Of the 19 centers that have contributed data to the RETC, 18 remain active at the present time (Table 1). The number of procedures performed each year is shown in Figure 1. The entire series encompasses 7023 procedures. Data, including follow-up information, are missing from the records of 12 cases, which have not been included in the analyses; thus, the final sample consisted of 7011 cases. Of the 248 procedures carried out, 29 (11.7%) were performed in pediatric patients (age<16 years). The types of procedures documented in 2013 and in the time series as a whole are summarized in Table 2.

Figure 1.

Total number of heart transplantations per year (1984-2013) and by age group.

(0.26MB).

The database consists of 175 clinical variables, established by consensus among all the transplantation teams, which include data on the recipient, donor, surgical technique, immunosuppression, and follow-up. Since 2013, the data are introduced and updated electronically, in real time, by means of an application specifically designed for this purpose and available on the internet. The database support is a Microsoft Excel file. This procedure replaced the preceding approach, in which each center conveyed the data to the director of the registry by e-mail in Microsoft Access format. Database management, quality control, and statistical analysis are outsourced to a CRO (contract research organization), at the present time, ODDS, S.L.

Ethics committee approval, auditing, and registration with the Spanish Ministry of Health, Social Services and Equality meet the requirements of the Spanish Data Protection Law 15/1999.

The continuous variables are expressed as mean (standard deviation) and the categorical variables as percentages. The results were classified by transplantation year, an approach for which the overall sample was divided into six 5-year groups (1984-1988, 1989-1993, 1994-1998, 1999-2003, 2004-200, and 2009-2013). The between-group differences were analyzed using a nonparametric test for the time trend (Kendall's tau). Survival curves were calculated using the Kaplan-Meier test and were compared using the log rank test. A P value < .05 was considered to indicate a significant difference.

In 2013, the recipients had a mean age of 47 (19) years (range, 0-70 years); 71% were men, and the most common underlying diagnoses were ischemic heart disease (33.6%), idiopathic dilated cardiomyopathy (37.2%), and valvular heart disease (8.1%), whereas the etiology of the remaining 21.1% varied. The characteristics of the patients corresponding to each transplantation period are summarized in Table 3. It is notable that 30% of the recipients in the most recent period were over 60 years of age and that more than 25% were women. There is also evidence of an increase in risk conditions such as renal dysfunction, diabetes mellitus, infection during the 15 days prior to transplantation, and the need for mechanical ventilation. In contrast, there was a significant trend toward a decrease in retransplantation in the most recent period, in which the rate was scarcely 2% of all the transplantation procedures, with an annual average of 2.4% for the entire time series.

The percentage of emergency procedures has increased progressively and very significantly (P<.0001) over time (Figure 2), reaching 39% in the most recent period (Table 3). It is striking that, in 2013, nearly half of the procedures were performed in the emergency setting (Figure 2).

Figure 2.

Yearly percentage of emergency transplantations among the overall recipient population (1984-2013).

(0.16MB).

In 2013, an extracorporeal membrane oxygenator was used in 11.7% of the cases, continuous-flow ventricular assist devices in 6.0%, and pulsatile ventricular assist devices in 5.2%, Thus, in that year, the use of these devices (22.9%) nearly doubled that of balloon counterpulsation as the only method of assistance (13.3%) prior to transplantation. From 2004 on, there was a constant increase in the use of mechanical circulatory support other than the standard intra-aortic balloon counterpulsation. The distribution of the ventricular assist devices used in each period is shown in Figure 3.

Figure 3.

Distribution of pretransplantation ventricular assist devices according to period. ECMO, extracorporeal membrane oxygenator; VAD, ventricular assist device.

(0.15MB).

In 2013, the mean age of the donors was 40.2 (16.1) years (44% were > 45 years of age) and 53.8% were men. In 25% of the cases, the donor body weight was 20% greater than that of the recipient, whereas the opposite was observed in 10.1%. In 27.8% of the cases, a male recipient received a graft from a female donor.

The donor characteristics corresponding to each 5-year period are shown in Table 4. The summary of the causes of donor death by period is provided in Figure 4. Over the course of the periods described, there was an increase in the report of stroke as the major cause of death, as opposed to traumatic brain injury.

Figure 4.

Changes in the causes of death of the heart donors by period.

(0.15MB).

The ischemia time has become increasingly prolonged throughout the time series: in the most recent period (2009-2013), it was nearly 1.5h longer than in the initial period (1984-1988). From 2009 to 2013, the ischemia time in nearly 30% of the procedures was > 4h (Table 4). In 2013, the mean ischemia time was 209.1 (59.6) min, and the ischemia time was > 4h in 27.9% of the cases.

In 2013, 87.1% of the recipients received some type of induction immunosuppressive therapy, basiliximab in the great majority of cases (85.1%). Figure 5 shows that the administration of induction therapy has increased progressively to the extent that it is now used in the great majority of patients. In the period from 2009 to 2013, induction was achieved in 80% of the recipients with interleukin 2 receptor antagonists (basiliximab or daclizumab, mainly the former), which replaced OKT3 as the most widely used agent in earlier periods.

Figure 5.

Drugs used in induction immunosuppression. ALG-ATG, antilymphocyte and antithymocyte globulins.

(0.17MB).

Initial immunosuppression in 2013 mostly consisted of tacrolimus (81.8%) as a calcineurin inhibitor, mycophenolate mofetil (97.1%) as an antiproliferative agent, and steroids (97.9%). Figure 6 summarizes the drugs used in initial immunosuppression and at the end of follow-up in the entire time series. After an average follow-up of 6.8 years, 58.1% of the patients continued to be treated with corticosteroids. As can be observed, at the end of follow-up, the use of tacrolimus tended to equal that of cyclosporine in immunosuppression, despite the predominance of the latter in the immunosuppressive regimens at the initiation of treatment. Azathioprine was administered very little and, surprisingly, 27.7% of the patients were being treated with mTOR inhibitors (everolimus or sirolimus) at the last follow-up.

Figure 6.

Initial and maintenance immunosuppression in the entire time series (1984-2013). Variations according to type of drug: at start of transplantation and at the end of follow-up. MMF, mycophenolate mofetil; MPS, mycophenolate sodium.

(0.11MB).

The changes from one year to another in the use of the different calcineurin inhibitors and antimycotic agents are shown in Figures 7 and 8, respectively. The use of tacrolimus equalled that of cyclosporine in 2005 and, since then, continued to exhibit an upward trend to ultimately become the predominant calcineurin inhibitor in initial immunosuppression. A similar trend was observed between mycophenolate mofetil and azathioprine, the use of which be came equalled between 1999 and 2001; mycophenolate mofetil became the predominant antimycotic agent in initial immunosuppression, relegating azathioprine to minimal use from 2009 on. The changes over time in the use of mTOR inhibitors (sirolimus, everolimus) in initial immunosuppression are illustrated in Figure 9. These drugs were initially used in a considerable number of cases in 2005-2007, but their use subsequently fell to minimum levels.

Figure 7.

Variations in the use of calcineurin inhibitors (cyclosporine and tacrolimus) in initial immunosuppression in the overall sample (1984-2013).

(0.19MB).

Figure 8.

Variations in the use of antimitotic agents (azathioprine and mycophenolate mofetil) in initial immunosuppression in the overall sample (1984-2013). MMF, mycophenolate mofetil.

(0.21MB).

Figure 9.

Variations in the use of mTOR inhibitors (sirolimus and everolimus) in initial immunosuppression in the overall sample (1984-2013).

(0.16MB).

Figure 10 shows the changes over the years in the operative mortality (within 30 days of transplantation). In 2013, it was 11.3%, slightly lower than that of the historical cohort, in which the annual average was 15%.

Figure 10.

Variations in the percentage of operative mortality (first 30 days after transplantation). Early mortality does not include early graft loss.

(0.15MB).

In the most recent update, dated 31 December 2013, the actuarial survivals at 1, 5, 10, 15, and 20 years in the entire time series are shown in Figure 11. This represents a mean annual mortality of approximately 2% to 3%, with a median survival of 10.8 years. There were significant differences depending on the age of the recipient at the time of transplantation and the type of procedure. The rate of survival of the patients < 16 years was significantly higher than that of patients aged 16 to 60 years, as was that of the latter group with respect to patients > 60 years of age (Figure 12). There were also highly significant differences between patients receiving a cardiac graft alone, those undergoing heart transplantation combined with kidney, liver, or lung transplantation, and cases of retransplantation (Figure 13).

Figure 11.

Survival curve for the entire time series.

(0.1MB).

Figure 12.

Comparison between survival curves according to age at the time of transplantation (< 16 years, 16-60 years, > 60 years).

(0.09MB).

Figure 13.

Comparison between survival curves for cardiac graft alone, heart transplantation combined with kidney, liver, or lung transplantation, and heart retransplantation.

(0.1MB).

The examination of the entire time series revealed highly significant differences between elective and emergency transplantation (Figure 14). Analysis of the period from 2004 to 2013, during which the use of mechanical assist devices increased considerably, survival in elective transplantation was not significantly different from that of emergency transplantation performed with the support of inotropic drugs alone or, in most cases, with intraaortic balloon counterpulsation (P=.46), but was significantly higher than the survival in emergency transplantation with mechanical assistance (P<.0001) (Figure 15). The survival rate was also significantly higher in emergency transplantation with balloon counterpulsation (P=.036) than in emergency transplantation performed after the use of ventricular assist devices (Figure 15).

Figure 14.

Comparison between survival curves for elective and emergency transplantations.

(0.09MB).

Figure 15.

Comparison between survival curves for elective transplantations, emergency transplantations without ventricular assist devices, and emergency transplantations with ventricular assist devices.

(0.14MB).

Beyond the first decade (1984-1993), there was a significant improvement in medium- and long-term survival, due mainly to the lower mortality rate during the early stages following transplantation (Figure 16). Over the past decade (2004-2013), with respect to the immediately preceding decade (1994-2003), we observe a nonsignificant trend toward an improvement in survival starting the fifth year after transplantation (Figure 16).

Figure 16.

Comparison of survival curves for the overall sample according to the period of transplantation (10-year intervals since 1984).

(0.1MB).

The causes of death changed according to the post-transplantation period under consideration (Figure 17). In the first month after transplantation, nearly 50% of the deaths were due to primary graft failure. After the first month, and up to the end of the first year, acute rejection and, above all, infections were the main causes of death. After the first year, the major causes were tumors and the different manifestations of graft vascular disease (chronic rejection, sudden cardiac death). Figure 18 shows the major causes of death in the entire time series. Overall, they were infection (13.9%), conditions mainly attributable to graft vascular disease (chronic rejection, sudden cardiac death) (12.4%), multiple organ failure (12%), and tumors (9.4%). Only 3.9% of all the deaths were due to acute rejection.

Figure 17.

Causes of death according to time since transplantation. AGF, acute graft failure.

(0.12MB).

Figure 18.

Causes of death of the overall recipient population (1984-2013). AGF, acute graft failure.

(0.08MB).