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a Division of Cardiothoracic Surgery, Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, New York
b Department of Health Policy, Mount Sinai School of Medicine, New York, New York
Accepted for publication December 5, 2008.
* Address correspondence to Dr Russo, New York-Presbyterian Hospital/Columbia, Milstein Hospital Bldg Room 7-435 GN, 177 Fort Washington Ave, New York, NY 10032 (Email: mr2143{at}columbia.edu).
Presented at the Forty-fourth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2008.
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Abstract |
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Methods: The United Network for Organ Sharing provided de-identified patient-level data. Analysis focused on patients undergoing heart transplantation between January 1, 1999, and December 31, 2005 (n = 13,024). High-risk criteria included age more than 65 years old, retransplantation, hepatitis C-positive, human immunodeficiency virus-positive, creatinine clearance less than 30 mL/min, diabetes mellitus with peripheral vascular disease, and diabetes with creatinine clearance less than 40 mL/min. Marginal donor criteria included age more than 55 years, diabetes mellitus, hepatitis C-positive, human immunodeficiency virus-positive, ejection fraction less than 45%, and donor:recipient weight less than 0.7.
Results: Survival in the standard transplant group, defined as non–high-risk patients who received nonmarginal organs, was better than in all other groups (p < 0.001). Alternate listing transplantation patients had the worst survival (p < 0.001). The 5-year survival for the alternate listing transplantation group was 51.4%, compared with 75.1% in the standard transplant group; the standard transplant patients, with the lowest incidence of in-hospital infection (21.1%) and dialysis (7.1%), also had the best transplant hospitalization outcomes (p < 0.001). In contrast, alternate listing transplantation patients had the highest incidence of in-hospital infection (35.4%; p < 0.001). Length of stay during transplant hospitalization was also shortest in the standard transplant group (18.8 days; p < 0.001).
Conclusions: Alternate listing transplantation is associated with greater morbidity and resource utilization compared with standard transplantation. However, this strategy offers a median survival of 5.2 years to patients who would otherwise be expected to live 1 year, and therefore, may be reasonably applied to expand the benefits of transplantation. Further studies examining the costs and quality of life related to this approach are needed.
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There is a critical scarcity of organs available for transplantation. Of an estimated 60,000 potential beneficiaries, fewer than 2,500 undergo cardiac transplantation annually. Given the significant disparities between the supply and demand for transplantable organs, strategies designed to offer transplantation to a greater number of candidates have the potential to provide substantial benefits.
To achieve this goal, some centers have advocated for the adoption of alternate listing transplantation. Under this strategy, high-risk (HR) candidates who fail to meet standard criteria for transplantation are considered for marginal donor (MD) organs—these organs do not meet standard donor criteria and would likely otherwise be left unused.
Alternate listing, however, often means matching the highest risk recipients with poor quality donor organs, a match that may be associated with significant morbidity. A number of small studies have described outcomes using this strategy [1–5]. These studies have largely found that alternate listing transplantation provides good long-term survival compared with that expected from end-stage heart failure patients who do not undergo transplantation. However, the studies described experience at only a single center and were limited in size and duration of follow-up. Therefore, it remains unclear whether the reported outcomes support continued endorsement of alternate list strategies.
The purpose of this study is to measure clinical outcomes associated with alternate listing transplantation. This study improves on previous studies by analyzing the national experience with heart transplantation by using the United Network for Organ Sharing (UNOS) database.
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Material and Methods |
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Study Population
All recipients aged 18 years and older undergoing heart transplantation between January 1, 1999, to December 31, 2005 were included in the study population. Follow-up data were provided through February 27, 2006. Patients were followed from the date of transplant until death, retransplantation (cardiac), or date of last known follow-up, which was the last day of follow-up data provided by UNOS. Mean follow-up time was 2.40 ± 1.97 years.
Alternate Listing Criteria
A systematic literature review was conducted of previous studies and professional committee guidelines [6–8] to determine which characteristics and thresholds would be included in the definitions for high-risk recipients and marginal donors. Patients with any of the following conditions were classified as high-risk recipients: advanced age (older than 65 years), retransplantation, hepatitis C seropositivity, human immunodeficiency virus positivity, creatinine clearance less than 30 mL/min, diabetes mellitus complicated by peripheral vascular disease, chronic renal failure defined as creatinine clearance less than 40 mL/min, or history of cerebrovascular accidents. Marginal donors were those who met at least one of the following characteristics: advanced age (more than 55 years), cocaine or intravenous drug use, diabetes mellitus, hepatitis C seropositivity, ejection fraction less than 45%, and a donor/recipient size mismatch (donor:recipient weight ratio less than 0.7). Owing to the limitations of registry data, which only provides data at limited time points, some criteria such as high pressor/inotrope requirements in donors and severe pulmonary hypertension in recipients were not included in the high-risk definitions. Paired recipients and donors were then stratified by recipient and donor characteristics into four categories: standard recipients paired with standard donors (STD), standard recipients paired with marginal donors (SR:MD), high-risk recipients paired with standard donors (HR:SD), and high-risk recipients paired with marginal donors (ALT).
Outcome Measures
The primary outcomes measures were actuarial posttransplant survival as expressed in years and incidence rate of death per 100 patient-years with 95% confidence intervals. Other outcomes of interest included in-hospital morbidity, as measured by incidence of retransplantation for primary graft failure, stroke, infection, and need for dialysis, as well as length of stay during the transplant hospitalization. Long-term outcomes measures included diabetes mellitus incidence rate, transplant coronary artery disease incidence rate, and posttransplantation chronic dialysis incidence rate.
Data Analysis
Continuous variables were reported as means ± SD and compared using the Student's t test. To compare categorical variables, the chi-square test was used. The conventional p value of 0.05 or less was used to determine level of statistical significance. All reported p values are two-sided. The hazard ratio and 95% confidence interval were reported for each factor. All data were analyzed using a statistical software package, Stata 9 (Stata Corp, College Station, TX).
The primary outcome measure was survival reported as median survival and incidence rate of death per 100 patient-years with 95% confidence intervals. Kaplan-Meier analysis with log-rank test was used for time-to-event analysis for actuarial survival, as well as transplant coronary artery disease incidence rate, chronic dialysis incidence rate, and diabetes mellitus incidence rate. For survival analysis, the outcome of interest was death or retransplant, whichever came first. Patients lost to follow-up or alive on February 27, 2006, were censored at the date of last known follow-up. To assess the impact of recipient and donor pairing on early and late mortality, the incidence rate of death per 100 patient-years was calculated at multiple time intervals (less than 30 days, 30 days to 1 year, 1 to 2 years, and 2 to 5 years).
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Results |
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Long-Term Complications of Transplantation
The chronic dialysis incidence rate of the standard group (2.5, 2.2 to 2.9) was better than both the high-risk recipient transplant groups (HR:SD 5.5, 4.5 to 6.6; ALT 5.0, 3.1 to 8.0), although no different than SR:MD (3.2, 2.3 to 4.4; Fig 4). The transplant coronary artery disease incidence rates in the standard population (6.7, 6.3 to 7.0) was lower than both transplant groups who received marginal donor hearts (SR:MD 10.3, 8.9 to 11.8; ALT 9.5, 7.3 to 12.5), but the same as high-risk patients who received a normal donor heart (6.3, 5.5 to 7.2). The diabetes incidence rate in the standard group (14.9, 14.3 to 15.5) was lower than both the high-risk recipient groups (HR:SD 20.4, 18.9 to 22.2; ALT 17.5, 17.5 to 25.9), but the same as SR:MD (16.7, 14.9 to 18.7).
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Comment |
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TopAbstractIntroductionMaterial and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
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Alternate waiting list strategies have been promoted as a means to maximize the use of so-called marginal donor hearts, and thereby offer the benefit of transplantation to a greater number of candidates. Under this strategy, high-risk patients who fail to meet standard criteria for transplantation are considered candidates for organs that would otherwise have been discarded. Paradoxically, as part of this strategy, the highest risk recipients are matched with higher-risk donor organs. This poses a number of clinical, ethical, and policy concerns.
Findings here demonstrate that standard recipients paired with standard donors realized the best survival, and high-risk recipients paired with marginal donors had the worst survival. Compared with the standard group, the alternate list group had significantly worse survival. There was a step wise decrease in survival moving from standard to intermediate to alternate list, but survival was similar between the intermediate-risk pairs (HR:SD and SR:MD).
Matching high-risk recipients and marginal donors offers a median survival of greater than 5 years to patients. Because this observed survival is significantly less than the median survival of the overall transplant population, it has been argued that it is unethical to offer marginal donor organs for transplantation. However, given a life expectancy of 6 to 12 months among these patients in the absence of heart transplantation [11], matching high-risk recipients with marginal donors should be considered as a treatment option.
When considering survival benefits of standard treatments for other potentially terminal diseases, such as surgical resection for pancreatic or esophageal cancer, where median survival for patients is less than 18 months, alternate listing provides significantly greater survival benefit [12, 13]. Furthermore, in the context of thoracic organ transplantation, providing marginal donor hearts to high-risk recipients offers survival similar to that provided by lung transplantation [14].
Posttransplant Morbidity and Resource Utilization
Additional findings here demonstrate that pairing high-risk recipients with marginal donor hearts is associated with greater morbidity and resource utilization compared with standard recipients and donors. Interestingly, the development of diabetes and the need for chronic dialysis appear to be correlated with high-risk recipient characteristics, whereas development of transplant coronary artery disease appears to be related to poor donor organ quality.
Given the constraints of our healthcare system and its finite resources, additional studies examining the cost effectiveness of this strategy are required to determine the place of this strategy alongside other heart failure therapies.
Future Studies
These findings suggest that developing a national, standardized mechanism for alternative list transplants, as has occurred in other organ systems, including liver and kidney, may further maximize the use of potential donor organs and expand the benefit of transplantation. Furthermore, this strategy may provide secondary benefit by risk-adjusting for recipients and transplant centers as we shift to stricter quality oversight and pay for performance, to avoid penalizing centers that transplant higher-risk patients.
However, additional studies are needed before a stratified system that pairs recipients and donors by risk can be appropriately employed. The purpose of this study was to measure clinical outcomes associated with the alternate list transplantation policies currently in place at transplant centers. However, objectively defining high-risk characteristics that are associated with worse outcomes is the ultimate goal and should be the focus of future studies. Secondly, although the favorable survival described in this analysis supports alternate listing as a clinically effective treatment strategy for patients who might not otherwise be candidates for transplantation, the impact of quality of life and the cost implications of this additional survival still need to be evaluated.
Limitations
This study suffers from a number of limitations. First, UNOS does not formally designate recipients as alternate list candidates. Therefore, outcomes in high-risk patients paired with marginal donors were used as a conservative proxy for alternate list transplantation outcomes. However, considering reports in previous studies that approximately one quarter of alternate list recipients receive organs from standard donors, this current analysis may underestimate survival under alternate list transplants [2]. Second, patient registries often suffer from variability in data entry. However, fields contained within this database were generally well populated with a 95% to 99% data entry rate for the majority of variables. Although the UNOS reporting system provided definitions for variables in data guidelines, definitions may vary by center.
In conclusion, alternate list transplantation is associated with greater morbidity, higher resource utilization, and diminished survival compared with standard list transplantations. However, end-stage heart failure is a terminal disease; life expectancy among these high-risk candidates is 6 to 12 months in the absence of heart transplantation. Transplantation within the alternate risk group conferred a median survival of more than 5 years.
These findings suggest that developing a national, standardized mechanism for alternate listing, as has occurred in other organ systems, including liver and kidney, may further maximize the use of potential donor organs and expand the benefit of transplantation. However, further studies examining the implications of costs and quality of life related to this approach are needed.
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Discussion |
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DR RUSSO: Thank you for your comments, Dr Merry. Prolonged ischemic time could certainly be a criterion for classification of a donor organ as marginal. We do not include it in the current analysis, because we focused on preoperative patient characteristics known at the time that an organ is considered for transplantation. Several factors impact ischemic time, including travel time and technical issues; some of these cannot be anticipated. However, in the past, we presented data that demonstrated an interaction between donor age and duration of ischemic time. Younger donors appeared to better tolerate longer ischemic time, as measured in terms of survival. So, we agree that it is an important consideration.
I should also emphasize again that there were other criteria typically considered markers for poorer recipient or donor quality, such as severe pulmonary hypertension in the recipient and high requirements for vasoactive medications in the donor. These were not included in this analysis, because these data, in our opinion, were confounded.
Regarding your second question, we did complete a stratified analysis considering all combinations of recipients and donors. However, in most of the groups, the numbers became too small to draw any definitive conclusions. Therefore, we chose not to present it at this time.
DR SEYEDHOSSEIN AHARINEJAD (Vienna, Austria): I have just one comment for you. I do agree with the inclusion of marginal donors for heart transplantation. I just believe that this is highly dependent on the center that is doing the job. Referring to the comment of our colleague in Australia, with the emerging new tools, we should be very careful which objectives we can include into those lists that we can recruit marginal donors, and again, I guess the center's abilities and who is doing the job are very crucial in that.
DR RUSSO: Thank you, Dr Aharinejad, for raising this important point. The strong correlation between higher volume and improved outcomes after a variety of complex surgical procedures has been well-established. The strongest associations are typically seen when evaluating complex surgical procedures. Therefore, we should expect that this relationship holds in heart transplant and likely is strongest when considering the highest risk donors. This is clearly an area in need of further studies, which could have important implications for referrals patterns.
DR O. H. FRAZIER (Houston, TX): As you know, the donor shortage is somewhat of a misnomer. What really exists is a maldistribution of donor hearts. In the United States every year, more than 50% of acceptable donors are not utilized. In the late 1980s and early 1990s, we had more than 100 people waiting for a heart in Houston at St. Luke's Episcopal and Methodist Hospitals. In that era, we placed the hearts from 90% to 95% of the kidney donors for whom we had also obtained consent for cardiac donation. Our approach was that for nearly every acceptable donor there would be a recipient, and we were able to match donors to suitable recipients without any impact on patient survival. Jim Young and I were able to do this by working together to obtain the best potential benefit for this important, but limited, resource. (At that time, Jim Young was director of Cardiac Transplantation at Methodist.) That type of cooperative effort is difficult today because of the complexities and logistics of the computerized allocation systems. Has the new 500-mile system had any impact on your placement of donors, or do you think it has improved donor-recipient matching?
DR RUSSO: Doctor Frazier, your insightful comments are always appreciated. You highlight an important implication from this study. When the best recipients and the best donors are matched, the expected median survival exceeds 10 years. However, we should not fail to offer a donor organ to a candidate simply because we anticipate the survival benefit will be less than 10 years. In the absence of transplantation, many potentials beneficiaries will progress to death in 6 to 12 months. Therefore, offering even marginal organs to some candidates, or potential candidates, may provide them with an additional 5 years of life, which is a significant improvement over the alternative. Again, there are other considerations, such as cost and quality of life, and so forth, but our findings certainly suggest that, as you say, we are underutilizing the donor pool.
DR FRAZIER: But if they die without a transplant, they don't count in your statistics.
DR RUSSO: Regarding organ allocation and utilization, DonorNet, although it has some drawbacks, attempts to improve donor organ placement by allowing wide distribution of donors simultaneously and instantaneously. Unfortunately, temporal trends in organ allocation are outside of the scope of this study; therefore, it is difficult for me to comment on the impact of specific changes in practice. Furthermore, while the OPOs maintain data regarding organ utilization, they are generally not available for analysis.
DR FRAZIER: The data are available, but they have only been published once because, in the past, placement suffered from logistical problems. Although this is understandable, we need to continue addressing these problems. So far, we have made very little progress in this area.
DR RUSSO: I absolutely agree with you. It is likely that, given current practices, many usable organs are discarded. Therefore, it is imperative that the transplant community develop a research agenda focused on more than outcomes related to donor and recipient selection; to maximize the benefits of transplantation, we must also evaluate the economic and policy issues related to transplantation, including evaluating the processes by which organs are allocated.
DR FRAZIER: Critically ill patients who are eligible for transplant but die before receiving a transplant don't count in heart transplantation statistics. Even though these patients may be more likely to die, heart transplantation clearly is an important therapeutic option for them. Thus, by judging transplant programs on mortality outcomes alone, donor utilization has been negatively impacted.
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