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Reprint requests: Josef Stehlik, MD, MPH, University of Utah Health, Division of Cardiovascular Medicine, U.T.A.H. Cardiac Transplant Program, 50 N Medical Dr, 4A100 SOM, Salt Lake City, UT 84132. Telephone: 801-585-2340. Fax: 801-581-7735
This year marks the 50th anniversary of the first heart transplant, performed in 1967. Since then, and in particular since the introduction of cyclosporine immunosuppression in the 1970s, heart transplantation has grown worldwide. This 34th adult heart transplant report is based on data submitted to the International Society for Heart and Lung Transplantation (ISHLT) Registry on 135,387 heart transplants in recipients of all ages (including 120,991 adult heart transplants) through June 30, 2016. With each year’s report we now also provide more detailed analyses on a particular focus theme. Since 2013, these have been donor and recipient age, retransplantation, early graft failure, indication for transplant, and in 2017, allograft ischemic time.
Data collection, conventions and statistical methods
National and multinational organ/data exchange organizations and individual centers submit data to the ISHLT Registry. Since the Registry’s inception, 472 heart transplant centers, 256 lung transplant centers, and 180 heart-lung transplant centers have reported data to the Registry. We estimate data submitted to the Registry currently represent approximately 75% of worldwide transplant activity.
An overview of donor and recipient characteristics and outcomes is presented throughout the report. The data are supplemented with additional and extended analyses presented in 3 separate online slide sets (named “Introduction,” “Heart-Overall,” and “Adult Heart Transplant,” http://ishlt.org/registries/slides.asp?slides=heartLungRegistry). Slide sets for previous annual reports are also available on this site. The study refers to specific online e-slides when particular data are discussed but not shown in the report due to space limitations; eSlide H(overall) numbers refer to the online overall heart transplant slides and eSlide H(a) numbers refer to the online adult heart transplant slides.
The Registry Web site (http://ishlt.org/registries/heartLungRegistry.asp) provides detailed spreadsheets of the data elements collected in the Registry. The Registry requires submission of core donor, recipient, and transplant procedure variables at baseline and at yearly follow-up, and these variables therefore have low rates of missingness. Nevertheless, data quality depends on accuracy and completeness of reporting. Rates of missingness may significantly increase for Registry variables that depend on voluntary reporting. The Registry uses various quality control measures to ensure acceptable data quality and completeness before including data for analyses.
Unless otherwise specified, heart-lung transplants are not included in analyses of heart transplants or lung transplants. Retransplant includes those with a previously reported transplant of the same organ type or same organ type in combination, or with a retransplant diagnosis. Because identification of all transplants for an individual may not be complete, the number of retransplant events maybe slightly underestimated. The Registry does not capture the exact occurrence date for most secondary outcomes (e.g., renal dysfunction), but it does capture the window of occurrence (i.e., the event occurred between the first-year and the second-year annual follow-up visits). For the annual report, the midpoint between annual follow-ups is used as a surrogate for the event date. There is some bias in reporting secondary outcomes and other information on the follow-up where a death is reported. To reduce the possibility of underestimating event rates or other outcomes, some analyses are limited to surviving patients. For time-to-event rates and cumulative morbidity rates, follow-up of recipients not experiencing the event of interest was censored at the last time the recipient was reported not to have had the event, either the most recent annual follow-up or the time of retransplantation. Time-to-event graphs (e.g., survival graphs) are truncated when the number of individuals still at risk was < 10. Additional information regarding the general statistical methods used for analyses and data interpretation is included in the Supplementary Material available online (www.ishltonline.org).
Focus Theme Methods: Allograft ischemic time
The Registry Steering Committee selected allograft ischemic time as the theme topic for the 2017 report. Allograft ischemic time was defined as the time elapsed between aortic cross-clamp performed during organ procurement surgery and coronary artery reperfusion during heart transplant surgery.
The reporting of allograft ischemic time varied significantly by geographic region, with high rates of data completeness from North American transplant centers, low rates of completeness from European centers, and moderate rates for centers from other regions. Thus, we recommend cautious interpretation of the theme data, especially for analyses that include geographic region and for generalizability to non-North American centers. The inconsistent reporting of different variables from different regions illustrates the trade-offs between worldwide broadly generalizable Registry data vs more internally valid but less generalizable data collected locally or regionally.
Core adult heart transplant statistics
After a decline between 1993 and 2004, heart transplant volumes reported to the ISHLT Transplant Registry have been steadily increasing, especially in the last 3 years, and reached an all-time high in 2015 at a total of 5,074 heart transplants (including 4,388 adult heart transplants but excluding combined heart-lung transplants) from 285 centers (Figure 1; overall adult and pediatric heart transplant volumes reported to the ISHLT over time). Increases are most pronounced in North America and other regions—countries not located in North America or Europe—whereas the number of transplants has remained fairly static in Europe. The number of data collectives and individual centers reporting to the ISHLT has increased in recent years; therefore, the increase in volume likely represents a combination of increased reporting as well as an absolute increase in heart transplantation volume.
Donor and recipient demographics and characteristics
Overall adult recipient and donor characteristics for the most recent era (2009–June 2016) are presented in Table 1, and for previous eras in eSlides H(a) 8–12. In a continuation of a trend discussed in detail in the 2013 report,
PRA was collected as a single percentage outside of United States. In United States, until March 2015, PRA was collected separately for Class I and Class II; after March 2015, calculated PRA is collected in United States as a single percentage.
a Continuous factors are expressed as median (5th–95th percentiles) and categoric variables as %.
b PRA was collected as a single percentage outside of United States. In United States, until March 2015, PRA was collected separately for Class I and Class II; after March 2015, calculated PRA is collected in United States as a single percentage.
c Based on non-United States transplants and March 2015 to June 2016 United States transplants.
d Based on 2009 to March 2015 United States transplants.
With the growing organ donor shortage, marginal donor organs may be increasingly accepted (which was one reason for this year’s focus on allograft ischemic time) and may partly explain the continued and dramatically increasing donor age (eSlide H(overall) 6), particularly in Europe (Figure 2). Mean donor age for adult transplants is now 35 years (Table 1). The potential interactions between donor age and other variables in affecting heart transplant outcomes are not well known.
the dominant underlying primary diagnoses in adult recipients are ischemic cardiomyopathy and idiopathic, nonischemic dilated cardiomyopathy (eSlides H(a) 4–6). Also increasing the complexity and risk of transplants is the growing use of combined organ transplants, particularly heart-kidney but also heart-liver. Heart transplants combined with transplant of another organ now exceed 4% of all heart transplant volume (Figure 3), whereas retransplantation remains constant (eSlide H(a) 7). The proportion of transplant recipients bridged with mechanical circulatory support (MCS) has increased dramatically since 2007, especially in older recipients,
but now appears to be levelling off at slightly more than 50% of transplants (eSlides H(a) 17–18).
For all 126,753 pediatric and adult heart transplants (excluding heart-lung transplants) performed from 1982 to June 2015, survival was better in the pediatric population, particularly in the long-term, with median survival of 10.7 years in adults and 16.1 years in pediatric recipients (eSlide H(overall) 15). Adult recipient unadjusted survival, particularly in the short-term, has continued to improve over time (Figure 4). In unadjusted analysis, there is no meaningful association between recipient age and early post-transplant survival (Figure 5), but over longer follow-up, older age is associated with lower survival (eSlide H(a) 54). Older donor age is more strongly associated with recipient post-transplant mortality, especially in the early post-transplant period (Figure 6). Women have slightly better survival than men (eSlides H(a) 57–58).
In more recent years (2005–June 2015), post-transplant survival is not adversely affected by pre-transplant MCS, with a notable exception of extracorporeal membrane oxygenation. Indeed, post-transplant survival is distinctly worse in a sub-group of patients bridged to transplant with extracorporeal membrane oxygenation (Figure 7). Although elevated pulmonary vascular resistance has been associated with worse short-term post-transplant adverse outcomes, no differences were found in unadjusted long-term survival by pulmonary vascular resistance for 2004 to June 2015 transplants (eSlide H(a) 66).
Causes of death
The leading cumulative causes of death are graft failure, non-cytomegalovirus (CMV) infection, and multiple organ failure (eSlides H(a) 79 and 81). Causes of death vary over time, with the incidence of graft failure death being highest in the first 30 days and then late after transplant, infection death being most prevalent in the first year, and long-term complications such as malignancy, cardiac allograft vasculopathy (CAV), and renal failure becoming progressively more important with increasing time after transplant (Figure 8, eSlides H(a) 77–78).
Induction immunosuppression therapy
Immunosuppressive induction use is just above 50% (eSlide H(a) 28) and considerably more frequent in North America than in Europe, especially the use of anti-lymphocyte globulins and anti-thymocyte globulins (eSlide H(a) 29). Induction strategy, in general, did not appear to be associated with differences in survival in unadjusted analysis (eSlide H(a) 30). However, a recent report from the ISHLT Adult Heart Transplant Registry suggested that anti-thymocyte globulin induction was associated with better outcomes compared to basiliximab induction.
Tacrolimus was the preferred calcineurin inhibitor and mycophenolate mofetil/mycophenolic acid the preferred cell cycle inhibitor (eSlide H(a) 31). The use of these agents has increased in recent eras, whereas the use of prednisone appears to be decreasing and is now used in slightly more than 80% of patients at 1 year after transplant (eSlide H(a) 32).
With improved immunosuppression, the incidence of any rejection or treated rejection between discharge and 1 year after transplant has continued to decrease (eSlides H(a) 35–36). The cumulative risk of treated rejection at 1 year after transplant was lowest in the absence of induction, possibly due to preferential use of induction in patients at higher perceived risk of rejection (eSlides H(a) 37–38), and in recipients treated with tacrolimus rather than cyclosporine (eSlides H(a) 39–40). The Registry does not collect data on the types of rejection; thus, analyses of cellular and antibody-mediated rejection cannot be performed separately.
Hypertension and hyperlipidemia are common morbidities after heart transplantation
but are no longer reported to the Registry. Renal dysfunction, diabetes, and CAV are other important post-transplant morbidities (Table 2). Of these, renal dysfunction and CAV, in addition to graft failure, infection, acute rejection, and malignancy described above, were the most important direct contributors to mortality (Figure 8, eSlides H(a) 77–81). Despite the risk of complications after transplant, nearly 60% of recipients are free from hospitalization in the first year after transplant and nearly 80% between 2 and 3 years and between 4 and 5 years (Figure 9). In the longer-term, malignancy becomes the most important cause of death (Figure 8). Skin malignancy (including melanoma) and lymphoma are the most common malignancy types, with skin cancer reaching nearly 20% at 10 years (Table 3).
Table 2Cumulative Morbidity Rates In Survivors Within 1, 5, and 10 Years Post-Transplant for Adult Heart Transplants Performed From January 1, 1994, to June 30, 2015
Compared with advanced heart failure before transplant, heart transplantation in appropriately selected candidates is associated with dramatic improvements in survival, functional status, and quality of life.
Functional status remained favorable at 1 to 3 years after transplant, (eSlide H(a) 83), but the extent of employment in heart transplant recipients appears disproportionately low (eSlides H(a) 84–85).
Unadjusted mortality and morbidity rates were described above. To determine the independent risk markers for and potential risk factors associated with subsequent mortality and morbidity, we performed multivariable proportional hazards regression analyses for recent transplant eras. The analyses establish independent associations between risk factors (technically, risk markers) and outcomes, but causality cannot be established. Categorical variables associated with post-transplant mortality risk at 1 year (Figure 10) include important markers of pre-transplant severity of illness, such as pre-transplant ventilator and dialysis use, retransplantation, and underlying diagnoses of congenital heart disease. Interestingly, ventricular assist device (VAD) and inotrope use before transplant are both associated with lower mortality at 1 year compared with patients listed without VAD or inotrope support. In unadjusted analysis (Figure 5) and after adjustment for potential confounders available in the Registry, older age is associated with a greater risk of 1-year mortality (Figure 11).
Because this year’s focus theme is allograft ischemic time, which affects primarily short-term outcomes, the tables and figures in the main report focus primarily on short-term outcomes. However, eSlides H(a) 108–162 show multivariable analyses for mortality within 1, 5, 10, 15, and 20 years. Categorical and continuous risk factors for post-transplant mortality will differ considerably by time since transplant. The long-term data reflect patients who received transplants in earlier eras, and the findings may not be applicable to current conditions. Specific associations observed among these data should therefore be interpreted with caution and are better explored in more detailed analyses from the Registry. Notable associations with post-transplant mortality (or specific complications such as early graft failure) shown in recent years include greater risk of death with lower donor/recipient weight ratio, gender mismatch,
Association of recipient age and causes of heart transplant mortality: Implications for personalization of post-transplant management–an analysis of the International Society for Heart and Lung Transplantation Registry.
In addition to recipient, donor, and recipient and donor interactions, post-transplant outcomes are also affected by factors surrounding the transplant procedure itself. Allograft ischemic time affects allograft viability
and may also be affected by geographic and other considerations for organ allocation. Therefore, for this 2017 report, we analyzed in detail the factors associated with allograft ischemic time and the association between allograft ischemic time and outcomes.
Allograft ischemic time and factors associated with allograft ischemic time
In the era 2009 to June 2016, median (5th–95th percentile) allograft ischemic time was 3.2 (1.5–5.0) hours (Table 1). Interestingly, median allograft ischemic time increased considerably between 1983 and the early 2000s, mainly due to a dramatic increase in acceptance of 4- to 6-hour ischemic times and a decline in < 2-hour ischemic times (Figure 12). Allograft ischemic time appears considerably longer in Europe, with more than 40% of transplants having an allograft ischemic time ≥ 4 hours (eSlide H(a) 178). However, during 2009 to June 2016, reporting of allograft ischemic times for adult heart transplants to the Registry was 38% from Europe, 56% from other regions, and 99% from North America. For these reasons, data on regional differences in allograft ischemic time should be viewed with caution.
In contrast to era and location, other potential factors do not appear strongly associated with allograft ischemic time in univariate analyses. Slightly longer allograft ischemic times appear to be more acceptable with younger recipients (Figure 13) and donors, but interestingly, also with the oldest donors (Figure 14). Recipients with congenital heart disease and retransplant diagnoses receive hearts with longer allograft ischemic times (eSlide H(a) 172), but there is no consistent pattern between allograft ischemic time and use of MCS at the time of transplant (eSlide H(a) 174), donor cause of death (eSlide H(a) 176), or transplant center volume (eSlide H(a) 179).
Survival by ischemic time
Figure 15 shows Kaplan-Meier survival in the first year 30 days after transplant and Figure 16 in the first 6 years after transplant, according to allograft ischemic time. Up to 30 days, allograft ischemic time < 4 hours is associated with considerably higher survival than allograft ischemic time ≥ 4 hours. Up to 6 years, allograft ischemic times of < 2 hours and 2 to < 4 hours result in similar survival; whereas an allograft ischemic time of 4 to < 6 hours is associated with lower survival compared with the 2 shorter allograft ischemic time groups, and an allograft ischemic time of ≥ 6 hours is associated with the lowest survival of the 4 groups. The survival curves separate in the first few months, suggesting allograft ischemic time affects predominantly early outcomes.
Allograft ischemic time in multivariable survival analyses
Given that we observed few associations between recipient or donor characteristics and allograft ischemic time, it is less likely that the association between allograft ischemic time and outcomes would be much different in multivariable compared with univariable analyses. In multivariable analysis, allograft ischemic time as a continuous variable in spline analyses was independently and nearly linearly associated with increased risk of death at 1 year, and the risk and the increase in risk were greater with older donor age (Figure 17). Conversely, older donor age was independently and linearly associated with greater risk of death at 1 year, and this risk was greater and increased more steeply with longer allograft ischemic time (eSlide H(a) 118). These data suggest an unfavorable interaction between 2 critical factors affecting the viability of the donor organ, the donor age, and allograft ischemic time, as has been reported in previous analyses from the United Network for Organ Sharing database.
The association between longer allograft ischemic time and mortality was present and statistically significant also up to 5 years (eSlide H(a) 124), 10 years (eSlide H(a) 142), 15 years (eSlide H(a) 151), and even 20 years after transplant (eSlide H(a) 159). However, the association became weaker with longer follow-up time and was absent when assessed conditional on survival to 1 year, suggesting that the adverse effect of longer allograft ischemic time occurs mainly during the early post-transplant period, also consistent with the Kaplan-Meier survival analyses that show early separation in Figure 15, Figure 16.
There was an association between longer allograft ischemic time and risk of treated rejection in the first year after transplant (Figure 18), but not with CAV (Figure 19) or severe renal dysfunction (eSlide H(a) 184) during the first 5 years of follow-up. Further supporting the conclusion that longer allograft ischemic time affects primarily early morbidity and mortality was the observation that post-transplant hospital length of stay was strongly associated with allograft ischemic time (Figure 20).
Thanks to the data reporting efforts of participating heart transplant centers and collectives worldwide, this Report brings to the public comprehensive and current information regarding developments and challenges in adult heart transplantation. In this 2017 Report we observed an encouraging sizable increase in the number of heart transplants reported to the Registry for the third consecutive year. Post-transplant survival is improving both in unadjusted analyses and after adjustment for baseline characteristics. MCS use in general, but not durable left VAD, remains associated with worse post-transplant outcomes and its use as bridge to transplantation has plateaued in the last 3 years at just over 50%.
This 2017 Focus Theme on allograft ischemic time explores the associations between recipient and donor characteristics and allograft ischemic time, and the potential role of allograft ischemic time in affecting outcomes. Allograft ischemic time is one of a number of factors to consider when evaluating donor organs and is affected by multiple geographic, logistical, and policy factors. The recent ISHLT heart transplant listing criteria guidelines
refrain from recommending any specific recipient prioritization or organ allocation algorithms, but allograft ischemic time certainly does affect organ allocation clinically. The role of allograft ischemic time may also change with potential future introduction of ex vivo allograft perfusion systems.
The data in this report provide a general overview; however, they do not analyze potential interactions between allograft ischemic time and donor and recipient characteristics or evaluate role of allograft ischemic time in any particular sub-groups. This report should be viewed as identifying opportunities for more detailed research aimed at improving donor heart selection and allocation.
D.C. received travel support from Astellas Pharma, Inc., and serves as a consultant and speaker for Roche Ltd. L.H.L. received research grant support to his institution from Novartis Inc. and Abbott Inc. J.W.R. and J.S. serve as consultants for Medtronic, Inc. None of the other authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.
Association of recipient age and causes of heart transplant mortality: Implications for personalization of post-transplant management–an analysis of the International Society for Heart and Lung Transplantation Registry.