CLINICAL RESEARCH: CARDIAC TRANSPLANT AND ASSIST DEVICES
Outcomes in cardiac transplant recipients using allografts from older donors versus mortality on the transplant waiting list
Implications for donor selection criteria
Katherine Lietz, MD, PhD*,
Ranjit John, MD*,*,
Donna M. Mancini, MD and
Niloo M. Edwards, MD*
* Cardiothoracic Surgery, New York, New YorkUSA
Cardiology, Columbia Presbyterian Medical Center, Columbia University, New York, New York, USA
Manuscript received June 6, 2003;
revised manuscript received August 9, 2003,
accepted August 18, 2003.
* Reprint requests and correspondence: Dr. Ranjit John, Division of Cardiothoracic Surgery, Columbia Presbyterian Medical Center, Milstein Hospital Building 7-435, 177 Fort Washington Avenue, New York, New York 10032, USA.
ranjitj{at}pol.net
 |
Abstract
|
|---|
OBJECTIVES: This study investigates the outcomes of cardiac transplantation using older donors.
BACKGROUND: Despite high mortality rates on waiting lists, transplanting hearts from older donors remains a relative contraindication.
METHODS: We retrospectively reviewed data on 479 adult heart transplant recipients, 352 status I patients, and 534 status II patients enrolled on a waiting list between 1992 and 1999. The Cox proportional hazards model was used for statistical analysis.
RESULTS: Of all donors, 20% were 40 to 50 years old and 8% were  50 years old. The risk of six-month mortality on the waiting list for patients who were not transplanted (status I: relative risk [RR] 8.5; status II: RR 3.7) significantly outweighed the risk of transplanting patients with a heart from donors >40 years old (status I: RR 1.6; status II: RR 2.1). Recipients of cardiac allografts from donors <40 years old had a one-month mortality rate of 5%, in contrast to 13% and 22% in those receiving allografts from donors 40 to 50 years old and 50 years old, respectively. Donor age did not influence long-term survival or frequency of rejections; however, it did correlate with the early presence of transplant-related coronary artery disease (TCAD). By the first annual angiogram, only 17% of recipients with donors <20 years old developed TCAD, in contrast to 26% to 30% and 34% of recipients who received allografts from donors age 20 to 40 years and >40 years, respectively.
CONCLUSIONS: Despite a strong association between older donor age and increased post-operative mortality and TCAD, it is more beneficial in terms of patient survival to receive an allograft from a donor >40 years old than to remain on the waiting list.
|
Abbreviations and Acronyms
| | CAD | = coronary artery disease | | CI | = confidence interval | | CVA | = cerebrovascular accident | | HLA | = human leukocyte antigen | | LVAD | = left ventricular assist device | | RR | = relative risk | | TCAD | = transplant-related coronary artery disease | | UNOS | = United Network of Organ Sharing |
|
A chronic shortage of suitable donor organs and an increasing demand for cardiac transplantation has led to the expansion of donor acceptance criteria, particularly with respect to donor age. Early in the experience of heart transplantation, the upper limit of donor age was 35 years (1). Major concerns about older donors were related to a greater susceptibility of early irreversible graft failure (2) and the transmission of coronary artery disease (CAD), hypertensive heart disease, or valvular degeneration from the donor heart (3). However, despite these concerns, as a result of an increased demand for cardiac transplantation and a decreasing donor pool, older donors are used with increasing frequency. According to the International Heart and Lung Transplantation Registry, the mean age of heart donors rose from 23 years in 1985 to 30 years between 1991 and 1996, with a slight decline to 27.5 years in 1999 (4).
The effect of liberalization of donor selection criteria on post-transplant recipient outcomes has been questioned. Many single-center analyses report that the use of older donor hearts has not affected post-transplant survival (5–13). However, large multi-institutional studies (14,15) and the International Heart and Lung Transplantation Registry (4) reported increased mortality in heart transplant recipients receiving older donor hearts. Discrepancies between previous single-center studies and results from large cohort analyses are probably related to a smaller number of patients and short observation times at individual institutions (16). The objective of this study was to investigate post-transplant outcomes in recipients of older donor hearts in a large-volume, single-center study. This current study provides adequate statistical power and follow-up periods and, more importantly, was performed during an era in which all recipients received standard triple immunosuppressive therapy. Furthermore, in order to study the risk/benefit ratio in patients receiving older donor hearts, we also compared post-transplant survival data in recipients who received older donor hearts with waiting list mortality for patients with end-stage heart failure awaiting cardiac transplantation.
|
Methods
|
|---|
Patients.
Between January 1992 and January 1999, 479 transplantations (448 primary and 31 re-transplants) were performed on adult recipients (age >18 years) at the Columbia Presbyterian Medical Center in New York City. The patients were predominantly male (78.1%) and Caucasian (79.5%), with a mean age of 50.1 ± 13.2 years. The majority of donors were male (60%) and Caucasian (80%), with a mean age of 31.6 ± 13.2 years. The major cause of death was head trauma (40%) and cerebrovascular accident (CVA) (38%), followed by anoxia (6%) and other causes (16%). The mean donor ischemia time was 173 ± 60 min. A complete mismatch at human leukocyte antigen (HLA) loci was present in HLA-A in 62%, HLA-B in 79%, and HLA-DR in 66% of patients. Of the 479 patients, between January 1992 and January 1999, 453 were enrolled by United Network of Organ Sharing (UNOS) on a waiting list: 187 (39%) as status I and 266 (61%) as status II. The mean waiting time to transplantation for patients enrolled as status I and status II was 4.1 and 13.4 months, respectively. The mean waiting times to surgery in consecutive eras of transplantation (i.e., 1992 to 1993, 1994 to 1996, and 1997 to 1999) were 1.6, 4.6, and 4.6 months for status I patients and 22.8, 13.6, and 14.1 months for status II patients, respectively. The UNOS data on the enrollment status for 26 patients transplanted before 1992 were not available. The one- and five-year patient survival rates were 80.9% and 66.9%, respectively, with a mean follow-up of 3.13 ± 2.26 years (range 0 to 8 years).
In addition, we evaluated the survival of 352 status I and 534 status II patients at Columbia Presbyterian Medical Center enrolled on the UNOS waiting list for primary heart transplantation between January 1992 and January 1999. Forty-five patients who were moved to another center while on the waiting list, transplanted at another center, or who received multiple organ transplants were excluded from the analysis. Of these 886 patients, 231 (26%) died while on waiting list and 172 (19%) were still awaiting transplantation.
Before undergoing heart transplantation, a left ventricular assist device (LVAD) was used in 125 patients, of whom 93 were successfully transplanted, 29 died after device insertion, and three were still awaiting transplantation at the time of analysis.
Clinical data.
The following pre-transplant variables were analyzed: recipient age, gender, ethnicity, pre-transplant diagnosis, donor age, gender, ethnicity, complete mismatch at HLA-A, -B, and -DR loci, pre-transplant LVAD support, and UNOS status at listing. Post-transplant data on acute rejection, transplant-related coronary artery disease (TCAD), and survival were evaluated.
Operative techniques.
Donor hearts were harvested from beating-heart, brain-dead individuals. Graft procurement and preservation employed cold cardioplegic arrest using the University of Wisconsin solution and topical hypothermia. From 1992 to 1996, orthotopic cardiac transplantation was performed using the biatrial technique described by Lower and Shumway (17). Since 1996, we have performed almost all transplants using the bicaval anastomosis technique (17).
Immunosuppressive regimen.
All patients received triple immunosuppression, consisting of cyclosporine, steroids, and azathioprine. Azathioprine was given at an initial pre-operative dose of 4 mg/kg/day, followed by a daily intravenous dose of 2 mg/kg until the patient could tolerate oral medication. Since 1996, azathioprine has been replaced by mycophenolate mofetil, starting at a dose of 1,000 mg twice daily. Cyclosporine was given at the initial dose of 1 to 2 mg/kg/day and adjusted to maintain trough whole-blood levels between 300 and 350 ng/dl. Between three and six months after transplantation, the cyclosporine dosage was adjusted to maintain blood levels between 150 and 250 ng/dl, and after six months, between 100 and 150 ng/dl. Intravenous methylprednisolone (500 mg) was administered during the operation and in the postoperative period at a dose of 125 mg every 8 h over 24 h. Prednisone was given in tapering doses of 1 mg/kg per day immediately post-operatively to 0.1 mg/kg/day by the fourth month. Rejection episodes were treated with oral or intravenous pulses of steroid 100 mg/day for three days, followed by a taper over one week to the baseline dose. Non-responders to steroid therapy were treated with cytolytic therapy.
Acute rejection.
Rejection was diagnosed by routine endomyocardial biopsy—weekly for the first 4 weeks, then every 2 weeks for the next 1 month, monthly for 4 months, then every 2 months for the next 6 months, followed by every 3 months for the next 6 months, and then every 6 to 12 months. The biopsy fragments were graded according to International Society for Heart and Lung Transplantation (ISHLT) criteria (18). High-grade cellular allograft rejection was defined pathologically as grade 3A or 3B.
Angiography/diagnosis of TCAD.
The diagnosis of TCAD was based on the following: 1) discrete lesions resulting in >50% obstruction of the proximal or mid-portions of major graft vessels; or 2) diffuse, concentric narrowing of the whole vessels, including their branches. If TCAD was identified, the frequency of angiography was increased to a biannual regimen. Patients were not given routine vasodilators before coronary injections. In patients with possible diffuse CAD, the intimal thickening was documented by vascular ultrasound. All coronary angiograms were reviewed by a cardiologist and compared with the previous year's films to detect the presence of luminal irregularities, discrete stenoses, loss of third-order branches, or pruning of vessels. Hearts explanted before retransplantation and postmortem heart autopsy specimens were examined for evidence of vessel occlusion and irregularities, ischemic damage, and the presence of acute cardiac rejection.
HLA typing.
Serologic typing of HLA-A and -B loci was performed by standard microcytotoxicity techniques. HLA-DR typing was performed by serologic analysis.
Statistical analysis.
Differences between groups were examined using the chi-square or Fisher exact test, if the number of expected frequencies in the examined group was less than five. The graphic distribution of recipient age in Table 1 was normal, and thus the Student t test was used to compare groups. Survival estimates were based on the Kaplan-Meier method, and curves were compared using a log-rank test (19). Univariate and multivariate analyses were performed to determine the independent impact of donor age on survival, the incidence of acute rejection episodes, and TCAD. All covariates listed in Table 2 were entered in the multivariate Cox proportional hazards model using stepwise selection. A subsequent multicollinearity analysis revealed a maximal variance inflation factor of 1.9 (mean 1.34). Hence, the parameter estimates have not been unduly influenced by collinearity between predictors in the multivariate analysis model. Results were considered significant at p < 0.05. Data are reported as the mean value ± SD. Data were analyzed using the SAS System software, version 7.0 (SAS Institute Inc., Cary, North Carolina).
|
Results
|
|---|
Donor age.
The mean donor age in this study population was 31.6 ± 13.2 years (range 5 to 66 years). As illustrated in Table 3, the mean age of heart donors rose, from 29 years during the period from 1992 to 1993, to 33 years during the 1994 to 1996 period, and it declined to 31 years from 1997 to 1999. The increase in mean donor age was related to a relative increase in the percentage of donors 40 years old. Between 1992 and 1993, only 20% of hearts from donors older than 40 years were accepted for transplantation, as compared with 32% after 1993 and 29% after 1997.
View this table:
[in this window]
[in a new window]
|
Table 3 Influence of Era on Acceptance of Older Donor Hearts for Transplantation and Effect of Older Donor Age on Early Post-Transplant Mortality
|
|
Older donor demographic data.
As shown in Table 1, 74 (56%) of 133 donors >40 years were females, in contrast to only 103 (30%) of 346 donors <40 years (p < 0.001). The major cause of death in the older donor population was CVA (74%), followed by head trauma (16%). Among donors younger than 40 years, the causes of death included head trauma (49%), followed by CVA (24%). Donor ethnicity, ischemic times, complete mismatch at HLA-A, -B, and -DR loci were similar across the donor age groups.
Demographic data of recipients of allografts from older donors.
More allografts from older donors (>40 years old) were transplanted into males than females; 114 (86%) of 133 older donors were transplanted into male recipients, as compared with 260 (75%) of 346 younger donors (p = 0.01). The mean age of patients receiving hearts from older donors was 53 years, as compared with a mean age of 49 years in recipients receiving hearts from donors <40 years old (p = 0.007). There were no differences in the demographic data of recipients who received hearts from older versus younger donors with respect to recipient ethnicity, listing status, retransplantation, and LVAD implantation before transplantation.
Influence of donor age on recipient survival after heart transplantation.
As seen in Figure 1, older donor age (>40 years) adversely influences survival after heart transplantation. The 30-day post-transplant mortality rate in recipients of hearts from donors <40 years old was 5% (19 of 346), in contrast to 13% (13 of 97) and 22% (8 of 36) in patients who received hearts from donors whose age was between 40 and 50 years and >50 years, respectively (p < 0.004). Compared with donors <40 years old, the risk of early post-operative mortality was 2.5 times (95% confidence interval [CI] 1.25 to 5.12) greater in recipients of hearts from donors between 40 and 50 years old (p = 0.01) and 4.3 times (95% CI 1.88 to 9.83) greater in recipients of hearts from donors >50 years old (p < 0.001). If patients who did not survive the first 30 days were excluded from the analysis, the long-term survival was no longer influenced by donor age, and the risk of post-transplant mortality decreased to 0.78 (95% CI 0.44 to 1.48) for recipients of hearts from donors between 40 and 50 years old (p = 0.39) and 1.51 (95% CI 0.73 to 3.14) for recipients of hearts from donors >50 years old (p = 0.27).
View larger version (19K):
[in this window]
[in a new window]
|
Figure 1 Kaplan-Meier survival after heart transplantation by donor age. Overlapping squares (top) = donor age  40 years (n = 346); triangles = donor age 40 to 50 years (n = 97); circles = donor age >50 years (n = 36).
|
|
As seen in Table 2, the multivariable Cox analysis confirmed that the risk of early post-operative mortality increased with donor age and became an independent risk factor for early post-operative death once donor age exceeded 50 years (relative risk [RR] 2.8, p = 0.02). Other risk factors for early post-transplant mortality included CVA as the cause of the donor's death (RR 3.7, p = 0.006), ischemic time exceeding 4 h (RR 2.47, p = 0.04), and the era of transplantation, with the RR of early post-transplant mortality in years 1997 to 1999 decreasing from 2.7 in years 1994 to 1996 (p = 0.03) and from 5.1 in years 1992 to 1993 (p < 0.001). As illustrated in Table 3, the early mortality in recipients of hearts from donors >40 years old improved throughout the consecutive eras, and in years 1997 to 1999, it was no longer significantly different from early mortality in recipients of younger donor hearts. Recipient gender, age, ethnicity, diagnosis of heart disease, complete mismatch at HLA-A, -B, and -DR loci, and pre-transplant LVAD support and re-transplantation were not associated with decreased post-operative survival.
The major causes of death within the first post-transplant month were sepsis (n = 12), heart failure (n = 11), hemorrhage (n = 5), acute rejection (n = 4), pulmonary embolism (n = 2), ischemic stroke (n = 2), multiorgan failure (n = 1), and technical problems (n = 2). There were no statistically significant differences in the distribution of the causes of death between recipients of hearts from donors younger and older than 40 years.
The use of pre-transplant mechanical support did not affect early mortality after transplantation in recipients of older donor hearts. Among 90 patients supported with LVAD before transplantation, early post-transplant death occurred in 2 (9%) of 22 recipients of hearts from donors >40 years old and 2 (3%) of 68 recipients of hearts from younger donors (p = 0.24).
Influence of donor age on high-grade acute rejection.
Older donor age (>40 years) is not associated with an increased risk of earlier acute rejection or an increased frequency of acute rejections within the first post-transplant year (Table 4). The incidences of at least one high-grade rejection episode within the first post-operative year in recipients who received hearts from donors age <40, 40 to 50, and >50 years were 41%, 47%, and 36%, respectively.
Influence of donor age on TCAD.
A direct correlation is seen between increasing donor age and early development of TCAD. Based on the results of the first annual angiograms, we have found that, when compared with donors younger than 20 years, the third, fourth, and fifth decades of donor life increase the risk of TCAD by 2.2-, 2.4-, and 2.6-fold, respectively (Table 5). As the risk of TCAD increases starting with the fourth decade of a donor's life, Figure 2 demonstrates the relationship between donor age >30 years and time to the onset of TCAD (p = 0.006). It is important to note that the correlation between development of TCAD and older donor age holds true only for the first post-transplant year (p = 0.02), and when we exclude patients who developed TCAD within the first year, no significant correlation is found between one and five years after transplantation (p = 0.16). The hazard function in Figure 2A illustrates that the role of donor age in the development of TCAD is confined to the first post-transplant year (p < 0.01).
View this table:
[in this window]
[in a new window]
|
Table 5 Influence of Donor Age on Diagnosis of Transplant-Related Coronary Artery Disease on First Annual Angiogram
|
|
View larger version (20K):
[in this window]
[in a new window]
|
Figure 2 Kaplan-Meier (A) freedom from transplant-related coronary artery disease (TCAD) and (B) hazard function for the presence of TCAD, as detected by annual coronary angiography. Squares = donor age 30 years (n = 169); triangles = donor age >30 years (n = 132).
|
|
Cardiac transplant waiting list mortality.
Because older donor hearts are associated with an increased risk of post-operative mortality, we compared mortality on the cardiac transplant waiting list to the mortality for a recipient receiving a cardiac allograft from an older donor. For those patients who underwent cardiac transplantation, survival on the waiting list was tied to post-transplant survival. A separate analysis was performed for patients initially enrolled in our institution as status I (n = 352) and status II (n = 534) on the UNOS waiting list between January 1992 and January 1999.
Table 6 shows a comparison of statistical analysis of six-month mortality of status I and status II enrolled patients who received a cardiac allograft from an older donor (age >40 years) or younger donor (<40 years), as compared with those patients who did not receive an allograft. Figures 3A and 3B represent this correlation graphically for status I and II patients, respectively. The risk of death within six months from enrollment in status I and status II patients who did not receive an allograft is 8.5- and 3.7-fold, respectively, higher than in patients who received an allograft. However, transplantation of a heart from an older donor (age >40 years) only slightly increases the risk of six-month mortality to 1.6 for status I patients and 2.1 for status II patients. This association does not reach statistical significance.
View this table:
[in this window]
[in a new window]
|
Table 6 Comparison of Six-Month Mortality of Status I and Status II Enrolled Patients Who Received a Transplant From an Older Donor (>40 Years) or Younger Donor (<40 Years) Versus No Transplant
|
|
View larger version (23K):
[in this window]
[in a new window]
|
Figure 3 Kaplan-Meier survival from enrollment on waiting lists for (A) status I and (B) status II patients.
|
|
|
Discussion
|
|---|
Our experience supports previous findings of multi-institutional (4,15) and single-center studies (16) of poorer survival in recipients of older donor hearts. The 346 patients who received a heart from donors <40 years old had a one-month mortality of 5%. In contrast, in 97 and 36 patients who received hearts from donors whose age was between 40 and 50 years and older than 50 years, the early post-operative mortality significantly increased to 13% (RR 2.5, p = 0.01) and 22% (RR 4.3, p < 0.001), respectively. Interestingly, our analyses show that the correlation between older donor age and poor survival was confined to the very early perioperative period, and no further association between older donor age and survival was found beyond the first post-transplant month. The major causes of early post-transplant death in our population included sepsis, heart failure, hemorrhage, and acute rejection, and their distribution was similar between recipients of hearts from younger and older donors.
It is important to note that with the advances in patient care in recent years, the early post-transplant outcomes at our center have significantly improved (20). In years 1997 to 1999, the RR of one-month post-transplant mortality was 2.5 times lower than that in years 1994 to 1996 and five times lower than that in years 1992 to 1993. Parallel to these changes, the adverse influences of transplanting hearts from older donors also gradually diminished. The post-transplant mortality rate in patients receiving hearts from donors older than 40 years decreased from 33% in years 1992 to 1993 to 16% in years 1994 to 1996 and to 7% in years 1997 to 1999. These eras represent important milestones in the care of heart recipients at our center. In 1994, azathioprine in the triple immunosuppressive regimen was replaced by mycophenolate mofetil, which has been previously described to correlate with improved survival in heart transplant recipients (21). Also, since 1996, the bicaval anastomosis technique was introduced to perform heart transplantation, instead of the previously used biatrial technique. Although other authors did not find bicaval anastomosis to be superior to older techniques in terms of graft survival (22), it is one of the many factors that could have contributed to improved peri-operative outcomes at our center.
Because the risk for death in patients who received hearts from older donors was greatest in the early post-transplant period, we investigated whether other factors that might affect the quality of the transplanted heart may correlate with a poor survival. Both the ISHLT registry data (4) and other independent investigators (14–16) have suggested that an ischemic time >4 h may increase the risk for death in recipients who receive hearts from donors older than 50 years. Our analysis revealed that ischemic time >4 h and donor death resulting from CVA significantly contributed to poor early post-transplant outcomes and outweighed the importance of recipient demographics and mechanical support before transplantation.
The association between TCAD and donor age is controversial. Some authors found no significant association between older donor age and accelerated TCAD (12,23,24), in contrast to a multi-institutional study (25). Gao et al. (23) showed that despite a higher incidence of moderate to severe intimal thickening, as detected by intravascular ultrasound in older donors, older donor age was not significantly associated with the subsequent development of TCAD. However, these authors state that knowledge of the extent to which advanced intimal thickening in older donor hearts is associated with a higher incidence of late TCAD on angiograms was limited by the small number of patients and short follow-up duration in this study. In this study, we demonstrate that the risk of TCAD increases with every decade of donor age (Table 6). By the end of the first post-transplant year, 17% of recipients of hearts from young donors (<20 years old) develop angiographic evidence of TCAD, compared with 26% of recipients of hearts from donors in their third decade, 30% of recipients of hearts from donors in their fourth decade, 34% of recipients of hearts from donors in their fifth decade, and 34% of recipients from donors >50 years old. As shown in Table 5, the donor's cutoff age at which the risk of TCAD starts to increase is 30 years (Fig. 3A). Interestingly, as the hazard function shows in Figure 3B, the risk of TCAD development is confined to the first post-transplant year and subsides thereafter. It is possible that the correlation between the donor age and incidence of TCAD limited to the first post-transplant annual angiogram may reflect the presence of pre-existing CAD in a donated heart, and not true development of transplant vasculopathy. Several previous studies showed that the use of older donor hearts was associated with preexisting CAD present before the donor's death (26). Although our center generally does not accept hearts from female donors >45 years old and male donors >40 years old with angiographic evidence of CAD in more than one major vessel, subtle pre-transplant lesions could lead to the post-transplant findings interpreted as transplant vasculopathy. Unfortunately, the majority of the donor coronary angiograms were obtained in other hospital centers, and we were not able to compare them with the first annual post-transplant angiograms taken in recipients.
Because frequent episodes of acute rejection may accelerate the development of TCAD (27), we investigated whether recipients of older donor hearts exhibit a higher alloreactivity to the donor allograft. However, no correlation was found between donor age and either the time to the first high-grade acute rejection or the annual cumulative rejection frequency. Ventura et al. (28) suggested that vessels from older hearts may be more susceptible to damage caused by rejection, and that multiple rejection episodes in recipients of older donor hearts may even further accelerate the development of allograft vasculopathy. Although similar trends were observed in our current series, no statistically significant associations were found.
The higher mortality for patients receiving hearts from older donors has raised questions regarding the criteria for donor selection. Is it worth transplanting hearts from older donors? It is clear that the upper limit of donor age has steadily increased over the past three decades. Rodeheffer et al. (29) reported a maximum donor age of 34 years among 2,749 heart transplant recipients in a multi-institutional study between 1990 and 1994. In contrast, of the 479 heart transplantations performed at our center, 133 (28%) were obtained from donors older than 40 years. In our experience, the mean age of heart donors varied depending on the proportion of hearts harvested from donors >40 years old and rose from 29 years old between 1992 to 1993 to 33 years between 1994 and 1996, with a slight decline to 31 years from 1997 to 1999.
It is important to keep in mind that patients with end-stage heart failure face a significant risk of death while awaiting heart transplantation. The UNOS registry data reveal that patients with blood group O have a median waiting time of 332 days; the median waiting time for patients >18 years old was 230 days (30). Bennett et al. (31) showed that despite an initial risk resulting from the transplant procedure, there was a clear long-term survival benefit for status I recipients who received older donor hearts. Their analysis revealed that 30 days after transplantation, the risk of death for recipients of 45- to 49-year-old donor hearts was lower than that if they remained on the waiting list, and at six months, the RR was 0.37. Further, for recipients of hearts from donors 50 years or older, the risk after transplantation was lower after 64 days, and by six months, the RR was 0.48. Our results support these important findings. Although recipients of older donor hearts had poorer early survival than did recipients of hearts from donors younger than 40 years, it was still much more beneficial to transplant an older donor heart than to remain on the waiting list, particularly for status I patients. For status I patients, six-month mortality on a waiting list was 70%, and the risk of death was 8.5 times higher than that of status I patients who received an allograft from donors <40 years old, with a resulting 14% six-month mortality. Transplantation of an older donor heart increased the risk of death in those recipients to 1.6 times but was not statistically significantly different from recipients who received hearts from donors <40 years old. Similarly, in status II recipients, those not transplanted had a mortality rate of 24% within the first six months from enrollment on a waiting list. This increased the risk of death 3.7 times, as compared with status II patients receiving a heart from a younger donor (<40 years old). Although status II recipients of older donor (>40 years old) hearts slightly increased the risk of death to twofold, this difference did not reach statistical significance. Thus, it is reasonable to conclude that expansion of donor age to 40 years is more beneficial, in terms of a risk/benefit ratio, than indefinitely waiting on the transplant list (32). These benefits may be even more evident in unstable UNOS status I patients who are critically ill and who appear to be deteriorating despite maximal hemodynamic support. The data we provide support the use of donors even older than 50 years in status I patients, as six-month survival is better, compared with remaining on the transplant waiting list. As UNOS status II patients do not have a dramatic survival improvement when transplanted with older donor hearts, as compared with UNOS status I patients, it would be advisable to consider transplantation of older donor hearts only to status I patients. It is important to note that the use of ventricular assist devices in status I patients may obviate the need to urgently use an older donor heart. However, if an older donor heart is used, it is important to avoid or at least minimize other known risk factors that adversely affect survival, such as a prolonged ischemic time. Further, clinical hemodynamic stability of the recipient would also improve the chances of the older donor cardiac allograft to function satisfactorily. In addition, it remains imperative that a more aggressive approach to detection of TCAD, as well as the development of therapies to treat TCAD in recipients of older donor allografts, is warranted in light of our findings of an increased prevalence of TCAD in these recipients.
Study limitations.
This study includes those limitations associated with a retrospectively performed study. It is also possible that older donor hearts were transplanted into sicker recipients who had a higher probability of death if they remained on the waiting list. This does not detract from our study conclusions, but only offers an additional explanation for the poorer survival in recipients of older donor hearts. Unlike several studies focusing on this problem, ours did not suffer from the lack of standardization associated with multicenter studies. We were also unable to analyze the UNOS status at the time of transplantation, as we were unable to obtain complete data on this variable. This is important, as the UNOS listing often changes as the clinical condition of patients with end-stage heart failure changes.
Conclusions.
The risk of early mortality after heart transplantation from donors older than 40 years is increased nearly threefold and is multifactorial in nature. Although the absolute risk of early mortality in recipients of older donor hearts has decreased over the advancing eras of institutional experience, the proportional increase of early mortality with the use of older donor hearts remained the same. The use of older donors is associated with an increase in the incidence of TCAD at one year. There is evidence in the literature to suggest that this increase may be due to native CAD in the donor. Angiograms should be reviewed by the recipient's institution to rule out noncritical CAD, which might worsen after transplantation due to immunologic stimulation or an increase in traditional risk factors after transplantation. If angiograms cannot be reviewed, recipients of older donor heart should undergo early coronary angiography to evaluate native atherosclerosis. There is no survival advantage for status II patients awaiting a heart transplant to receive older donor hearts; therefore, older donors should be used for critically ill status I patients. Patients most likely to die should be identified, allowing better utilization of devices or transplant organs.
|
References
|
|---|
- Griepp RB, Stinson EB, Clark DA, Dong E, Shumway NE. The cardiac donor. Surg Gynec Obstet. 1971;133:792–798
- De Bakey ME, Diethrich EB, Glick G, et al. Human cardiac transplantation: Clinical experience. J Thorac Cardiovasc Surg. 1969;58:303–317[Medline]
- English TAH, Spratt P, Wallwork J, Cory-Pearce R, Wheeldon D. Selection and procurement of hearts for transplantation. BMJ. 1984;288:1889–1891[Medline]
- Hosenpud JD, Bennett LE, Keck BM, Fiol B, Boucek MM, Novick RJ. The Registry of the International Society of Heart and Lung Transplantation: Sixteenth official report—1999. J Heart Lung Transplant. 1999;18:611–626[CrossRef][Medline]
- Hoecher K, Young JB, McCarthy PM, Smedira N, Price LL, Stewart KW. Long term mortality and morbidity with use of older donors in cardiac transplantation: A single center experience (abstr). Transplantation. 1998;65 Suppl:S104
- McCarthy JF, McCarthy PM, Massad MG, et al. Risk factors for death after heart transplantation: Does a single center experience correlated with multicenter registries? Ann Thorac Surg. 1998;65:1564–1569[Free Full Text]
- Livi U, Bortolotti U, Luciani GB, et al. Donor shortage in heart transplantation: Is extension of donor age limits justified? J Thorac Cardiovasc Surg. 1994;107:1346–1355[Abstract/Free Full Text]
- Drinkwater DC, Laks H, Blitz A, et al. Outcomes of patients undergoing transplantation with older donor hearts. J Heart Lung Transplant. 1996;15:684–691[Medline]
- Pflugfelder PW, Singh NR, McKenzie FN, Menkis AH, Novick RJ, Kostuk WJ. Extending cardiac allograft ischemic time and donor age: Effect on survival and long-term cardiac function. J Heart Lung Transplant. 1991;10:394–400[Medline]
- Menkis AH, Novick RJ, Kostuk WJ, et al. Successful use of the ‘unacceptable’ heart donor. J Heart Lung Transplant. 1991;10:28–32[Medline]
- Pflugfelder PW, Thomson D, Singh NR, Menkis AH, McKenzie FN, Kostuk WJ. Cardiac allograft ischemic time: Relation to graft survival and cardiac function. Circulation. 1989;80(Suppl II):III116, III121
- Mulvagh SL, Thorton B, Frazier OH, et al. The older cardiac transplant donor: Relation to graft function and recipient survival longer than 6 years. Circulation. 1989;80(Suppl III):III126, III132
- Tenderich G, Koerner MM, Stuettgen B, et al. Extended donor criteria: Hemodynamic follow-up of heart transplant recipients receiving a cardiac allograft from donors 60 years of age. Transplantation. 1998;66:1109–1113[Medline]
- Young JB, Naftel DC, Bourge RC, et al. Matching the heart donor and heart transplant recipient. Clues for successful expansion of the donor pool: A multivariable, multi-institutional report. J Heart Lung Transplant. 1994;13:353–365[Medline]
- Bourge RC, Naftel DC, Constanzo-Nordin MR, et al. Pretransplantation risk factors for death after heart transplantation: A multi-institutional study. J Heart Lung Transplant. 1993;12:549–562[Medline]
- Del Rizzo DF, Menkis AH, Pflugfelder PW, et al. The role of donor age and ischemic time of survival following orthotopic heart transplantation. J Heart Lung Transplant. 1999;18:310–319[CrossRef][Medline]
- Lower RR, Shumway NE. Studies of orthotopic cardiac homotransplantations of the canine heart. Surg Forum. 1960;11:18–19[Medline]
- Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart rejection study group. the international society for heart transplantation. J Heart Transplantation. 1990;9:587–593[Medline]
- Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–481[CrossRef]
- John R, Rajasinghe H, Chen JM, et al. Impact of current management practices on early and late death in more than 500 consecutive cardiac transplant recipients. Ann Surg. 2000;232:302–311[CrossRef][Medline]
- Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation. 1998;66:507–515[CrossRef][Medline]
- Grande AM, Rinaldi M, D'Armini AM, et al. Orthotopic heart transplantation: Standard versus bicaval technique. Am J Cardiol. 2000;85:1329–1333[Medline]
- Gao S, 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;29:623–629[Abstract]
- Schuler S, Matschke K, Loebe M, Hummel M, Fleck E, Hetzer R. Coronary artery disease in patients with hearts from older donors: Morphologic features and therapeutic implications. J Heart Lung Transplant. 1993;12:100–109[Medline]
- Constanzo MR, Naftel DC, Pritzker MR, et al. Heart transplant coronary artery disease detected by coronary angiography: a multi-institutional study of the preoperative donor and recipient risk factors. J Heart Lung Transplant 1998;744–53.
- Grauhan O, Patzurek J, Hummel M, et al. Donor transmitted coronary artherosclerosis. J Heart Lung Transplant. 2003;22:568–573[CrossRef][Medline]
- Young JB, Winsdor NT, Kleiman NS, Lowry R, Cocanougher B, Lawrence EC. The relationship of soluble interleukin-2 receptor levels to allograft arteriopathy after heart transplantation. J Heart Lung Transplant. 1992;11:579–582
- Ventura HO, Mehra MR, Smart FW, Stapleton DD. Cardiac allograft vasculopathy: Current concepts. Am Heart J. 1995;129:791–799[CrossRef][Medline]
- Rodeheffer RJ, Naftel DC, Stevenson LW, et al. Secular trends in cardiac transplant recipient and donor management in the United States, 1990–1994: A multi-institutional study. Circulation. 1996;94:2883–2889[Abstract/Free Full Text]
- Kauffmann MH, McBride MA, Shield CF, Daily OP, Wolf JS, Kirklin JK. Determinants of waiting time for heart transplants in the United States. J Heart Lung Transplant. 1999;18:414–419[Medline]
- Bennett LE, Edwards EB, Hosenpud JD. 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 sharing thoracic registry. J Heart Lung Transplant. 1998;17:901–905[Medline]
- Young JB. Age before beauty: The use of ‘older’ donor hearts for cardiac transplantation. J Heart Lung Transplant. 1999;18:488–491[Medline]
This article has been cited by other articles:
|
|
|
|
 
L. U. Nwakanma, A. S. Shah, J. V. Conte, and W. A. Baumgartner
Heart Transplantation
Card. Surg. Adult,
January 1, 2008;
3(2008):
1539 - 1578.
[Full Text]
|
|
|
|
|
|
|
K. J. Shea, N. A Sopko, K. Ludrosky, K. Hoercher, N. G. Smedira, D. O. Taylor, R. C. Starling, and G. V. Gonzalez-Stawinski
The effect of a donor's history of active substance on outcomes following orthotopic heart transplantation
Eur. J. Cardiothorac. Surg.,
March 1, 2007;
31(3):
452 - 456.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Li, K. Tanaka, H. Anzai, B. Oeser, D. Lai, J. A. Kobashigawa, and J. M. Tobis
Influence of Pre-Existing Donor Atherosclerosis on the Development of Cardiac Allograft Vasculopathy and Outcomes in Heart Transplant Recipients
J. Am. Coll. Cardiol.,
June 20, 2006;
47(12):
2470 - 2476.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods