The Registry of the International Society for Heart and Lung Transplantation: Twenty-seventh official adult heart transplant report—2010

Abstract

The 27th Official Report of the International Society for Heart and Lung Transplantation (ISHLT) Transplant Registry is based on information submitted by participating transplant centers worldwide. Since 1983, data on close to 89,000 heart transplants have been reported to the Registry. To provide contemporary information relevant to current heart transplantation practice, similar to prior reports,1Taylor D.O. Stehlik J. Edwards L.B. et al.Registry of the International Society for Heart and Lung Transplantation: twenty-sixth official adult heart transplant report—2009.J Heart Lung Transplant. 2009; 28: 1007-1022Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar, 2Taylor D.O. Edwards Aurora P. et al.Registry of the International Society for Heart and Lung Transplantation: twenty-fifth official adult heart transplant report—2008.J Heart Lung Transplant. 2008; 27: 943-956Abstract Full Text Full Text PDF PubMed Scopus (357) Google Scholar, 3Taylor D.O. Edwards L.B. Boucek M.M. et al.The Registry of the International Society for Heart and Lung Transplantation: twenty-fourth official adult heart transplant report—2007.J Heart Lung Transplant. 2007; 26: 769-781Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar, 4Taylor D.O. Edwards L.B. Boucek M.M. et al.The Registry of the International Society for Heart and Lung Transplantation: twenty-third official adult heart transplant report—2006.J Heart Lung Transplant. 2006; 25: 869-879Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar, 5Taylor D.O. Edwards L.B. Boucek M.M. et al.The Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report—2005.J Heart Lung Transplant. 2005; 24: 945-955Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar many of the analyses will focus on recent transplant recipients. Important statistics for the entire cohort of patients are also provided. The first part of the report reviews important donor, recipient, and medical center demographics and is followed by overview of immunosuppressive therapies used after transplantation. The second part of the report examines survival, mortality risk factors, and causes of death after adult heart transplantation.Statistical methodsRecipient and donor demographics, immunosuppressive treatments, morbidity, hospitalization, causes of death and functional status are summarized using percentages or median with 5th and 95th percentile, as appropriate.Survival rates were calculated using the Kaplan-Meier method6Kaplan E.L. Meier P. Nonparametric estimation from incomplete observations.J Am Stat Assoc. 1957; 53: 457-481Crossref Scopus (47677) Google Scholar and compared using the log rank test. Multivariable analyses were performed using Cox proportional hazard regression analysis.7Cox D.R. Oakes D. Analysis of survival data. Chapman and Hall/CRC, Boca Raton1984Google Scholar Results of the multivariable analyses are reported as relative risk (RR) with corresponding 95% confidence intervals or p-value, or both. A RR significantly >1.0 indicates that the factor examined is associated with an increased likelihood of occurrence of the event of interest (eg, death, rejection, etc). Conversely, a RR <1.0 indicates that the event is less likely to occur when that factor is present.Heart transplant demographicsTransplant volumesAlthough the number of heart transplants reported to the Registry peaked in the mid-1990s, at more than 4,000 patents per year, this number has remained relatively stable in the current decade, with more than 3,000 patients being reported to the Registry every year (Figure 1). We have previously estimated that 2,000 heart transplants performed yearly worldwide are not reported to the Registry.5Taylor D.O. Edwards L.B. Boucek M.M. et al.The Registry of the International Society for Heart and Lung Transplantation: twenty-second official adult heart transplant report—2005.J Heart Lung Transplant. 2005; 24: 945-955Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar Therefore, the number of heart transplants being performed worldwide likely exceeds 5,000 per year. The ISHLT continues its effort to encourage and facilitate the participation of additional centers in the Registry.There are significant differences in transplant volume among the centers participating in the Registry. Data averaged over the past 5 years show that smaller centers (1–9 transplants per year) represent 40% of transplant programs and are responsible for 12% of transplants performed. More than 33% of the centers perform between 10 and 19 transplants per year, which corresponds to 36% of the transplants reported to the Registry. Another 33% of the patients undergo transplant in centers that average 20 to 39 transplants per year (17% of the centers). The 5% of the centers that perform 40 or more transplants per year are responsible for the remaining 20% of patients who receive an allograft.Recipient demographicsIn the last 5 years (January 2005–June 2009), the leading etiology of heart disease for which adult patients received heart transplantation has been non-ischemic cardiomyopathy (53% of the recipients), followed by ischemic cardiomyopathy (38% of the recipients). Retransplantation (3%), adult congenital heart disease (3%), valvular heart disease (3%), and a small number of patients with other diagnoses accounted for the remaining transplants. The gradual change that has favored nonischemic cardiomyopathy as the primary indication in heart transplantation has again been seen in the most recent data (Figure 2).Figure 2Etiology of heart disease resulting in adult heart transplantation stratified by geographic location. CAD, ischemic cardiomyopathy; myopathy, non-ischemic cardiomyopathy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)In addition, there appears to be substantial geographic variation in the proportions of patients with these two leading diagnoses who receive allografts. In European centers, non-ischemic cardiomyopathy has been the leading diagnosis since 1989 and has further increased since 1997, so that 63% of transplant recipients in 2008 had a diagnosis of non-ischemic cardiomyopathy. In North America, non-ischemic cardiomyopathy became the leading diagnosis in 2004 and has since increased to 52% in 2008. Why these changes have occurred is not readily apparent, but it is likely that improving medical and surgical therapies for chronic heart failure, and advances in mechanical circulatory support in particular, may have influenced the selection of patients for transplantation.A number of additional recipient demographics are listed in Table 1; for comparison, characteristics of transplant recipients from a decade earlier are also shown. A higher number of older patients received allografts in the most recent era—10.5% of recipients between 2002 and June 2009 were aged 65 years or older and 1% of recipients were 70 years or older (also see the complete Registry slide set). More than 75% of recipients were male. The proportion of recipients with comorbidities at the time of transplant also continues to increase—22% have diabetes mellitus, 41% have hypertension, 47% have a history of cigarette use, and 42% have had previous cardiac surgery.Table 1Recipient Characteristics at the Time of Transplant for Transplants Performed in Two Eras: 1992–2001 and 2002–6/20091992–20012002–6/2009Variables(N = 36,836)(N = 21,862)p-valuePre-transplant diagnosis, %<0.0001 Ischemic cardiomyopathy45.939.9… Non-ischemic cardiomyopathy46.451.4… Valvular cardiomyopathy3.42.8… Retransplant1.92.4… Congenital heart disease1.82.5… Other causes0.51.0…Age, years54.0 ± 11.0 (28.0–65.0)54.0 ± 12.4 (25.0–67.0)0.0906 18–34, %9.212.3… 35–49, %25.624.3… 50–59, %40.935.1… 60–64, %17.717.7… ≥65, %6.610.5…Male gender, %80.177.1<0.0001Weight, kg75.0 ± 17.1 (51.0–102.0)78.0 ± 17.2 (53.0–108.4)<0.0001Height, cm173.0 ± 11.3 (157.0–188.0)174.0 ± 10.6 (157.5–188.0)<0.0001Body mass index, kg/m225.0 ± 4.3 (18.9–32.8)25.7 ± 4.7 (19.2–34.3)<0.0001History of cigarette use…aData available for July 2004–June 2009 transplants.47.2aData available for July 2004–June 2009 transplants.…Comorbidities, % Diabetes mellitus14.2bData available for April 1994–2001 transplants.22.4<0.0001 Hypertension34.5bData available for April 1994–2001 transplants.40.5<0.0001 Peripheral vascular disease4.0bData available for April 1994–2001 transplants.2.9<0.0001 COPD3.3bData available for April 1994–2001 transplants.3.50.3202 Prior malignancy3.5bData available for April 1994–2001 transplants.5.1<0.0001 Prior cardiac surgery…aData available for July 2004–June 2009 transplants.41.6aData available for July 2004–June 2009 transplants.… Serum creatinine, mg/dl1.2 ± 15.0 (0.7–2.7)1.2 ± 0.9 (0.7–2.3)0.0001 PVR (Wood units)2.2 ± 2.3 (0.4–6.1)bData available for April 1994–2001 transplants.2.1 ± 2.0 (0.3–5.6)<0.0001Panel reactive antibody >10%cUntil mid-2004 panel reactive antibody was collected in the U.S. as a single percentage. After this date, panel reactive antibody was collected separately for class I and class II antibodies.Overall (U.S. 1992–6/2004, non-U.S. 1992–6/2009), %7.89.00.0063Class I (U.S. 6/2004–6/2009), %…12.9…Class II (U.S. 6/2004–6/2009), %…8.8…Hospitalized at time of transplant, %58.646.3<0.0001Mechanical ventilation, %3.13.00.4058Pre-op inotropic, circulatory support, % Intravenous inotropes55.3bData available for April 1994–2001 transplants.44.5<0.0001 Left ventricular assist device13.4dData available for November 1999–2001 transplants.20.1<0.0001 Intraaortic balloon pump6.86.70.7447 Right ventricular assist device0.5dData available for November 1999–2001 transplants.3.1<0.0001 Total artificial heart0.7dData available for November 1999–2001 transplants.0.50.0498 Extracorporeal membrane oxygenation0.3eData available for April 1995–2001 transplants.0.7<0.0001Donor/recipient HLA mismatches, %0.0008 0–24.84.2 3–441.640.4… 5–653.755.4…Allograft ischemic time, hours2.6 ± 1.5 (0.0–4.6)3.0 ± 1.5 (0.0–5.0)<0.0001COPD, chronic obstructive pulmonary disease; HLA, human leukocyte antigen; PVR, peripheral vascular resistance.Continuous data are expressed as median ± standard deviation (5th–95th percentiles).a Data available for July 2004–June 2009 transplants.b Data available for April 1994–2001 transplants.c Until mid-2004 panel reactive antibody was collected in the U.S. as a single percentage. After this date, panel reactive antibody was collected separately for class I and class II antibodies.d Data available for November 1999–2001 transplants.e Data available for April 1995–2001 transplants. Open table in a new tab The proportion of patients who are sensitized has increased—9% of patients now have a serum panel reactive antibody (PRA) level in excess of 10%. Compared with a decade ago, the number of patients with mechanical circulatory support devices has increased dramatically—20% of recipients have a left ventricular assist device (LVAD) and 3% a right ventricular assist device (RVAD) at the time of transplant. Within the last 10 years, the proportion of patients bridged to transplantation with mechanical circulatory support devices has remained essentially unchanged (Figure 3). Median allograft ischemic time has increased and is 3.0 hours in the most recent era. Altogether, the recipient demographics illustrate that the average recent heart transplant recipient is more likely to have higher number of characteristics associated with risk of morbidity and mortality after transplant than an average recipient 10 years ago.Figure 3Adult patients bridged to heart transplantation with mechanical circulatory support, including left ventricular assist device (LVAD), right ventricular assist device (RVAD), or biventricular support (LVAD plus RVAD, total artificial heart).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Donor demographicsThe average donor age increased significantly in the 1990s, from 27 years in 1990 to 31 years in 1999, mostly through increased use of donors aged 35 to 59 years old (Figure 4). In the past 10 years, donor age distribution has remained fairly stable. Use of allografts from donors aged 60 years or older remains unusual; nevertheless, 40 to 50 such heart transplants (approximately 1.5% of all transplants) are reported yearly to the Registry. Interestingly, there are substantial geographic variations in average donor age (Figure 5): Donors in Europe are more than 6 years older on average than donors in North America. It is possible that very short allograft ischemic times in Europe (<2 hours in 63% of transplants; Figure 6) facilitate the use of allografts from older donors. Additional donor characteristics are presented in Table 2.Figure 4Changes in the age distribution of heart donors over time. Colored areas represent proportion of donors in the appropriate age group; corresponding y-axis is on the left. The red line represents mean donor age; corresponding y-axis is on the right.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 5Age distribution of donor hearts in different geographic locations for adult heart transplants performed between January 2000 and June 2009.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 6Allograft ischemic time distribution in different geographic locations for adult heart transplants performed between January 2000 and June 2009.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 2Donor Characteristics at the Time of Transplant Presented in Two Eras: 1992–2001 and 2002–6/20091992–20012002–6/2009Donor characteristic(N = 36,836)(N = 21,862)p-valueCause of death, %<0.0001 Head trauma45.251.2… Stroke28.329.0… Other26.519.7…Age, years31.0 ± 12.9 (15.0–54.0)33.0 ± 13.0 (16.0–55.0)<0.0001Male gender, %67.969.40.0001Weight, kg75.0 ± 17.5 (52.0–103.4)aData available for April 1994–2001 transplants.78.0 ± 17.0 (55.5–110.0)<0.0001Height, cm175.0 ± 18.9 (155.0–188.0)aData available for April 1994–2001 transplants.175.0 ± 10.2 (159.0–190.0)<0.0001Body mass index, kg/m224.2 ± 4.5 (18.8–33.0)aData available for April 1994–2001 transplants.25.1 ± 4.9 (19.7–35.2)<0.0001History of cigarette use, %37.5aData available for April 1994–2001 transplants.24.4<0.0001History of hypertension, %10.8aData available for April 1994–2001 transplants.12.00.0006Continuous data are expressed as median ± standard deviation (5th–95th percentiles).a Data available for April 1994–2001 transplants. Open table in a new tab Combined organ transplantationThe number of heart-kidney transplants has increased steadily between 2000 (n = 34) and 2008 (n = 73), with similar gains seen in the number of heart-liver transplants (n = 2 in 2000, n = 13 in 2008). Although combined solid organ transplantation is a frequently discussed topic, the number of patients receiving heart-kidney or heart-liver transplants remains low.Post-operative immunosuppressionImmunosuppressive induction therapy continues to be used frequently (Figure 7). In the first 6 months of 2009, 54% of patients received immunosuppressive induction compared with 53% in 2002 and 38% in 1997. Most of the patients receive interleukin-2 receptor (IL2R) antagonists (27% of patients) or polyclonal antilymphocytic antibodies (23%), and we newly see the use of the induction agent alemtuzumab (Campath). The use of monoclonal anti-CD3 antibody OKT3 for immunosuppressive induction is now infrequent, with only 1% of patients in 2009 reported to have received OKT3.Figure 7Immunosuppressive induction therapy for adult heart transplants performed between January 2002 and June 2009. ALG, anti-lymphocyte globulin; ATG, anti-thymocyte globulin; IL-2R, interleukin-2 receptor.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Tacrolimus, mycophenolate mofetil or mycophenolic acid, and prednisone continue to be the dominant immunosuppressive choices after heart transplantation (Figure 8). Among recipients who had their 1-year post-transplant follow-up between January 2007 and June 2009, 69% were taking tacrolimus, 29% cyclosporine, 84% mycophenolate mofetil or mycophenolic acid, and 4% azathioprine. The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus are used in 11% of patients 1 year after transplant, and in 23% of patients seen for a 5-year follow-up in the same time-period (January 2007–June 2009). At 1 and 5 years after transplant, 89% and 52% of patients, respectively, continue to receive corticosteroids. More detailed information, including review of the frequencies of the various combinations of maintenance immunosuppressive agents use, can be found in the online Registry slide set (available at www.ishlt.org/registries/).Figure 8Maintenance immunosuppressive agents at the 1- and 5-year post-transplant follow-up. This includes adult heart recipients with follow-up between January 2007 and June 2009. MMF, mycophenolate mofetil; MPA, mycophenolic acid.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Post-transplant outcomesSurvivalThe median survival after transplant, or the time at which 50% of those who received an allograft remain alive, is currently 10 years for the entire cohort of adult and pediatric heart recipients who received allografts since the initiation of the Registry in 1982, with a median survival of 13 years for those surviving to 1 year (Figure 9). Median survival has steadily improved—from 8.3 years during the 1980s to 10.4 years during the 1990s—and survival has further improved since 2000 (Figure 10). The mortality risk is highest in the first 6 months after transplant, and the improvement in survival associated with a more recent era of transplant is mainly a result of lower mortality during this early post-transplant period (Figure 10). Past 1 year after transplant, the mortality rate is fairly constant, at approximately 3% to 4% per year, which is higher than the mortality rate of a general population. In the last 20 years, long-term survival of those patients who are alive at 1 year has not significantly improved (Figure 11), and it is likely that the potential for further survival improvement now lies in approaches that could reduce this long-term mortality rate.Figure 9Survival for adult and pediatric heart transplants performed between January 1982 and June 2008. Conditional median survival is the time to 50% survival for those recipients surviving the first post-transplantation year.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 10Survival for adult heart transplants performed between January 1982 and June 2008, stratified by era of transplant. NA, not available.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 11Survival for adult heart transplants performed between January 1982 and June 2008 and surviving to 1 year after transplant, stratified by era of transplant. NA, not available.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Additional survival analyses are available in the complete online Registry data set (www.ishlt.org/registries/). Of note, these data show that survival has improved in patients with all pre-transplant cardiac diagnoses, with the greatest improvement in patients undergoing retransplantation. Survival after retransplantation used to be dramatically worse than that of other heart transplant recipients, but this is no longer true in the most recent era.Previous ISHLT reports demonstrated that patients undergoing retransplantation for acute graft failure early after the original heart transplant had a 40% to 60% risk of 1-year mortality. It appears that this information contributed to a change in selection of candidates for retransplantation as evidenced in the most recent era: only 16% of retransplant patients underwent the original transplant within the preceding year, and the survival at 1 year after retransplant in this group was 63%. On the other hand, 69% of retransplants now occur in patients more than 5 years after the original transplant, and survival is 84% at 1 year after retransplant, similar to other patient groups (Figure 12).Figure 12Survival at 1 year after adult heart retransplant, stratified by era and time elapsed between original transplant and retransplant. The absolute number of retransplants performed is shown in vertical bars.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Risk factors for 1-year mortalityWe performed a multivariable analysis using a proportional hazards model to analyze risk factors for 1-year post-transplant mortality in a contemporary group of recipients who received transplants between January 2003 and June 2008 (Table 3). Categoric risk factors are ordered by strength of their association with mortality (RR), and we also list the number of patients with the particular characteristic to provide further insight into the clinical relevance of the individual factors. Continuous risk factors are listed in the second part of Table 3, and the RRs associated with the different values of the continuous variables are expressed in a number of graphs available in the Registry slide set (www.ishlt.org/registries/).Table 3Risk Factors for Mortality Within 1 Year of Transplant for Patients Who Received Transplants From January 2003 Through June 2008 (N = 10,547)VariableNo.RR95% CIp-valueCategoric variables Temporary circulatory supportaTemporary circulatory support includes extracorporeal membrane oxygenation and Abiomed BVS. Note that there were too few temporary continuous-flow devices to analyze.1652.732.02–3.68<0.0001 Diagnosis: congenital vs non-ischemic cardiomyopathy2632.271.71–3.02<0.0001 Recipient history of dialysis2941.651.30–2.09<0.0001 Recipient on ventilator at time of transplant2671.611.24–2.090.0004 Long-term continuous-flow device4401.331.02–1.730.0364 Prior transfusion2,0561.241.07–1.440.0048 Recipient infection requiring IV drug therapy ≤2 wks pre-Tx1,0651.241.05–1.470.0113 Chronic pulsatile flow device1,6211.221.03–1.450.0211 Not ABO identical1,6041.191.03–1.370.0197 Diagnosis: ischemic vs non-ischemic cardiomyopathy4,5271.161.02–1.330.0213Categoric variables with borderline statistical significance Total artificial heart381.940.93–3.930.0650 Panel reactive antibody ≥ 10%1,0291.170.99–1.400.0731Continuous variables Recipient age………<0.0001 Recipient height………<0.0001 Donor age………<0.0001 Donor/recipient weight ratio………0.0430 Transplant center volume………0.0170 Allograft ischemic time………0.0035 Serum bilirubin………0.0064 Serum creatinine………<0.0001 Pulmonary artery diastolic pressure………0.0007 Pulmonary vascular resistance………0.0067CI, confidence interval; IV, intravenous; RR, relative risk; Tx, transplant.a Temporary circulatory support includes extracorporeal membrane oxygenation and Abiomed BVS. Note that there were too few temporary continuous-flow devices to analyze. Open table in a new tab Patients bridged to heart transplantation with mechanical circulatory support devices appear to have a higher risk of death after transplant. Compared with patients without mechanical circulatory support bridge, the RR of mortality is 2.73 for temporary circulatory support (extracorporal membrane oxygenation Abiomed), 1.94 for total artificial heart (borderline significant p = 0.07), 1.33 for continuous-flow, and 1.24 for pulsatile-flow VADs. Congenital etiology of pre-transplant heart disease results in increased risk (RR, 2.27), and patients with ischemic cardiomyopathy fare somewhat worse than those with non-ischemic cardiomyopathy (RR, 1.16). Comorbidities that are significant risk factors include the need for hemodialysis, mechanical ventilation, prior need for blood transfusion, and recent infection. As expected, a number of continuous factors identified in prior reports also affect survival; the most important are recipient and donor age, allograft ischemic time, and serum markers of hepatic and renal dysfunction. The risk relationship is linear for most of these factors, but a relationship between recipient age and post-transplant survival is not. Recipients at both ends of the age spectrum have elevated risk of death (Figure 13 and Registry slide set available at www.ishlt.org/registries/).Figure 13Recipient age and relative risk of mortality at 1 year after transplant, for transplants performed January 2003—June 2008. The dashed lines show the 95% confidence intervals.View Large Image Figure ViewerDownload Hi-res image Download (PPT)As already noted, the need for mechanical circulatory bridge to transplant was associated with risk of post-transplant mortality in our multivariable model. A limitation of this analysis is that the multivariable adjustment uses variables recorded not at the time of assist device implant but at the time of transplant. Recipient characteristics may be altered by the device implant, and some of the characteristics used in the multivariable adjustment may be correlated with mechanical assist use, bringing the accuracy of such risk assessment under some scrutiny.The risk associated with VAD use appears to be less pronounced in univariate analyses (Figure 14), and our data show improvement in post-transplant survival in patients bridged with VADs in the most recent era. In addition, the excess risk appears to be limited to the early post-transplant period, with no significant differences in survival past 6 months after transplant (Figure 15). It is important to remember that our analyses examine post-transplant survival, and that the effect of VAD use during the pre-transplant period cannot be assessed with our data set.Figure 14Survival after adult heart transplants performed between January 2002 and June 2008 in patients bridged with left ventricular assist devices (LVAD).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 15Survival in patients bridged with ventricular assist devices (LVAD), for adult heart transplants performed between January 1999 and June 2008, conditional on survival to 6 months.View Large Image Figure ViewerDownload Hi-res image Download (PPT)It is also important to mention that clinical practice has a major effect on the impact of risk factors on post-transplant survival. Transplant candidates are very carefully screened, and clinicians make targeted decisions in defining the risk as prohibitive for successful transplant or as acceptable, at which time additional steps are taken to mitigate risk, such as adjustment of donor selection or modification of post-transplant therapies. We believe it is for that reason that changes have been seen over the years in relative risk associated with certain risk factors or in the statistical significance of these associations. For example, the fact that recipient gender, recipient history of malignancy, or donor-recipient CMV mismatch are no longer risk factors for mortality, or that elevated PRA does not currently result in significantly increased mortality at 1 year after transplant, are likely a result of changing practice and expanding therapeutic options.Risk factors for 5-year mortalityMortality at 5 years is affected to a great degree by factors similar to those affecting 1-year mortality (detailed data included in the online Registry slide set). Additional risk factors identified in a multivariable analysis include recipient history of pregnancy (RR, 1.28; p = 0.02