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Original Articles: Adult Cardiac

Identifying Recipients at High Risk for Graft Failure After Heart Retransplantation

^a Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^b Section of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut

Accepted for publication October 25, 2011.

^_* Address correspondence to Dr Yuh, Division of Cardiac Surgery, Yale University School of Medicine, PO Box 208039, New Haven, CT 06510 (Email: david.yuh{at}yale.edu).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 
Background: The aim of this study was to identify recipient factors that are associated with a high risk of graft failure after heart retransplantation (HRT).

Methods: The prospectively collected United Network for Organ Sharing registry was used to identify patients undergoing HRT among 24,477 patients who had undergone cardiac transplantation between 1997 and 2009. The primary outcome was graft failure within 1 year of HRT. The impact of 35 recipient variables on the primary outcome was tested in exploratory univariate logistic regression analysis. Those factors found to be significantly associated with graft failure were entered into a multivariable logistic regression model.

Results: A total of 671 patients underwent HRT during the study period. Overall, 302 (45%) grafts failed after HRT at a mean follow-up of 4.3 ± 3.7 years. Three recipient factors were found to be associated with 1-year graft failure in the multivariate model: older age, increasing serum creatinine, and mechanical ventilation before HRT. Moreover, each decade increase in recipient age was associated with a 20% increase in odds of 1-year graft failure (odds ratio, 1.02; 95% confidence interval, 1.01 to 1.04; p = 0.005). Similarly, each 1-mg/dL increase in serum creatinine increased odds of graft failure by 58% (odds ratio, 1.58; 95% confidence interval, 1.27 to 1.97; p < 0.001). Patients who were mechanically ventilated had a fourfold higher likelihood of 1-year graft failure (odds ratio, 4.32; 95% confidence interval, 2.28 to 8.18; p < 0.001).

Conclusions: The risk of graft failure after HRT increases with an increasing number of significant recipient risk factors, namely older age, increasing serum creatinine, and mechanical ventilation. These risk factors should serve as relative contraindications to HRT, especially when present in combination, given the higher rate of graft failure in these patients.

	Introduction

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Heart transplantation remains the gold standard therapy for end-stage heart failure. According to the International Society of Heart and Lung Transplantation Registry, about 50% of heart transplant recipients survive to 10 years [1]. Among patients who do not survive, recurrent end-stage heart failure is a major cause of morbidity and mortality. Heart failure after transplantation can result from a variety of etiologies, including acute or chronic rejection, primary graft failure, or transplant coronary artery disease. Management of the failing heart in this setting also varies, and may include medical therapy, heart retransplantation (HRT), and ventricular assist devices as destination therapy or bridge to HRT. Heart retransplantation offers the potential for long-term survival; however, its ethical and logistical basis has been challenged because outcomes tend to be worse than in primary transplantation [2–5]. Identifying recipient factors that may contribute to outcomes in HRT may provide a useful guide to prognostication and help care providers in making the decision as to who should undergo retransplantation. The aim of this study was to identify recipients at high risk for graft failure in HRT.

	Patients and Methods

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Data Source
The data source used for this study was the Standard Transplant Analysis and Research files from the United Network for Organ Sharing. These files contain de-identified, prospectively collected data on patients undergoing transplantation in the United States. Follow-up data were available through 2010. The Johns Hopkins institutional review board approved this study.

Study Design
All cardiac transplantations between January 1997 and December 2009 in the United Network for Organ Sharing registry were reviewed. The study population was composed of adult (18 years old) patients undergoing HRT during this era. Patients undergoing transplantation of another organ in conjunction with HRT were excluded (n = 79).

Because the primary focus was to identify pre-HRT recipient factors that would be associated with graft failure, all variables that were assessed related to the recipient. This included variables solely attributable to the recipient (eg, age, race) as well as variables that reflected other processes of care in matching the recipient to a suitable donor (eg, days on waitlist, time between initial transplant and HRT). Overall, a total of 35 recipient variables were evaluated. These included age, sex, anastomotic technique, serum creatinine, weight, body mass index, race, mechanical ventilation, hypertension, diabetes mellitus, intraaortic balloon pump, serum cytomegalovirus status, blood type, indication for HRT (primary graft failure, transplant coronary artery disease, hyperacute rejection, acute rejection, chronic rejection), mean pulmonary artery pressure, pulmonary vascular resistance, cardiac output, cardiac index, pulmonary capillary wedge pressure, transpulmonary gradient, year of transplant, days on waitlist, time between initial transplant and HRT, race matching, human leukocyte antigen matching, sex matching, serum cytomegalovirus status matching, ABO compatibility, donor–recipient body mass index ratio, bridging with ventricular assist devices, and center volume. The primary end point was graft failure within 1 year of HRT. Graft failure was defined according to the Organ Procurement and Transplantation Network as when organ removal, death, or replacement on chronic allograft support system had occurred. All causes of death or repeat retransplantation were considered as achieving this end point.

Analysis
We examined the 35 recipient variables to determine their impact on graft function or patient survival. Those recipient variables associated with 1-year graft failure on exploratory univariate logistic regression analysis (p < 0.05) were incorporated into a multivariable logistic regression model. Models were constructed by casewise deletion, with covariates with more than 15% missing data in the registry being excluded. Significant interactions between covariates were tested. The multivariate model and inclusion of covariates were assessed using the Akaike information criterion, likelihood ratio test, and area under the receiver-operating curve. A second multivariable analysis was also conducted to evaluate the effect of these recipient variables on graft failure after adjusting for significant donor variables. This was done in an effort to ensure that significant recipient risk factors were applicable across various donor strata. Donor variables examined for potential significance included age, race, sex, body mass index, cytomegalovirus status, blood type, diabetes, inotropic agent usage, ischemic time, weight, cigarette use, terminal creatinine, mechanism of death, and antihypertensive use.

Cumulative freedom from graft failure stratified by number of significant recipient risk factors as identified in multivariate analysis was estimated using the Kaplan-Meier method focused on time intervals with adequate follow-up. Censoring occurred for grafts lost to follow-up and grafts that had not failed by the end of the study time. For the purposes of this Kaplan-Meier analysis, we conducted receiver-operating curve analysis for continuous variables to identify optimal cutoffs. The optimal cutoff was defined as being associated with the highest area under the receiver-operating curve. A patient with a continuous risk factor above the optimal cutoff was therefore categorized as having that risk factor.

Statistical significance was defined for all analyses at the conventional two-tailed probability value of less than 0.05. Odds ratios that were calculated in logistic regression analysis were presented with 95% confidence intervals. All statistical analyses were performed with STATA software (v11, StataCorp LP, College Station, TX).

	Results

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Study Population
Of 24,477 adult patients undergoing cardiac transplantation during the study period, 671 (2.7%) had undergone HRT. The mean age of HRT patients was 45.9 ± 14.4 years (Table 1). There were 479 (71.4%) male patients. The average number of days on the waitlist was 215.6 ± 412.3. The mean time between the initial heart transplant and retransplantation was 7.8 ± 5.5 years. A total of 95 (14.2%) patients had undergone HRT within 1 year of their initial transplant.

Overall, 302 (45.0%) grafts had failed at a mean follow-up of 4.3 ± 3.7 years. The mean time to graft failure was 2.5 ± 3.1 years. During the same follow-up, all-cause mortality had occurred in 290 (43.2%) patients. The Kaplan-Meier graft failure rate within 1 year was 22.3%. A total of 17 (2.5%) grafts were lost to follow-up.

Predictors of Graft Failure
Exploratory univariate logistic regression demonstrated seven recipient variables to significantly affect odds of 1-year graft failure (Table 2). These covariates included recipient age, serum creatinine, mechanical ventilation before HRT, transplant coronary artery disease, primary graft failure, intraaortic balloon pump before HRT, and interval between initial transplant and HRT. Three of these covariates were found to significantly increase risk of 1-year graft failure in multivariable analysis: increasing recipient age, increasing creatinine, and mechanical ventilation. The inclusion of each of these three risk factors improved the multivariate model as demonstrated by improvements in the c index, Akaike information criterion, and likelihood ratio test (p < 0.005 for inclusion of each covariate).

Effect of Donor Factors
To evaluate whether these recipient risk factors independently affected graft failure or whether donor factors contributed to the differences, we adjusted for significant donor variables in an additional multivariate analysis. Moreover, in separate univariate logistic regression analysis evaluating only donor variables, donor age and ischemic time were found to be the only donor covariates that significantly affected odds of 1-year graft failure (each p < 0.05). After adjusting for these donor variables, the presence of each previously identified recipient risk factor persisted as a significantly increased risk of graft failure. Moreover, each decade increase in recipient age still conferred a 20% increase in graft failure rate, each 1-mg/dL increase in creatinine increased graft failure odds by 59%, and mechanical ventilation increased graft failure odds by more than 3.5-fold after adjusting for ischemic time and donor age (each p < 0.05).

Long-Term Freedom From Graft Failure
For the purposes of Kaplan-Meier analysis in which recipients would be stratified by number of risk factors, we used receiver-operating curve analysis to determine optimal cutoff values for age and serum creatinine as these were both continuous data. The optimal cutoff values (ie, associated with highest area under receiver-operating curve) were 50 years for age and 2.0 mg/dL for serum creatinine.

Risk factors for Kaplan-Meier purposes were therefore defined as age of at least 50, creatinine of at least 2.0 mg/dL, and mechanical ventilation. There was a decrease in Kaplan-Meier estimates of 5-year freedom from graft failure with each additional recipient risk factor (log-rank test for trend: p < 0.001), particularly when at least two risk factors were present (Fig 1). Moreover, the gap between 5-year freedom from graft failure was 32% in those with no risk factors versus those with all three risk factors, and the largest decrease occurred in going from one risk factor to two risk factors (23% decrease).

View larger version (26K): [in this window] [in a new window]   Fig 1. Kaplan-Meier 5-year freedom from graft failure stratified by number of recipient risk factors.

	Comment

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Despite these concerns, HRT is a potentially long-term solution for failed primary transplantation, and remains a vital component in the armamentarium in managing patients with a failing graft. Because donor organs represent a scarce resource, being able to identify recipients who are at high risk of losing their graft after retransplantation would be important and could theoretically lead to more optimal organ allocation.

As such, the aim of this study was to identify recipient factors that are associated with a high risk of graft failure after retransplantation. Three recipient factors—namely older recipient age, increasing serum creatinine, and mechanical ventilation—were found to significantly increase 1-year graft failure rates after HRT. Not only did these risk factors independently affect graft failure but when present in combination, the risk of graft failure strongly increased. More specifically, patients with all three factors had a 32% higher risk of graft failure within 5 years as compared with patients with no risk factors.

The finding that these three particular covariates were significant risk factors for graft failure is not surprising given prior data showing these effects. For instance, with respect to advanced recipient age, an analysis of the joint International Society of Heart and Lung Transplantation and United Network for Organ Sharing registries demonstrated older age to be associated with worse survival specifically in HRT [8]. It was interesting to note that in our study that an age of 50 years appeared to be the most discriminatory cutoff for odds of graft failure.

Mechanical ventilation can augment the risk of graft failure for multiple reasons. The need for mechanical ventilation is a surrogate for poor cardiopulmonary reserve in the patient. Furthermore, ventilated patients tend to have lengthier hospital and intensive care unit stays, which themselves can lead to higher rates of graft failure owing to nosocomial infection, nutritional depletion, and generalized deconditioning.

Elevated serum creatinine was also found to be a risk factor for 1-year graft failure in HRT. Heart retransplantation recipients can theoretically be more prone to preexisting renal dysfunction as compared with primary transplant candidates as a result of longer exposure to nephrotoxic immunosuppressive agents and potentially more marginal cardiac status. This was evidenced by the fact that 25% of recipients in this study had a serum creatinine of more than 2.0 mg/dL. Preexisting renal dysfunction in turn leads to higher rates of postoperative renal failure, and this is known to affect survival and cardiac allograft failure rates [9].

Although patients undergoing acute HRT (ie, shorter interval between initial transplant and HRT) were found to have higher risk of graft failure in univariate analysis, this did not persist after adjusting for other significant factors. Similarly, transplant coronary artery disease and primary graft failure, although significant in univariate analysis, did not show an independent impact in multivariate analysis. This is in contrast to other reports of HRT that have demonstrated longer intervals between initial transplant and retransplantation as well as transplant coronary artery disease as being associated with improved outcomes in HRT [10–13].

Center volume has also been shown in prior studies to affect survival after heart transplantation [14, 15]. This effect may be mediated not only by center or surgeon experience, but also other processes of care such as nurse-to-patient ratios, surgical house staff, and intensive care unit resources. In the current study, heart transplantation volume did not affect 1-year graft failure rates after HRT. This may in part be explained by the fact that the mean number of annual heart transplants performed by centers in this study was high at 31.5 per year (median annual volume of 24.3). These data suggest that complicated cases such as HRT tend to be performed in higher volume centers, and that whether a center performs 25 or 40 cardiac transplants per year may not necessarily translate into different outcomes in this patient population.

Impact of Donor Factors
We choose to limit our analysis to recipient factors because we believed this would have more clinical applicability in terms of allowing the practitioner to evaluate a potential HRT candidate before listing or evaluating potential donors. However, it is important to note that poor candidates may tend to receive poor donor organs, and this may drive higher graft failure rates. Because of this potential confounder, we secondarily evaluated the impact of the three recipient risk factors adjusting for significant donor variables to ensure that these risk factors were applicable to various cohorts of donors. Moreover, the donor factors adjusted for included donor age and ischemic time, both of which were found in separate univariate analysis to affect 1-year graft failure, and both of which are known to affect cardiac transplant outcomes from prior studies [16, 17]. This additional multivariate analysis revealed that each of these recipient risk factors persisted as being associated with a higher risk of graft failure after adjusting for these donor variables.

Limitations
This study is subject to the inherent limitations of conducting a retrospective review of an administrative dataset. More specifically, there was no control of the variables that were available, and some variables that may have an impact on graft failure could therefore not be evaluated. Additionally, there are inherent reporting biases with these registries, and some variables have missing data. We attempted to limit this effect by excluding covariates with more than 15% missing data. Variables that were excluded from the multivariable model as a result of missing data were hypertension, bridging with ventricular assist devices, and all of the hemodynamic variables.

Another bias that may be evident in our study design is that we only looked at recipient risk factors, and poor donor organ quality may confound these results as high-risk organs may be allocated to high-risk recipients. We attempted to control for this factor by assessing the impact of significant recipient risk factors, adjusting for donor variables that affected graft failure in separate univariate analysis. The observation that each risk factor increased odds of 1-year graft failure after adjusting for these donor factors suggests that these recipient risk factors indeed have a significant independent effect and are applicable across various donor strata.

Conclusions
We evaluated 671 HRT patients from the United Network for Organ Sharing registry to identify recipient factors that significantly increased risk of graft failure. We chose to limit the study to recipient factors to aid clinicians and providers involved in organ allocation in assessing potential HRT candidates before listing or beginning the donor evaluation process. Three significant recipient risk factors were identified: older age, increasing serum creatinine, and mechanical ventilation. Each of these factors significantly increased the risk of both early and late graft failure. These effects persisted after controlling for donor factors. Given these findings and the shortage of available organs for transplantation, the presence of these risk factors in a potential HRT recipient, especially when present in combination, should prompt serious caution in proceeding with retransplantation given the high risk of graft failure.

	Acknowledgments

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This study was supported by departmental funds from the Department of Surgery, Johns Hopkins Hospital. There are no relevant disclosures.

	References

Top Abstract Introduction Patients and Methods Results Comment Acknowledgments References

 

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14. Weiss ES, Meguid RA, Patel ND, et al. Increased mortality at low-volume orthotopic heart transplantation centers: should current standards change? Ann Thorac Surg 2008;86:1250-1260.[Abstract/Free Full Text]
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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Arman Kilic Eric S. Weiss George J. Arnaoutakis John V. Conte Ashish S. Shah David D. Yuh Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kilic, A. Articles by Yuh, D. D. Search for Related Content PubMed PubMed Citation Articles by Kilic, A. Articles by Yuh, D. D. Related Collections Transplantation - heart Related Article