Alternate Waiting List Strategies for Heart Transplantation Maximize Donor Organ Utilization

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1 Alternate Waiting List Strategies for Heart Transplantation Maximize Donor Organ Utilization Jonathan M. Chen, MD, Mark J. Russo, MD, MS, Kim M. Hammond, RN, Donna M. Mancini, MD, Aftab R. Kherani, MD, Jen M. Fal, BA, Pamela A. Mazzeo, BA, Sean P. Pinney, MD, Niloo M. Edwards, MD, and Yoshifumi Naka, MD, PhD Divisions of Cardiothoracic Surgery and Cardiology, Columbia University College of Physicians and Surgeons, New York, New York; Division of Cardiology, Mount Sinai School of Medicine, New York, New York; and Department of Cardiothoracic Surgery, University of Wisconsin, Madison, Wisconsin Background. Alternate waiting list strategies have been promoted as a means to offer the benefit of heart transplantation to a greater number of candidates. We undertook the current study to evaluate our experience with transplantation in alternate list (AL) candidates. Methods. Adults undergoing heart transplantation from January 1, 2001, through April 15, 2004, were evaluated. Selected patients who did not meet criteria for standard listing for heart transplantation were offered alternate listing. Primary posttransplant outcomes included 30-day, 90-day, and more than 90-day mortality, and determinants of perioperative morbidity. Results. Thirty-seven patients (14.3%) met alternate list criteria. Among these alternate list patients, contraindications to standard listing included age greater than 65 years, amyloidosis, severe diabetes mellitus and peripheral vascular disease, human immunodeficiency virus, and high-risk retransplant. The average age of alternate list donors was years. Survival analysis revealed no posttransplant survival advantage for standard list recipients However, mean ventilatory support time was significantly (p < 0.001) longer in the alternate list group ( days) compared with the standard group ( days), and significantly more sternal wound infections (p 0.03) were observed in the alternate list group (6 [16.2%]) compared with the standard group (13 [5.9%]). Conclusions. The alternate list patients demonstrated comparable survival with standard list patients, but did exhibit more ventilatory dependence and sternal wound infections. More than half of alternate list donor organs in the future could be considered for standard list candidates as well. Use of the alternate list reinforces the assertion that, even today, our donor criteria remain too stringent. (Ann Thorac Surg 2005;80:224 8) 2005 by The Society of Thoracic Surgeons Continuing improvements in transplant outcomes have allowed increasingly high risk patients to be considered for transplantation. A growing body of evidence suggests that many patients who fail to meet prior standard criteria for transplantation may in fact have outcomes comparable to those of standard list candidates [1 5]. Nonetheless, at a time when a critical shortage of donors leaves many patients who meet standard criteria without a suitable organ, implementation of less restrictive recipient criteria without increasing the donor supply will likely only further exaggerate the donor organ shortage. Since the mid-1990s, 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 [6]. Under this strategy, patients who fail to meet standard criteria for transplantation are considered candidates for organs that would otherwise have been discarded. Paradoxically, this often has meant matching the Accepted for publication Jan 4, Address reprint requests to Dr Chen, Division of Cardiothoracic Surgery, Pediatric Cardiac Surgery, 3959 Broadway, Suite 2-273, New York, NY 10032; jmc23@columbia.edu. highest risk patients with high-risk donors, a phenomenon that can often presage significant morbidity. However, whether the outcomes of these patients prohibit continued endorsement of alternate list strategies remains unclear. The purpose of this study was threefold: (1) to assess whether alternate list recipients experience higher posttransplant morbidity or impaired posttransplant survival; (2) to establish whether alternate list patients truly receive high-risk organs; and (3) to determine whether certain diagnoses or combinations of diagnoses should preclude their inclusion as alternate list criteria. Patients and Methods Study Population All adults (aged 18 years) undergoing heart transplantation from January 1, 2001, through April 15, 2004, at the This article has been selected for the open discussion forum on the CTSNet Web Site: by The Society of Thoracic Surgeons /05/$30.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg CHEN ET AL 2005;80:224 8 ALTERNATE LIST FOR HEART TRANSPLANTATION Table 1. Alternate List Characteristics in the Study Cohort Characteristics n % Alternate list donor characteristics None Hepatits B/C seropositivity Age 55 years Size mismatch Risk factors 2 (hypertension and or smoker), no catheter Coronary artery disease Ejection fraction 45% Wall motion abnormality (Moderate to Severe) Valvular Disease (Moderate to Severe) Left Ventricular Hypertropy (Moderate to Severe) Cardiomegaly (Moderate to Severe) Number of alternate list characteristics Number of cardiac abnormalities per donor Columbia University Medical Center were evaluated; the posttransplant follow-up period extended through July 15, Patients listed under standard criteria were designated as controls, and patients listed under alternate criteria comprised the study group. Patients who did not meet criteria for standard listing for heart transplantation were offered alternate listing only if their medical condition and concomitant morbidities were considered acceptable by a multidisciplinary transplant consortium. Study patients were informed that they would only be considered as candidates for transplantation if a heart became available that could not be used for a patient on the standard list; this included both (1) normal hearts for which no suitable standard list recipient was available, and (2) hearts meeting only extended criteria, namely, one or more characteristics that would otherwise render them unsuitable for a standard list recipient. All patients in the alternate list program signed informed consent regarding this process. Extended criteria delineating marginal donors included hepatitis C seropositivity, hepatitis core immunoglobulin G (IgG) antibody positivity, significant electrocardiographic or echocardiographic abnormalities (including diminished systolic function [ejection fraction 45%], wall motion abnormalities, moderate valvular disease (2 or greater valvular insufficiency, valvular stenosis [qualitative]), left ventricular hypertrophy [qualitiative], and cardiomegaly [qualitative]), coronary artery disease ( 20% stenosis by angiogram), advanced age ( 50 years), size mismatch greater than a ratio of 2:1, and two or more risk factors for coronary disease (age 55 years, history of smoking or hypertension) in a donor hospital without cardiac catheterization capabilities. Clinical information regarding each patient was obtained from a retrospective review of the patients medical record. In addition, a review of alternate list donors clinical information was completed from respective United Network of Organ Sharing (UNOS) data forms. Outcome Measures Primary posttransplant outcomes included 30-day, 90- day, and long-term (more than 90 days) mortality. Additional outcome measures included 30-day graft failure; intensive care unit length of stay; overall length of stay, ventilatory support time, and tracheostomy; need for posttransplant continuous venovenous hemofiltration; need for posttransplant circulatory-assist devices including intra-aortic balloon pump or ventricular assist device; cerebrovascular accidents; and sternal wound infections. Analysis Comparisons of control and alternate list patient risk factors and postoperative outcomes were performed using Student s unpaired t test for continuous variables, and 2 analysis for ordinal variables. Actuarial survival curves were created for both control and alternate list patients and compared using log-rank analysis. Cox regression analysis was used to identify factors predictive of The conventional p value of 0.05 or less was used to determine level of statistical significance. Immunosuppression Therapy All patients received comparable immunosuppressive regimens, involving daclizumab induction, calcineurininhibitor based therapy, myocphenolate mofetil, and steroids. Those with renal insufficiency received either rapamycin or antithymocyte globulin as alternative immunosuppression while awaiting renal recovery. Fig 1. Kaplan-Meier actuarial analysis comparing high-risk list recipient (dotted line) and standard list recipient (solid line) posttransplant survival (p 0.05). 225 CARDIOVASCULAR

3 226 CHEN ET AL Ann Thorac Surg ALTERNATE LIST FOR HEART TRANSPLANTATION 2005;80:224 8 Table 2. Outcome Measures in Study and Control Cohorts Control Alternate Total p Value Total (n) Dead (n) 29, 13.1% 8, 21.6% 37, 14.3% Day mortality (n) 11, 5.0% 0, 0.0% 11, 4.3% Day mortality (n) 19, 8.6% 3, 8.1% 22, 8.5% Day graft failure (n) 5, 2.3% 0, 0.0% 5, 1.9% 0.36 Mean ICU length of stay (days) Mean overall hospital length of stay (days) Reexploration, posttransplant (n) 34, 15.4% 2, 5.4% 36, 14.0% 0.10 Circulatory-assist devices, posttransplant (n) 13, 5.9% 2, 5.4% 15, 5.8% 0.43 CVVH, posttransplant (n) 26, 11.8% 8, 21.6% 34, 13.2% 0.10 Mean ventilatory time (days) Reintubation (n) 13, 5.9% 3.0, 8.1% 16, 6.2% 0.65 Tracheostomy (n) 4, 1.8% 2, 5.4% 6, 2.3% 0.18 Cerebrovascular accident (n) 11, 5.0% 1, 2.7% 12, 4.7% 0.54 Sternal wound infection (n) 13, 5.9% 6, 16.2% 19, 7.4% 0.03 CVVH continuous venovenous hemofiltration; ICU intensive care unit. Results Recipient Characteristics Two hundred fifty-eight patients underwent transplantation during the study period. Among these, 221 patients (85.7%) met standard criteria, and 37 (14.3%) met alternate list criteria. Among the standard and alternate list patients, the number who had prior cardiac surgery, a ventricular assist device pretransplant, or a previous transplant were 122 (55.2%), 56 (25.3%), and 13 (5.9%) versus 17 (45.9%), 1 (2.7%), and 1 (2.7%), respectively. Among the 221 patients in the control group, 173 (78.3%) were male. The mean age was years (range, 18 to 70). The mean waiting time after listing for transplantation was days (range, 2 to 1,641). At transplant, the number of patients listed as UNOS status 1A, 1B, and 2 were 102 (45.9%), 106 (48.2%), and 14 (6.1%), respectively. The alternate list group included 37 patients, of whom 24 (68.6%) were male. The mean age was years (range, 22 to 70). The mean waiting time to transplantation was days (range, 2 to 230). At transplant, the number of patients listed as UNOS status 1A, 1B, and 2 were 0 (0%), 25 (67.6%), and 12 (32.4%), respectively; 1B most often represented patients on inotropes equivalent to 1B. Among the alternate list patients, contraindications to standard listing included age more than 65 years (24 [64.9%]), amyloidosis (8 [21.6%]), severe diabetes mellitus and peripheral vascular disease (3 [8.1%]), human immunodeficiency virus (HIV, 1 [2.7%]), and high-risk retransplant (1 [2.7%]). Alternate List Donor Characteristics The average age of alternate list donors was years, and 22 (59.5%) were male. Causes of death among donors were cerebrovascular accident (14), trauma (9), intracranial hemorrhage (6), anoxia (5), seizure (1), tumor (1), and acute cerebral edema (1). Among the alternate list group, 9 (24.3%) donor hearts were from normal donors with no suitable standard recipient. The remaining 28 donors had one or more high-risk characteristics (Table 1). These included: hepatitis B/C seropositivity (12 [34.3%]), advanced age greater than 55 years (9 [24.3%]), coronary artery disease (8 [21.6%]), left ventricular hypertrophy (8 [21.6%]), moderate wall motion abnormalities (6 [16.2%]), ejection fraction less than 45% (4 [10.8%]), two or more risk factors for coronary disease in a donor hospital without cardiac catheterization capabilities (4 [10.8%]), moderate to severe valvular disease (3 [8.1%]), and cardiomegaly (1 [2.7%]). In total, 9 (24.3%) of the donor hearts had none, 12 (32.4%) had one, 8 (21.6%) had two, 7 (18.9%) had three, and 1 (2.7%) had four high-risk characteristics. The number of high-risk characteristics was not predictive of Posttransplant Outcomes Survival analysis revealed no posttransplant survival advantage for standard list recipients (Fig 1). The time at risk totaled 160,292 days, with a median follow-up of 637days and maximal follow-up of 1289 days. No patients were lost to follow-up, and 1-year follow-up data were available on 29 of 37 alternate list patients (82.9%) and 171 of 221 patients (83.82%) in the control group. Primary posttransplant outcome measures are described in Table 2. During the study period, there were 37 deaths, 8 (21.6%) in the alternate list group and 29 (13.1%) in the control group (p not significant). At 30-day follow-up, there were no deaths among the alternate list patients compared with 11 deaths (5.0%) in the control group (p not significant). At 90-day follow-up, there were 3 deaths (8.1%) in the alternate list group and 19 additional deaths (8.6%) in the control group (p not significant). Eight alternate list patients died late after transplant; causes of death included sepsis (5), cancer (1), congestive

4 Ann Thorac Surg CHEN ET AL 2005;80:224 8 ALTERNATE LIST FOR HEART TRANSPLANTATION heart failure (1), and complications related to cytomegalovirus infection (1). No high-risk related diagnosis was associated with significantly diminished When comparing the alternate list to the standard group, there was no significant difference in 30-day graft failure, intensive care unit length of stay, overall hospital length of stay, posttransplant circulatory support, posttransplant continuous venovenous hemofiltration, posttransplant cerebrovascular accident, need for reintubation, or tracheostomy. The 1 patient who died late of congestive heart failure had received a heart from a 12-year-old donor, with a 158-minute ischemic time; this patient required biventricular assist device support of perioperative poor graft function but subsequently recovered and had been discharged home. Conversely, mean ventilatory support time was significantly (p 0.001) longer in the alternate list group ( ) compared with the standard group ( ), and significantly more sternal wound infections (p 0.03) were observed in the alternate list group (6 [16.2%]) compared with the standard group (13 [5.9%]). In the multivariable Cox analysis (data not shown), only previous cardiac surgery was predictive of diminished No individual donor characteristics in the alternate list group were predictive of posttransplant Comment Both continuing improvements in transplant outcomes and a relative plateau in the number of donors available have encouraged major transplant centers to broaden the criteria for transplant candidacy for donors and recipients alike. Alternate waiting list strategies have thus been promoted by some centers since the mid 1990s as a means of offering the benefit of transplantation to a greater number of potential candidates [5]. Despite this, others have maintained that the adoption of alternate risk policies often means that high risk organs are being matched with the highest risk recipients, a combination with a propensity for suboptimal outcomes. The purpose of this study was to answer three questions regarding the use of alternate list strategies. First, compared with standard transplant patients, do alternate list patients experience greater posttransplant morbidity or mortality? Second, did these patients tend to receive marginal organs, or would hearts allocated to alternate list patients have been suitable for standard list candidates had an appropriate match been available? Finally, were there any comorbidities, or combination of comorbidities, that should preclude listing even on the alternate list? Survival analysis (Fig 1) revealed no statistical difference in posttransplant survival when alternate list patients were compared with their standard list counterparts. Interestingly, in a separate study comparing standard-risk to high-risk patients, Laks and colleagues [5] found significantly better 90-day survival among the standard group. However, our data demonstrate no survival difference between the two groups at 30- or 90-day 227 follow-up. Only with further longitudinal follow-up will subtle differences in long-term morbidity be evident between these groups. Of note, by design, no patients on the alternate list group were status IA, as status IA patients would receive these donor offers anyway. Among measures of posttransplant morbidity, only mean ventilatory support time and number of sternal wound infections were significantly greater among the alternate list group; there was no demonstrable difference between the two groups in rate of 30-day graft failure or cerebrovascular accident, mean intensive care unit length of stay or overall hospital length of stay, or need for circulatory-assist device, continuous venovenous hemofiltration device, or tracheostomy. Although it seems logical to attribute these two morbidities (increased ventilatory support time and sternal wound infection) to the increased mean age of the alternate list cohort, in a separate analysis (data not shown), neither the preoperative pulmonary function tests, nor the postoperative pulmonary complications were statistically impaired in those alternate list candidates older than 65 years. The increased rate of sternal wound infections is likely due to a variety of compounding factors (multiple reoperative sternotomies, increased age, diabetes) which collectively may impair overall sternal integrity and wound healing. However, given that none of the patients transplanted from the alternate list demonstrated early ( 30 day) rejection, a tailored immunosupprssion regimen is being considered for older patients in the cohort in an effort to reduce the risk of sternal wound infections. No differences in survival could attributed to any highrisk characteristic of the donor organs. This includes presence of diminished left ventricular systolic function (ejection fraction 45%) or coronary artery disease. However, while none of these characteristics were associated with diminished survival during the follow-up period, late differences certainly may become evident with longer follow-up. Nine patients from the alternate transplant list received normal organs for which no suitable standard list recipient was identified; if not for this alternate list strategy, these 9 normal donor organs would otherwise have been discarded. In addition to these 9 normal donors organs, 10 more donors provided a functionally and structurally normal heart but were considered high risk secondary to age or hepatitis seropositivity. Thus, in total, 19 alternative list donor organs (51.4%) revealed no functional or structural abnormalities. None of the comorbities directing assignment to the alternate transplant list was individually associated with impaired As previously noted, approximately two thirds of the alternate list patients were excluded from the standard listing on the basis of advanced age. As in previous studies demonstrating long-term survival among transplant recipients of advanced age, survival in our alternate list subgroup was comparable to standard patients [1 3]. Moreover, among the 12 patients receiving an organ from a hepatitis seropositive donor, only 1 seroconverted during the study period; at present, this recipient shows no signs or symptoms of liver disease. CARDIOVASCULAR

5 228 CHEN ET AL Ann Thorac Surg ALTERNATE LIST FOR HEART TRANSPLANTATION 2005;80:224 8 The second most common reason for alternate listing was amyloidosis. Limited data are available on amyloid patients after cardiac transplant. Available data suggest that amyloid-related cardiac disease frequently recurs in the transplanted organ and patients may have impaired survival [7, 8]. Our center has developed a protocol for patients with amyloid heart disease including autologous bone marrow transplantation followed by cardiac transplantation. Among the 8 amyloid patients in this study, 2 (25%) died during the study period. One of these 2 patients died from lymphoma that she likely acquired from the donor, as each of the 2 patients who received a kidney from the same donor similarly died of lymphomas. The second patient died of complications related to failure of bone marrow to engraft, and ultimately sepsis. Although we initially had considerable reservations about pursuing this strategy further owing to these 2 early deaths, we have continued to offer the therapy to highly selected candidates. In short-term follow-up, none of the surviving 6 patients has demonstrated amyloid disease on biopsy of their transplanted hearts. Among the remaining alternate list patients, 3 had severe diabetes mellitus and peripheral vascular disease, 1 was HIV positive, and 1 was considered a high-risk transplant. The patient with HIV had demonstrated normal T-cell counts with low viral activity and has done remarkably well posttransplant, without the need for significant alteration of his immunosuppressive regimen. The high-risk retransplant patient died postoperatively of multiorgan failure; no conclusions can be drawn from this single case, but notably, among all study patients, retransplantation was not predictive of impaired The selection of donors and recipients for cardiac transplantation represents a careful balance of risks. More often, the number of marginal characteristics manifest in a donor accepted for transplantation better reflects the acuity of the recipient in question, than the absolute criteria of a given transplant program. The continued extension of donor criteria is derivative of these acceptable outcomes attained in such cases of critical need. Despite this, several significant exclusion criteria persist in clinical heart transplantation. The application of an alternate list for transplantation has allowed us to refute many of these criteria as a way to offer transplantation to more patients. Having an alternate list lowered our threshold to investigate hearts (with on-site visualization) that we might otherwise have passed over, owing to poor quality echocardiograms, or lack of on-site cardiac catheterization. What evolved was the increasing realization that fully half of these alternate hearts are otherwise physiologically normal, and in the future could be considered for standard list candidates as well. Indeed, perhaps the use of the alternate list simply reinforces the assertion that, even today, our donor criteria remain too stringent. Although none of the characteristics that made these patients suboptimal candidates for standard listing singularly predicted poor outcomes or survival, as with the balancing of risks in routine transplantation, so too in transplanting alternate list candidates one cannot stack too many risk factors. Thus, combining renal failure with advanced age and multiple sternotomies undoubtedly would presage poor outcomes. With further long-term follow-up, we hope to better define what impact if any alternate listing has on long-term morbidity and mortality. Until then, acknowledging the caveat of center-specificity, we report successful use of alternate list strategies in an effort to maximize donor heart utilization. References 1. Morgan JA, John R, Weiberg AD, et al. Long-term results of cardiac transplantation in patients 65 years of age and older: a comparative analysis. Ann Thorac Surg 2003;76: Everett JE, Djalilian AR, Kubo SH, et al. Heart transplantation for patients over age 60. Clin Transplant 1996;10: Blanche C, Blanche DA, Kearney B, et al. Heart transplantation in patients seventy years of age and older: a comparative analysis of outcome. J Thorac Cardiovasc Surg 2001;121: Marelli D, Bresson J, Laks H, et al. Hepatitis C-positive donors in heart transplantation. Am J Transplant 2002;2: Laks H, Marelli D, Fonarow GC, et al. Use of two recipient lists for adults requiring heart transplantation. J Thorac Cardiovasc Surg 2003;125: Alexander JW, Zola JC. Expanding the donor pool: use of marginal donors for solid organ transplantation. Clin Transplant 1996;10: Hosenpud JD, DeMarco T, Frazier OH, et al. Progression of systemic disease and reduced long-term survival in patients with cardiac amyloidosis undergoing heart transplantation. Follow-up results of a multicenter survey. Circulation 1991; 84(Suppl 3): Dubrey SW, Burke MM, Khaghani A, et al. Long term results of heart transplantation in patients with amyloid heart disease. Heart 2001;85:202 7.