- Email: [email protected]
Impact of Donor Origin on Survival After Orthotopic Heart Transplantation
The Impact of Donor Origin on Survival After Orthotopic Heart Transplantation Omid Kiamanesha, Amit Khoslab, Erica Johanssonb, Sean Viranib, Margot Davisb, Anson Cheungc, Jamil Bashirc, Bradley Muntb, Andrew Ignaszewskib, Annemarie Kaanb, and Mustafa Tomab,* a Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; bDivision of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada; and cDivision of Cardiac Surgery, University of British Columbia, Vancouver, British Columbia, Canada
ABSTRACT Heart transplantation is the definitive management for select patients with end-stage heart failure. Owing to an ongoing organ donor shortage, organs are sometimes allocated from distant locales. These organs may be perceived as less desirable because of donor risk factors and ischemic times. We compared survival after heart transplantation by donors originating from British Columbia (BC), other Canadian provinces, and the United States. This retrospective cohort analysis included all patients transplanted in BC between December 1, 1988, and October 21, 2014, and excluded those with missing data or retransplantation. Among 382 patients, 297 (77.7%) recipients and 238 (62.3%) donors were male. The median recipient age was 54.6 years (interquartile range, 46.0-61.0 years) and the median donor age was 33 years (interquartile range, 22-46 years). Overall 10-year survival was 62.1% (95% confidence interval, 56.3-67.4). There was no difference in 10year survival when comparing donors from BC, other Canadian provinces, and the United States despite significantly lower median ischemic times in donors from BC. Donor location was not predictive of mortality after controlling for recipient age, donor age, and cold ischemic time. Donor origin did not impact 10-year survival after heart transplantation despite increased ischemic time, suggesting that distant donors result in similar outcomes in BC.
H
EART transplantation remains the definitive management of patients with end-stage heart failure that is refractory to medical care. The procedure is performed approximately 4500 times worldwide per year [1]. However, the availability of heart transplantation is limited by an ongoing donor shortage despite increased demand [2,3]. Organs are also declined because of strict, yet unstandardized, selection criteria [4]. Organ allocation in North America is protocolled by the Canadian Cardiac Transplant Network (in Canada) and the United Network of Organ Sharing (in the United States) to promote the optimal allocation of donor organs. When a suitable local match is not identified, the Organ Procurement Organizations will engage in organ-sharing with their national and international counterparts to ensure that donor organs are used. In British Columbia (BC), the geographic origin of donors for heart transplantation may be local or distant,
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e3 (2019)
including other Canadian provinces (Canada) or the United States. While distant donors are carefully screened for suitability, they may be perceived as marginal donor organs because of donor risk factors and increased ischemic times. We describe long-term outcomes following heart transplantation in BC stratified by donor geographic origin. METHODS This single-center, retrospective cohort analysis evaluated all patients who underwent heart transplantation between December 1, 1988, and October 21, 2014, through the BC Heart Transplant Program. We excluded patients with missing data or retransplantation. The
*Address correspondence to Dr Mustafa Toma, St. Paul's Hospital, 475A-1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada. Tel: 604 806 9986; Fax: 604 806 9927. E-mail: mtoma@ providencehealth.bc.ca 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.08.032
1
2
KIAMANESH, KHOSLA, JOHANSSON ET AL Table 1. Characteristics of Heart Transplant Donors and Recipients Characteristic
Overall
BC
Canada
United States
Table 2. Cold Ischemic Time Stratified by Donor Origin Cold Ischemic Time
P Value
Recipient n ¼ 382 n ¼ 281 n ¼ 53 n ¼ 48 Age, median, y 54.6 54.0 54.9 59.7 Age, IQR, y 46.0-61.0 45.7-60.1 47.7-62.1 48.7-64.4 Male, n (%) 297 (77.7) 229 (81.5) 37 (69.8) 31 (64.6) Donor Age, median, y 33 33 40 31 Age, IQR, y 22-46 22-46 24-45 22-45 Male, n (%) 238 (62.3) 188 (66.9) 28 (52.8) 22 (45.8) <
.09 .01 .35 .01
Abbreviations: BC, British Columbia; IQR, interquartile range.
remaining patients were grouped by geographic origin. These groups were donors originating from BC, Canada, or the United States via the United Network for Organ Sharing. The primary outcome was survival at 10 years stratified by donor origin. Other outcomes were cold ischemic time stratified by donor origin and 10-year survival for the overall study population. Pretransplant donor and recipient characteristics were determined for the overall population as well as donor origin groups. Kaplan-Meier curves were generated for 10-year survival stratified by donor origin and compared using the log-rank test. Median cold ischemic times and interquartile ranges (IQRs) were determined by donor origin and compared using the log-rank test. Finally, a multivariate model addressing the relationship between donor origin and 10-year survival was constructed, controlling for donor age, recipient age, and cold ischemic time. In this model, continuous variables were dichotomized based on clinical cutoff points. Statistical analyses were performed using Stata 13.0 (StataCorp, College Station, TX, United States).
BC Canada United States Overall
Median, min
Interquartile Range
P Value
168 243 244 205
107.5-228.0 204.5-291.0 217.3-278.8 124.0-249.0
< .01
Abbreviation: BC, British Columbia.
similar in terms of recipient and donor age (Table 1). The United States group had the lowest proportion of male recipients and donors (64.6% and 45.8%, respectively). Overall survival at 10 years was 62.1% (95% confidence interval [CI], 56.3%-67.4%). There was no significant difference in 10-year survival (Fig 1) when comparing donors from BC (62.0%, 95% CI, 55.4%-68.0%), Canada (63.2%, 95% CI, 46.2%-76.2%), and the United States (57.3%; 95% CI, 32.4%-75.9%) (P ¼ .89). There was a significant difference in median cold ischemic time between donor groups, with longer ischemic times noted in the Canada (243 min [IQR 204.5-291.0 min]) and the United States (244 min [IQR 217.3-278.8 min]) groups vs the BC group (168 min [IQR 107.5-228.0 min]) (P < .01) (Table 2). After adjusting for recipient age, donor age, and cold ischemic time, there was no significant difference in 10-year survival for donors from Canada (hazard ratio 0.81, 95% CI, 0.46-1.43) or the United States (hazard ratio 0.86, 95% CI, 0.47-1.57) compared to BC donors (Table 3).
DISCUSSION RESULTS
Of the 406 patients who had been transplanted during the study period, 24 (5.9%) were excluded based on missing data or multiple transplants. The remaining 382 patients were included in this study. Donor origin groups were
In this study, there was no significant difference in 10-year survival following heart transplantation based on donor geographic origin. A multivariate model further demonstrated no relationship between donor geographic origin and survival when correcting for recipient age, donor age, and cold ischemic time. Donor origin from outside of BC
100% p=0.89
Survival
75%
50%
25%
Fig 1. Survival following orthotopic heart transplantation stratified by donor geographic origin. BC, British Columbia; CI, confidence interval.
62.0, 95% CI [55.4, 68.0] BC Canada 63.2, 95% CI [46.2, 76.2] 57.3, 95% CI [32.4, 75.9] USA
0% 0
2
4
6 Time (years)
8
10
DONOR ORIGIN AND HEART TRANSPLANT SURVIVAL Table 3. Multivariate Analysis of 10-Year Survival Characteristic
Hazard Ratio
95% Confidence Interval
Recipient age < 50 y Donor age < 50 y Cold ischemic time < 4 h Foreign donors Canada United States
1.02 0.94 0.77
0.70-1.48 0.55-1.60 0.51-1.15
0.81 0.86
0.46-1.43 0.47-1.57
was associated with longer cold ischemic times, with median cold ischemic times slightly above the clinical threshold of 4 hours. These findings are consistent with and extend those from Baran et al [5], who found no difference in survival following transplantation when comparing local vs distant donors at a single center in the United States. To our knowledge, this is the first study of Canadian patients and the first study to stratify distant donors as domestic vs international. Criteria for the acceptance of suboptimal donor organs vary across jurisdictions. Donor organs are commonly declined for advanced age, poor heart function, size mismatch, coronary artery disease, left ventricular hypertrophy, social history, Centers for Disease Control high risk status, recipient factors, or HLA mismatcherelated issues [6]. Despite being declined in or reallocated from their own locale, distant donor organs in this study resulted in not only acceptable but similar short- and long-term outcomes in orthotopic heart transplant recipients in BC. The implications of this study are significant. Incorporating these findings into organ allocation protocols may extend criteria for donor selection, thereby increasing the donor pool and organ availability. These data must be interpreted in the context of the study design. This single-center retrospective cohort study cannot correct for all variables that affect survival post-transplant. Further study is required to determine if these studies are applicable to other jurisdictions. Therefore, careful
3
attention should continue to be applied to donor selection, especially in the case of distant donors.
CONCLUSION
In a retrospective cohort study of heart transplant recipients in British Columbia, donor geographic origin was not associated with a significant difference in 10-year survival in univariate and multivariate models. Distant donor origin was associated with a significant increase in cold ischemic time. These findings suggest that the utilization of distant donors can result in similar long-term outcomes posteheart transplantation.
REFERENCES [1] Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult heart transplantation reportd2015; focus theme: early graft failure. J Hear Lung Transplant 2015;34:1244e54. https://doi.org/10. 1016/j.healun.2015.08.003. [2] Khush KK, Zaroff JG, Nguyen J, Menza R, Goldstein BA. National decline in donor heart utilization with regional variability: 1995-2010. Am J Transplant 2015;15:642e9. https://doi.org/10.1111/ ajt.13055. [3] Colvin-Adams M, Smith JM, Heubner BM, Skeans MA, Edwards LB, Waller CD, et al. OPTN/SRTR 2013 annual data report: heart. Am J Transplant 2015;15:1e28. https://doi.org/10. 1111/ajt.13199. [4] Kobashigawa J, Khush K, Colvin M, Acker M, Van Bakel A, Eisen H, et al. Report from the American Society of Transplantation Conference on Donor Heart Selection in Adult Cardiac Transplantation in the United States. Am J Transplant 2017;17: 2559e66. https://doi.org/10.1111/ajt.14354. [5] Baran DA, Jaiswal A, Adzic A, Pieretti J, Gidea C, Morlend R, et al. Does sequence matter? Outcomes of donors rejected by local centers. J Hear Lung Transplant 2014;33:S268. https://doi.org/10.1016/j.healun.2014.01.709. [6] Patel J, Kittleson M, Czer L, Chang D, Aintablian T, Norris EC, et al. Donor heart turn down, is it rational? J Heart Lung Transplant 2016;35:S213. https://doi.org/10.1016/j.healun. 2016.01.600.
ABSTRACT Heart transplantation is the definitive management for select patients with end-stage heart failure. Owing to an ongoing organ donor shortage, organs are sometimes allocated from distant locales. These organs may be perceived as less desirable because of donor risk factors and ischemic times. We compared survival after heart transplantation by donors originating from British Columbia (BC), other Canadian provinces, and the United States. This retrospective cohort analysis included all patients transplanted in BC between December 1, 1988, and October 21, 2014, and excluded those with missing data or retransplantation. Among 382 patients, 297 (77.7%) recipients and 238 (62.3%) donors were male. The median recipient age was 54.6 years (interquartile range, 46.0-61.0 years) and the median donor age was 33 years (interquartile range, 22-46 years). Overall 10-year survival was 62.1% (95% confidence interval, 56.3-67.4). There was no difference in 10year survival when comparing donors from BC, other Canadian provinces, and the United States despite significantly lower median ischemic times in donors from BC. Donor location was not predictive of mortality after controlling for recipient age, donor age, and cold ischemic time. Donor origin did not impact 10-year survival after heart transplantation despite increased ischemic time, suggesting that distant donors result in similar outcomes in BC.
H
EART transplantation remains the definitive management of patients with end-stage heart failure that is refractory to medical care. The procedure is performed approximately 4500 times worldwide per year [1]. However, the availability of heart transplantation is limited by an ongoing donor shortage despite increased demand [2,3]. Organs are also declined because of strict, yet unstandardized, selection criteria [4]. Organ allocation in North America is protocolled by the Canadian Cardiac Transplant Network (in Canada) and the United Network of Organ Sharing (in the United States) to promote the optimal allocation of donor organs. When a suitable local match is not identified, the Organ Procurement Organizations will engage in organ-sharing with their national and international counterparts to ensure that donor organs are used. In British Columbia (BC), the geographic origin of donors for heart transplantation may be local or distant,
ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, XX, 1e3 (2019)
including other Canadian provinces (Canada) or the United States. While distant donors are carefully screened for suitability, they may be perceived as marginal donor organs because of donor risk factors and increased ischemic times. We describe long-term outcomes following heart transplantation in BC stratified by donor geographic origin. METHODS This single-center, retrospective cohort analysis evaluated all patients who underwent heart transplantation between December 1, 1988, and October 21, 2014, through the BC Heart Transplant Program. We excluded patients with missing data or retransplantation. The
*Address correspondence to Dr Mustafa Toma, St. Paul's Hospital, 475A-1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada. Tel: 604 806 9986; Fax: 604 806 9927. E-mail: mtoma@ providencehealth.bc.ca 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.08.032
1
2
KIAMANESH, KHOSLA, JOHANSSON ET AL Table 1. Characteristics of Heart Transplant Donors and Recipients Characteristic
Overall
BC
Canada
United States
Table 2. Cold Ischemic Time Stratified by Donor Origin Cold Ischemic Time
P Value
Recipient n ¼ 382 n ¼ 281 n ¼ 53 n ¼ 48 Age, median, y 54.6 54.0 54.9 59.7 Age, IQR, y 46.0-61.0 45.7-60.1 47.7-62.1 48.7-64.4 Male, n (%) 297 (77.7) 229 (81.5) 37 (69.8) 31 (64.6) Donor Age, median, y 33 33 40 31 Age, IQR, y 22-46 22-46 24-45 22-45 Male, n (%) 238 (62.3) 188 (66.9) 28 (52.8) 22 (45.8) <
.09 .01 .35 .01
Abbreviations: BC, British Columbia; IQR, interquartile range.
remaining patients were grouped by geographic origin. These groups were donors originating from BC, Canada, or the United States via the United Network for Organ Sharing. The primary outcome was survival at 10 years stratified by donor origin. Other outcomes were cold ischemic time stratified by donor origin and 10-year survival for the overall study population. Pretransplant donor and recipient characteristics were determined for the overall population as well as donor origin groups. Kaplan-Meier curves were generated for 10-year survival stratified by donor origin and compared using the log-rank test. Median cold ischemic times and interquartile ranges (IQRs) were determined by donor origin and compared using the log-rank test. Finally, a multivariate model addressing the relationship between donor origin and 10-year survival was constructed, controlling for donor age, recipient age, and cold ischemic time. In this model, continuous variables were dichotomized based on clinical cutoff points. Statistical analyses were performed using Stata 13.0 (StataCorp, College Station, TX, United States).
BC Canada United States Overall
Median, min
Interquartile Range
P Value
168 243 244 205
107.5-228.0 204.5-291.0 217.3-278.8 124.0-249.0
< .01
Abbreviation: BC, British Columbia.
similar in terms of recipient and donor age (Table 1). The United States group had the lowest proportion of male recipients and donors (64.6% and 45.8%, respectively). Overall survival at 10 years was 62.1% (95% confidence interval [CI], 56.3%-67.4%). There was no significant difference in 10-year survival (Fig 1) when comparing donors from BC (62.0%, 95% CI, 55.4%-68.0%), Canada (63.2%, 95% CI, 46.2%-76.2%), and the United States (57.3%; 95% CI, 32.4%-75.9%) (P ¼ .89). There was a significant difference in median cold ischemic time between donor groups, with longer ischemic times noted in the Canada (243 min [IQR 204.5-291.0 min]) and the United States (244 min [IQR 217.3-278.8 min]) groups vs the BC group (168 min [IQR 107.5-228.0 min]) (P < .01) (Table 2). After adjusting for recipient age, donor age, and cold ischemic time, there was no significant difference in 10-year survival for donors from Canada (hazard ratio 0.81, 95% CI, 0.46-1.43) or the United States (hazard ratio 0.86, 95% CI, 0.47-1.57) compared to BC donors (Table 3).
DISCUSSION RESULTS
Of the 406 patients who had been transplanted during the study period, 24 (5.9%) were excluded based on missing data or multiple transplants. The remaining 382 patients were included in this study. Donor origin groups were
In this study, there was no significant difference in 10-year survival following heart transplantation based on donor geographic origin. A multivariate model further demonstrated no relationship between donor geographic origin and survival when correcting for recipient age, donor age, and cold ischemic time. Donor origin from outside of BC
100% p=0.89
Survival
75%
50%
25%
Fig 1. Survival following orthotopic heart transplantation stratified by donor geographic origin. BC, British Columbia; CI, confidence interval.
62.0, 95% CI [55.4, 68.0] BC Canada 63.2, 95% CI [46.2, 76.2] 57.3, 95% CI [32.4, 75.9] USA
0% 0
2
4
6 Time (years)
8
10
DONOR ORIGIN AND HEART TRANSPLANT SURVIVAL Table 3. Multivariate Analysis of 10-Year Survival Characteristic
Hazard Ratio
95% Confidence Interval
Recipient age < 50 y Donor age < 50 y Cold ischemic time < 4 h Foreign donors Canada United States
1.02 0.94 0.77
0.70-1.48 0.55-1.60 0.51-1.15
0.81 0.86
0.46-1.43 0.47-1.57
was associated with longer cold ischemic times, with median cold ischemic times slightly above the clinical threshold of 4 hours. These findings are consistent with and extend those from Baran et al [5], who found no difference in survival following transplantation when comparing local vs distant donors at a single center in the United States. To our knowledge, this is the first study of Canadian patients and the first study to stratify distant donors as domestic vs international. Criteria for the acceptance of suboptimal donor organs vary across jurisdictions. Donor organs are commonly declined for advanced age, poor heart function, size mismatch, coronary artery disease, left ventricular hypertrophy, social history, Centers for Disease Control high risk status, recipient factors, or HLA mismatcherelated issues [6]. Despite being declined in or reallocated from their own locale, distant donor organs in this study resulted in not only acceptable but similar short- and long-term outcomes in orthotopic heart transplant recipients in BC. The implications of this study are significant. Incorporating these findings into organ allocation protocols may extend criteria for donor selection, thereby increasing the donor pool and organ availability. These data must be interpreted in the context of the study design. This single-center retrospective cohort study cannot correct for all variables that affect survival post-transplant. Further study is required to determine if these studies are applicable to other jurisdictions. Therefore, careful
3
attention should continue to be applied to donor selection, especially in the case of distant donors.
CONCLUSION
In a retrospective cohort study of heart transplant recipients in British Columbia, donor geographic origin was not associated with a significant difference in 10-year survival in univariate and multivariate models. Distant donor origin was associated with a significant increase in cold ischemic time. These findings suggest that the utilization of distant donors can result in similar long-term outcomes posteheart transplantation.
REFERENCES [1] Lund LH, Edwards LB, Kucheryavaya AY, Benden C, Dipchand AI, Goldfarb S, et al. The Registry of the International Society for Heart and Lung Transplantation: thirty-second official adult heart transplantation reportd2015; focus theme: early graft failure. J Hear Lung Transplant 2015;34:1244e54. https://doi.org/10. 1016/j.healun.2015.08.003. [2] Khush KK, Zaroff JG, Nguyen J, Menza R, Goldstein BA. National decline in donor heart utilization with regional variability: 1995-2010. Am J Transplant 2015;15:642e9. https://doi.org/10.1111/ ajt.13055. [3] Colvin-Adams M, Smith JM, Heubner BM, Skeans MA, Edwards LB, Waller CD, et al. OPTN/SRTR 2013 annual data report: heart. Am J Transplant 2015;15:1e28. https://doi.org/10. 1111/ajt.13199. [4] Kobashigawa J, Khush K, Colvin M, Acker M, Van Bakel A, Eisen H, et al. Report from the American Society of Transplantation Conference on Donor Heart Selection in Adult Cardiac Transplantation in the United States. Am J Transplant 2017;17: 2559e66. https://doi.org/10.1111/ajt.14354. [5] Baran DA, Jaiswal A, Adzic A, Pieretti J, Gidea C, Morlend R, et al. Does sequence matter? Outcomes of donors rejected by local centers. J Hear Lung Transplant 2014;33:S268. https://doi.org/10.1016/j.healun.2014.01.709. [6] Patel J, Kittleson M, Czer L, Chang D, Aintablian T, Norris EC, et al. Donor heart turn down, is it rational? J Heart Lung Transplant 2016;35:S213. https://doi.org/10.1016/j.healun. 2016.01.600.