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Ann Thorac Surg 2003;76:1982-1987
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Long-term results of cardiac transplantation in patients 65 years of age and older: a comparative analysis

^a Department of Surgery, Division of Cardiothoracic Surgery, College of Physicians and Surgeons, Columbia University, New York, New York, USA

Accepted for publication June 6, 2003.

^* Address reprint requests to Dr Morgan, College of Physicians and Surgeons, Columbia University, College of Physicians and Surgeons, 177 Fort Washington Ave, Milstein 7GN-435, New York, NY, USA 10032
e-mail: jm2240{at}columbia.edu

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: Advanced age is viewed by some transplant centers as a contraindication for heart transplantation secondary to concerns regarding decreased survival.

METHODS: Between January 1992 and June 2002, 63 of 881 (7.2%) orthotopic heart transplants were performed in patients above 65 years. These patients were compared to 63 recipients below age 65 who were matched for sex, etiology of heart failure, United Network for Organ Sharing status, and immunosuppression therapy era.

RESULTS: Mean age was 67.1 ± 2.3 years (range, 65.0 to 74.8) for the older group and 48.1 ± 14.5 years (range, 18.3 to 64.4) for the younger group (p < 0.001). There was no significant difference in the incidence of diabetes, hypertension, chronic obstructive pulmonary disease, or peripheral vascular disease between the groups (p = not significant) although there were more patients with prior myocardial infarctions in the older group (p < 0.001). There was no significant difference in overall survival between the groups, with 1-, 3-, 5-, and 10-year actuarial survival of 85.8%, 80.3%, 73.1%, and 49.9% for the older group; and 86.9%, 83.4%, 75.0%, and 57.0% for the younger group (p = 0.597). Postoperative intensive care unit stay and overall hospital stay were similar for the two groups (p = not significant). There was no significant difference between the groups in freedom from infection or rejection at 1, 3, or 5 years after transplant (p = not significant) although the incidence of transplant coronary artery disease was higher in the older group (p = 0.025).

CONCLUSIONS: These data demonstrate similar short-term and long-term results for elderly and young recipients undergoing cardiac transplantation. This supports proceeding with transplantation in carefully selected elderly patients.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Life expectancy has been steadily increasing, with a current mean life expectancy of 76.9 years. The elderly have become the fastest growing segment of the population in the United States [1]. For persons older than 65 years of age, the mean life expectancy is 81.3 years for men and 84.2 years for women [2].

With an increasing life expectancy and an increasing number of elderly patients, it is not surprising that there is an increased need for cardiac surgical procedures in the elderly [3]. More elderly patients are presenting to cardiologists and cardiac surgeons with end-stage heart failure [3]. Although transplantation is an effective treatment for end-stage heart failure, many transplant centers still consider advanced age to be a relative contraindication for transplantation [4–6]. This heart transplant study was conducted to analyze and compare older patients (above 65 years) with younger patients (below 65) regarding perioperative and long-term survival, intensive care unit stay, hospital stay, development of infection, rejection, and transplant coronary artery disease (TCAD).

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Between January 1992 and June 2002, 881 orthotopic cardiac transplants were performed at the New York Presbyterian Hospital–Columbia Medical Center. Of these, 63 (7.2%) were performed in patients aged 65 years or older (range, 65.0 to 74.8). These patients were compared to a group of 63 recipients matched for sex, etiology of heart failure, United Network for Organ Sharing (UNOS) status, and immunosuppression therapy era, who were aged less than 65 years (range, 18.3 to 64.4) at the time of their transplant. Pediatric patients (younger than 18 years; n = 114) were excluded. Outcome measures included posttransplant survival, intensive care unit and overall hospital stay, incidence of infection, rejection, and TCAD.

Definition of infection
Posttransplant infection was defined by the presence of a positive culture in the blood, respiratory tract, sternum, throat, urine, stool, or viral/cytomegalovirus, and was evaluated in both groups.

Diagnosis and treatment of rejection
Rejection was defined by the presence of a positive endomyocardial biopsy, which was performed weekly for the first 4 weeks, then every 2 weeks for the next month, monthly for 4 months, every 2 months for the next 6 months, followed by every 3 months for the next 6 months, and then every 6 to 12 months. Routine treatment of grade 3A or greater rejection consisted of an increase in oral prednisone to 100 mg daily for 3 days followed by a taper for 1 week to the baseline dose. If rejection persisted based on a repeat endomyocardial biopsy or if rejection was accompanied by altered hemodynamics, intravenous methylprednisolone (1 g daily for 3 days) was used. Intravenous OKT3 (5 mg/d) was used in two conditions: grade 3A/3B or 4 rejection that persisted despite the use of a second intravenous steroid pulse or rejection with severely compromised hemodynamics. Four weeks after completion of the OKT3 course, antibodies against murine OKT3 were measured. Patients with titers of anti-OKT3 antibodies greater than 1:100 and persistent cellular rejection in the setting of compromised hemodynamics were treated with antithymocyte globulin. Hemodynamically stable patients with either persistent grade 3A/3B or 4 rejection despite multiple courses of steroids, OKT3, and antithymocyte globulin, or recurrence of grade 3A/3B rejection within 2 weeks of having completed therapy with OKT3 or antithymocyte globulin were candidates for photopheresis therapy.

Detection of transplant coronary artery disease
All patients underwent annual coronary angiography to evaluate for TCAD. The diagnosis was based on the following: (1) discrete lesions resulting in 50% or greater obstruction of the proximal or midportion of major graft vessels; or (2) diffuse, concentric narrowing of whole vessels, including their branches. If a patient had TCAD, the frequency of angiography was increased to biannually. Patients were not given routine vasodilators before coronary injections. All angiograms were reviewed by a cardiologist and compared with the previous year's films to detect the presence of luminal irregularities, discrete stenoses, loss of third-order branches, or pruning of vessels.

Donor acceptance criteria
Donor and recipients were matched for ABO blood type, compatibility, and size (generally within 20% of body weight). Prospective HLA matching was not use except in recipients with high levels of panel reactive anti-HLA antibodies (more than 20%) who underwent a prospective crossmatch. Male donors less than 40 years of age and female donors less than 45 years of age met criteria as suitable donors provided there was no evidence of preexisting heart disease or impaired myocardial dysfunction by echocardiography. Older persons also met criteria as suitable donors provided that coronary atherosclerotic lesions could be excluded, ideally by cardiac catheterization. Persons with serologies positive for human immunodeficiency virus, hepatitis B (hepatitis B sAg) hepatitis C, or nonprimary brain cancer were excluded from being donors.

Graft procurement
Donor hearts were harvested from beating heart, brain-dead patients. Graft procurement and preservation were performed using cold University of Wisconsin solution (Viaspan; DuPont Pharmaceuticals, Wilmington, DE) and topical hypothermia. Before 1996, orthotopic cardiac transplantation was performed using the biatrial technique described by Lower and Shumway [7, 8]. Since 1996, almost all transplants were performed using the bicaval anastomosis technique [9, 10].

Immunosuppressive drug regimen
Until January 1996, all patients received cyclosporine, steroids, and azathioprine. Dosing of cyclosporine consisted of a preoperative oral dose of 3 to 6 mg/kg followed by an intravenous dose of 1 to 2 mg/kg every 24 hours until oral intake was tolerated. Daily oral doses of 3 to 6 mg/kg were adjusted to maintain a serum level of 300 to 350 mg/mL. After 6 to 12 months, cyclosporine doses were reduced to maintain a serum level between 100 to 150 ng/mL. Azathioprine was also administered preoperatively as an oral dose of 4 mg/kg followed by daily doses of 2 mg/kg with adjustments in dosing made based on the patient's white blood cell count, platelet count, and hepatic function.

Since 1996, MMF starting at a dose of 1,000 mg twice daily replaced azathioprine as part of cyclosporine-based therapy. Intravenous methylprednisolone (500 mg) was administered during the operation and postoperatively with 125 mg every 8 hours for 3 doses. Prednisone was then instituted at a daily dose of 1 mg/kg and gradually tapered more than 4 months to 0.1 mg/kg daily. Intravenous murine monoclonal antibody OKT3 (5 mg/d) took the place of cyclosporine for the first 4 days after transplantation for patients with severe renal dysfunction. Beginning in 1998, induction therapy using dacluzimab was added to our standard immunosuppression therapy regimen.

Exclusion criteria
Exclusion criteria for cardiac transplantation were factors that adversely impacted long-term survival (eg, cancer), increased perioperative morbidity and mortality (eg, pulmonary hypertension, recent pulmonary embolus, active infection), or affected a patient's ability to care for himself/herself (eg, untreated major psychiatric illness, recent substance abuse). Pretransplant pulmonary hypertension, defined as greater than 6 Woods units, was also considered to be a relative contraindication to transplantation. Many of these comorbidities however are being reevaluated given our favorable experience in transplanting patients once perceived to be high risk (eg, diabetics).

Statistical analysis
Data were represented as frequency distributions and percentages. Values of continuous variables were expressed as a mean ± SD. Continuous variables were compared using paired t tests whereas categorical variables were compared by means of ² tests. For all analyses, a p value of less than 0.05 was considered statistically significant. Kaplan-Meier analysis was used to calculate survival along with a log-rank p value when comparing groups. Actuarial survival at 1, 3, 5, and 10 years after transplant was calculated by constructing life tables. Significant predictors of survival were identified using multivariate Cox Proportional Hazard Models. All data were analyzed utilizing SPSS 11.5 (SPSS, Chicago, IL).

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Recipient data
Table 1 outlines the baseline clinical demographics of both groups. Mean age for patients in the older group was 67.1 ± 2.3 years (range, 65.0 to 74.8) as compared to 48.1 ± 14.5 years (range, 18.3 to 64.4) for patients in the younger group (p < 0.001). Sex distribution and etiology of heart failure were similar for both groups. Each group was composed of 65 (88.9%) men and 7 (11.1%) women with etiology of heart disease secondary to coronary artery disease in 35 (55.6%), idiopathic cardiomyopathy in 23 (36.5%), and other in 5 (7.9%). In each group, 50 patients (79.4%) were UNOS status 1 and 13 patients (20.6%) were UNOS status 2. Left ventricular assist devices were present in significantly more patients below age 65 (15 versus 6 in the older group; p = 0.031). There was no significant difference in the incidence of diabetes, hypertension, chronic obstructive pulmonary disease, or peripheral vascular disease between the groups (p = not significant), although there were more patients with prior myocardial infarctions in the older group (49 compared with 24 in the younger group; p = < 0.001).

Survival
Overall survival is depicted in Figure 1. There was no significant difference in overall survival between the groups, with median survival of 9.0 years for the older group and 10.4 years for the younger group (p = 0.597). Actuarial survival at 1, 3, 5, and 10 years was 85.8%, 80.3%, 73.1%, and 49.9%, respectively, for the older group; and 86.9%, 83.4%, 75.0%, and 57.0%, respectively, for the younger group.

View larger version (19K): [in this window] [in a new window]   Fig 1. Long-term survival after cardiac transplantation for recipients above age 65 years (light line) and below age 65 (heavy dashed line). There was no statistically significant difference in overall survival between the groups, with median survival of 9.0 years for the older group and 10.4 years for the younger group (p = 0.597).

Infection
The incidence of infection was higher in the older group although the difference was not statistically significant. The mean number of infections per patient was 0.25 ± 0.34 in the older group compared with 0.10 ± 0.27 in the younger group (p = 0.135). Freedom from infection at 1, 3, and 5 years was 88.7%, 56.0%, and 36.2%, respectively, for the older group as compared with 98.0%, 74.8%, and 49.7% for the younger group (p = 0.406; Fig 2). The most common infection in both groups was pneumonia, occurring in 10 older patients (15.9%) and in 4 younger patients (6.3%). Median time to infection was 1350.5 days for the older group and 1788.5 days for the younger group (p = 0.082).

View larger version (22K): [in this window] [in a new window]   Fig 2. Freedom from infection after cardiac transplantation for recipients above age 65 years (light line) and below age 65 (heavy line). Median time to infection was 1350.5 days for the older group and 1788.5 days for the younger group (p = 0.406).

Transplant coronary artery disease
Freedom from TCAD at 1, 3, and 5 years was 79.3%, 44.6%, and 31.0%, respectively, for the older group as compared with 93.0%, 72.6%, and 44.2% for the younger group (p = 0.025; Fig 3). Diagnosis of TCAD occurred at a median number of days of 985.5 for the older group and 1715.5 for the younger group (p = 0.026).

View larger version (21K): [in this window] [in a new window]   Fig 3. Freedom from transplant coronary artery disease (CAD) after cardiac transplantation for recipients above age 65 years (light line) and below age 65 (heavy line). Diagnosis of transplant coronary artery disease occurred at a median number of days of 985.5 for the older group and 1715.5 for the younger group (p = 0.025).

	Comment

Top Abstract Introduction Patients and methods Results Comment References

In our series of patients older than 65 years at the time of transplantation, there was no significant difference in perioperative or long-term survival when comparing these recipients with patients younger than 65 years who were matched for sex, etiology of heart failure, UNOS status, and immunosuppression therapy era. Additionally, both groups had similar postoperative intensive care unit and overall hospital length of stays. Although not statistically significant, patients in the older group demonstrated a lower incidence of rejection and an increased incidence of infection. The former may be due to an age-associated decrease in cell-mediated immune function [21, 23]. As cardiac allograft rejection is primarily orchestrated by T-cell–mediated immune processes it would follow that elderly patients with decreased cell-mediated activity and responsiveness would exhibit a lower incidence of rejection [14, 21, 23]. That raises the issue of whether immunosuppression therapy for the elderly should be altered secondary to decreased requirement. Decreasing immunosuppressive medications in the elderly may also serve to lower their incidence of infection.

Limitations of this study include those related to a retrospectively performed analysis. Identification of demographic variables such as etiology of heart failure and comorbidities were obtained by chart review, which have inherent limitations such as access and accuracy of the data.

In conclusion, elderly patients should not be denied a transplant on the sole basis of their advanced age. We are not advocating the indiscriminate expansion of the recipient pool in the face of a static or even declining number of cardiac donors. Rather, based upon our results, we are suggesting that older recipients (more than 65 years of age) deserve a careful evaluation to assess whether they are appropriate candidates for cardiac transplantation in a manner similar to that given younger patients presenting for transplant. Our results argue that carefully selected elderly patients should be considered candidates for heart transplantation. The procedure can be performed with morbidity, mortality, hospital stay, and survival similar to that of younger patients. Advanced recipient age is not a negative predictor of survival and should not serve as a contraindication for transplantation.

In an effort to define the upper limit of safety with respect to advanced recipient age, we are in the process of reviewing our results for recipients who were more than 70 years of age at the time of cardiac transplantation. Over the last 11 years, we performed transplants for 10 patients (1.1%) who were older than 70 years at the time of transplant. We will compare this cohort of patients to recipients below 70 years of age at the time of cardiac transplantation for various outcome measures including short- and long-term survival, development of infection, rejection, and TCAD.

As one of the goals of cardiac transplantation is to increase the functional capacity of recipient patients, a quality of life analysis should be undertaken to evaluate if there are differences in the magnitude of improvement in quality of life in elderly as compared to younger recipients. Those studies would further clarify the role of heart transplantation in the elderly and such studies are underway at our institution.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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This Article Abstract Full Text (PDF) 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): Ranjit John Deon W. Vigilance Gianluigi Bisleri Mehmet C. Oz Niloo M. Edwards Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morgan, J. A. Articles by Edwards, N. M. Search for Related Content PubMed PubMed Citation Articles by Morgan, J. A. Articles by Edwards, N. M. Related Collections Transplantation - heart