Should Orthotopic Heart Transplantation Using Marginal Donors Be Limited to Higher Volume Centers?

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1 ORIGINAL ARTICLES: ADULT CARDIAC ADULT CARDIAC SURGERY: The Annals of Thoracic Surgery CME Program is located online at To take the CME activity related to this article, you must have either an STS member or an individual non-member subscription to the journal. ADULT CARDIAC Should Orthotopic Heart Transplantation Using Marginal Donors Be Limited to Higher Volume Centers? Arman Kilic, MD, Eric S. Weiss, MD, MPH, Jeremiah G. Allen, MD, Timothy J. George, MD, David D. Yuh, MD, Ashish S. Shah, MD, and John V. Conte, MD Division of Cardiac Surgery, Department of Surgery, Johns Hopkins Hospital, Baltimore, Maryland; and Section of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Connecticut Background. This study examined whether institutional volume impacts outcomes after orthotopic heart transplantation (OHT) utilizing marginal donors. Methods. Adult patients undergoing OHT with the use of marginal donors between 2000 and 2010 were identified in the United Network for Organ Sharing database. A previously derived and validated donor risk score (range, 1 to 15) was used to define marginal donors as those in the 90th percentile of risk (score >7). Patients were stratified into equal-size tertiles based on overall institutional OHT volume. Posttransplant outcomes were compared between these center cohorts. Results. A total of 3,176 OHTs utilizing marginal donors were identified. In Cox regression analysis, recipients undergoing OHT at low-volume centers were at significantly increased risk of 30-day (hazard ratio 1.82 [1.31 to 2.54], p < 0.001), 1-year (hazard ratio 1.40 [1.14 to 1.73], p 0.002), and 5-year posttransplant mortality (hazard ratio 1.29 [1.10 to 1.52], p 0.02). These findings persisted after adjusting for recipient risk, differences in donor risk score, and year of transplantation (each p < 0.05). In Kaplan-Meier analysis, there was a similar trend of decreasing 1-year survival with decreasing center volume: high (86.0%), intermediate (85.7%), and low (81.2%; log rank p 0.003). Drug-treated rejection within the first post-oht year was more common in lowvolume versus high-volume centers (34.3% versus 24.2%, p < 0.001). At an overall mean follow-up of years, low-volume centers also had higher incidences of death due to malignancy (2.8% versus 1.3%, p 0.01) or infection (6.2% versus 4.1%, p 0.02). Conclusions. Consolidating the use of marginal donors to higher volume centers may be prudent in improving post-oht outcomes in this higher risk patient subset. (Ann Thorac Surg 2012;94: ) 2012 by The Society of Thoracic Surgeons The strategy of offering orthotopic heart transplantation (OHT) with marginal donor organs to high-risk candidates who do not meet standard listing criteria appears to offer some survival benefit to these patients, whose life expectancy is likely limited to several months without transplant.[1 3] Although OHT offers prolonged survival to these recipients as compared with medical therapy, these cases are often associated with worse outcomes than the standard OHT with a lower risk recipient or donor. Given the increasing number of reports demonstrating the association between higher Accepted for publication March 29, Presented at the Poster Session of the Forty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28 Feb 1, Address correspondence to Dr Conte, Division of Cardiac Surgery, The Johns Hopkins Hospital, Blalock 618, 600 N Wolfe St, Baltimore, MD 21287; jconte@jhmi.edu. procedural volume and improved outcomes, the question arises as to whether these higher risk OHT cases should be limited to centers with higher OHT volumes [4 8]. The purpose of the current study was to examine whether institutional volume impacts outcomes after OHT utilizing marginal donors. Patients and Methods Study Design The UNOS database contains recipient, donor, and transplant data on all thoracic organ transplantations performed in the United States. The dataset is de-identified. The Institutional Review Board approved the study protocol. Inclusion criteria included adult patients aged 18 years or older undergoing OHT with the use of a marginal donor between 2000 and 2010 as identified in the UNOS 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 ADULT CARDIAC 696 KILIC ET AL Ann Thorac Surg VOLUME EFFECT IN MARGINAL DONOR OHT 2012;94: Table 1. Donor Risk Score Component Points Assigned Donor age 40 years 0 40 to 49 years 3 50 years 5 Ischemic time 2 hours 1 2 to 3.9 hours 2 4 to 5.9 hours 3 6 to 7.9 hours 4 8 hours 5 Race mismatch 2 Blood urea nitrogen to creatinine ratio 30 3 Total points possible 15 registry. Patients undergoing cardiac retransplantation or multivisceral transplantation were excluded from this analysis. Marginal donors were defined according to a previously derived and validated donor risk score (Table 1) [9]. Moreover, the score was developed in a cohort of more than 17,000 patients in the UNOS registry, and validated in a separate random sample of more than 4,000 UNOS patients, and subsequently validated again in an external study of 1,181 OHT recipients in the United Kingdom [10]. This risk score predicts recipient posttransplant mortality using variables limited to or involving the donor. The score ranges from 1 (lowest risk) to 15 (highest risk). We defined a marginal donor as having a score above the 90th percentile of donor risk in all primary, single-organ OHTs during the study period, which corresponded to a score of 7 or higher (Fig 1). Data and Statistical Analysis Recipients were initially stratified into equal-size tertiles based on overall OHT volume, and these were used to define low-, intermediate-, and high-volume centers. The primary outcome was 1-year all-cause mortality after OHT. Other outcomes included postoperative complications such as infection, stroke, renal failure requiring dialysis, reoperation, arrhythmia requiring pacemaker implantation, and drug-treated rejection within the first posttransplant year. Causes of death were also compared between center cohorts. To ensure that the effect of center volume was not limited to the 1-year period, 30-day and 5-year mortality were also examined in separate analyses. Univariate Cox regression analysis was initially used to evaluate the effect of center volume on post-oht mortality, with center volume modeled either as a continuous or a categorical variable. In addition, a multivariable model that risk-adjusted for recipient risk, year of transplantation, as well as differences in donor risk score was conducted. In this risk-adjusted model, recipient risk was defined according to the Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score, a 50-point validated risk index based on 12 pretransplant recipient variables (Table 2) [11]. In addition to Cox regression analysis, Kaplan-Meier survival curves were constructed and compared between center cohorts using the log rank test. Continuous data were presented as mean SD, and categorical data as number with percentage. Analysis of variance was used for comparing continuous variables and the 2 test for comparing categorical data. The conventional two-tailed p value of less than 0.05 was considered statistically significant. Data and statistical analyses were performed Fig 1. Distribution of donor risk score in the overall study population. Marginal donors were defined as having a score of 7 or greater (90th percentile).

3 Ann Thorac Surg KILIC ET AL 2012;94: VOLUME EFFECT IN MARGINAL DONOR OHT Table 2. Index for Mortality Prediction After Cardiac Transplantation Recipient Risk Score Recipient Variable Points Assigned Age 60 years 3 Serum bilirubin, mg/dl 0 to to to Creatinine clearance, ml/min to Dialysis between listing and transplant 4 Female 3 Heart failure etiology Idiopathic 0 Ischemic 2 Congenital 5 Other 1 Recent infection 3 Intraaortic balloon pump 3 Mechanical ventilation before transplant 5 Race Caucasian 0 African American 3 Hispanic 0 Other 0 Temporary circulatory support a 7 Ventricular assist device Older generation pulsatile 3 Newer generation continuous b 5 Heartmate II 0 Total points possible 50 a Temporary circulatory support includes extracorporeal membrane oxygenation and extracorporeal ventricular assist device support. b Excluding Heartmate II. using STATA software (version 11; StataCorp, College Station, TX). 697 Results Overall Study Population A total of 19,268 adult patients underwent primary, single-organ OHT during the study period. The mean donor risk score for the overall cohort was (Fig 1). The donor score was confirmed to be a significant predictor of recipient mortality in the overall cohort, with each incremental 1-point increase in the score being associated with an 11% increase in the risk of 1-year mortality (odds ratio 1.11, 95% confidence interval [CI]: 1.09 to 1.14; p 0.001). When examined in disjoint categories, patients with a donor score of more than 10 were at a more than twofold increased risk of mortality compared with those with a score 5 (odds ratio 2.28, 95% CI: 1.23 to 4.24; p 0.009). Furthermore, the likelihood ratio 2 for the model was (p 0.001) with a Hosmer-Lemeshow goodness-of-fit that was nonsignificant (p 0.51), suggesting that the model was an appropriate fit of the data. A total of 3,176 OHTs had a donor score of 7 or higher and were therefore classified as having used marginal donors. The overall mean annual number of cardiac transplants performed by each center in our study was OHTs per year. In dividing patients into equal-size tertiles based on center volume, this corresponded to low-volume centers performing fewer than 14 OHTs per year, intermediate-volume centers performing 14 to 25 OHTs per year, and high-volume centers performing more than 25 OHTs per year. Marginal Versus Standard Donors Recipients of marginal donors were higher risk at baseline than standard donor recipients, with an average IMPACT score of versus , respectively (p 0.001). However, not all recipients of marginal donors were high risk, as 32.2% of them had an IMPACT score of 4 or less, which corresponds to a projected 1-year post-oht survival rate of greater than 90% not taking into account donor factors [11]. With regard to posttransplant outcomes, patients undergoing OHT with a marginal donor were found to have a 42% higher likelihood of postoperative mortality compared with standard donor recipients (hazard ratio [HR] 1.42, 95% CI: 1.32 to 1.53; p 0.001). This finding persisted after adjusting for recipient risk and year of transplantation (HR 1.32, 95% CI: 1.23 to 1.42; p 0.001). A higher proportion of OHTs at high-volume centers were performed with the use of a marginal donor (high 22.4%, intermediate 14.4%, low 16.2%; p 0.001). When analyzed on an annual basis, there were no statistically significant trends identified in the utilization of marginal donors over the study period. However, there were significant differences when compared by UNOS region (p 0.001). The proportion of OHTs performed with marginal donors ranged from 11.4% in UNOS region 8 to 24.7% in region 9. Baseline Donor Differences in Centers Using Marginal Donors In cases using marginal donors, high-volume centers had the highest average donor risk index (p 0.01; Table 3). Moreover, high-volume centers tended to use older marginal donors with a higher proportion of females. A blood urea nitrogen to creatinine ratio of 30 or higher was present more frequently in lower volume centers. Additionally, there was a statistical trend (p 0.05) observed with regard to differences in the distribution of causes of marginal donor death, largely driven by higher traumatic death rates and lower cerebrovascular event rates in the intermediate-volume group. Recipient Characteristics There were several significant baseline recipient differences between center volume cohorts in cases using marginal donors (Table 4). High-volume centers tended ADULT CARDIAC

4 ADULT CARDIAC 698 KILIC ET AL Ann Thorac Surg VOLUME EFFECT IN MARGINAL DONOR OHT 2012;94: Table 3. Comparison of Donor Characteristics Between Centers Using Marginal Donors Donor Variable High Volume ( 25 OHT/Yr) (n 1,295) Intermediate Volume (14 25 OHT/Yr) (n 896) Low Volume ( 14 OHT/Yr) (n 985) p Value a Overall risk score 7.85 ( 1.14) 7.72 ( 0.98) 7.75 ( 1.12) 0.01 Risk score variables Donor age, years 48.9 ( 8.3) 47.2 ( 8.8) 47.6 ( 8.8) Ischemic time, hours 3.44 ( 1.05) 3.40 ( 1.05) 3.38 ( 0.98) 0.42 Race mismatch 828/1,263 (65.6%) 590/880 (67.1%) 629/968 (65.0%) 0.63 BUN to creatinine ratio /1,295 (13.1%) 143/896 (16.0%) 166/985 (16.9%) 0.03 Donor variables not included in risk score Cause of donor death 0.05 Nontraumatic 777/1,294 (60.1%) 512/896 (57.1%) 586/983 (59.6%) Cerebrovascular event Trauma 362/1,294 (28.0%) 300/896 (33.5%) 294/983 (29.9%) Other 155/1,294 (12.0%) 84/896 (9.4%) 103/983 (10.5%) Male 728/1,295 (56.2%) 511/896 (57.0%) 612/985 (62.1%) 0.01 Body mass index, kg/m ( 5.6) 27.5 ( 5.8) 27.7 ( 5.7) 0.73 Inotropes 565/979 (57.7%) 387/652 (59.4%) 418/704 (59.4%) 0.73 Ejection fraction 45% 8/1,252 (0.6%) 4/867 (0.5%) 5/952 (0.5%) 0.86 Cytomegalovirus positive 841/1,291 (65.1%) 575/893 (64.4%) 621/979 (63.4%) 0.70 Continuous data presented as mean ( SD), categorical data as number (percentage). variables) or 2 test (categorical variables). BUN blood urea nitrogen; OHT orthotopic heart transplantation. a The p values are based on analysis of variance (continuous to transplant marginal donors into older recipients as compared with lower volume centers. Also, the indications for OHT were different between centers, with high-volume centers having a greater proportion of higher risk indications, such as congenital heart disease. High-volume centers also transplanted marginal donors less frequently into African Americans and those with recent infection. Bridging therapy was also different, such that high-volume center recipients were bridged with extracorporeal ventricular assist devices or extracorporeal membrane oxygenation more frequently, but with newer generation ventricular assist devices less frequently. Although it did not reach statistical significance, there was a trend seen in overall baseline recipient risk as assessed by the IMPACT score, such that high- and low-volume centers transplanted higher risk recipients as compared with intermediate-volume centers (p 0.09). Posttransplant Mortality In univariate Cox regression analysis, marginal donor recipients transplanted at low-volume centers were found to be at a significantly increased risk of post-oht mortality as compared with high-volume centers (p 0.002; Table 5). This finding persisted after adjusting for recipient risk, year of transplantation, and differences in donor risk score in the multivariable model (p 0.002). Furthermore, center volume was shown to be significantly associated with posttransplant mortality when analyzed as a continuous variable in both univariate (p 0.02) and multivariate (p 0.01) Cox regression analysis. In a secondary analysis, recipients of marginal donors were stratified into nonmarginal and marginal recipients (based on an IMPACT recipient risk score of 10, which corresponded to the 90th percentile). Although institutional volume impacted both strata, the effect was more profound in cases where marginal donors were transplanted into marginal recipients (Fig 2). In Kaplan-Meier analysis, there was a significant trend of decreasing 1-year survival with decreasing center volume, such that high-volume centers had 86.0% 1-year survival compared with 81.2% in low-volume centers (log rank p 0.003; Fig 3). These trends were also observed with 30-day and 5-year mortality, where low-volume centers were at a significantly increased risk of mortality, a finding that persisted after risk adjustment (30-day HR 1.82, 95% CI: 1.29 to 2.56, p 0.001; 5-year HR 1.30, 95% CI: 1.10 to 1.54, p 0.002). Posttransplant Complications The rates of most postoperative complications were comparable across center cohorts (each p 0.05; Fig 4). There was, however, a significant difference observed with rejection. Moreover, high-volume centers had a 24.2% 1-year rejection rate compared with a 29.3% and 34.3% rate in intermediate- and low-volume centers, respectively (p 0.001). Causes of Death The mean follow-up in all cases utilizing marginal donors was years. By center cohort, mean follow-up was years for high-volume, years for intermediate-volume, and years for low-volume centers (p 0.008). In comparing the causes of recipient

5 Ann Thorac Surg KILIC ET AL 2012;94: VOLUME EFFECT IN MARGINAL DONOR OHT Table 4. Comparison of Recipient Characteristics Between Centers Using Marginal Donors Recipient Variable High Volume ( 25 OHT/Yr) (n 1,295) Intermediate Volume (14 25 OHT/Yr) (n 896) 699 Low Volume ( 14 OHT/Yr) (n 985) p Value a ADULT CARDIAC IMPACT recipient risk score 6.45 ( 3.92) 6.16 ( 3.69) 6.55 ( 3.90) 0.09 Age, years 55.1 ( 11.4) 53.6 ( 11.2) 53.3 ( 11.4) Male 983/1,295 (75.9%) 672/896 (75.0%) 715/985 (72.6%) 0.19 African American 278/1,293 (21.5%) 220/896 (24.6%) 280/981 (28.5%) Etiology of heart failure Idiopathic 526/1,295 (40.6%) 411/896 (45.9%) 463/985 (47.0%) Ischemic 572/1,295 (44.2%) 376/896 (42.0%) 434/985 (44.1%) Congenital 35/1,295 (2.7%) 9/896 (1.0%) 8/985 (0.8%) Other 162/1,295 (12.5%) 100/896 (11.2%) 80/985 (8.1%) Dialysis on waitlist 31/1,223 (2.5%) 19/890 (2.1%) 21/979 (2.2%) 0.77 Serum creatinine, mg/dl 1.35 ( 0.60) 1.36 ( 0.79) 1.30 ( 0.53) 0.11 Serum bilirubin, mg/dl 1.23 ( 2.07) 1.25 ( 2.01) 1.38 ( 2.43) 0.26 Recent infection 127/1,196 (10.6%) 110/879 (12.5%) 149/970 (15.4%) Intraaortic balloon pump 79/1,295 (6.1%) 53/896 (5.9%) 52/985 (5.3%) 0.70 Mechanical ventilation 41/1,295 (3.2%) 22/896 (2.5%) 34/985 (3.5%) 0.44 Bridging with VADs Older generation 155/1,295 (12.0%) 122/896 (13.6%) 147/985 (14.9%) 0.12 Newer generation 4/1,295 (0.3%) 3/896 (0.3%) 10/985 (1.0%) 0.05 Heartmate II 69/1,295 (5.3%) 72/896 (8.0%) 71/985 (7.2%) 0.03 Extracorporeal VAD or ECMO 41/1,295 (3.2%) 10/896 (1.1%) 18/985 (1.8%) Continuous data presented as mean ( standard deviation), categorical data as number (percentage). a The p values are based on analysis of variance (continuous variables) or chi-square test (categorical variables). ECMO extracorporeal membrane oxygenation; IMPACT Index for Mortality Prediction After Cardiac Transplantation; OHT orthotopic heart transplantation; VAD ventricular assist device. mortality, low-volume centers were found to have significantly higher rates of death due to infection or malignancy (each p 0.05; Fig 5). Comment Volume and Posttransplant Mortality in Marginal Donor OHT The principal finding in our analysis of more than 3,000 OHT cases using marginal donors was that low-volume centers had significantly higher posttransplant mortality rates, a finding that persisted after adjusting for significant recipient, donor, and transplant variables. Although our study was designed only to examine the associative relationship between volume and outcomes, a few potential explanations for these findings could be postulated. One potential reason why higher volume centers have improved survival rates may be related to the complexity of the case. Marginal donor OHTs are known to be more complex than the standard OHT owing to several factors, including higher recipient risk, higher donor risk by definition, potentially higher complication rates such as primary graft dysfunction, and more complex donor management and optimization before heart explantation Table 5. Univariate and Multivariate Cox Proportional Hazards Regression Model for One-Year Mortality in Orthotopic Heart Transplantations Using Marginal Donors Covariate Univariate Analysis HR (95% CI) p Value Multivariable Analysis HR (95% CI) p Value Decreasing center volume (continuous) 1.01 ( ) ( ) 0.01 Center volume (categorical) High ( 25 OHT/yr) Ref. Ref. Ref. Ref. Intermediate (14-25 OHT/yr) 1.03 ( ) ( ) 0.27 Low ( 14 OHT/yr) 1.40 ( ) ( ) Increasing donor risk score 1.13 ( ) ( ) Increasing IMPACT recipient risk score 1.11 ( ) ( ) Year of transplant, earlier 1.03 ( ) ( ) 0.63 CI confidence interval; HR hazard ratio; IMPACT Index for Mortality Prediction After Cardiac Transplantation; OHT orthotopic heart transplantation; Ref. reference.

6 ADULT CARDIAC 700 KILIC ET AL Ann Thorac Surg VOLUME EFFECT IN MARGINAL DONOR OHT 2012;94: Fig 2. Effect of center volume in marginal donor orthotopic heart transplantation (OHT) stratified by nonmarginal versus marginal recipients, the latter being defined as having an Index for Mortality Prediction After Cardiac Transplantation (IMPACT) score greater than 10 (90th percentile of recipient risk). [12, 13], In these more challenging cases, prior center experience may play a more important role as compared with more straightforward procedures where event rates (ie, mortality) are lower and, therefore, separation of outcomes is more difficult. Furthermore, higher volume centers may have improved process of care that become even more relevant in these high-risk cases, such as standardized clinical pathways and dedicated intensive care unit staff and resources [14, 15]. The notion of volume impacting outcomes more profoundly in high-risk cases is supported by a prior study utilizing the UNOS database [8]. Moreover, in their study, Arnaoutakis and coworkers [8] found that recipient risk modified the impact of institutional volume on post-oht mortality. The effect of volume on outcomes was less profound in low recipient risk cases, and more profound in recipients with higher baseline risk. This finding supported the policy that high-risk recipients should undergo OHT at high-volume centers, irrespective of donor characteristics. Our findings supplement these findings, and suggest that high-risk donor organs be preferentially allocated to centers with higher volumes, irrespective of recipient characteristics. One argument that could be made regarding our study is that we are simply reiterating the findings of the study by Arnaoutakis and coworkers [8] because marginal donor recipients tend to be high risk, and, therefore. volume would be expected to impact outcomes. It is important to recognize, however, that recipient risk was adjusted for in our multivariable model, and therefore the volume-mortality relationship was significant irrespective of recipient risk. Moreover, although baseline recipient risk was higher in marginal versus standard donors in our analysis, not all recipients of marginal donors were high risk. In fact, nearly one third of marginal donor recipients had an IMPACT score of 4 or less, which corresponds to a projected 1-year survival of more than 90% [11]. In addition, as depicted in Figure 2, institutional volume significantly impacted outcomes using marginal donors in both nonmarginal and marginal Fig 3. Kaplan-Meier 1-year survival curves: high volume, more than 25 orthotopic heart transplantation (OHT) per year (solid black line); intermediate volume, 14 to 25 OHT per year (broken line); and low volume, less than 14 OHT per year (solid gray line).

7 Ann Thorac Surg KILIC ET AL 2012;94: VOLUME EFFECT IN MARGINAL DONOR OHT 701 Fig 4. Rates of postoperative adverse events: high volume, more than 25 orthotopic heart transplantation (OHT) per year (black bars); intermediate volume, 14 to 25 OHT per year (hatched bars); and low volume, less than 14 OHT per year (gray bars). ADULT CARDIAC recipients. Therefore, we believe these data support consolidating the use of high-risk donor organs to higher volume centers irrespective of the recipient s baseline risk. That being stated, this policy would likely be most effective in cases of alternate list OHT, where high-risk organs are transplanted into high-risk recipients. Given the data provided by our study and that by Arnaoutakis and associates [8], it would be expected that the mortality risk would be exponentially higher in lower volume centers in these highest risk cases. This was indeed demonstrated in Figure 2, where the effect of center volume was most profound in high-risk donors matched with high-risk recipients. We also found in our analysis that the IMPACT score was the highest in low-volume centers, suggesting that these institutions transplant marginal donor organs into even higher risk recipients than high or intermediate-volume centers. Although higher volume centers can achieve acceptable outcomes in the pairing of high-risk recipients and donors, our data suggests significantly worse outcomes with this strategy in low-volume centers. Therefore, this should prompt low-volume centers to reevaluate their recipient selection in cases using marginal donors. For instance, the recipient who is elderly, bridged with a ventricular assist device, and mechanically ventilated in the intensive care unit before OHT should not be transplanted with a marginal donor at a low-volume center. This recommendation is supported by a study by Russo and colleagues [7], who albeit utilizing different criteria for high risk, similarly found that institutional volume impacts outcomes most profoundly in the highest risk recipientdonor pairings. Volume and Secondary Outcomes Another finding in our study was that rejection as well as death due to infection or malignancy was more frequent in low-volume centers performing marginal donor OHT. Given these findings, there may be significant differences in immunosuppression protocols between centers in these cases. It is conceivable that low-volume centers have suboptimal regimens in marginal donor cases leading to higher rates of early rejection, and requiring boosts in immunosuppression that result in its well-known complications such as infection and malignancy. Unfortunately, immunosuppression protocols are not well Fig 5. Causes of posttransplant death: high volume, more than 25 orthotopic heart transplantation (OHT) per year (solid black line); intermediate volume, 14 to 25 OHT per year (broken line); and low volume, less than 14 OHT per year (solid gray line). (PGF primary graft failure.)

8 ADULT CARDIAC 702 KILIC ET AL Ann Thorac Surg VOLUME EFFECT IN MARGINAL DONOR OHT 2012;94: coded in the UNOS database to make these comparisons. Therefore, this remains an area for future investigation. Study Limitations Our study suffers from several limitations, the major one of which is that we were not able to examine other institutional factors beyond procedural volume that may impact outcomes. These include specific processes of care such as intensive care unit resources, quality of housestaff, and individual surgeon experience. Furthermore, the broader impact of implementing policies to exclude lower volume centers with poor outcomes from higher risk transplants cannot be determined from our study. It is certainly conceivable that implementing such policies would prevent some recipients from undergoing cardiac transplantation given the scarcity of standard donors. It is important to note, however, that our analysis is not meant to impugn all low-volume centers, as some have acceptable outcomes, but rather demonstrate that as a whole, centers with lower volumes have worse outcomes particularly in these higher risk cases. Another limitation of this study was that missing data entries are present in the UNOS database. With regard to our study design, the definition of a marginal donor is subjective, and therefore, any definition put forth in such a study will be under scrutiny. There are also statistical limitations to using logistic regression and retrospective data to develop predictive models. While readers may disagree with components of the risk score we used to define marginal donor, we do believe that using a validated risk index was the most objective method of defining our study population [9, 10]. In conclusion, in this study, we found that recipients undergoing OHT with marginal donors at low-volume centers were at increased risk of post-oht mortality, rejection in the first postoperative year, and death specifically due to infection or malignancy. These data collectively suggest that limiting marginal donors to centers with higher volumes would result in improved OHT outcomes for these higher risk cases. Identifying the processes of care that lead to improved outcomes in high-volume centers may also be prudent in improving nationwide outcomes of OHT using marginal donors. References 1. Laks H, Marelli D, Fonarow GC, et al. Use of two recipient lists for adults requiring heart transplantation. J Thorac Cardiovasc Surg 2003;125: Chen JM, Russo MJ, Hammond KM, et al. Alternate waiting list strategies for heart transplantation maximize donor organ utilization. Ann Thorac Surg 2005;80: Felker GM, Milano CA, Yager JE, et al. Outcomes with an alternate list strategy for heart transplantation. J Heart Lung Transplant 2005;24: Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002;346: Dewey TM, Herbert MA, Ryan WH, et al. Influence of surgeon volume on outcomes with aortic valve replacement. Ann Thorac Surg 2012 Jan 5 [E-pub ahead of print]. 6. 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: Russo MJ, Iribarne A, Easterwood R, et al. Post-heart transplant survival is inferior at low-volume centers across all risk strata. Circulation 2010;122(Suppl): Arnaoutakis GJ, George TJ, Allen JG, et al. Institutional volume and the effect of recipient risk on short-term mortality after orthotopic heart transplant. J Thorac Cardiovasc Surg 2012;143: Weiss ES, Allen JG, Kilic A, et al. Development of a quantitative donor risk index to predict short-term mortality in orthotopic heart transplantation. J Heart Lung Transplant 2011 Nov 15 [E-pub ahead of print]. 10. Rogers CA, Akan E, Bonser RS, Banner NR. US-derived quantitative donor risk score predicts mortality after orthotopic heart transplantation in the UK. J Heart Lung Transplant 2011;30(Suppl): Weiss ES, Allen JG, Arnaoutakis GJ, et al. Creation of a quantitative recipient risk index for mortality prediction after cardiac transplantation (IMPACT). Ann Thorac Surg 2011;92: Russo MJ, Iribarne A, Hong KN, et al. Factors associated with primary graft failure after heart transplantation. Transplantation 2010;90: Kutsogiannis DJ, Pagliarello G, Doig C, Ross H, Shemie SD. Medical management to optimize donor organ potential: review of the literature. Can J Anaesth 2006;53: Dimick JB, Pronovost PJ, Heitmiller RF, Lipsett PA. Intensive care unit physician staffing is associated with decreased length of stay, hospital cost, and complications after esophageal resection. Crit Care Med 2001;29: Zehr KJ, Dawson PB, Yang SC, Heitmiller RF. Standardized clinical care pathways for major thoracic cases reduce hospital costs. Ann Thorac Surg 1998;66:914 9.