Nineteen centers contributed data to the Spanish Heart Transplantation Registry, 18 of which are currently still active (Table 1). Two centers are dedicated solely to pediatric transplantation and 3 others perform both adult and pediatric transplantation. The number of procedures performed annually is summarized in Figure 1. The whole series consists of 7289 procedures. Data were lost in 12 cases, including information on follow-up. Those cases were not included in the analysis, and the final sample size was 7277 cases. Of the 266 procedures carried out in 2014, 12 (4.5%) were performed in pediatric patients (age<16 years). The types of procedures carried out in 2014 and in the whole series are summarized in Table 2.

Figure 1.

Annual number of transplantations (1984-2014), total and by age group.

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The database comprises 175 clinical variables, pre-established by consensus from all groups, collecting data on the recipient, donor, surgical technique, immunosuppression, and follow-up. As of 2013, data are introduced and updated electronically and in real time using an application available on the internet and specifically designed for this purpose. The database support is a Microsoft Excel file. This method replaces the previous one, in which each center sent data to the registry director in Microsoft Access format via e-mail. An external CRO (contract research organization)—currently ODDS, S.L.—is responsible for database maintenance, quality control, and statistical analysis.

Ethics committee approval, auditing, and registration with the Ministry of Health were carried out in line with the Spanish Organic Law on Data Protection 15/1999.

Continuous quantitative variables are reported as mean±standard deviation, and categorical quantitative variables are reported as percentages. Results are organized according to year of transplantation, dividing the total sample into 3 groups (1984-1993, 1994-2003, and 2004-2014). In some variables (such as donor age, emergency transplant, and ischemia time), the data were also analyzed annually for the whole series. Differences between groups were analyzed using a nonparametric test for temporal trends (Kendall's tau) for categorical variables, and analysis of variance with polynomial fit for quantitative variables. Survival curves were calculated using the Kaplan-Meier method, and survival curves were compared with the log rank test. A P value <.05 was considered statistically significant.

In 2014, mean recipient age was 50±16 years (0.02-73 years); 75% were men. The most common underlying diagnoses were ischemic cardiomyopathy (25.9%, dilated nonischemic cardiomyopathy (27.8%), cardiomyopathy of valvular origin (4.5%), and other causes (41.7%). Recipient patient characteristics by transplantation period are summarized in Table 3. There were significant trends toward older recipients, female sex, and unusual causes of underlying heart disease. There was an increase in pre-transplant existing conditions known to affect prognosis, such as insulin-dependent diabetes, infection, and cardiac surgery or mechanical ventilation prior to transplantation. Retransplantation frequency remained stable at around 2.4% in the period 1984-2014. In contrast, pulmonary vascular resistance values prior to transplantation were significantly reduced throughout the time series.

Although fewer emergency transplantations were carried out in 2014 than in 2013, a strongly increasing trend was observed in emergency transplantation over the whole time series (P<.00001) (Figure 2). At the same time, the use of mechanical circulatory assist devices increased (P<.00001) compared with traditional balloon counterpulsation, with mechanical circulatory assist devices coming into use significantly in the last decade (Figure 3). Use of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices–both pulsatile and continuous flow–is particularly evident from 2009 onward (Figure 4). Between 2009 and 2014, the use of ECMO doubled, and that of continuous flow support increased exponentially (from 2.0% in 2009 to 15.7% in 2014).

Figure 2.

Annual percentage of emergency transplantations of the total population (1984-2014).

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Figure 3.

Distribution of type of pretransplant circulatory support, by time period. ECMO, extracorporeal membrane oxygenation; VAD, ventricular assist device.

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Figure 4.

Distribution of type of pretransplant circulatory support in the period 2009-2014. ECMO, extracorporeal membrane oxygenation; VAD, ventricular assist device.

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Donor characteristics by time interval and for 2014 are summarized in Table 4. Donor age increased significantly over the whole series, with>50% of donors considered suboptimal (age>45 years) in 2014 (Figure 5). The number of female donors progressively increased, as did the percentage of transplants to a male recipient from a female donor (22.9% in 2014). Increases were also found in cardiac arrest prior to donation (17.4% in 2014), and in ventricular dysfunction on echocardiography prior to extraction (3.3% in 2014). Also, the number of donors who died due to stroke increased, with a decrease in those dying from trauma (Figure 6).

Figure 5.

Annual changes in donor age and percentage of donors older than 45 years (1984-2014). 95%CI, 95% confidence interval.

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Figure 6.

Changes by time period of causes of death of heart donors.

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Ischemia time increased over the whole series. In 2014, as in the previous decade, more than one quarter of patients received a transplant with an ischemia time of>240min (Table 4, Figure 7).

Figure 7.

Annual changes in ischemia time and percentage with ischemia time>240min (1984-2014). 95%CI, 95% confidence interval.

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In 2014, 87.9% of recipients received some type of induction immunosuppressive therapy, mostly basiliximab (84.5%). Figure 8 shows the progressive increase of basiliximab in induction immunosuppression to its current predominant use. In the period 2009-2014, 80% of patients were induced with interleukin-2 inhibitors (basiliximab or daclizumab, primarily basiliximab), replacing the widespread use of OKT3 in earlier periods.

Figure 8.

Drugs used in induction immunosuppression. ALG, antilymphocyte globulin; ATG, antithymocite globulin.

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Initial immunosuppression in 2014 was predominantly with tacrolimus (86.7%) as a calcineurin inhibitor, mycophenolate mofetil or mycophenolic acid (96.1%) as an antiproliferative, and steroids (96.9%). Figure 9 shows the immunosuppressors used initially and at the end of follow-up for the whole series. Over an average follow-up of 7 years, 61.6% of patients remained on corticoids. As can be seen, toward the end of follow-up, tacrolimus was used almost as much as cyclosporin, despite the predominant use of cyclosporin in initial immunosuppression regimens. Azathioprine use remains almost anecdotal, and notably, 27.9% of patients were on treatment with mTOR inhibitors (everolimus or sirolimus) at the most recent follow-up.

Figure 9.

Initial and maintenance immunosuppression for the whole series (1984-2014). Progressive changes by type of drug: at time of transplantation and at end of follow-up. MMF, mycophenolate mofetil; MPS, mycophenolate sodium.

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Annual changes in the use of the different calcineurin inhibitors and antimitotics are shown in Figures 10 and 11, respectively. Tacrolimus use equaled cyclosporin use in 2005, and tacrolimus use has continued to increase since then, becoming the most-used calcineurin inhibitor in initial immunosuppression. A similar trend was seen between mycophenolate mofetil and azathioprine, which were used equally between 1999 and 2001, then from 2009 mycophenolate became the predominant antimitotic in initial immunosuppression, with azathioprine being used minimally. The annual changes in the use of mTOR inhibitors (sirolimus, everolimus) in initial immunosuppression are shown in Figure 12. These drugs were used initially at an appreciable percentage between 2005 and 2007; then their use fell to minimal.

Figure 10.

Annual changes in use of calcineurin inhibitors (cyclosporin and tacrolimus) in initial immunosuppression in the total sample (1984-2014).

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Figure 11.

Annual changes in use of antimitotics (azathioprine and mycophenolate mofetil/mycophenolic acid) in initial immunosuppression in the total sample (1984-2014). MMA, mycophenolic acid; MMF, mycophenolate mofetil.

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Figure 12.

Annual changes in use of mTOR inhibitors (sirolimus and everolimus) in initial immunosuppression in the total sample (1984-2014). The differences in values compared with reports from previous years are due to rounding or to differences owing to the continued updating of the database by participating groups.

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The actuarial survival for the whole series at 1, 5, 10, 15, and 20 years at 31 December 2014 is summarized in Figure 13. This represents an average mortality of approximately 2% to 3% per year after the first post-transplant year, with a median survival of 10.9 years. There were significant differences depending on recipient age at the time of transplantation and the type of procedure. Survival was significantly better in patients younger than 16 years than in those aged 16 to 60 years. Likewise, survival was significantly better in patients aged 16 to 60 years than in those older than 60 years (Figure 14). There were also highly significant differences between heart transplantation alone; combined cardiac and renal, hepatic, or pulmonary transplantation; and retransplantation (Figure 15). Survival was also significantly affected by donor age older than 45 years (Figure 16).

Figure 13.

Overall survival curve for the whole series.

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Figure 14.

Survival curve comparison by recipient age at time of transplant (<16 years, 16-60 years, and >60 years).

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Figure 15.

Survival curve comparison for heart transplant alone; combined heart and kidney, liver, or lung transplant; and heart retransplantation.

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Figure 16.

Survival curve comparison for heart transplant by donor age.

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In the whole series, highly significant differences (P<.00001) were found in survival between elective transplantation and emergency transplantation (Figure 17). Analysis of the period 2009-2014, in which use of mechanical assist devices increased appreciably, showed that the worst survival was in emergency transplantations done with ECMO assistance; there were no significant differences between emergency and elective transplantations that used counterpulsation balloon or ventricular assist devices (Figure 18). The differences between the types of transplant according to the condition of the patient at the time of intervention are established over the first 6 months post-transplant, with a subsequent parallel curve pattern.

Figure 17.

Survival curve comparison between elective and emergency transplantations.

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Figure 18.

Survival curve comparison between elective transplantations, emergency transplantations without ventricular assistance, and emergency transplantations with ventricular assistance (2009-2014). ECMO, extracorporeal membrane oxygenation; VAD, ventricular assist device.

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After the first decade (1984-1993), there was a significant improvement in mid-term and long-term survival, influenced mainly by a lower mortality in the early post-transplant stages (Figure 19). Over the last decade (2004-2013), there was a non-significant trend (P=.064) toward improved survival from the third or fourth post-transplant year compared with the decade immediately prior (1994-2003) (Figure 19).

Figure 19.

Survival curve comparison of the total sample by period of transplantation (10-year intervals since 1984).

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In the total population, the most common cause of death was vascular disease of the graft/sudden death (19.7%), followed by infection (16.5%), primary graft failure (14.3%), and neoplasia (12.5%) (Figure 20). Cause of death changed depending on time post-transplant (Figure 20). In the first post-transplant month, almost 50% of deaths were due to primary graft failure. From 1 month to 1 year post-transplant, the most common causes of death were acute rejection (15.6%) and, above all, infection (35.4%). After the first year, the most common causes were the different manifestations of vascular disease of the graft (29.5%), and tumors (21.3%). Over time, the main causes of death in the first year have changed significantly, with more deaths due to primary graft failure and fewer deaths due to acute rejection (Figure 21). However, between the first and fifth years post-transplant, only deaths due to vascular disease of the graft/sudden death have decreased significantly, while deaths due to acute rejection have increased (Figure 22).

Figure 20.

Causes of death, by time since transplantation and in the whole series (1984-2014). SD, sudden death; VDG, vascular disease of the graft.

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Figure 21.

Causes of death in first year after transplantation in the whole series (1984-2014).

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Figure 22.

Cause of deaths occurring in the first year and fifth year after transplantation in the whole series (1984-2014). SD, sudden death; VDG, vascular disease of the graft.

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