- Email: [email protected]
Medium-term results of heart transplantation using older donor organs
Medium-Term Results of Heart Transplantation Using Older Donor Organs Matthias Loebe, MD, PhD, Evgenij V. Potapov, MD, Manfred Hummel, MD, PhD, Yuguo Weng, MD, Wolfgang Bocksch, MD, and Roland Hetzer, MD, PhD Background: Donor heart shortage has necessitated the expansion of the donor pool by the use of older hearts. Patients and Methods: In a 13-year period, 1,070 heart transplants were performed in 1,035 adults at the German Heart Institute Berlin. We divided the patients into 3 groups: Group I, donor age ⬍35 years (n ⫽ 524); Group II, donor age 35 to 50 years (n ⫽ 379); Group III, donor age ⬎50 years (n ⫽ 167). We analyzed post-operative mortality (up to 30 days), cumulative survival rates, cardiac dependent morbidity, and changes in the left/right ventricular ejection fraction as well as freedom from cytomegalovirus infection and freedom from acute rejection episodes grade ⱖ 2 (International Society for Heart and Lung Transplantation). We also calculated the rate of cardiac interventions per patient in the groups. Results: Recipients in Group III were significantly older, compared with Groups I and II. The post-operative mortality was 16.8% in Group I, 29.8% in Group II, and 23.4% in Group III. The differences were significant (p ⫽ 0.00001) between Group I and Group II. The long-term cumulative survival rates were significantly better in Group I when compared with Groups II and III (p ⬍ 0.00001, p ⫽ 0.014), but it did not differ between Groups II and III (p ⫽ 0.18). However, cardiac morbidity in Groups I and II was significantly lower when compared with Group III (p ⫽ 0.0009, p ⫽ 0.037). Mean left and right ventricular ejection fraction was ⬎55% and did not significantly change in groups for up to 10 years. Freedom from cytomegalovirus infection was not significantly different between Groups II and III (p ⫽ 0.09). Significantly fewer percutaneous transluminal coronary angioplasties were performed in Group I, but comparable numbers were carried out in Groups II and III (p ⫽ 0.53). For retransplantation a similar situation occurred. Conclusion: We did not find significant differences in the mid-term follow-up between patients who received hearts from 35- to 50-year-old donors and from those who had received hearts from donors ⬎50 years, despite increased cardiac morbidity in Group III. Close monitoring of the coronary situation after heart transplantation and expanded indications for revascularization in Group III makes heart transplantation with older hearts a suitable option to save the lives of patients in end-stage heart failure. J Heart Lung Transplant 2000;19:957–963.
From the Deutsches Herzzentrum Berlin, Berlin, Germany. Presented at the 20th Annual Meeting of the International Society of Heart and Lung Transplantation, in Osaka, Japan, April 2000. Submitted February 18, 2000; accepted July 12, 2000. Reprint requests: Matthias Loebe, MD, PhD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Ger-
many. Telephone: ⫹49-30-4593-1000. Fax: ⫹49-30-4593-2100. E-mail: [email protected]. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00178-9
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nd-stage heart failure is commonly treated by heart transplantation. The number of patients on the waiting list for heart transplantation is continually more than the supply of hearts because of donor shortage.1 Since 1988 the median waiting time has doubled,1,2 which early on resulted in our use of older donor hearts.3 By 1997 the mean donor age reported by the International Society for Heart and Lung Transplantation (ISHLT) database, reached ⬎ 30 years1, and in our institution it remains fairly stable at 40 years.4 The acceptable upper age limit for donors remains controversial because many studies have shown that using older donor hearts results in a decreased survival rate.1,5–7 Increased risk of coronary heart disease has also been reported.8 However, a number of centers have reported favorable results with older donor hearts,9 –15 including our center where we have used hearts ⬎ 63 years.16 Poorer results may be attributable to the fact that older donor hearts were primarily allocated to marginal recipients,17 whereas with the better outcomes, older donor hearts were used regardless of recipient condition. The following phenomena have forced us to use older donor hearts: 1. positive initial experience with older donors,3 2. an extensive waiting list, and 3. the large number of ventricular assist device implantations undertaken at our institution.18 In this study, we analyzed follow-up after heart transplantation (HTx) in 3 groups based on donor age.
PATIENTS AND METHODS Between April 1986 and June 1999, a total of 1,070 HTx were performed in 1,035 adults, 885 men and 185 women. We retrospectively and arbitrarily divided the patients into 3 groups: Group I, donor age was ⬍ 35 years (n ⫽ 524, mean recipient age was 48.4 ⫾ 10.8 years, median was 51 years, range was 19.5 to 67.5 years); Group II, donor age was 35 to 50 years (n ⫽ 379, mean recipient age was 48.5 ⫾ 10.3 years, median was 50.3 years, range was 17.2 to 70.7 years); Group III, donor age was ⬎50 years (n ⫽ 167, mean recipient age was 50.8 ⫾ 10.8 years, median was 53.8 years, range was 17.4 to 68.5 years). Heart preservation was routinely performed with 3 liters of ice-cold HTK-Bretschneider solution. In all 3 groups, immunosuppression was based on tripledrug therapy with cyclosporine, azathioprine, and prednisone. Only cytomegalovirus (CMV) negativerecipients, who received a CMV positive donor
The Journal of Heart and Lung Transplantation October 2000
heart, were treated with gancyclovir IV. The CMV surface antigen PP65 was measured to monitor the effect. No special medication for phrophylaxis of transplant vasulopathy (TVP) was used. In addition to routine intramyocardial electrogram (IMEG) data, electrocardiogram, echocardiography, and clinical evaluation, all patients underwent routine coronary angiography and ventriculography once a year. We analyzed multiple factors in the groups, which included post-operative mortality (up to 30 days), cumulative survival rates, cardiac dependent morbidity (myocardial infarction, malignant arrhythmias, coronary stenosis, ⬎ 50% in 1 of the main coronary arteries, and transplant vasculopathy diagnosed according to Stanford intravascular ultrasound criteria), and changes in the left/right ventricular ejection fraction (LVEF/RVEF). A cardiologist, who was blinded to donor age, calculated the LVEF and RVEF based on routine left and right ventriculography. No echocardiographically calculated ejection fractions (EFs) were involved in the evaluation. We also analyzed freedom from CMV infection (2-fold rise of titer or seroconversion) and freedom from acute rejection episodes grade ⱖ 2 ISHLT. We also calculated the rate of cardiac interventions per patient in the groups.
Statistical Analysis We performed statistical analysis using SPSS 7.5 for Windows. The distributions were analyzed using a Kolmogorov-Smirnov test. Mann-Whitney-U test or chi-square test (nonparametric data) confirmed significant differences. Pearson rank test was applied to evaluate correlation. The freedom from events and cumulative survival were examined using a KaplanMeier actuarial analysis and compared with a logrank test. We considered p ⬍ 0.05 as statistically significant.
RESULTS We observed no differences in gender, etiology of heart failure, or ischemic time among the groups. Patients in Group III were significantly older than those in Groups I and II (p ⫽ 0.003 and p ⫽ 0.002). The difference between Group I and Group II was not significant (p ⫽ 0.9). In Group III, significantly fewer hearts offered were used for HTx (47.7%) when compared with Group I (87%, p ⫽ 0.006) and Group II (76.9%, p ⫽ 0.027). The difference between Group I and Group II was not significant (p ⫽ 0.6). The common cause for refusing an inspected donor heart in Groups II and III was coronary artery
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FIGURE 1 Heart function in the groups 1, 5, and 10 years after transplantation. Mean
values and 95% confidence intervals are shown. We noted no statistical differences among the groups or within the groups. EF, ejection fraction; HTx, heart transplantation; LVEF, left ventricular ejection fraction; RVEF, right ventricular ejection fraction.
sclerosis (54% and 55%), whereas in Group I it was impaired myocardiac function (57%). Mean EF in the recipients was ⬎ 55% at all times and did not significantly change in groups for up to 10 years (Figure 1). The mean follow-up in Group I was 4.6 ⫾ 3.9 years; in Group II, 3.1 ⫾ 3.6 years; and in Group III, 3.0 ⫾ 3.1 years. Follow-up in Group I was significantly longer (p ⫽ 0.0001) than in groups II and III, but did not differ between Groups II and III (p ⫽ 0.59). Post-operative mortality (30 days) in Group I was 16.8%; in Group II, 29.8%; and in Group III, 23.4%. The differences were significant (p ⫽ 0.00001) between Groups I and II but not significant between Group III and Groups I or II (p ⫽ 0.45, p ⫽ 0.12). The long-term cumulative survival rate was better in Group I when compared with Groups II and III (p ⬍ 0.00001, p ⫽ 0.014), but this was similar between Groups II and III (p ⫽ 0.18). Figure 2 shows the cumulative survival curves of the groups. The graft half-life in Group I was 10.9 years; in Group II, 4 years; and in Group III, 6 years. A total of 35 re-HTx were performed. Significantly fewer early (up to 30 days) re-HTx were performed in Group III (p ⫽ 0.039) when compared
with Group II, but this was not significant when compared with Group I (p ⫽ 0.77). The difference between Groups I and II was not significant (p ⫽ 0.13). The analysis of frequency of early (⬍ 30 days after HTx) and late re-HTx showed significant differences between Groups I and III (Table I). Cardiac events occurred significantly more frequently in Group III (p ⫽ 0.0009) when compared
FIGURE 2 Long-term cumulative survival curves.
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TABLE I Cardiac diagnostic and intervention procedures Number of Re-HTx
Group I (n ⫽ 524) Group II (n ⫽ 379) Group III (n ⫽ 167)
Number of CABG
PTCA/patient
<30 POD
Late
Concomitant
Late
0.1* 0.16 0.18
7 9*** 2***
5*** 8 4***
0 0 1
2** 2 3**
*p ⬍ 0.00001; **p ⬍ 0.016; ***p ⬍ 0.04. CABG, coronary artery bypass grafting; HTx, heart transplantation; POD, postoperative day; PTCA, percutaneous transluminal coronary angioplasty.
with Group I, but not to such a degree of significance with Group II (p ⫽ 0.037). The difference between Groups I and II was not significant (p ⫽ 0.16, Figure 3). Longevity of organ survival did not correlate with the age of the donors (r ⫽ 0.095, p ⫽ 0.001). Long-term freedom from CMV infection in Group I was significantly higher when compared with Group III (p ⫽ 0.005), but not significantly different between Groups II and III (p ⫽ 0.09) or between Groups I and II (p ⫽ 0.25) (Figure 4). Long-term freedom from acute rejection episodes was not significantly different among groups. Table I shows analysis of interventional procedures in the groups. We noted significantly fewer percutaneous transluminal coronary angioplasties (PTCAs) were performed in Group I.
DISCUSSION Our analysis of 1,070 heart transplantations at a single center showed that hearts from donors aged ⬎ 50 could safely be used for transplantation with acceptable long-term results. However, the
FIGURE 3 Long-term freedom from cardiac events
(myocardial infarction, malignant arrhythmias, coronary stenosis, transplant vasculopathy).
results obtained with hearts from donors aged ⬍ 35 were comparably better. Given the fact that up to 30% of patients die while on the waiting list for heart transplantation, the use of older donor hearts substantially extends the number of available organs for heart transplantation. In our program, ⬍ 49% of transplanted hearts come from donors aged ⬍ 35. However, many centers have been reluctant to use hearts from donors older than 35 years because of the potential for rapidly progressive coronary artery disease in these organs. In 1988, our group reported favorable experience with extended donor age in cardiac transplantation.19 At that time, patients who received hearts from donors aged between 36 and 54 years were shown to have heart function comparable to that of patients who had received younger donor hearts. This report prompted several centers to consider extended donor age criteria. Since then, the debate on the use of hearts from older donors has been extensive. Many centers have reported positive experiences,9 –15 but their statistical plausibility, because of small numbers of patients, has been discussed.20 Statistical analysis of the data from the Registry of the ISHLT continues to show in-
FIGURE 4 Freedom from cytomegalovirus (CMV) infection (rise of titer or seroconversion).
The Journal of Heart and Lung Transplantation Volume 19, Number 10
creased risk with the use of older hearts for HTx. The odds ratio for 1-year mortality for donors aged ⬎ 50 years is 1.48.1 However, the analysis of the joint ISHLT/United Network of Organ Sharing Thoracic Registry, performed in 1998 by Bennett et al,21 showed clear long-term benefit in transplanting older hearts into relatively stable patients. Others recommended older donor hearts for marginal recipients through a so-called alternative waiting list.17 This report presents our experience with older donor hearts accepted for transplantation. Aware of the limitations of a single-center experience, we nevertheless strongly believe that this report helps answer several questions. First, the long-term experience presented does emphasize that even donor hearts aged ⬎ 50 should be offered and evaluated for transplantation. However, the surgeon who undertakes the explantation must carefully inspect these organs. Pre-explantation coronary angiography, which is not routinely available in our donor region, helps to reduce the number of failed donor runs. Robiscek22 suggested bench coronary angiography for marginal donor hearts, a technique with which we have no experience. In our practice, we have relied on the expertise of the surgeons who undertake the explantation, which is based on medical history, catecholamine requirements, and if possible, transesophageal echocardiography. Perhaps this is why several older hearts revealed coronary angiopathy early after transplantation. Most of the hearts in Groups II and III were refused because of coronary artery sclerosis, whereas with young donors, refusal was because of impaired myocardiac function. In light of these facts, pre-operative angiography in older donors should be used more extensively. Revascularization at the time of transplantation may help to cope with this condition and has been used on several occasions. Recipients in Groups II and III did not differ significantly in long-term cumulative survival rate (Figure 2). Longevity after HTx did not correlate with donor age. The extension of donor age compared between Groups II and III, per se, did not affect post-transplant survival. This finding somewhat contradicts reports in the literature.1,5–7 Acceptance of donor hearts was based on function and hemodynamic performance in the absence of coronary artery disease, regardless of the donor age. These organs were not allocated to more severely ill patients, as has been suggested by some.17 We believe that the increased risk associated with older donor age, demonstrated in the statistical analysis of
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data from the ISHLT Registry,1 is in no small part due to the fact that older donor hearts may have been transplanted into marginal recipients. However, we do admit that we have had a tendency to use hearts from older donors in older recipients who were otherwise stable. Based on our experience, we feel that it is not justifiable to decline donor organs solely because of advanced donor age. Undoubtedly, we were more selective in accepting older donor hearts. We used ⬍ 50% of the hearts from donors ⬎ 50 years of age, despite an 81.1% rate of use from younger donors. Decision making requires careful hemodynamic monitoring before explantation, as well as the visual inspection of the heart. At our institution, patients with older donor hearts undergo early post-transplant coronary angiography. Except for this first examination, which takes place approximately 3 months after the surgical procedure, all patients are investigated once a year with coronary angiography. As in the Stanford experience,9 the patients who received older donor hearts had more cardiac events, because of coronary stenoses, than did patients in Group I, and had significantly more PTCAs per patient. However, significantly more coronary artery bypass grafting and re-HTx, due to TVP, were performed in Group III when compared with Group I (Table I). This table shows a tendency in the treatment of TVP, which is dependent on donor age. The recipients with organs from older donors have extensive multivessel coronary disease that cannot be treated by transcatheter therapy alone. Several reasons for the advent of rapidly progressive TVP have been discussed,9 including frequency of rejection episodes and herpes virus infection. Daily monitoring for rejection in all patients with the IMEG system23 and close adaptation of immunosuppressive therapy may also have contributed to preserving ventricular function after HTx (Figure 1). The higher rate of CMV infection in Group III (Figure 4) may accelerate macroangiopathy in older hearts.24 Older patients tend to have a higher percentage of CMV seropositivity,25, 26 and this may have had some impact on both the donor and the recipient because of reactivation or transmission of CMV infection. One may speculate whether preexisting focal lesions in the coronary arteries after transplantation and under immunosuppressive medication progress more rapidly or whether transplant vasculopathy is totally distinct from general arteriosclerotic coronary heart disease. Further investigations will address this matter. However, focal steno-
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ses can be successfully treated with PTCA.27 We noted significantly more PTCAs per patient in Group III. The trend of a lower rejection rate in Group III may be because of older recipients and grafts, which could reconcile this immunologic imbalance.
8.
CONCLUSION
9.
Use of hearts from older donors for HTx is a safe option to expand the scarce donor pool. However, this study found significant differences in the freedom from cardiac events, because more coronary stenoses develop in older donor hearts, and in the freedom from CMV infection, but did not find significant differences in long-term survival between patients who received hearts from donors aged 35 to 50 and patients who received hearts from those ⬎ 50 years. The acceptance of donors ⬎50 years for HTx does not increase the risk of recipient mortality. Older donors hearts have an acceptable survival, albeit worse than for very young donor hearts. Careful selection of older donors, close monitoring of the coronary situation after HTx, and expanded indications for revascularization of older hearts enables us to extend the age limit for donor hearts. The long-term results obtained with these donor organs justify routine use of older donor hearts, and thereby may increase the number of donor organs available for heart transplantation. The authors thank Tonie Derwent for assisting in manuscript preparation, B. Wu ¨pper for data acquisition, and K. Grosse, MD, from the German Foundation of Organ Transplantation (DSO) for supplying data.
10.
11.
12.
13.
14.
15.
16.
17.
18.
REFERENCES 1. Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: fifteenth official report— 1998. J Heart Lung Transplant 1998;17:656 – 68. 2. Harper AM, Rosendale JD. The UNOS OPTN Waiting List and Donor Registry: 1988 –1996. Clin Transpl 1996;12:69 –90. 3. Schu ¨ler S, Warnecke H, Loebe M, Fleck E, Hetzer R. Expanded donor age in cardiac transplantation. Circulation 1989;80:III133–9. 4. Pasic M, Loebe M, Hummel M, et al. Heart transplantation: a single-center experience. Ann Thorac Surg 1996;62:1685– 90. 5. Ibrahim M, Masters RG, Hendry PJ, et al. Determinants of hospital survival after cardiac transplantation. Ann Thorac Surg 1995;59:604 – 8. 6. Carrier M, Rivard M, Latter D, Kostuk W. Predictors of early mortality after heart transplantation: the Canadian transplant experience from 1981 to 1992. The CASCADE Investigators. Canadian Study of Cardiac Transplant Atherosclerosis Determinants. Can J Cardiol 1998;14:703–7. 7. Pierson RN, 3rd, Reed GW, Bennett LE, Keck BM, Hosen-
19.
20. 21.
22.
23.
24.
pud JD. Short- and intermediate-term implications of using older donors for heart transplantation. Transplant Proc 1997;29:593– 4. Costanzo MR, Naftel DC, Pritzker MR, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998;17:744 –53. Gao HZ, Hunt SA, Alderman EL, Liang D, Yeung AC, Schroeder JS. Relation of donor age and preexisting coronary artery disease on angiography and intracoronary ultrasound to later development of accelerated allograft coronary artery disease. J Am Coll Cardiol 1997;29:623–9. Drinkwater DC, Laks H, Blitz A, et al. Outcomes of patients undergoing transplantation with older donor hearts. J Heart Lung Transplant 1996;15:684 –91. 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 – 8;1578 –9. Chau EM, McGregor CG, Rodeheffer RJ, et al. Increased incidence of chronotropic incompetence in older donor hearts. J Heart Lung Transplant 1995;14:743– 8. Jacobbi LM, McBride V, Like K, Rose D. Increasing the donor pool: recovery of hearts from older donors. Transplant Proc 1997;29:3297– 8. Mercer P, Sharples L, Edmunds J, et al. Evaluating the donor pool: impact of using hearts from donors over the age of 49 years. Transplant Proc 1997;29:3293– 6. Kirsch M, Baufreton C, Naftel DC, Benvenuti C, Loisance DY. Pretransplantation risk factors for death after heart transplantation: the Henri Mondor experience. J Heart Lung Transplant 1998;17:268 –77. Potapov EV, Loebe M, Hubler M, et al. Medium-term results of heart transplantation using donors over 63 years of age. Transplantation 1999;68:1834 – 8. Laks H, Scholl FG, Drinkwater DC, et al. The alternate recipient list for heart transplantation: does it work? J Heart Lung Transplant 1997;16:735– 42. Loebe M, Hennig E, Muller J, Spiegelsberger S, Weng Y, Hetzer R. Long-term mechanical circulatory support as a bridge to transplantation, for recovery from cardiomyopathy, and for permanent replacement. Eur J Cardiothoracic Surg 1997;11:S18 –24. Schu ¨ler S, Parnt R, Warnecke H, Matheis G, Hetzer R. Extended donor criteria for heart transplantation. J Heart Transplant 1988;7:326 –30. Hosenpud JD. Invited commentary. Ann Thoracic Surg 1998;65:1578. Bennett L, Edwards E, Hosenpud J. Transplantation with older donor hearts for presumed “stable” recipients: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Transplantation Sharing Thoracic Registry. J Heart Lung Transplant 1998;17: 901–5. Robicsek F, Masters T, Tomley A, Riece H, Morales-Reyna J. Bench coronary cineangiography. A possible way to increase the number of hearts available for transplantation. J Thorac Cardiovasc Surg 1992;103:1490 –5. Warnecke H, Tietze U, Hetzer R. Noninvasive monitoring of cardiac allograft rejection by intramyocardial electrogram recordings. Circulation 1986;74:72. Loebe M, Schu ¨ler S, Zais O, Warnecke W, Fleck E, Hetzer
The Journal of Heart and Lung Transplantation Volume 19, Number 10 R. Role of cytomegalovirus infection in the development of coronary artery disease in the transplanted heart. J Heart Transplant 1990;9:707–11. 25. Weymouth L, Gomolin I, Brennan T, Sirpenski S, Mayo D. Cytomegalovirus antibody in the elderly. Intervirology 1990; 31:223–9. 26. Natali A, Valcavi P, Medici MC, Dieci E, Montali S, Chezzi
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C. Cytomegalovirus infection in an Italian population: antibody prevalence, virus excretion and maternal transmission. New Microbiol 1997;20:123–33. 27. Musci M, Loebe M, Wellnhofer E, et al. Coronary angioplasty, bypass surgery, and retransplantation in cardiac transplant patients with graft coronary disease. Thorac Cardiovasc Surg 1998;46:268 –74.
From the Deutsches Herzzentrum Berlin, Berlin, Germany. Presented at the 20th Annual Meeting of the International Society of Heart and Lung Transplantation, in Osaka, Japan, April 2000. Submitted February 18, 2000; accepted July 12, 2000. Reprint requests: Matthias Loebe, MD, PhD, Deutsches Herzzentrum Berlin, Augustenburger Platz 1, 13353 Berlin, Ger-
many. Telephone: ⫹49-30-4593-1000. Fax: ⫹49-30-4593-2100. E-mail: [email protected]. Copyright © 2000 by the International Society for Heart and Lung Transplantation. 1053-2498/00/$–see front matter PII S1053-2498(00)00178-9
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nd-stage heart failure is commonly treated by heart transplantation. The number of patients on the waiting list for heart transplantation is continually more than the supply of hearts because of donor shortage.1 Since 1988 the median waiting time has doubled,1,2 which early on resulted in our use of older donor hearts.3 By 1997 the mean donor age reported by the International Society for Heart and Lung Transplantation (ISHLT) database, reached ⬎ 30 years1, and in our institution it remains fairly stable at 40 years.4 The acceptable upper age limit for donors remains controversial because many studies have shown that using older donor hearts results in a decreased survival rate.1,5–7 Increased risk of coronary heart disease has also been reported.8 However, a number of centers have reported favorable results with older donor hearts,9 –15 including our center where we have used hearts ⬎ 63 years.16 Poorer results may be attributable to the fact that older donor hearts were primarily allocated to marginal recipients,17 whereas with the better outcomes, older donor hearts were used regardless of recipient condition. The following phenomena have forced us to use older donor hearts: 1. positive initial experience with older donors,3 2. an extensive waiting list, and 3. the large number of ventricular assist device implantations undertaken at our institution.18 In this study, we analyzed follow-up after heart transplantation (HTx) in 3 groups based on donor age.
PATIENTS AND METHODS Between April 1986 and June 1999, a total of 1,070 HTx were performed in 1,035 adults, 885 men and 185 women. We retrospectively and arbitrarily divided the patients into 3 groups: Group I, donor age was ⬍ 35 years (n ⫽ 524, mean recipient age was 48.4 ⫾ 10.8 years, median was 51 years, range was 19.5 to 67.5 years); Group II, donor age was 35 to 50 years (n ⫽ 379, mean recipient age was 48.5 ⫾ 10.3 years, median was 50.3 years, range was 17.2 to 70.7 years); Group III, donor age was ⬎50 years (n ⫽ 167, mean recipient age was 50.8 ⫾ 10.8 years, median was 53.8 years, range was 17.4 to 68.5 years). Heart preservation was routinely performed with 3 liters of ice-cold HTK-Bretschneider solution. In all 3 groups, immunosuppression was based on tripledrug therapy with cyclosporine, azathioprine, and prednisone. Only cytomegalovirus (CMV) negativerecipients, who received a CMV positive donor
The Journal of Heart and Lung Transplantation October 2000
heart, were treated with gancyclovir IV. The CMV surface antigen PP65 was measured to monitor the effect. No special medication for phrophylaxis of transplant vasulopathy (TVP) was used. In addition to routine intramyocardial electrogram (IMEG) data, electrocardiogram, echocardiography, and clinical evaluation, all patients underwent routine coronary angiography and ventriculography once a year. We analyzed multiple factors in the groups, which included post-operative mortality (up to 30 days), cumulative survival rates, cardiac dependent morbidity (myocardial infarction, malignant arrhythmias, coronary stenosis, ⬎ 50% in 1 of the main coronary arteries, and transplant vasculopathy diagnosed according to Stanford intravascular ultrasound criteria), and changes in the left/right ventricular ejection fraction (LVEF/RVEF). A cardiologist, who was blinded to donor age, calculated the LVEF and RVEF based on routine left and right ventriculography. No echocardiographically calculated ejection fractions (EFs) were involved in the evaluation. We also analyzed freedom from CMV infection (2-fold rise of titer or seroconversion) and freedom from acute rejection episodes grade ⱖ 2 ISHLT. We also calculated the rate of cardiac interventions per patient in the groups.
Statistical Analysis We performed statistical analysis using SPSS 7.5 for Windows. The distributions were analyzed using a Kolmogorov-Smirnov test. Mann-Whitney-U test or chi-square test (nonparametric data) confirmed significant differences. Pearson rank test was applied to evaluate correlation. The freedom from events and cumulative survival were examined using a KaplanMeier actuarial analysis and compared with a logrank test. We considered p ⬍ 0.05 as statistically significant.
RESULTS We observed no differences in gender, etiology of heart failure, or ischemic time among the groups. Patients in Group III were significantly older than those in Groups I and II (p ⫽ 0.003 and p ⫽ 0.002). The difference between Group I and Group II was not significant (p ⫽ 0.9). In Group III, significantly fewer hearts offered were used for HTx (47.7%) when compared with Group I (87%, p ⫽ 0.006) and Group II (76.9%, p ⫽ 0.027). The difference between Group I and Group II was not significant (p ⫽ 0.6). The common cause for refusing an inspected donor heart in Groups II and III was coronary artery
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FIGURE 1 Heart function in the groups 1, 5, and 10 years after transplantation. Mean
values and 95% confidence intervals are shown. We noted no statistical differences among the groups or within the groups. EF, ejection fraction; HTx, heart transplantation; LVEF, left ventricular ejection fraction; RVEF, right ventricular ejection fraction.
sclerosis (54% and 55%), whereas in Group I it was impaired myocardiac function (57%). Mean EF in the recipients was ⬎ 55% at all times and did not significantly change in groups for up to 10 years (Figure 1). The mean follow-up in Group I was 4.6 ⫾ 3.9 years; in Group II, 3.1 ⫾ 3.6 years; and in Group III, 3.0 ⫾ 3.1 years. Follow-up in Group I was significantly longer (p ⫽ 0.0001) than in groups II and III, but did not differ between Groups II and III (p ⫽ 0.59). Post-operative mortality (30 days) in Group I was 16.8%; in Group II, 29.8%; and in Group III, 23.4%. The differences were significant (p ⫽ 0.00001) between Groups I and II but not significant between Group III and Groups I or II (p ⫽ 0.45, p ⫽ 0.12). The long-term cumulative survival rate was better in Group I when compared with Groups II and III (p ⬍ 0.00001, p ⫽ 0.014), but this was similar between Groups II and III (p ⫽ 0.18). Figure 2 shows the cumulative survival curves of the groups. The graft half-life in Group I was 10.9 years; in Group II, 4 years; and in Group III, 6 years. A total of 35 re-HTx were performed. Significantly fewer early (up to 30 days) re-HTx were performed in Group III (p ⫽ 0.039) when compared
with Group II, but this was not significant when compared with Group I (p ⫽ 0.77). The difference between Groups I and II was not significant (p ⫽ 0.13). The analysis of frequency of early (⬍ 30 days after HTx) and late re-HTx showed significant differences between Groups I and III (Table I). Cardiac events occurred significantly more frequently in Group III (p ⫽ 0.0009) when compared
FIGURE 2 Long-term cumulative survival curves.
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TABLE I Cardiac diagnostic and intervention procedures Number of Re-HTx
Group I (n ⫽ 524) Group II (n ⫽ 379) Group III (n ⫽ 167)
Number of CABG
PTCA/patient
<30 POD
Late
Concomitant
Late
0.1* 0.16 0.18
7 9*** 2***
5*** 8 4***
0 0 1
2** 2 3**
*p ⬍ 0.00001; **p ⬍ 0.016; ***p ⬍ 0.04. CABG, coronary artery bypass grafting; HTx, heart transplantation; POD, postoperative day; PTCA, percutaneous transluminal coronary angioplasty.
with Group I, but not to such a degree of significance with Group II (p ⫽ 0.037). The difference between Groups I and II was not significant (p ⫽ 0.16, Figure 3). Longevity of organ survival did not correlate with the age of the donors (r ⫽ 0.095, p ⫽ 0.001). Long-term freedom from CMV infection in Group I was significantly higher when compared with Group III (p ⫽ 0.005), but not significantly different between Groups II and III (p ⫽ 0.09) or between Groups I and II (p ⫽ 0.25) (Figure 4). Long-term freedom from acute rejection episodes was not significantly different among groups. Table I shows analysis of interventional procedures in the groups. We noted significantly fewer percutaneous transluminal coronary angioplasties (PTCAs) were performed in Group I.
DISCUSSION Our analysis of 1,070 heart transplantations at a single center showed that hearts from donors aged ⬎ 50 could safely be used for transplantation with acceptable long-term results. However, the
FIGURE 3 Long-term freedom from cardiac events
(myocardial infarction, malignant arrhythmias, coronary stenosis, transplant vasculopathy).
results obtained with hearts from donors aged ⬍ 35 were comparably better. Given the fact that up to 30% of patients die while on the waiting list for heart transplantation, the use of older donor hearts substantially extends the number of available organs for heart transplantation. In our program, ⬍ 49% of transplanted hearts come from donors aged ⬍ 35. However, many centers have been reluctant to use hearts from donors older than 35 years because of the potential for rapidly progressive coronary artery disease in these organs. In 1988, our group reported favorable experience with extended donor age in cardiac transplantation.19 At that time, patients who received hearts from donors aged between 36 and 54 years were shown to have heart function comparable to that of patients who had received younger donor hearts. This report prompted several centers to consider extended donor age criteria. Since then, the debate on the use of hearts from older donors has been extensive. Many centers have reported positive experiences,9 –15 but their statistical plausibility, because of small numbers of patients, has been discussed.20 Statistical analysis of the data from the Registry of the ISHLT continues to show in-
FIGURE 4 Freedom from cytomegalovirus (CMV) infection (rise of titer or seroconversion).
The Journal of Heart and Lung Transplantation Volume 19, Number 10
creased risk with the use of older hearts for HTx. The odds ratio for 1-year mortality for donors aged ⬎ 50 years is 1.48.1 However, the analysis of the joint ISHLT/United Network of Organ Sharing Thoracic Registry, performed in 1998 by Bennett et al,21 showed clear long-term benefit in transplanting older hearts into relatively stable patients. Others recommended older donor hearts for marginal recipients through a so-called alternative waiting list.17 This report presents our experience with older donor hearts accepted for transplantation. Aware of the limitations of a single-center experience, we nevertheless strongly believe that this report helps answer several questions. First, the long-term experience presented does emphasize that even donor hearts aged ⬎ 50 should be offered and evaluated for transplantation. However, the surgeon who undertakes the explantation must carefully inspect these organs. Pre-explantation coronary angiography, which is not routinely available in our donor region, helps to reduce the number of failed donor runs. Robiscek22 suggested bench coronary angiography for marginal donor hearts, a technique with which we have no experience. In our practice, we have relied on the expertise of the surgeons who undertake the explantation, which is based on medical history, catecholamine requirements, and if possible, transesophageal echocardiography. Perhaps this is why several older hearts revealed coronary angiopathy early after transplantation. Most of the hearts in Groups II and III were refused because of coronary artery sclerosis, whereas with young donors, refusal was because of impaired myocardiac function. In light of these facts, pre-operative angiography in older donors should be used more extensively. Revascularization at the time of transplantation may help to cope with this condition and has been used on several occasions. Recipients in Groups II and III did not differ significantly in long-term cumulative survival rate (Figure 2). Longevity after HTx did not correlate with donor age. The extension of donor age compared between Groups II and III, per se, did not affect post-transplant survival. This finding somewhat contradicts reports in the literature.1,5–7 Acceptance of donor hearts was based on function and hemodynamic performance in the absence of coronary artery disease, regardless of the donor age. These organs were not allocated to more severely ill patients, as has been suggested by some.17 We believe that the increased risk associated with older donor age, demonstrated in the statistical analysis of
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data from the ISHLT Registry,1 is in no small part due to the fact that older donor hearts may have been transplanted into marginal recipients. However, we do admit that we have had a tendency to use hearts from older donors in older recipients who were otherwise stable. Based on our experience, we feel that it is not justifiable to decline donor organs solely because of advanced donor age. Undoubtedly, we were more selective in accepting older donor hearts. We used ⬍ 50% of the hearts from donors ⬎ 50 years of age, despite an 81.1% rate of use from younger donors. Decision making requires careful hemodynamic monitoring before explantation, as well as the visual inspection of the heart. At our institution, patients with older donor hearts undergo early post-transplant coronary angiography. Except for this first examination, which takes place approximately 3 months after the surgical procedure, all patients are investigated once a year with coronary angiography. As in the Stanford experience,9 the patients who received older donor hearts had more cardiac events, because of coronary stenoses, than did patients in Group I, and had significantly more PTCAs per patient. However, significantly more coronary artery bypass grafting and re-HTx, due to TVP, were performed in Group III when compared with Group I (Table I). This table shows a tendency in the treatment of TVP, which is dependent on donor age. The recipients with organs from older donors have extensive multivessel coronary disease that cannot be treated by transcatheter therapy alone. Several reasons for the advent of rapidly progressive TVP have been discussed,9 including frequency of rejection episodes and herpes virus infection. Daily monitoring for rejection in all patients with the IMEG system23 and close adaptation of immunosuppressive therapy may also have contributed to preserving ventricular function after HTx (Figure 1). The higher rate of CMV infection in Group III (Figure 4) may accelerate macroangiopathy in older hearts.24 Older patients tend to have a higher percentage of CMV seropositivity,25, 26 and this may have had some impact on both the donor and the recipient because of reactivation or transmission of CMV infection. One may speculate whether preexisting focal lesions in the coronary arteries after transplantation and under immunosuppressive medication progress more rapidly or whether transplant vasculopathy is totally distinct from general arteriosclerotic coronary heart disease. Further investigations will address this matter. However, focal steno-
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ses can be successfully treated with PTCA.27 We noted significantly more PTCAs per patient in Group III. The trend of a lower rejection rate in Group III may be because of older recipients and grafts, which could reconcile this immunologic imbalance.
8.
CONCLUSION
9.
Use of hearts from older donors for HTx is a safe option to expand the scarce donor pool. However, this study found significant differences in the freedom from cardiac events, because more coronary stenoses develop in older donor hearts, and in the freedom from CMV infection, but did not find significant differences in long-term survival between patients who received hearts from donors aged 35 to 50 and patients who received hearts from those ⬎ 50 years. The acceptance of donors ⬎50 years for HTx does not increase the risk of recipient mortality. Older donors hearts have an acceptable survival, albeit worse than for very young donor hearts. Careful selection of older donors, close monitoring of the coronary situation after HTx, and expanded indications for revascularization of older hearts enables us to extend the age limit for donor hearts. The long-term results obtained with these donor organs justify routine use of older donor hearts, and thereby may increase the number of donor organs available for heart transplantation. The authors thank Tonie Derwent for assisting in manuscript preparation, B. Wu ¨pper for data acquisition, and K. Grosse, MD, from the German Foundation of Organ Transplantation (DSO) for supplying data.
10.
11.
12.
13.
14.
15.
16.
17.
18.
REFERENCES 1. Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: fifteenth official report— 1998. J Heart Lung Transplant 1998;17:656 – 68. 2. Harper AM, Rosendale JD. The UNOS OPTN Waiting List and Donor Registry: 1988 –1996. Clin Transpl 1996;12:69 –90. 3. Schu ¨ler S, Warnecke H, Loebe M, Fleck E, Hetzer R. Expanded donor age in cardiac transplantation. Circulation 1989;80:III133–9. 4. Pasic M, Loebe M, Hummel M, et al. Heart transplantation: a single-center experience. Ann Thorac Surg 1996;62:1685– 90. 5. Ibrahim M, Masters RG, Hendry PJ, et al. Determinants of hospital survival after cardiac transplantation. Ann Thorac Surg 1995;59:604 – 8. 6. Carrier M, Rivard M, Latter D, Kostuk W. Predictors of early mortality after heart transplantation: the Canadian transplant experience from 1981 to 1992. The CASCADE Investigators. Canadian Study of Cardiac Transplant Atherosclerosis Determinants. Can J Cardiol 1998;14:703–7. 7. Pierson RN, 3rd, Reed GW, Bennett LE, Keck BM, Hosen-
19.
20. 21.
22.
23.
24.
pud JD. Short- and intermediate-term implications of using older donors for heart transplantation. Transplant Proc 1997;29:593– 4. Costanzo MR, Naftel DC, Pritzker MR, et al. Heart transplant coronary artery disease detected by coronary angiography: a multiinstitutional study of preoperative donor and recipient risk factors. Cardiac Transplant Research Database. J Heart Lung Transplant 1998;17:744 –53. Gao HZ, Hunt SA, Alderman EL, Liang D, Yeung AC, Schroeder JS. Relation of donor age and preexisting coronary artery disease on angiography and intracoronary ultrasound to later development of accelerated allograft coronary artery disease. J Am Coll Cardiol 1997;29:623–9. Drinkwater DC, Laks H, Blitz A, et al. Outcomes of patients undergoing transplantation with older donor hearts. J Heart Lung Transplant 1996;15:684 –91. 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 – 8;1578 –9. Chau EM, McGregor CG, Rodeheffer RJ, et al. Increased incidence of chronotropic incompetence in older donor hearts. J Heart Lung Transplant 1995;14:743– 8. Jacobbi LM, McBride V, Like K, Rose D. Increasing the donor pool: recovery of hearts from older donors. Transplant Proc 1997;29:3297– 8. Mercer P, Sharples L, Edmunds J, et al. Evaluating the donor pool: impact of using hearts from donors over the age of 49 years. Transplant Proc 1997;29:3293– 6. Kirsch M, Baufreton C, Naftel DC, Benvenuti C, Loisance DY. Pretransplantation risk factors for death after heart transplantation: the Henri Mondor experience. J Heart Lung Transplant 1998;17:268 –77. Potapov EV, Loebe M, Hubler M, et al. Medium-term results of heart transplantation using donors over 63 years of age. Transplantation 1999;68:1834 – 8. Laks H, Scholl FG, Drinkwater DC, et al. The alternate recipient list for heart transplantation: does it work? J Heart Lung Transplant 1997;16:735– 42. Loebe M, Hennig E, Muller J, Spiegelsberger S, Weng Y, Hetzer R. Long-term mechanical circulatory support as a bridge to transplantation, for recovery from cardiomyopathy, and for permanent replacement. Eur J Cardiothoracic Surg 1997;11:S18 –24. Schu ¨ler S, Parnt R, Warnecke H, Matheis G, Hetzer R. Extended donor criteria for heart transplantation. J Heart Transplant 1988;7:326 –30. Hosenpud JD. Invited commentary. Ann Thoracic Surg 1998;65:1578. Bennett L, Edwards E, Hosenpud J. Transplantation with older donor hearts for presumed “stable” recipients: an analysis of the Joint International Society for Heart and Lung Transplantation/United Network for Organ Transplantation Sharing Thoracic Registry. J Heart Lung Transplant 1998;17: 901–5. Robicsek F, Masters T, Tomley A, Riece H, Morales-Reyna J. Bench coronary cineangiography. A possible way to increase the number of hearts available for transplantation. J Thorac Cardiovasc Surg 1992;103:1490 –5. Warnecke H, Tietze U, Hetzer R. Noninvasive monitoring of cardiac allograft rejection by intramyocardial electrogram recordings. Circulation 1986;74:72. Loebe M, Schu ¨ler S, Zais O, Warnecke W, Fleck E, Hetzer
The Journal of Heart and Lung Transplantation Volume 19, Number 10 R. Role of cytomegalovirus infection in the development of coronary artery disease in the transplanted heart. J Heart Transplant 1990;9:707–11. 25. Weymouth L, Gomolin I, Brennan T, Sirpenski S, Mayo D. Cytomegalovirus antibody in the elderly. Intervirology 1990; 31:223–9. 26. Natali A, Valcavi P, Medici MC, Dieci E, Montali S, Chezzi
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C. Cytomegalovirus infection in an Italian population: antibody prevalence, virus excretion and maternal transmission. New Microbiol 1997;20:123–33. 27. Musci M, Loebe M, Wellnhofer E, et al. Coronary angioplasty, bypass surgery, and retransplantation in cardiac transplant patients with graft coronary disease. Thorac Cardiovasc Surg 1998;46:268 –74.