- Email: [email protected]
Heart Transplantation in Patients Aged 70 Years and Older: A Two-Decade Experience
Heart Transplantation in Patients Aged 70 Years and Older: A Two-Decade Experience D. Daneshvar, L.S.C. Czer, A. Phan, E.R. Schwarz, M. De Robertis, J. Mirocha, M. Rafiei, J.R. Pixton, R.M. Kass, and A. Trento ABSTRACT Objective. Advanced age has been viewed as a contraindication to orthotopic heart transplantation (OHT). We analyzed the outcome of OHT in patients who were aged 70 years or older and compared the results with those in younger patients during a two-decade period. Methods. A total of 519 patients underwent first-time single-organ OHT at our institution from 1988 to 2009. Patients were divided into three groups by age: ⱖ 70-years old (group 1, n ⫽ 37), 60 to 69-years old (group 2, n ⫽ 206), and ⱕ60-years old (group 3, n ⫽ 276). Primary endpoints were 30-days, and 1-, 5-, and 10-years survival. Secondary outcomes included re-operation for bleeding, postoperative need for dialysis, and length of postoperative intubation. Results. There was no significant difference in survival between the greater than or equal to 70-year-old group and the two younger age groups for the first 10 years after OHT. Survival rates at 30 days, and 1-, 5-, and 10-years, and median survival in group 1 recipients were 100%, 94.6%, 83.2%, 51.7%, and 10.9 years (CI 7.1–11.0), respectively; in group 2 those numbers were 97.6%, 92.7%, 73.8%, 47.7%, and 9.1 years (CI 6.7–10.9), respectively; and in group 3 those numbers were 96.4%, 92.0%, 74.7%, 57.1%, and 12.2 years (CI 10.7–15.4; P ⫽ NS), respectively. There was no significant difference in secondary outcomes of re-operation for bleeding, postoperative need for dialysis, and prolonged intubation among the three age groups. Conclusions. Patients who are aged 70 years and older can undergo heart transplantation with similar morbidity and mortality when compared with younger recipients. Advanced heart failure patients who are aged 70 years and older should not be excluded from transplant consideration based solely on an age criterion. Stringent patient selection, however, is necessary. EART failure (HF) remains one of the most common chronic diseases affecting the population, with a prevalence of 5.7 million people in the United States alone.1 During the last 30 years, the number of deaths resulting from HF has doubled and the prevalence of HF continues to increase despite improvements in medical and surgical therapies.2 Moreover, as the population continues to age and more patients survive myocardial infarctions, the number of patients with HF is expected to increase.3 Although medical management has improved the prognosis of heart failure, orthotopic heart transplantation (OHT) remains an effective therapy for end-stage HF with 5-year
H
survival rates of 70% as opposed to only 20% to 30% without transplantation.4 Advanced age has traditionally been viewed as a contraindication for OHT. An age limit of 55 years was initially proposed to assure improved survival.5 Prior reports have From the Divisions of Cardiology and Cardiothoracic Surgery, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States. Address correspondence to Lawrence S.C. Czer, MD, Medical Director, Heart Transplant Program, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail: [email protected]
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.08.086
Transplantation Proceedings, 43, 3851–3856 (2011)
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described increased infection rates and malignancies, longer hospital stays, and poorer survival in patients with advanced age; however, recent studies have shown similar survival outcomes in carefully selected elderly patients when compared with younger patients undergoing OHT.6 –11 Based on these encouraging findings, the incidence of cardiac transplants has steadily increased in those patients older than 65 years of age.12 Despite the improved outcomes of OHT in elderly patients, the upper age limit remains poorly defined, due in part to the high demand for transplants and the scarcity of donor organs. The International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 modified the listing criteria for OHT to address the issue of transplantation in patients with advanced age. The recommendations were based on findings at multiple centers showing comparable survival rates between the older and younger age groups.13–17 The class I recommendations state that “patients should be considered for cardiac transplantation if they are ⱕ 70 years of age” (Level of Evidence: C).18 The class IIb recommendations then address patients who are ⱖ70-years old and note that “carefully selected patients ⱖ 70 years of age may be considered for cardiac transplantation” (Level of Evidence: C).18 Based on similar results with the older OHT recipient age group as described in earlier reports, 37 carefully selected patients ⱖ70-years of age have undergone cardiac transplantation at Cedars-Sinai Medical Center since December 1988 for end-stage HF refractory to medical management. This study was conducted over a two-decade period to investigate whether OHT survival and complication rates were similar in the older age group when compared with younger recipients. PATIENTS AND METHODS Consecutive recipients of single-organ OHT performed at CedarsSinai Medical Center from December 1988 to December 2009 were reviewed. Recipients were divided into three groups based on age at transplant: ⱖ 70-years old (group 1), 60- to 69-years old (group 2), and ⬍ 60-years old (group 3). Primary endpoints were 30 days and 1-, 5-, and 10-years survival, respectively. Secondary outcomes included re-operation for bleeding, postoperative need for dialysis, and postoperative intubation and persistent mechanical ventilation for more than 48 hours after transplant. The collection and analysis of data for this study was approved by the institutional review board.
Surgical Technique Three techniques for OHT were used. A total of 64 patients underwent the standard biatrial technique originally described by Shumway et al, including 41 patients who were ⬍ 60-years old, 23 patients who were 60- to 69-years old, and none who were ⱖ70-years old.19 An alternative surgical approach, previously described as total excision of the recipient atria with cardiac allograft implantation performed using bicaval and pulmonary venous anastomoses, had been used in patients since October 1991.20 This surgical technique was used in 85 patients who were ⬍ 60-years old, 79 patients who were 60- to 69-years old, and 12 patients who were
DANESHVAR, CZER, PHAN ET AL among the oldest age group. Finally, a third (modified) surgical approach was used consisting of left atrial and bicaval anastomoses in a total of 279 patients, of whom 149 patients were younger than 60 years, 105 patients were 60- to 69-years old, and 25 patients were ⱖ70-years old.
Immunosuppressive Therapy Induction therapy with either muromonab-CD3 (until 2000) or antithymocyte globulin (ATG) was used (in 2000 and thereafter). Muromonab-CD3 induction therapy was administered with 5 mg intravenously daily for 7, 10, or 14 days.21,22 Those who received antithymocyte ATG globulin were treated with 1.5 mg/kg intravenously for either 5 or 7 days, and adjusted according to platelet and white blood cell count on a daily basis.23 The same maintenance immunosuppressive therapy was used for all age groups and comprised triple therapy with calcineurin inhibitors, antiproliferative agents, and corticosteroids. Calcineurin inhibitors included either cyclosporine or tacrolimus. Cyclosporine was started at 50 mg every 12 hours once induction therapy was finished and the creatinine level was less than 2 mg/dL, with dose adjusted for blood target level of 200 to 400 ng/mL within the first 12 weeks after transplantation, then for a level of 100 to 200 mg/mL. Tacrolimus was started after induction therapy was completed and the creatinine level was less than 2 mg/dL, with dose adjusted for blood target level of 10 to 20 ng/mL during the first 12 weeks, then 6 to 10 ng/mL thereafter. Antiproliferative agents used were mycophenolate mofetil or azathioprine. Mycophenolate mofetil was started at 250 mg by mouth twice daily and increased to a target dose of 1 g by mouth twice daily (with cyclosporine) and 500 mg by mouth twice daily (with tacrolimus). Azathioprine was given the day after induction therapy was completed at a dose of 2 mg/kg and adjusted according to the white blood cell count. Patients were administered methylprednisolone intravenously during induction therapy, then transitioned to oral prednisone at 0.5 mg/kg per day, and tapered according to previously described criteria.21–23
Statistical Methods Patient preoperative group characteristics and secondary endpoints were compared using either the two-sample t test for continuous variables or the Fisher exact test for categorical data. Posttransplantation survival was modeled using the Kaplan-Meier method. The log-rank test was used to compare survival across the three age groups.
RESULTS
We reviewed 519 consecutive first-time single-organ OHTs at Cedars-Sinai Medical Center from December 1988 through December 2009. The mean age was 48.5 ⫾ 10.0 years (range, 14.8 years to 59.9 years) in the youngest group, 64.9 ⫾ 2.8 years (range, 60.0 years to 69.8 years) in patients 60- to 69-years old, and 73.3 ⫾ 2.1 years (range, 70.0 years to 77.7 years) in the oldest age group. Preoperative patient characteristics and donor characteristics by age groups are listed in Table 1 and Table 2, respectively. No statistical difference was found in the frequency of New York Heart Association functional class IV across the three age groups. The percentage of patients with diabetes mellitus was not different among the age groups. All other cardiac risk
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3853 Table 1. Preoperative Patient Characteristics
2
BMI (kg/M ) EF (%) CO (L/min) CI (L/min/M2) Creatinine (mg/dL) Males NYHA class IV Previous sternotomy Previous CABG CAD HTN Hyperlipidemia Diabetes Mellitus History of tobacco use
Age ⬍ 60 Years (n ⫽ 276)
Age 60 to 69 Years (n ⫽ 207)
Age ⱖ 70 Years (n ⫽ 37)
P Value
26.3 ⫾ 5.2 21.4 ⫾ 10.2 4.2 ⫾ 1.4 2.1 ⫾ 0.7 1.2 ⫾ 0.4 74.3% 63.0% 42.0% 23.2% 52.2% 38.9% 41% 13.4% 60.9%
25.2 ⫾ 4.0 22.9 ⫾ 8.1 4.0 ⫾ 1.2 2.1 ⫾ 0.6 1.4 ⫾ 0.9 86% 58.5% 58.5% 45.4% 79.2% 53.6% 56.8% 16.4% 68.4%
24.8 ⫾ 3.4 23.0 ⫾ 9.4 3.8 ⫾ 1.0 2.0 ⫾ 0.7 1.4 ⫾ 0.3 91.9% 56.8% 64.9% 56.8% 86.5% 37.8% 44.4% 11.1% 47.1%
.001 .52 .0003 ⬍.0001 ⬍.0001 .004 .005 .012 .0004
Abbreviations: BMI, body mass index; EF, ejection fraction; CO, cardiac output; CI, cardiac index; NYHA, New York Heart Association; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; HTN, hypertension.
factors, including hypertension, hyperlipidemia, and history of tobacco use were found to be significantly different among the three age groups. Patients who were ⱖ70-years old were more likely to have coronary artery disease, prior cardiac bypass surgery, and sternotomy, yet lower rates of hypertension, diabetes mellitus, and smoking when compared with the youngest age group. Survival did not differ between the ⱖ70-year-old group and the younger age groups for the first 10 years after OHT (Fig 1). The 30 day (operative) survivals for those ⬍ 60-years old, 60- to- 69-years old, and ⱖ70-years old were 96.4%, 97.6%, and 100%, respectively (P ⫽ .76). Percentage survival rates at 1, 5, and 10 years for those patients ⬍ 60-years old were 92.0%, 74.7%, and 57.1%, respectively, and median survival was 12.2 years (95% confidence interval [CI] 10.7–15.4); for those 60- to 69-years old, they were 92.7%, 73.8%, and 47.7%, respectively, and median survival was 9.1 years (CI 6.7–10.9); and for the oldest age group, the rates were 94.6%, 83.2%, and 51.7% respectively, and median survival was 9.1 years (CI 7.1–11.0). No significant statistical difference was found in survival between the older and younger patients for the first 10 years after OHT. There was no significant difference in re-operation for bleeding, postoperative need for dialysis, and prolonged intubation among the three age groups (Table 3).
DISCUSSION
This study describes the largest cohort of OHT recipients to date who were ⱖ70 years old of age at the time of transplant, and reveals similar morbidity and mortality when compared with younger recipients. Thirty-day (operative) survival, along with 10-year survival after heart transplantation in the oldest age group was similar to recipients between 60 and 69 years of age and those ⱕ60-years old. The main criticism of OHT in elderly patients has been that they may not have the same duration of benefit from heart transplantation, especially when considering the critical shortage of organ supply. Yet the recovery and length of survival posttransplantation which this study shows bodes well for further studies in this elderly age group. Reports from Morgan et al and Blanche et al were previously the only studies analyzing OHT in septuagenarians with the conclusion that advanced age alone should not be considered an absolute contraindication to transplantation.10,24 The proportion of people in the United States who are considered elderly has steadily increased during the last 20 years, notably for those people who are older than 75 years. As life expectancy continues to increase, with the current average life expectancy in the United States at ⬎78 years,
Table 2. Donor Characteristics Variable
Overall (N ⫽ 519)
Age ⬍ 60 Years (N ⫽ 275)
Age 60 to 69 Years (N ⫽ 207)
Age ⱖ 70 Years (N ⫽ 37)
P Value
Donor male, % (n/N) Donor age (y) Donor height (cm) Donor weight (kg) Donor BSA (M2) Donor/recipient Weight ratio Weight Mismatch, % (n/N)
72.6 (376/518) 31.2 ⫾ 12.3 (509) 173.9 ⫾ 10.6 (516) 78.5 ⫾ 18.0 (516) 1.94 ⫾ 0.25 (516) 1.03 ⫾ 0.26 (516) 25.8 (133/516)
74.1 (203/274) 30.3 ⫾ 12.1 (269) 174.4 ⫾ 10.5 (274) 77.6 ⫾ 17.2 (274) 1.93 ⫾ 0.25 (274) 1.01 ⫾ 0.28 (274) 25.2 (69/274)
73.4 (152/207) 31.4 ⫾ 12.2 (203) 174.2 ⫾ 9.6 (205) 79.6 ⫾ 18.7 (205) 1.95 ⫾ 0.24 (205) 1.07 ⫾ 0.27 (205) 26.3 (54/205)
56.8 (21/37) 35.8 ⫾ 13.0 (37) 169.1 ⫾ 14.1 (37) 78.2 ⫾ 20.6 (37) 1.91 ⫾ 0.30 (37) 1.04 ⫾ 0.28 (37) 27.0 (10/37)
.092 .036 .015 .48 .47 .034 .94
Numerical variables: Mean ⫾ SD (N). Categorical variables: % (n/N). Abbreviation: BSA, body surface area.
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Fig 1. Survival curves after heart transplantation by age group.
prior age contraindications to transplantation must be reconsidered.25 Still, many programs exclude recipients who are ⱖ 65 because many believe that advanced age is a risk factor for poor long-term prognosis.26 The upper age limit for OHT, initially 55 years of age, is currently undefined.27 According to data from the Organ Procurement and Transplantation Network, as of 2008, there have been 45,275 transplantations in the United States alone, with 3357 performed in patients who are ⱖ 65-years old.28 Recipient survival rates between 1997 and 2004 listed in the databank indicate that patients with advanced age ⬎ 65 years have higher mortality than other age groups, with survival rates of 84.3% and 65.4% at 1-year and 5-years, respectively.29 Despite the lower survival rate and the decrease in number of overall cardiac transplants, there continues to be an increase in the number of OHTs in elderly recipients. In fact, older candidates have the highest percentage increase in transplantation among the different age groups while on the waiting list.30 According to the United Network for Organ Sharing (UNOS) data, 11.7% of transplants in 2008 were in patients who were older than 65 years, up from 2.1% only 10 years earlier.28 Interestingly, the majority of OHTs in the elderly population who are ⱖ 65-years old occur in North America.31 After several studies showed proficiency in OHT in patients who were ⬎ 55-years old, two groups reported on their results in septuagenarians.32,33 Blanche et al from our group described an initial experience in six patients who were ⱖ 70-years old who underwent OHT.24 The findings showed no significant difference in morbidity and shortterm survival when comparing younger recipients with patients who were ⱖ 70-years old. A later report in 2001 by our group found that actuarial survival at 1 year and 4 years was not statistically different when comparing patients who were older with those who were younger than 70 years, 93.3% ⫾ 6.4% versus 88.3% ⫾ 3.3% and 73.5% ⫾ 13.6% versus 69.1% ⫾ 5.8%, respectively.14 These findings were
DANESHVAR, CZER, PHAN ET AL
reinforced by Morgan et al who found no significant differences in short- or long-term survival rates in recipients who were more than 70-years old when compared with those of younger recipients.10 The consensus was that age older than 70 years should not serve as an exclusion criterion for heart transplantation based on the comparable morbidity and mortality in carefully selected individuals. Although much of the literature on this topic has been from single-center studies, a retrospective analysis of the UNOS database was performed over a 7-year period to review OHT outcomes in recipients who were ⱖ 60-years old in comparison with younger patients, aged 18- to 59-years old.34 During that period, 212 patients who were ⱖ 70-years old underwent OHT with a 5-year survival rate of 61%, compared to 5-year survival rates of 75% and 69% in recipients ⬍60-years old, and those between 60- and 69years old, respectively. An important factor in these results was that the elderly transplantation candidates were typically placed on a separate list to receive higher-risk donors, a possible explanation for higher mortality rates.35 Several factors exist for the favorable outcome in the elderly age group in the current study. The patients who were ⱖ 70-years old were carefully selected to optimize outcomes when receiving such a scarce organ. As expected, the elderly age group had a higher incidence of coronary artery disease and prior cardiac bypass surgery. Elderly patients with increased risk factors compared to younger OHT candidates were not listed for transplantation. They were less likely to be listed for transplantation if they had other comorbidities such as hypertension, diabetes mellitus, hyperlipidemia, obesity, and use of inotrope therapy. Also, advances in posttransplantation management of these patients, including the monitoring of acute cellular and antibodymediated rejection and advances in the detection and management of infection and malignancy, have contributed to improved survival.36 Also, despite the more common use of alternative transplantation lists for higher-risk patients, including elderly candidates awaiting OHT, patients in this study were placed on a single list receiving similar cardiac donors. Based on prior favorable outcomes in patients who were ⱖ70-years old with the use of a separate list, marginal donors are no longer used for elderly patients at this institution to avoid age discrimination.14,24 Although the concept of an alternative list and use of marginal donors may seem rational based on the critical shortage of donor hearts, the issue remains controversial for several reasons. Elderly patients Table 3. Postoperative Complications Age ⬍ 60 Years n ⫽ 276
Re-operation for bleeding Postoperative dialysis Ventilator for ⬎ 48 hours
Age 60 to 69 Years n ⫽ 206
Age ⱖ 70 Years n ⫽ 37
P Value
9.5%
9.7%
8.1%
⬎.95
7.1% 18.1%
6.8% 16.3%
5.4% 32%
⬎.95 .19
HEART TRANSPLANTATION IN ELDERLY
placed on such a list may have artificially higher mortality rates because they are receiving higher-risk donor organs. This may partially explain why other studies show a higher mortality in this population. The alternative list may further be disadvantageous for those younger patients on the standard transplantation list if the marginal donor hearts in fact have favorable outcomes in higher-risk recipients. Given the conflicting evidence, the issue of whether older patients should be considered equally for OHT is still a matter of great debate. The problematic issue is the critical shortage of donor organs which has been further exacerbated by the extension of the recipient age limit. Yet, with continued advances in medical and surgical therapies, such as cardiac resynchronization therapy, mortality rates have continued to decrease in the past decade.37 Also, the increased use of mechanical circulatory support therapy, such as ventricular-assist devices as bridging and destination therapy, has provided more treatment options for end-stage heart disease, especially for those patients unable to undergo transplantation.38,39 Study Limitations
Limitations of this study include those attributed to a single center nonrandomized retrospective experience with a small sample size for elderly patients who were ⱖ70 years of age. The selection process for transplantation candidates was not uniform in this study because elderly patients with comorbidities were excluded. Although the data is incomplete over the 20-year period, the prior study by Blanche et al showed an equivalent recipient-acceptance ratio between the elderly and younger age groups.14 CONCLUSION
The findings in this study comparing septuagenarians to younger OHT recipients reveal that advanced age should not be a contraindication for heart transplantation. As life expectancy continues to increase, it will be necessary to continually redefine what is considered elderly. At the current time, there are no guidelines on the upper age limit for OHT, but this study shows promising results for those patients who are ⱖ70 years of age. Although there is a growing gap between cardiac organ donors and recipients, older recipients deserve a careful and thorough evaluation for undergoing transplantation when other medical therapies for end-stage HF have failed. Many questions regarding this difficult topic remain unanswered. As the population ages, the demand for OHT will further grow, and the issue of age limits will need to be re-addressed with the widened recipient pool. Also, the study raises the issue whether transplantation in the elderly age group should be restricted to specialized centers with experience in the field. The use of the alternate-list strategy requires additional examination given the disadvantage it can have for older and younger recipients as well. The current ISHLT listing criteria guidelines supports transplantation in patients who are ⱖ70 years of age if they meet
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specific criteria and recommend the use of an alternate list to avoid the worsening shortage of donor hearts for younger patients.40 Further studies are necessary to address the growing transplantation waiting list and the experience of recipients who are ⱖ70-years old. In conclusion, our 20-year experience with OHT in the elderly indicates that there was no significant difference in long-term survival between the elderly age group (ⱖ70years old) and the younger age groups after transplantation. Despite advanced age, appropriate candidates for OHT should be allowed placement on the transplantation waiting list after careful evaluation and screening as transplantation remains their best option for long-term survival. REFERENCES 1. Lloyd-Jones D, Adams R, Carnethon M, et al: Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119:e21, 2009 2. Bleumink GS, Knetsch AM, Sturkenboom MC, et al: Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J 1614, 2004 3. Braunwald E: Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw Hill; 1998 4. Hertz MI, Taylor DO, Trulock EP, et al: The registry of the international society for heart and lung transplantation: nineteenth official report-2002. J Heart Lung Transplant 21:950, 2002 5. Defraigne JO, Demoulin JC, Beaujean MA, et al: Cardiac transplantation beyond 55 years of age. Transpl Int 3:59, 1990 6. Borkon AM, Muehlebach GF, Jones PG, et al: An analysis of the effect of age on survival after heart transplant. J Heart Lung Transplant 18:668, 1999 7. 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 111:423, 1996; [discussion 7] 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 12:573, 1993 [discussion 8] 9. Forni A, Faggian G, Chiominto B, et al: Heart transplantation in older candidates. Transplant Proc 39:1963, 2007 10. Morgan JA, John R, Mancini DM, et al: Should heart transplantation be considered as a treatment option for patients aged 70 years and older? J Thorac Cardiovasc Surg 127:1817, 2004 11. Nagendran J, Wildhirt SM, Modry D, et al: A comparative analysis of outcome after heart transplantation in patients aged 60 years and older: the University of Alberta experience. J Card Surg 19:559, 2004 12. Taylor DO, Edwards LB, Boucek MM, et al: Registry of the International Society for Heart and Lung Transplantation: twentysecond official adult heart transplant report—2005. J Heart Lung Transplant 24:945, 2005 13. Laks H, Marelli D, Fonarow GC, et al: Use of two recipient lists for adults requiring heart transplantation. J Thorac Cardiovasc Surg 125:49, 2003 14. 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 121:532, 2001 15. Zuckermann A, Dunkler D, Deviatko E, et al: Long-term survival (⬎10 years) of patients ⬎ 60 years with induction therapy after cardiac transplantation. Eur J Cardiothorac Surg 24:283, 2003 16. Demers P, Moffatt S, Oyer PE, et al: Long-term results of heart transplantation in patients older than 60 years. J Thorac Cardiovasc Surg 126:224, 2003
3856 17. Kobashigawa JA: Early and late complications in the elderly heart transplant recipient. Cardiol Elderly 4:15, 1996 18. Mehra MR, Kobashigawa J, Starling R, et al: Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant 1024, 2006 19. Shumway NE, Lower RR, Stofer RC: Transplantation of the heart. Adv Surg 2:265, 1966 20. Blanche C, Valenza M, Aleksic I, et al: 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 (Torino) 35:283, 1994 21. Aleksic I, Freimark D, Blanche C, et al: The duration of administration of monoclonal antibody OKT3 for induction immunosuppression after heart transplantation. Thoracic Cardiovasc Surg 45:190, 1997 22. Aleksic A, Freimark D, Blanche C, et al: Hemodynamics during humoral rejection events with total versus standard orthotopic heart transplantation. Ann Thorac Cardiovasc Surg 10: 285, 2004 23. Goland S, Czer LS, Coleman B, et al: Induction therapy with thymoglobulin after heart transplantation: impact of therapy duration on lymphocyte depletion and recovery, rejection, and CMV infection rates. J Heart Lung Transplant 27:1115, 2008 24. Blanche C, Matloff JM, Denton TA, et al: Heart transplantation in patients 70 years of age and older: initial experience. Ann Thorac Surg 62:1731, 1996 25. US Census Bureau: Available at: http://www.census.gov/ compendia/statab/cats/births_deaths_marriages_divorces/life_expectancy. html. Accessed June 22, 2011 26. Taylor DO, Edwards LB, Boucek MM, et al: The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report—2004. J Heart Lung Transplant 23:796, 2004 27. Copeland JG, Stinson EB: Human heart transplantation. Curr Probl Cardiol 4:1, 1979 28. Organ Procurement and Transplantation Network. Organ by age. United Network for Organ Sharing, 2007. Available at: http://www.optn.org/latestData/rptData.asp. Accessed June 22, 2011
DANESHVAR, CZER, PHAN ET AL 29. 2006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1996 –2005; Available at: http:// www.optn.transplant.hrsa.gov/data/annualreport.asp. Accessed June 22, 2011 30. Taylor DO, Edwards LB, Boucek MM, et al: Registry of the International Society for Heart and Lung Transplantation: twentythird official adult heart transplantation report—2006. J Heart Lung Transplant 25:869, 2006 31. The International Society for Heart & Lung Transplantation. ISHLT Transplant Quarterly Reports for Heart in North America. 2008. Available at: http://www.ishlt.org/registries. Accessed June 22, 2011 32. Olivari MT, Antolick A, Kaye MP, et al: Heart transplantation in elderly patients. J Heart Transplant 7:258, 1988 33. Frazier OH, Macris MP, Duncan JM, et al: Cardiac transplantation in patients over 60 years of age. Ann Thorac Surg 45:129, 1988 34. Weiss ES, Nwakanma LU, Patel ND, et al: Outcomes in patients older than 60 years of age undergoing orthotopic heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant 27:184, 2008 35. Robbins RC: Ethical implications of heart transplantation in elderly patients. J Thorac Cardiovasc Surg 121:434, 2001 36. Itescu S, Tung TC, Burke EM, et al: An immunological algorithm to predict risk of high-grade rejection in cardiac transplant recipients. Lancet 352:263, 1998 37. Cleland JG, Daubert JC, Erdmann E, et al: The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352:1539, 2005 38. de Jonge N, Kirkels H, Lahpor JR, et al: Exercise performance in patients with end-stage heart failure after implantation of a left ventricular assist device and after heart transplantation: an outlook for permanent assisting? J Am Coll Cardiol 37:1794, 2001 39. Rose EA, Gelijns AC, Moskowitz AJ, et al: Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 345:1435, 2001 40. Mehra MR, Kobashigawa J, Starling R, et al: Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant 1024, 2006
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survival rates of 70% as opposed to only 20% to 30% without transplantation.4 Advanced age has traditionally been viewed as a contraindication for OHT. An age limit of 55 years was initially proposed to assure improved survival.5 Prior reports have From the Divisions of Cardiology and Cardiothoracic Surgery, Cedars-Sinai Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States. Address correspondence to Lawrence S.C. Czer, MD, Medical Director, Heart Transplant Program, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail: [email protected]
© 2011 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.08.086
Transplantation Proceedings, 43, 3851–3856 (2011)
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described increased infection rates and malignancies, longer hospital stays, and poorer survival in patients with advanced age; however, recent studies have shown similar survival outcomes in carefully selected elderly patients when compared with younger patients undergoing OHT.6 –11 Based on these encouraging findings, the incidence of cardiac transplants has steadily increased in those patients older than 65 years of age.12 Despite the improved outcomes of OHT in elderly patients, the upper age limit remains poorly defined, due in part to the high demand for transplants and the scarcity of donor organs. The International Society for Heart and Lung Transplantation (ISHLT) guidelines in 2006 modified the listing criteria for OHT to address the issue of transplantation in patients with advanced age. The recommendations were based on findings at multiple centers showing comparable survival rates between the older and younger age groups.13–17 The class I recommendations state that “patients should be considered for cardiac transplantation if they are ⱕ 70 years of age” (Level of Evidence: C).18 The class IIb recommendations then address patients who are ⱖ70-years old and note that “carefully selected patients ⱖ 70 years of age may be considered for cardiac transplantation” (Level of Evidence: C).18 Based on similar results with the older OHT recipient age group as described in earlier reports, 37 carefully selected patients ⱖ70-years of age have undergone cardiac transplantation at Cedars-Sinai Medical Center since December 1988 for end-stage HF refractory to medical management. This study was conducted over a two-decade period to investigate whether OHT survival and complication rates were similar in the older age group when compared with younger recipients. PATIENTS AND METHODS Consecutive recipients of single-organ OHT performed at CedarsSinai Medical Center from December 1988 to December 2009 were reviewed. Recipients were divided into three groups based on age at transplant: ⱖ 70-years old (group 1), 60- to 69-years old (group 2), and ⬍ 60-years old (group 3). Primary endpoints were 30 days and 1-, 5-, and 10-years survival, respectively. Secondary outcomes included re-operation for bleeding, postoperative need for dialysis, and postoperative intubation and persistent mechanical ventilation for more than 48 hours after transplant. The collection and analysis of data for this study was approved by the institutional review board.
Surgical Technique Three techniques for OHT were used. A total of 64 patients underwent the standard biatrial technique originally described by Shumway et al, including 41 patients who were ⬍ 60-years old, 23 patients who were 60- to 69-years old, and none who were ⱖ70-years old.19 An alternative surgical approach, previously described as total excision of the recipient atria with cardiac allograft implantation performed using bicaval and pulmonary venous anastomoses, had been used in patients since October 1991.20 This surgical technique was used in 85 patients who were ⬍ 60-years old, 79 patients who were 60- to 69-years old, and 12 patients who were
DANESHVAR, CZER, PHAN ET AL among the oldest age group. Finally, a third (modified) surgical approach was used consisting of left atrial and bicaval anastomoses in a total of 279 patients, of whom 149 patients were younger than 60 years, 105 patients were 60- to 69-years old, and 25 patients were ⱖ70-years old.
Immunosuppressive Therapy Induction therapy with either muromonab-CD3 (until 2000) or antithymocyte globulin (ATG) was used (in 2000 and thereafter). Muromonab-CD3 induction therapy was administered with 5 mg intravenously daily for 7, 10, or 14 days.21,22 Those who received antithymocyte ATG globulin were treated with 1.5 mg/kg intravenously for either 5 or 7 days, and adjusted according to platelet and white blood cell count on a daily basis.23 The same maintenance immunosuppressive therapy was used for all age groups and comprised triple therapy with calcineurin inhibitors, antiproliferative agents, and corticosteroids. Calcineurin inhibitors included either cyclosporine or tacrolimus. Cyclosporine was started at 50 mg every 12 hours once induction therapy was finished and the creatinine level was less than 2 mg/dL, with dose adjusted for blood target level of 200 to 400 ng/mL within the first 12 weeks after transplantation, then for a level of 100 to 200 mg/mL. Tacrolimus was started after induction therapy was completed and the creatinine level was less than 2 mg/dL, with dose adjusted for blood target level of 10 to 20 ng/mL during the first 12 weeks, then 6 to 10 ng/mL thereafter. Antiproliferative agents used were mycophenolate mofetil or azathioprine. Mycophenolate mofetil was started at 250 mg by mouth twice daily and increased to a target dose of 1 g by mouth twice daily (with cyclosporine) and 500 mg by mouth twice daily (with tacrolimus). Azathioprine was given the day after induction therapy was completed at a dose of 2 mg/kg and adjusted according to the white blood cell count. Patients were administered methylprednisolone intravenously during induction therapy, then transitioned to oral prednisone at 0.5 mg/kg per day, and tapered according to previously described criteria.21–23
Statistical Methods Patient preoperative group characteristics and secondary endpoints were compared using either the two-sample t test for continuous variables or the Fisher exact test for categorical data. Posttransplantation survival was modeled using the Kaplan-Meier method. The log-rank test was used to compare survival across the three age groups.
RESULTS
We reviewed 519 consecutive first-time single-organ OHTs at Cedars-Sinai Medical Center from December 1988 through December 2009. The mean age was 48.5 ⫾ 10.0 years (range, 14.8 years to 59.9 years) in the youngest group, 64.9 ⫾ 2.8 years (range, 60.0 years to 69.8 years) in patients 60- to 69-years old, and 73.3 ⫾ 2.1 years (range, 70.0 years to 77.7 years) in the oldest age group. Preoperative patient characteristics and donor characteristics by age groups are listed in Table 1 and Table 2, respectively. No statistical difference was found in the frequency of New York Heart Association functional class IV across the three age groups. The percentage of patients with diabetes mellitus was not different among the age groups. All other cardiac risk
HEART TRANSPLANTATION IN ELDERLY
3853 Table 1. Preoperative Patient Characteristics
2
BMI (kg/M ) EF (%) CO (L/min) CI (L/min/M2) Creatinine (mg/dL) Males NYHA class IV Previous sternotomy Previous CABG CAD HTN Hyperlipidemia Diabetes Mellitus History of tobacco use
Age ⬍ 60 Years (n ⫽ 276)
Age 60 to 69 Years (n ⫽ 207)
Age ⱖ 70 Years (n ⫽ 37)
P Value
26.3 ⫾ 5.2 21.4 ⫾ 10.2 4.2 ⫾ 1.4 2.1 ⫾ 0.7 1.2 ⫾ 0.4 74.3% 63.0% 42.0% 23.2% 52.2% 38.9% 41% 13.4% 60.9%
25.2 ⫾ 4.0 22.9 ⫾ 8.1 4.0 ⫾ 1.2 2.1 ⫾ 0.6 1.4 ⫾ 0.9 86% 58.5% 58.5% 45.4% 79.2% 53.6% 56.8% 16.4% 68.4%
24.8 ⫾ 3.4 23.0 ⫾ 9.4 3.8 ⫾ 1.0 2.0 ⫾ 0.7 1.4 ⫾ 0.3 91.9% 56.8% 64.9% 56.8% 86.5% 37.8% 44.4% 11.1% 47.1%
.001 .52 .0003 ⬍.0001 ⬍.0001 .004 .005 .012 .0004
Abbreviations: BMI, body mass index; EF, ejection fraction; CO, cardiac output; CI, cardiac index; NYHA, New York Heart Association; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; HTN, hypertension.
factors, including hypertension, hyperlipidemia, and history of tobacco use were found to be significantly different among the three age groups. Patients who were ⱖ70-years old were more likely to have coronary artery disease, prior cardiac bypass surgery, and sternotomy, yet lower rates of hypertension, diabetes mellitus, and smoking when compared with the youngest age group. Survival did not differ between the ⱖ70-year-old group and the younger age groups for the first 10 years after OHT (Fig 1). The 30 day (operative) survivals for those ⬍ 60-years old, 60- to- 69-years old, and ⱖ70-years old were 96.4%, 97.6%, and 100%, respectively (P ⫽ .76). Percentage survival rates at 1, 5, and 10 years for those patients ⬍ 60-years old were 92.0%, 74.7%, and 57.1%, respectively, and median survival was 12.2 years (95% confidence interval [CI] 10.7–15.4); for those 60- to 69-years old, they were 92.7%, 73.8%, and 47.7%, respectively, and median survival was 9.1 years (CI 6.7–10.9); and for the oldest age group, the rates were 94.6%, 83.2%, and 51.7% respectively, and median survival was 9.1 years (CI 7.1–11.0). No significant statistical difference was found in survival between the older and younger patients for the first 10 years after OHT. There was no significant difference in re-operation for bleeding, postoperative need for dialysis, and prolonged intubation among the three age groups (Table 3).
DISCUSSION
This study describes the largest cohort of OHT recipients to date who were ⱖ70 years old of age at the time of transplant, and reveals similar morbidity and mortality when compared with younger recipients. Thirty-day (operative) survival, along with 10-year survival after heart transplantation in the oldest age group was similar to recipients between 60 and 69 years of age and those ⱕ60-years old. The main criticism of OHT in elderly patients has been that they may not have the same duration of benefit from heart transplantation, especially when considering the critical shortage of organ supply. Yet the recovery and length of survival posttransplantation which this study shows bodes well for further studies in this elderly age group. Reports from Morgan et al and Blanche et al were previously the only studies analyzing OHT in septuagenarians with the conclusion that advanced age alone should not be considered an absolute contraindication to transplantation.10,24 The proportion of people in the United States who are considered elderly has steadily increased during the last 20 years, notably for those people who are older than 75 years. As life expectancy continues to increase, with the current average life expectancy in the United States at ⬎78 years,
Table 2. Donor Characteristics Variable
Overall (N ⫽ 519)
Age ⬍ 60 Years (N ⫽ 275)
Age 60 to 69 Years (N ⫽ 207)
Age ⱖ 70 Years (N ⫽ 37)
P Value
Donor male, % (n/N) Donor age (y) Donor height (cm) Donor weight (kg) Donor BSA (M2) Donor/recipient Weight ratio Weight Mismatch, % (n/N)
72.6 (376/518) 31.2 ⫾ 12.3 (509) 173.9 ⫾ 10.6 (516) 78.5 ⫾ 18.0 (516) 1.94 ⫾ 0.25 (516) 1.03 ⫾ 0.26 (516) 25.8 (133/516)
74.1 (203/274) 30.3 ⫾ 12.1 (269) 174.4 ⫾ 10.5 (274) 77.6 ⫾ 17.2 (274) 1.93 ⫾ 0.25 (274) 1.01 ⫾ 0.28 (274) 25.2 (69/274)
73.4 (152/207) 31.4 ⫾ 12.2 (203) 174.2 ⫾ 9.6 (205) 79.6 ⫾ 18.7 (205) 1.95 ⫾ 0.24 (205) 1.07 ⫾ 0.27 (205) 26.3 (54/205)
56.8 (21/37) 35.8 ⫾ 13.0 (37) 169.1 ⫾ 14.1 (37) 78.2 ⫾ 20.6 (37) 1.91 ⫾ 0.30 (37) 1.04 ⫾ 0.28 (37) 27.0 (10/37)
.092 .036 .015 .48 .47 .034 .94
Numerical variables: Mean ⫾ SD (N). Categorical variables: % (n/N). Abbreviation: BSA, body surface area.
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Fig 1. Survival curves after heart transplantation by age group.
prior age contraindications to transplantation must be reconsidered.25 Still, many programs exclude recipients who are ⱖ 65 because many believe that advanced age is a risk factor for poor long-term prognosis.26 The upper age limit for OHT, initially 55 years of age, is currently undefined.27 According to data from the Organ Procurement and Transplantation Network, as of 2008, there have been 45,275 transplantations in the United States alone, with 3357 performed in patients who are ⱖ 65-years old.28 Recipient survival rates between 1997 and 2004 listed in the databank indicate that patients with advanced age ⬎ 65 years have higher mortality than other age groups, with survival rates of 84.3% and 65.4% at 1-year and 5-years, respectively.29 Despite the lower survival rate and the decrease in number of overall cardiac transplants, there continues to be an increase in the number of OHTs in elderly recipients. In fact, older candidates have the highest percentage increase in transplantation among the different age groups while on the waiting list.30 According to the United Network for Organ Sharing (UNOS) data, 11.7% of transplants in 2008 were in patients who were older than 65 years, up from 2.1% only 10 years earlier.28 Interestingly, the majority of OHTs in the elderly population who are ⱖ 65-years old occur in North America.31 After several studies showed proficiency in OHT in patients who were ⬎ 55-years old, two groups reported on their results in septuagenarians.32,33 Blanche et al from our group described an initial experience in six patients who were ⱖ 70-years old who underwent OHT.24 The findings showed no significant difference in morbidity and shortterm survival when comparing younger recipients with patients who were ⱖ 70-years old. A later report in 2001 by our group found that actuarial survival at 1 year and 4 years was not statistically different when comparing patients who were older with those who were younger than 70 years, 93.3% ⫾ 6.4% versus 88.3% ⫾ 3.3% and 73.5% ⫾ 13.6% versus 69.1% ⫾ 5.8%, respectively.14 These findings were
DANESHVAR, CZER, PHAN ET AL
reinforced by Morgan et al who found no significant differences in short- or long-term survival rates in recipients who were more than 70-years old when compared with those of younger recipients.10 The consensus was that age older than 70 years should not serve as an exclusion criterion for heart transplantation based on the comparable morbidity and mortality in carefully selected individuals. Although much of the literature on this topic has been from single-center studies, a retrospective analysis of the UNOS database was performed over a 7-year period to review OHT outcomes in recipients who were ⱖ 60-years old in comparison with younger patients, aged 18- to 59-years old.34 During that period, 212 patients who were ⱖ 70-years old underwent OHT with a 5-year survival rate of 61%, compared to 5-year survival rates of 75% and 69% in recipients ⬍60-years old, and those between 60- and 69years old, respectively. An important factor in these results was that the elderly transplantation candidates were typically placed on a separate list to receive higher-risk donors, a possible explanation for higher mortality rates.35 Several factors exist for the favorable outcome in the elderly age group in the current study. The patients who were ⱖ 70-years old were carefully selected to optimize outcomes when receiving such a scarce organ. As expected, the elderly age group had a higher incidence of coronary artery disease and prior cardiac bypass surgery. Elderly patients with increased risk factors compared to younger OHT candidates were not listed for transplantation. They were less likely to be listed for transplantation if they had other comorbidities such as hypertension, diabetes mellitus, hyperlipidemia, obesity, and use of inotrope therapy. Also, advances in posttransplantation management of these patients, including the monitoring of acute cellular and antibodymediated rejection and advances in the detection and management of infection and malignancy, have contributed to improved survival.36 Also, despite the more common use of alternative transplantation lists for higher-risk patients, including elderly candidates awaiting OHT, patients in this study were placed on a single list receiving similar cardiac donors. Based on prior favorable outcomes in patients who were ⱖ70-years old with the use of a separate list, marginal donors are no longer used for elderly patients at this institution to avoid age discrimination.14,24 Although the concept of an alternative list and use of marginal donors may seem rational based on the critical shortage of donor hearts, the issue remains controversial for several reasons. Elderly patients Table 3. Postoperative Complications Age ⬍ 60 Years n ⫽ 276
Re-operation for bleeding Postoperative dialysis Ventilator for ⬎ 48 hours
Age 60 to 69 Years n ⫽ 206
Age ⱖ 70 Years n ⫽ 37
P Value
9.5%
9.7%
8.1%
⬎.95
7.1% 18.1%
6.8% 16.3%
5.4% 32%
⬎.95 .19
HEART TRANSPLANTATION IN ELDERLY
placed on such a list may have artificially higher mortality rates because they are receiving higher-risk donor organs. This may partially explain why other studies show a higher mortality in this population. The alternative list may further be disadvantageous for those younger patients on the standard transplantation list if the marginal donor hearts in fact have favorable outcomes in higher-risk recipients. Given the conflicting evidence, the issue of whether older patients should be considered equally for OHT is still a matter of great debate. The problematic issue is the critical shortage of donor organs which has been further exacerbated by the extension of the recipient age limit. Yet, with continued advances in medical and surgical therapies, such as cardiac resynchronization therapy, mortality rates have continued to decrease in the past decade.37 Also, the increased use of mechanical circulatory support therapy, such as ventricular-assist devices as bridging and destination therapy, has provided more treatment options for end-stage heart disease, especially for those patients unable to undergo transplantation.38,39 Study Limitations
Limitations of this study include those attributed to a single center nonrandomized retrospective experience with a small sample size for elderly patients who were ⱖ70 years of age. The selection process for transplantation candidates was not uniform in this study because elderly patients with comorbidities were excluded. Although the data is incomplete over the 20-year period, the prior study by Blanche et al showed an equivalent recipient-acceptance ratio between the elderly and younger age groups.14 CONCLUSION
The findings in this study comparing septuagenarians to younger OHT recipients reveal that advanced age should not be a contraindication for heart transplantation. As life expectancy continues to increase, it will be necessary to continually redefine what is considered elderly. At the current time, there are no guidelines on the upper age limit for OHT, but this study shows promising results for those patients who are ⱖ70 years of age. Although there is a growing gap between cardiac organ donors and recipients, older recipients deserve a careful and thorough evaluation for undergoing transplantation when other medical therapies for end-stage HF have failed. Many questions regarding this difficult topic remain unanswered. As the population ages, the demand for OHT will further grow, and the issue of age limits will need to be re-addressed with the widened recipient pool. Also, the study raises the issue whether transplantation in the elderly age group should be restricted to specialized centers with experience in the field. The use of the alternate-list strategy requires additional examination given the disadvantage it can have for older and younger recipients as well. The current ISHLT listing criteria guidelines supports transplantation in patients who are ⱖ70 years of age if they meet
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specific criteria and recommend the use of an alternate list to avoid the worsening shortage of donor hearts for younger patients.40 Further studies are necessary to address the growing transplantation waiting list and the experience of recipients who are ⱖ70-years old. In conclusion, our 20-year experience with OHT in the elderly indicates that there was no significant difference in long-term survival between the elderly age group (ⱖ70years old) and the younger age groups after transplantation. Despite advanced age, appropriate candidates for OHT should be allowed placement on the transplantation waiting list after careful evaluation and screening as transplantation remains their best option for long-term survival. REFERENCES 1. Lloyd-Jones D, Adams R, Carnethon M, et al: Heart disease and stroke statistics—2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 119:e21, 2009 2. Bleumink GS, Knetsch AM, Sturkenboom MC, et al: Quantifying the heart failure epidemic: prevalence, incidence rate, lifetime risk and prognosis of heart failure The Rotterdam Study. Eur Heart J 1614, 2004 3. Braunwald E: Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw Hill; 1998 4. Hertz MI, Taylor DO, Trulock EP, et al: The registry of the international society for heart and lung transplantation: nineteenth official report-2002. J Heart Lung Transplant 21:950, 2002 5. Defraigne JO, Demoulin JC, Beaujean MA, et al: Cardiac transplantation beyond 55 years of age. Transpl Int 3:59, 1990 6. Borkon AM, Muehlebach GF, Jones PG, et al: An analysis of the effect of age on survival after heart transplant. J Heart Lung Transplant 18:668, 1999 7. 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 111:423, 1996; [discussion 7] 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 12:573, 1993 [discussion 8] 9. Forni A, Faggian G, Chiominto B, et al: Heart transplantation in older candidates. Transplant Proc 39:1963, 2007 10. Morgan JA, John R, Mancini DM, et al: Should heart transplantation be considered as a treatment option for patients aged 70 years and older? J Thorac Cardiovasc Surg 127:1817, 2004 11. Nagendran J, Wildhirt SM, Modry D, et al: A comparative analysis of outcome after heart transplantation in patients aged 60 years and older: the University of Alberta experience. J Card Surg 19:559, 2004 12. Taylor DO, Edwards LB, Boucek MM, et al: Registry of the International Society for Heart and Lung Transplantation: twentysecond official adult heart transplant report—2005. J Heart Lung Transplant 24:945, 2005 13. Laks H, Marelli D, Fonarow GC, et al: Use of two recipient lists for adults requiring heart transplantation. J Thorac Cardiovasc Surg 125:49, 2003 14. 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 121:532, 2001 15. Zuckermann A, Dunkler D, Deviatko E, et al: Long-term survival (⬎10 years) of patients ⬎ 60 years with induction therapy after cardiac transplantation. Eur J Cardiothorac Surg 24:283, 2003 16. Demers P, Moffatt S, Oyer PE, et al: Long-term results of heart transplantation in patients older than 60 years. J Thorac Cardiovasc Surg 126:224, 2003
3856 17. Kobashigawa JA: Early and late complications in the elderly heart transplant recipient. Cardiol Elderly 4:15, 1996 18. Mehra MR, Kobashigawa J, Starling R, et al: Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant 1024, 2006 19. Shumway NE, Lower RR, Stofer RC: Transplantation of the heart. Adv Surg 2:265, 1966 20. Blanche C, Valenza M, Aleksic I, et al: 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 (Torino) 35:283, 1994 21. Aleksic I, Freimark D, Blanche C, et al: The duration of administration of monoclonal antibody OKT3 for induction immunosuppression after heart transplantation. Thoracic Cardiovasc Surg 45:190, 1997 22. Aleksic A, Freimark D, Blanche C, et al: Hemodynamics during humoral rejection events with total versus standard orthotopic heart transplantation. Ann Thorac Cardiovasc Surg 10: 285, 2004 23. Goland S, Czer LS, Coleman B, et al: Induction therapy with thymoglobulin after heart transplantation: impact of therapy duration on lymphocyte depletion and recovery, rejection, and CMV infection rates. J Heart Lung Transplant 27:1115, 2008 24. Blanche C, Matloff JM, Denton TA, et al: Heart transplantation in patients 70 years of age and older: initial experience. Ann Thorac Surg 62:1731, 1996 25. US Census Bureau: Available at: http://www.census.gov/ compendia/statab/cats/births_deaths_marriages_divorces/life_expectancy. html. Accessed June 22, 2011 26. Taylor DO, Edwards LB, Boucek MM, et al: The Registry of the International Society for Heart and Lung Transplantation: twenty-first official adult heart transplant report—2004. J Heart Lung Transplant 23:796, 2004 27. Copeland JG, Stinson EB: Human heart transplantation. Curr Probl Cardiol 4:1, 1979 28. Organ Procurement and Transplantation Network. Organ by age. United Network for Organ Sharing, 2007. Available at: http://www.optn.org/latestData/rptData.asp. Accessed June 22, 2011
DANESHVAR, CZER, PHAN ET AL 29. 2006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 1996 –2005; Available at: http:// www.optn.transplant.hrsa.gov/data/annualreport.asp. Accessed June 22, 2011 30. Taylor DO, Edwards LB, Boucek MM, et al: Registry of the International Society for Heart and Lung Transplantation: twentythird official adult heart transplantation report—2006. J Heart Lung Transplant 25:869, 2006 31. The International Society for Heart & Lung Transplantation. ISHLT Transplant Quarterly Reports for Heart in North America. 2008. Available at: http://www.ishlt.org/registries. Accessed June 22, 2011 32. Olivari MT, Antolick A, Kaye MP, et al: Heart transplantation in elderly patients. J Heart Transplant 7:258, 1988 33. Frazier OH, Macris MP, Duncan JM, et al: Cardiac transplantation in patients over 60 years of age. Ann Thorac Surg 45:129, 1988 34. Weiss ES, Nwakanma LU, Patel ND, et al: Outcomes in patients older than 60 years of age undergoing orthotopic heart transplantation: an analysis of the UNOS database. J Heart Lung Transplant 27:184, 2008 35. Robbins RC: Ethical implications of heart transplantation in elderly patients. J Thorac Cardiovasc Surg 121:434, 2001 36. Itescu S, Tung TC, Burke EM, et al: An immunological algorithm to predict risk of high-grade rejection in cardiac transplant recipients. Lancet 352:263, 1998 37. Cleland JG, Daubert JC, Erdmann E, et al: The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 352:1539, 2005 38. de Jonge N, Kirkels H, Lahpor JR, et al: Exercise performance in patients with end-stage heart failure after implantation of a left ventricular assist device and after heart transplantation: an outlook for permanent assisting? J Am Coll Cardiol 37:1794, 2001 39. Rose EA, Gelijns AC, Moskowitz AJ, et al: Long-term use of a left ventricular assist device for end-stage heart failure. N Engl J Med 345:1435, 2001 40. Mehra MR, Kobashigawa J, Starling R, et al: Listing criteria for heart transplantation: International Society for Heart and Lung Transplantation guidelines for the care of cardiac transplant candidates—2006. J Heart Lung Transplant 1024, 2006