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Evolving practice patterns in heart transplantation: a single-center experience over 15 years
Evolving Practice Patterns in Heart Transplantation: A Single-Center Experience Over 15 Years L.S. De Santo, C. Amarelli, G. Romano, A. Della Corte, M. Torella, C. Mastroianni, M. De Feo, R. Utili, and M. Cotrufo ABSTRACT This analysis is a retrospective characterization of evolving patterns in donor and recipient risk factors for early and late outcomes (survival and freedom from rejection) along with determinants of hospital and 1-year mortality after heart transplantation over a 15-year experience in a single center. Profiles and outcomes were evaluated for procedures performed between 1988 and 1995 (group A, n ⫽ 105) versus 1996 and 2003 (group B, n ⫽ 218). The following parameters were considered: pretransplant diagnosis, recipient age UNOS status, donor age, total postretrieval ischemic time, donor/recipient size match, and degree of myocardial necrosis at biopsy. Recipients in group B were significantly more compromised as demonstrated by UNOS status (11.4% vs 19.3%; P ⫽ .05) and pretransplant pulmonary vascular resistance (2.3 ⫾ 1.5 vs 3.1 ⫾ 1.5; P ⫽ .04). Marginal donors were more frequently used for group B procedures (21.9% vs 47.7%; P ⬍ .0001). Outcomes were significantly more favorable among group B patients in terms of hospital mortality (18.1% vs 10.6%; P ⫽ .046), and 1- and 5-year actuarial survival (72.4% vs 83.4%, 60% vs 73.3%, respectively; P ⫽ .006). Analysis of the causes of death disclosed a significant reduction in fatal events due to graft failure and acute rejection in group B. No difference emerged with regard to actual freedom from acute rejection. Determinants of hospital mortality were pretransplant diagnosis, UNOS status, donor age, and cardioplegic solution. Transplant era, recipient age, infectious episodes, and ischemic necrosis at biopsy were risk factors for 1-year mortality. We conclude that despite extensive usage of marginal donors and selection of worse candidates, significantly better outcomes were achieved due to improvements in global management strategies.
G
ROWING PRESSURE to liberalize heart transplant eligibility has further exacerbated the widening gap between the number of waiting recipients and available donors. As a consequence, listed patients experience high mortality rates, and there is a steep increase in the percentage of recipients undergoing transplant as status I. These, in turn, may jeopardize the achieved survival rates. To increase donor supply, criteria for acceptance of organs have been stretched to include “marginal donors.” The impact of these trends over an extended period are still uncertain. The present study sought to describe the evolution of practice patterns in one center over 15 years, particularly the effects of changing donor and recipient characteristics on early and late survival. Table 1 and 2
PATIENTS AND METHODS The study population included 321 patients transplanted between January 1988 and January 2003. All recipients underwent standard © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 627– 630 (2004)
orthotopic transplantation by the same group of surgeons using the atrial anastomotic technique. Donor procurement was performed with a standard technique. Myocardial protection was achieved by infusion of St Thomas (n ⫽ 31, 1988 to 1991), Wisconsin (n ⫽ 96, 1991 to 1996), or Celsior (n ⫽ 196, 1996 on) solutions. Immunosuppressive therapy used methylprednisolone, azathioprine and cyclosporine with mycophenolate mophetil substituted for azathioprine since January 2001. All patients were administered induction therapy with polyclonal antibodies. Based on an approximately equal chronologic division during the 15-year experience, two groups were discerned for this analysis. Group A (n ⫽ 105) transplanted between 1988 and 1995; and group B (n ⫽ 218), From the Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, Italy. Address reprint requests to Luca Salvatore De Santo, Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, V Monaldi Hospital, Via L Bianchi 5, 80131 Naples, Italy. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.02.052 627
628
DE SANTO, AMARELLI, ROMANO ET AL Table 1. Characteristics of Donors and Recipients in the Two Study Groups
Recipient and donor profiles
Previous cardiac surgery Recipient PVRIa Recipient diagnosis Ischemic cardiomiopathy Idiopathic cardiomyopathy Postvalvular cardiomyopathy Others UNOS status I Marginal donorsb Donor age Size mismatch (⬎0.2) Ischemic time a
Group A (n ⫽ 105)
Group B (n ⫽ 218)
10 (9.5%) 2.3 ⫾ 1.5
32 (14.7%) 3.1 ⫾ 1.5
45 (42.9%) 46 (43.8%) 8 (7.6%) 6 (5.7%) 12 (11.4%) 23 (21.9%) 29.9 ⫾ 10.5 0 155.8 ⫾ 33.3
69 (31.7%) 102 (46.8%) 17 (7.8%) 30 (13.8%) 42 (19.3%) 95 (47.7%) 32.8 ⫾ 12.2 18 (8.3%) 166.4 ⫾ 46.0
P value
.132 .04 .075
.05 ⬍.001 .044 .001 .034
Pulmonary venous resistance index. Defined in the text.
b
between 1996 and 2003. The following parameters were considered: pretransplant diagnosis, recipient age, and gender, UNOS status, donor age, total postretrieval ischemic time, donor/recipient size match, and evidence of myocardial necrosis on endomyocardial biopsies. Additional characteristics were incidence of marginal donors (defined as having at least two of the following parameters: ⬎45 years, donor/recipient size match ⱕ0.8, ischemic time ⬎180 minutes), hospital, 1- and 5-year mortality, causes of death (categorized as: early graft failure, acute rejection, chronic rejection, and other [including infection]) along with freedom from acute rejection and determinants of survival. Statistical analyses were performed by SPSS software package. Results are expressed as mean values ⫾ standard deviations. An unpaired t-test was used to compare continuous variables, and the Fisher exact test for discrete variables. The Kaplan-Meier method was used for survival analysis with differences between groups analyzed by the log-rank test. Multivariate analysis of survival determinants was performed by logistic regression.
RESULTS
No significant differences were observed with regard to recipient age (47.33 ⫾ 12.07 vs 47.33 ⫾ 12.60) or gender (14.3% vs 17.4% women). Group B recipients showed a worse UNOS status (11.4% vs 19.3%; P ⫽ .05) and higher pulmonary vascular resistance (2.3 ⫾ 1.5 vs 3.1 ⫾ 1.5; P ⫽ .04). Marginal donors were more frequently used in group B procedures (21.9% vs 47.7%, P ⬍ .0001). Furthermore, donor age (29.9 ⫾ 10.5 vs 32.8 ⫾ 2.2 years, P ⫽ .044), total ischemic time (155.8 ⫾ 33.3 vs 166.4 ⫾ 46.1 minutes, P ⫽
.034), incidence of severe size mismatch (0% vs 8.3%, P ⫽ .001) were all significantly greater in the more recent experience (Table 1). Myocardial necrosis at endomyocardial biopsy was more frequently seen among patients transplanted before 1996 (36.4% vs 15.2%; P ⫽ .0001). Outcomes in group B were significantly better in terms of hospital mortality (18.1% vs 10.6%; P ⫽ .046), as well as 1and 5-year actuarial survival (72.4% vs 83.4%, 60% vs 73.3%, respectively; P ⫽ .006) (Fig 1). Analysis of causes of death disclosed a significant reduction of fatal events due to graft failure and acute rejection in group B (6.4% vs 12.4% and 2.8% vs 5.7%, respectively; P ⬍ .0001). No difference emerged in terms of actuarial freedom from acute rejection (80.2% vs 88.5%; P ⫽ .17) (Table 2). Determinants of hospital mortality included pretransplant diagnosis, UNOS status, donor age, and cardioplegic solution. Transplant era, infectious episodes, and ischemic necrosis at biopsy were risk factors for 1-year mortality. The results of multivariate analyses are provided in Table 3. DISCUSSION
The effects of changing donor and recipient characteristics on early and late survival were sought in a single-center 15-year experience. Our data reflect the worldwide trends toward liberalization of recipient criteria and expansion of the donor pool.1– 4 In fact a significant increase was seen in the proportion of transplants to urgent (status 1), and in
Table 2. Outcomes Results
Hospital mortality Cause of death: Graft failure Acute rejection Noncardiac Ischemic necrosis on early biopsy 1-year freedom from acute rejection (⬎2)
Group A (n ⫽ 105)
Group B (n ⫽ 218)
19 (18.1%)
23 (10.6%)
13 (12.4%) 6 (5.7%) 22 (21%) 32/88 (36.4%) 80.2 ⫾ 4.3
14 (6.4%) 6 (2.8%) 11 (5%) 30/198 (15.2%) 88.5 ⫾ 2.3
P value
.046 ⬍.001
⬍.001 .17
EVOLVING PRACTICE PATTERNS
629
Fig 1.
Actuarial Survival Curve.
general treatment of more compromised recipients. Simultaneously, marginal donors were more frequently employed. In particular, there was a gradual increase in ischemic time, in mean donor age, and in acceptance of undersized donors. In our experience, expansion of the donor pool was mostly achieved by the extension of donor age acceptability. The trend toward increased ischemic times, although usually within the conventional 4-hour limit, closely related to a greater confidence in current cardioplegia solutions. Indeed, in accordance with published data on myocardial preservation with Celsior, a significant decrease in myocardial necrosis, and
above all, the incidence of graft failure was noted in the recent cohort of patients despite the unfavourable donor profile.5,6 These “secular trends” in clinical heart transplant practice raised concerns of poorer postoperative survival and of less effective usage of donor organs.7 Analysis of our program data demonstrates that despite these evident changes the early and late survival rates have significantly improved presumably due to significant refinements in global management strategies, including pretransplant medical therapy, timing, and route of hemodynamic support, myocardial protection, perioperative intensive care, and immunosuppression. Fig 1
Table 3. Determinants of Hospital and 1-Year Mortality: Multivariate Analyses Hospital mortality
Recipient diagnosis Ischemic cardiomiopathy Postvalvular Cardiomyopathy Others UNOS status I Donor age Cardioplegia Wisconsin Celsior One-year mortality Transplant era (1988 –1995) Infectious episodes Ischemic necrosis on early biopsies

OR
95% CI
2.1 2.6 0.13
0.93– 4.67 0.83– 8.3 0.15–1.14
5.6 1.04
2.24 –13.84 1.01–1.07
⫺1.40 ⫺1.56
0.25 0.20
0.85– 0.74 0.76 – 0.57
0.76 1.89 0.82
2.14 6.60 2.28
1.04 – 4.6 2.78 –15.65 1.01–5.14
P
.027 0.73 0.97 ⫺2.03 1.7 0.042
⬍.001 .007 .009
.049 ⬍.001 .047
630
REFERENCES 1. Hauptman PJ, Kartashow AI, Couper GS, et al: Changing patterns in donor and recipient risk: a 10-year evolution in one heart transplant center. J Heart Lung Transplant 14:654, 1995 2. Ranjit J, Rajasinghe HA, Chen JM, et al: Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy. Ann Thorac Surg 72:440, 2001 3. Chen JM, Sinha P, Rajasinghe HA, et al: Do donor characteristics really matter? Short- and long-term impact of donor characteristics on recipient survival, 1995–1999. J Heart Lung Transplant 21:608, 2002 4. Rodeheffer RJ, Naftel DC, Stevenson LW, et al: Secular trends in cardiac transplant recipient and donor management in
DE SANTO, AMARELLI, ROMANO ET AL the United States, 1990 to 1994. A multi-institutional study. Cardiac Transplant Research Database Group. Circulation 94: 2883, 1996 5. Vega JD, Ochsner JL, Jeevanandam V, et al: A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts. Ann Thorac Surg 71:1442, 2001 6. Remadi JP, Baron O, Roussel JC, et al: Myocardial preservation using Celsior solution in cardiac transplantation: early results and 5-year follow-up of a multicenter prospective study of 70 cardiac transplantations. Ann Thorac Surg 73:1495, 2002 7. Stevenson LW, Warner SL, Steimle AE, et al: The impending crisis awaiting cardiac transplantation. Modeling a solution based on selection. Circulation 89:450, 1994
G
ROWING PRESSURE to liberalize heart transplant eligibility has further exacerbated the widening gap between the number of waiting recipients and available donors. As a consequence, listed patients experience high mortality rates, and there is a steep increase in the percentage of recipients undergoing transplant as status I. These, in turn, may jeopardize the achieved survival rates. To increase donor supply, criteria for acceptance of organs have been stretched to include “marginal donors.” The impact of these trends over an extended period are still uncertain. The present study sought to describe the evolution of practice patterns in one center over 15 years, particularly the effects of changing donor and recipient characteristics on early and late survival. Table 1 and 2
PATIENTS AND METHODS The study population included 321 patients transplanted between January 1988 and January 2003. All recipients underwent standard © 2004 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 36, 627– 630 (2004)
orthotopic transplantation by the same group of surgeons using the atrial anastomotic technique. Donor procurement was performed with a standard technique. Myocardial protection was achieved by infusion of St Thomas (n ⫽ 31, 1988 to 1991), Wisconsin (n ⫽ 96, 1991 to 1996), or Celsior (n ⫽ 196, 1996 on) solutions. Immunosuppressive therapy used methylprednisolone, azathioprine and cyclosporine with mycophenolate mophetil substituted for azathioprine since January 2001. All patients were administered induction therapy with polyclonal antibodies. Based on an approximately equal chronologic division during the 15-year experience, two groups were discerned for this analysis. Group A (n ⫽ 105) transplanted between 1988 and 1995; and group B (n ⫽ 218), From the Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, Naples, Italy. Address reprint requests to Luca Salvatore De Santo, Department of Cardio-Thoracic and Respiratory Sciences, Second University of Naples, V Monaldi Hospital, Via L Bianchi 5, 80131 Naples, Italy. E-mail: [email protected] 0041-1345/04/$–see front matter doi:10.1016/j.transproceed.2004.02.052 627
628
DE SANTO, AMARELLI, ROMANO ET AL Table 1. Characteristics of Donors and Recipients in the Two Study Groups
Recipient and donor profiles
Previous cardiac surgery Recipient PVRIa Recipient diagnosis Ischemic cardiomiopathy Idiopathic cardiomyopathy Postvalvular cardiomyopathy Others UNOS status I Marginal donorsb Donor age Size mismatch (⬎0.2) Ischemic time a
Group A (n ⫽ 105)
Group B (n ⫽ 218)
10 (9.5%) 2.3 ⫾ 1.5
32 (14.7%) 3.1 ⫾ 1.5
45 (42.9%) 46 (43.8%) 8 (7.6%) 6 (5.7%) 12 (11.4%) 23 (21.9%) 29.9 ⫾ 10.5 0 155.8 ⫾ 33.3
69 (31.7%) 102 (46.8%) 17 (7.8%) 30 (13.8%) 42 (19.3%) 95 (47.7%) 32.8 ⫾ 12.2 18 (8.3%) 166.4 ⫾ 46.0
P value
.132 .04 .075
.05 ⬍.001 .044 .001 .034
Pulmonary venous resistance index. Defined in the text.
b
between 1996 and 2003. The following parameters were considered: pretransplant diagnosis, recipient age, and gender, UNOS status, donor age, total postretrieval ischemic time, donor/recipient size match, and evidence of myocardial necrosis on endomyocardial biopsies. Additional characteristics were incidence of marginal donors (defined as having at least two of the following parameters: ⬎45 years, donor/recipient size match ⱕ0.8, ischemic time ⬎180 minutes), hospital, 1- and 5-year mortality, causes of death (categorized as: early graft failure, acute rejection, chronic rejection, and other [including infection]) along with freedom from acute rejection and determinants of survival. Statistical analyses were performed by SPSS software package. Results are expressed as mean values ⫾ standard deviations. An unpaired t-test was used to compare continuous variables, and the Fisher exact test for discrete variables. The Kaplan-Meier method was used for survival analysis with differences between groups analyzed by the log-rank test. Multivariate analysis of survival determinants was performed by logistic regression.
RESULTS
No significant differences were observed with regard to recipient age (47.33 ⫾ 12.07 vs 47.33 ⫾ 12.60) or gender (14.3% vs 17.4% women). Group B recipients showed a worse UNOS status (11.4% vs 19.3%; P ⫽ .05) and higher pulmonary vascular resistance (2.3 ⫾ 1.5 vs 3.1 ⫾ 1.5; P ⫽ .04). Marginal donors were more frequently used in group B procedures (21.9% vs 47.7%, P ⬍ .0001). Furthermore, donor age (29.9 ⫾ 10.5 vs 32.8 ⫾ 2.2 years, P ⫽ .044), total ischemic time (155.8 ⫾ 33.3 vs 166.4 ⫾ 46.1 minutes, P ⫽
.034), incidence of severe size mismatch (0% vs 8.3%, P ⫽ .001) were all significantly greater in the more recent experience (Table 1). Myocardial necrosis at endomyocardial biopsy was more frequently seen among patients transplanted before 1996 (36.4% vs 15.2%; P ⫽ .0001). Outcomes in group B were significantly better in terms of hospital mortality (18.1% vs 10.6%; P ⫽ .046), as well as 1and 5-year actuarial survival (72.4% vs 83.4%, 60% vs 73.3%, respectively; P ⫽ .006) (Fig 1). Analysis of causes of death disclosed a significant reduction of fatal events due to graft failure and acute rejection in group B (6.4% vs 12.4% and 2.8% vs 5.7%, respectively; P ⬍ .0001). No difference emerged in terms of actuarial freedom from acute rejection (80.2% vs 88.5%; P ⫽ .17) (Table 2). Determinants of hospital mortality included pretransplant diagnosis, UNOS status, donor age, and cardioplegic solution. Transplant era, infectious episodes, and ischemic necrosis at biopsy were risk factors for 1-year mortality. The results of multivariate analyses are provided in Table 3. DISCUSSION
The effects of changing donor and recipient characteristics on early and late survival were sought in a single-center 15-year experience. Our data reflect the worldwide trends toward liberalization of recipient criteria and expansion of the donor pool.1– 4 In fact a significant increase was seen in the proportion of transplants to urgent (status 1), and in
Table 2. Outcomes Results
Hospital mortality Cause of death: Graft failure Acute rejection Noncardiac Ischemic necrosis on early biopsy 1-year freedom from acute rejection (⬎2)
Group A (n ⫽ 105)
Group B (n ⫽ 218)
19 (18.1%)
23 (10.6%)
13 (12.4%) 6 (5.7%) 22 (21%) 32/88 (36.4%) 80.2 ⫾ 4.3
14 (6.4%) 6 (2.8%) 11 (5%) 30/198 (15.2%) 88.5 ⫾ 2.3
P value
.046 ⬍.001
⬍.001 .17
EVOLVING PRACTICE PATTERNS
629
Fig 1.
Actuarial Survival Curve.
general treatment of more compromised recipients. Simultaneously, marginal donors were more frequently employed. In particular, there was a gradual increase in ischemic time, in mean donor age, and in acceptance of undersized donors. In our experience, expansion of the donor pool was mostly achieved by the extension of donor age acceptability. The trend toward increased ischemic times, although usually within the conventional 4-hour limit, closely related to a greater confidence in current cardioplegia solutions. Indeed, in accordance with published data on myocardial preservation with Celsior, a significant decrease in myocardial necrosis, and
above all, the incidence of graft failure was noted in the recent cohort of patients despite the unfavourable donor profile.5,6 These “secular trends” in clinical heart transplant practice raised concerns of poorer postoperative survival and of less effective usage of donor organs.7 Analysis of our program data demonstrates that despite these evident changes the early and late survival rates have significantly improved presumably due to significant refinements in global management strategies, including pretransplant medical therapy, timing, and route of hemodynamic support, myocardial protection, perioperative intensive care, and immunosuppression. Fig 1
Table 3. Determinants of Hospital and 1-Year Mortality: Multivariate Analyses Hospital mortality
Recipient diagnosis Ischemic cardiomiopathy Postvalvular Cardiomyopathy Others UNOS status I Donor age Cardioplegia Wisconsin Celsior One-year mortality Transplant era (1988 –1995) Infectious episodes Ischemic necrosis on early biopsies

OR
95% CI
2.1 2.6 0.13
0.93– 4.67 0.83– 8.3 0.15–1.14
5.6 1.04
2.24 –13.84 1.01–1.07
⫺1.40 ⫺1.56
0.25 0.20
0.85– 0.74 0.76 – 0.57
0.76 1.89 0.82
2.14 6.60 2.28
1.04 – 4.6 2.78 –15.65 1.01–5.14
P
.027 0.73 0.97 ⫺2.03 1.7 0.042
⬍.001 .007 .009
.049 ⬍.001 .047
630
REFERENCES 1. Hauptman PJ, Kartashow AI, Couper GS, et al: Changing patterns in donor and recipient risk: a 10-year evolution in one heart transplant center. J Heart Lung Transplant 14:654, 1995 2. Ranjit J, Rajasinghe HA, Chen JM, et al: Long-term outcomes after cardiac transplantation: an experience based on different eras of immunosuppressive therapy. Ann Thorac Surg 72:440, 2001 3. Chen JM, Sinha P, Rajasinghe HA, et al: Do donor characteristics really matter? Short- and long-term impact of donor characteristics on recipient survival, 1995–1999. J Heart Lung Transplant 21:608, 2002 4. Rodeheffer RJ, Naftel DC, Stevenson LW, et al: Secular trends in cardiac transplant recipient and donor management in
DE SANTO, AMARELLI, ROMANO ET AL the United States, 1990 to 1994. A multi-institutional study. Cardiac Transplant Research Database Group. Circulation 94: 2883, 1996 5. Vega JD, Ochsner JL, Jeevanandam V, et al: A multicenter, randomized, controlled trial of Celsior for flush and hypothermic storage of cardiac allografts. Ann Thorac Surg 71:1442, 2001 6. Remadi JP, Baron O, Roussel JC, et al: Myocardial preservation using Celsior solution in cardiac transplantation: early results and 5-year follow-up of a multicenter prospective study of 70 cardiac transplantations. Ann Thorac Surg 73:1495, 2002 7. Stevenson LW, Warner SL, Steimle AE, et al: The impending crisis awaiting cardiac transplantation. Modeling a solution based on selection. Circulation 89:450, 1994