The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Pediatric Heart Transplantation Report—2015; Focus Theme: Early Graft Failure

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Data collection and statistical methods

Data are submitted to the ISHLT Registry by national and multinational organ/data exchange organizations and individual centers. Since the Registry’s inception, 418 heart transplant centers, 242 lung transplant centers and 174 heart–lung transplant centers have reported data. The Registry website (www.ishlt.org/registries) provides spreadsheets that show data elements collected in the Registry. The online slide set (http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry) provides

General methods

This report has utilized standard statistical methodology for analyses and reporting. For assessing time-to-event rates (e.g., survival), we employed the Kaplan–Meier method. Survival graphs (i.e., time-to-event graphs) were truncated when the number of analyzable individuals was less <10. Follow-up of surviving recipients was censored at the time last reported to be alive (i.e., most recent annual follow-up) or at the time of retransplantation. Median time to event estimated the time-point at

Focus theme methods

For this report, the registry steering committee selected the focus theme of early graft failure (EGF). The granularity of data collected in the Registry influenced the definition of EGF. We defined EGF as a composite end-point of death or retransplant associated with graft failure within the first 30 days after transplant. Death or retransplant events associated with causes we believed were not due to intrinsic graft failure were excluded from the EGF definition. Because our EGF definition

Centers and activity

There were 577 heart transplants in children (<18 years age) performed in 2013 reported to the Registry, the largest number reported in the history of the Registry (Figure 1). These comprise 13% of all cardiac transplants reported to the Registry.3 The proportion of pediatric transplants by recipient age has remained relatively stable over the last 2 decades. Of the centers reporting pediatric heart transplants performed in 2013, 58 were in North America, 41 in Europe and 9 in other parts of

Indications for transplantation

Indications for heart transplantation have remained relatively stable during the most recent era (2009 to June 2014) (Figure 3). Congenital heart disease remains the most common indication for heart transplant in the infant age group (53%), but it decreased over time, whereas cardiomyopathy increased from 37% in the period 2004 to 2008 to 44% in the most recent era. For the older age groups, the indications for pediatric heart transplantation have remained remarkably stable over time;

Recipient characteristics

The proportion of transplant recipients by age remains stable with 24% infants (age <1 year), 23% between 1 and 5 years, 15% between 6 and 10 years and 38% between 11 and 17 years of age (Figure 1). Infants make up a greater proportion in North America (29%), compared with Europe (12%) and the rest of the world (2%) (eSlide 11).

The proportion of children bridged to transplantation with mechanical circulatory support (MCS) increased to 34% in 2013 (Figure 5). Ventricular assist device (VAD) use

Donor characteristics

A quarter of pediatric recipients received a heart from an adult donor (≥18 years) (eSlide 12). Donor age >50 years made up 3.5% of the donors in Europe and 5% of the donors in other parts of the world compared with almost none in North America (0.1%) (eSlide 14). The donor–recipient weight ratio has been unchanged for the last decade; 1.0 to 1.9 in 68% of transplants with extremes of >2.5 and <0.75 reported in 4% and 3%, respectively (eSlide 15).

Induction

During the last decade, the use of induction therapy increased from 59% in 2004 to 2008 to 68% in 2009 to June 2014, with anti-thymocyte globulin use increasing from 40% to 47% and interleukin-2 receptor antagonist use increasing from 19% to 24% (Figure 6). This occurred despite no difference in survival (conditional on survival to 14 days post-transplant) over the period encompassing both time frames between patients with no induction and those in whom some form of induction was given (eSlide

Survival

Long-term survival stratified by various factors can now be reported out to 28 years post-transplant.

Conditional survival

For recipients surviving the first year post-transplant, the conditional survival was significantly different between almost all age groups (Figure 11). The median 1-year conditional survival was 21.5 years for those transplanted between 1 and 5 years of age, 16.2 years for those transplanted between 6 and 10 years of age, and 15.4 years for adolescents. Although there is a higher early mortality within the first few months after transplant, most notably in the infant age group, there is also a

Pre-transplant diagnosis and gender

In last decade (2004 to June 2013), there was a significant survival advantage for cardiomyopathy patients compared with congenital patients across the age spectrum (Figure 12). There was no significant difference in survival by recipient gender or donor/recipient gender combination (eSlides 37 and 38).

Mechanical circulatory support

Recipients who had pre-transplant support with VAD or TAH had a 4-year survival similar to those who did not receive MCS (86% vs 85%, respectively) (Figure 13). Outcomes after ECMO use as a bridge to transplantation continue to be associated with a significant peri-operative and early post-transplant mortality, and a 4-year survival of 66%.

Immunosuppression

Use of induction, type of CNI and combination of immunosuppressive agents at hospital discharge is not associated with a significant effect on overall survival (eSlides 57 and 58). Prednisone use at discharge and 1 year, conditional on survival to 1 year post-transplant (2004 to 2013), is associated with decreased survival out to 9 years post-transplant (p < 0.03) (eSlide 56). In the cohort transplanted between 2004 and June 2008, and conditional on survival to 5 years, there remains a

Mortality

Table 2 summarizes the causes of death in pediatric heart transplant recipients over the last decade. The highest mortality risk is in the first year post-transplant (Figure 10). Leading causes of death have changed compared with last year’s report (deaths from 2000 onward); that is, graft failure and technical issues (32%), multisystem organ failure (17%) and acute rejection (12%) remain among the top 4 causes, but cerebrovascular (9%) is now just behind infection (10%). Cerebrovascular causes

Risk factors for 1-year mortality

Overall risk factors for 1-year mortality are summarized in Figure 15. Retransplantation remains the highest risk factor for 1-year mortality with an HR of 2.4. As reported previously, ECMO support, although decreased overall in numbers as noted earlier, remains significant, especially for age <1 year (HR 2.3) vs age ≥1 year (HR 1.7). Dialysis (HR 2.2) and transplant for congenital heart disease (HR 1.6) are the other most significant factors. Table 3 summarizes significant risk factors

Risk factors for 5-, 10- and 15-year mortality

Overall risk factors for 5-, 10- and 15-year mortality are summarized in Figure 20, Figure 21, Figure 22 with continuous risk factors in Table 4. Consistent with past analyses, mechanical circulatory support (in its different forms over the years) remains a significant risk factor for mortality out to 15 years post-transplant; as do a congenital diagnosis, dialysis and retransplantation (eSlides 138 to 153).

Functional status

Functional status (January 2009 to June 2014) is assessed using the Lansky score and predominantly reflects the transplants in the USA where submission is mandatory. A score of 100 represents full activity, 90 represents minor restrictions to strenuous activity, and 80 indicates that the patient tires more quickly yet capable of participating in physical activity. At 3 years post-transplant, 94% of surviving recipients have a score of ≥80 (eSlide 45).

For the cohort followed-up between 2009 and

Coronary allograft vasculopathy

Freedom from CAV in adult heart transplant recipients has shown statistically significant improvement for the last decade compared with previous decades.3 For pediatric heart recipients, this has also become apparent for the most recent decade (Figure 24). In addition to this higher freedom from CAV out to 9 years in all age groups, differences in freedom from CAV still persist between individual age groups (p < 0.001); 16% of infants had developed CAV by 9 years post-transplant, 26% of 1- to

Renal dysfunction

Freedom from severe renal dysfunction (creatinine >2.5 mg/dl or dialysis) for the last decade at 10 years post-transplant was 95% for infants, 97% for 1- to 5-year-olds, 87% for 6- 10-year-olds and 91% for 11- to 17-year-olds (eSlide 82). In the entire cohort (1994 to June 2014), need for renal replacement therapy ranged from 6% to 17% (depending on age group) by 16 years post-transplant (eSlide 84). Among recipients without severe renal dysfunction pre-transplant and surviving to

Malignancy

No changes were seen in this year’s limited analysis examining malignancy, including the lack of influence of induction therapy or choice of maintenance immunosuppression. Overall, 17% of patients developed a malignancy by 15 years post-transplant. The cumulative malignancy rate in 10-year survivors is 10% (eSlides 85 to 89).

Retransplantation

Retransplantation was covered in detail in the 2013 Registry report in addition to a detailed sub-analysis from the Registry.2, 4 Only 21 retransplants performed in 2013 were reported to the Registry, making up 3.6% of total pediatric heart transplants. Figure 3 shows the relative frequency of retransplant diagnosis by age group. Retransplantation diagnosis remains higher in North America (6%) compared with Europe (2%) and the rest of the world (3%) (Figure 4). Longer intertransplant interval

Focus theme: Early graft failure (eSlides 172 to 192)

One hundred and six (2.4%) primary pediatric patients transplanted from 2005 to 2013 met the early graft failure definition, 93 (88%) of whom died and 13 (12%) having undergone retransplantation. Cumulative incidence appears to have decreased in the most recent era (Figure 26), although the possibility remains that more patients are surviving >30 days and thus are not meeting our strict definition of early graft failure. There was no statistically significant difference in early graft failure

Conclusions

This analysis of the ISHLT Registry highlights the ongoing improvement in survival and other outcomes for pediatric heart transplant recipients in the most recent era (2009 to 2014), as compared with previous eras. Ventricular assist device implantation is associated with better survival than ECMO support. Early graft failure, although uncommon, is associated with modifiable risk factors, the knowledge of which may assist in clinical decision-making.

Disclosure statement

All relevant disclosures for the Registry Director, Executive Committee members and authors are on file with the ISHLT and can be made available for review by contacting the executive director of the ISHLT.

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