435.[Free Full Text]
  7. Blanche C, Blanche DA, Kearney B, et al. Heart transplantation in patients seventy years of age and older: A comparative analysis of outcome J Thorac Cardiovasc Surg 2001;121:532-541.[Abstract/Free Full Text]
  8. Demers P, Moffatt S, Oyer PE, Hunt SA, Reitz BA, Robbins RC. Long-term results of heart transplantation in patients older than 60 years J Thorac Cardiovasc Surg 2003;126:224-231.[Abstract/Free Full Text]
  9. McCarthy JF, McCarthy PM, Massad MG, et al. Risk factors for death after heart transplantation: does a single-center experience correlate with multicenter registries? Ann Thorac Surg 1998;65:1574-1578.[Abstract/Free Full Text]
  10. Morgan JA, John R, Weinberg AD, et al. Long-term results of cardiac transplantation in patients 65 years of age and older: a comparative analysis Ann Thorac Surg 2003;76:1982-1987.[Abstract/Free Full Text]
  11. Nagendran J, Wildhirt SM, Modry D, Mullen J, Koshal A, Wang SH. A comparative analysis of outcome after heart transplantation in patients aged 60 years and older: the University of Alberta experience J Card Surg 2004;19:559-562.[Medline]
  12. Grattan MT, Moreno-Cabral CE, Starnes VA, Oyer PE, Stinson EB, Shumway NE. Eight-year results of cyclosporine-treated patients with cardiac transplants J Thorac Cardiovasc Surg 1990;99:500-509.[Abstract]
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  16. Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant 1990;9:587-593.[Medline]
  17. Defraigne JO, Demoulin JC, Beaujean MA, Delbouille MH, Meurisse M, Limet R. Cardiac transplantation beyond 55 years of age Transpl Int 1990;3:59-61.[Medline]
  18. Fonarow GC. How old is too old for heart transplantation? Curr Opin Cardiol 2000;15:97-103.[Medline]
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  20. Carrier M, Emery RW, Riley JE, Levinson MM, Copeland JG. Cardiac transplantation in patients over 50 years of age J Am Coll Cardiol 1986;8:285-288.[Abstract]
  21. Olivari MT, Antolick A, Kaye MP, Jamieson SW, Ring WS. Heart transplantation in elderly patients J Heart Transplant 1988;7:258-264.[Medline]
  22. Peraira JR, Segovia J, Fuentes R, et al. Differential characteristics of heart transplantation in patients older than 60 years Transplant Proc 2003;35:1959-1961.[Medline]
  23. Taylor DO, Edwards LB, Boucek MM, et al. Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplantation report–2006 J Heart Lung Transplant 2006;25:869-879.[Medline]
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Invited Commentary
Michel Carrier
Ann. Thorac. Surg. 2008 85: 2055-2056. [Extract] [Full Text] [PDF]



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Ann. Thorac. Surg., June 1, 2008; 85(6): 2055 - 2056.
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