Twenty-Year Survivors of Heart Transplantation at Stanford University

Transcription

1 American Journal of Transplantation 2008; 8: Wiley Periodicals Inc. Special Article C 2008 The Authors Journal compilation C 2008 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Twenty-Year Survivors of Heart Transplantation at Stanford University T. Deuse a,, F. Haddad b, M. Pham b, S. Hunt b, H. Valantine b, M. J. Bates a, H. R. Mallidi a, P. E. Oyer a, R. C. Robbins a and B. A. Reitz a a Department of Cardiothoracic Surgery and b Department of Cardiothoracic Medicine, Stanford University School of Medicine, Stanford, CA Corresponding author: Tobias Deuse, deuse@stanford.edu Human heart transplantation started 40 years ago. Medical records of all cardiac transplants performed at Stanford were reviewed. A total of 1446 heart transplantations have been performed between January 1968 and December 2007 with an increase of 1-year survival from 43.1% to 90.2%. Sixty patients who were transplanted between 1968 and 1987 were identified who survived at least 20 years. Twenty-year survivors had a mean age at transplant of 29.4 ± 13.6 years. Rejection-free and infection-free 1-year survivals were 14.3% and 18.8%, respectively. At their last follow-up, 86.7% of long-term survivors were treated for hypertension, 28.3% showed chronic renal dysfunction, 6.7% required hemodialysis, 10% were status postkidney transplantation, 13.3% were treated for diabetes mellitus, 36.7% had a history of malignancy and 43.3% had evidence of allograft vasculopathy. The half-life conditional on survival to 20 years was 28.1 years. Eleven patients received a second heart transplant after 11.9 ± 8.0 years. The most common causes of death were allograft vasculopathy (56.3%) and nonlymphoid malignancy (25.0%). Twenty-year survival was achieved in 12.5% of patients transplanted before Although still associated with considerable morbidity, long-term survival is expected to occur at much higher rates in the future due to major advances in the field over the past decade. Key words: Heart transplantation, long-term graft survival, morbidity Received 21 March 2008 and accepted for publication 03 May 2008 Introduction Data from the International Society for Heart and Lung Transplantation (ISHLT) database show that the transplant half-life for adult and pediatric heart recipients is currently 10 years, with a conditional half-life of 13 years for those surviving the first year. Perioperative and 1-year survival has dramatically improved over the years due to major improvements in both diagnosis and treatment of graft dysfunction, rejection and infection. However, allograft vasculopathy, late graft failure and malignancies, amongst other causes, continue to decrease survival after the first year at an apparently linear rate of approximately 3.4% per year and preclude routine long-term success of heart transplantation (1). Stanford University is looking back on 4 decades of heart transplantation since the first human cardiac transplant operation at Stanford was performed on January 6, 1968 (2) and it is the only center with a continuously active heart transplant program ever since (3). We here report the characteristics of long-term survivors beyond 20 years after heart transplantation, of which many are among the longest living heart transplant recipients ever. Materials and Methods Patients The Stanford Transplant Database and medical records of all cardiac transplants performed at Stanford University Medical Center from 1968 to 1987 were reviewed. Pediatric and adult patients were included. Operative technique Donor hearts were arrested using simple topical hypothermia (4) or were preserved with cold hyperkalemic crystalloid Stanford cardioplegic solution and stored in cold saline solution during transportation. Implantation was performed according to the biatrial technique developed by Lower and Shumway (5). Immunosuppression From 1968 to December 1980, patients received azathioprine (1 3 mg/kg), prednisone (1 mg/kg) and polyclonal rabbit antithymocyte globulin (RATG) (Stanford). Thereafter, cyclosporine (CsA) was introduced and became the mainstay of immunosuppressive therapy. Polyclonal RATG or polyclonal horse antithymocyte globulin (ATGAM, Upjohn Co, Kalamazoo, MI) was used for induction therapy until June 1987 and was then replaced by the monoclonal antibody OKT3 (Ortho Pharmaceutical Corp, Raritan, NJ). With the evolution of newer immunosuppressive agents, patient regimens were modified during follow-up visits and switched to tacrolimus, mycophenolate mofetil (MMF) or sirolimus, as appropriate. Routine cytomegalovirus (CMV) prophylaxis with gancyclovir, diltiazem and lipid-lowering agents were not used in this early patient population. 1769

2 Deuse et al. CsA target levels were ng/ml within the first 12 weeks after transplantationand ng/ml thereafter. After 5 years, target CsA concentrations of approximately 100 ng/ml were used (6). Follow-up Patients have been closely followed by the Stanford posttransplant cardiologists together with the patients primary care physicians. Graft function and rejection was monitored by endomyocardial biopsy (EMB) since 1972 (7) and echocardiography since 1987 (8). Right and left heart catheterization, coronary angiography, and more recently, intravascular coronary ultrasonography (IVUS) was additionally used to assess hemodynamic parameters and allograft vasculopathy. No long-term surviving patient was lost to follow-up. The incidence of death, rejection requiring steroid pulse therapy, infection, allograft vasculopathy, lymphoid and nonlymphoid malignancy has been recorded in most (>90%) of the patients. Statistical analysis Results are shown as mean ± standard deviation. Survival analysis was performed using the Kaplan Meier method. Independent t-test and v 2 - test was utilized to compare numeric and categorical variables between two groups, respectively. Statistical significance was defined as a p value <0.05. Results Survival after heart transplantation Between January 1968 and December 2007, a total of 1446 heart transplantations have been performed at Stanford University. Cumulative survival after heart transplantation continuously improved with every successive 5-year period (Figure 1). Until December 1987, 524 heart transplantations have been performed in 479 patients of which 43 patients received a second and two patients a third graft. Sixty patients survived 20 years or more and are summarized in this article. Survival of these 60 patients who survived a minimum of 20 years is shown in Figure 1B. The conditional half-life in this patient population was 28.1 years. The 16 deaths in these long-term survivors were related to allograft vasculopathy (n = 9), nonlymphoid malignancy (n = 4), infection (n = 1), lymphoma (n = 1) and multiorgan failure with infection and dialysis after severe kidney allograft rejection (n = 1). Patient demographics of long-term survivors The diagnoses leading to heart transplantation in the 60 long-term survivors are shown in Figure 2A. Forty-eight patients were male and 12 female. The mean BMI was 22.2 ± The mean age at transplant was 29.4 ± 13.6 years and the age distribution is depicted in Figure 2B. Twelve patients (20%) had previous heart surgery and two patients (3.3%) had previous thoracotomy. The mean waiting time to transplant was 32 ± 36 days. Eleven patients received a second heart transplant 11.9 ± 8.0 years after their initial transplant. The 45 adult long-term survivors were significantly younger (35.0 ± 10.5 years) than the 391 patients receiving their heart transplant during the same time period and living less than 20 years, who were 43.1 ± 9.5 years of age (p < 0.001). Among adult long-term survivors, the underlying disease was significantly more often cardiomyopathy and significantly less frequent coronary artery disease compared to non-long-term survivors (p = 0.046). Donor characteristics and transplant operation The donors had a mean age of 21.7 ± 8.0 years, ranging from 0.4 to 44 years of age. The most common causes of death were motor vehicle or motorcycle accidents (55%), gun-shot wounds (17%), bike accidents (7%), head trauma (7%), anoxia (5%), cerebrovascular accident (3%) and others (6%). The gender match was male male (n = 41), female male (n = 7), male female (n = 6) and female female (n = 6). The mean cardiopulmonary bypass time was 113 ± 48 min, the mean ischemic time for Figure 1: (A) This part shows the cumulative survival of all heart transplant recipients at Stanford University over the 40-year period, broken down into 5-year intervals. The cumulative survival continuously improved with every successive 5-year period. (B) This part presents the survival after heart transplantation conditional on survival to 20 years. The conditional half-life in this population of 60 patients was 27.1 years. The improvements of the 1-, 5-, 10- and 20-year survivals over the 40-year period are depicted in (C) American Journal of Transplantation 2008; 8:

3 Twenty-Year Survivors of Heart Transplantation Figure 2: The diagnoses (A) and age groups (B) of the 60 long-term survivors after heart transplantation are presented. the graft was 138 ± 74 min, and the mean hospital stay was 35.7 ± 17.1 days. No significant difference was found for donor age comparing adult long-term survivors (22.8 ± 7.1 years) and non-long-term survivors (24.2 ± 7.5 years; p = 0.21). Also, the percentages of female donors for male recipients were not significantly different between adult long-term survivors (11.1%) and non-long-term survivors (14.8%; p = 0.66). HLA matching Only HLA-A and HLA-B loci were typed before 1990, and thus, a maximum of four matches were possible. In 14 cases, HLA matching had either not been performed or was not reported. Sixteen patients had no HLA match, 21 patients had one match and nine patients had two matches. There were no patients with three or four HLA matches. Rejection Rejection-free 1-year and overall survival are depicted in Figure 3. In total, the patients experienced a mean of 3.6 ± 2.7 rejection episodes requiring hospitalization and treatment. Infection The most common infections within the first 90 days after transplant were viral (46.7%), usually oral herpes simplex virus (HSV) infections (24.4%) and CMV infections (17.8%). Bacterial infections (44.4%) most frequently affected the urinary tract, the lung or the bowel. Fungal infections were rare (6.7%). Later infections could be attributed to a similar extent to viral (49.1%) and bacterial pathogens (39.6%). Infection-free 1-year and overall survival are shown in Figure 4. Morbidity at last follow-up Hypertension requiring medical treatment was present in 52 patients (86.7%). Chronic renal dysfunction with a baseline plasma creatinine level 1.5 mg/dl was found in 17 long-term survivors (28.3%), another four patients (6.7%) required hemodialysis and six patients (10%) were status post kidney transplantation. Only eight (13.3%) patients were treated for diabetes mellitus. Bradycardia and heart block was treated with pacer implantation in eight (13.3%) patients. Figure 3: Shown is the rejection-free overall survival and the rejection-free 1-year survival (inset) for the 60 long-term survivors who lived more than 20 years after heart transplantation. Most recent immunosuppressive regimen The immunosuppressive therapy after 20 years was unavailable in eight patients (13.3%). In four of 11 patients American Journal of Transplantation 2008; 8:

4 Deuse et al. Allograft vasculopathy Of the 43 patients with coronary angiography available for review, allograft vasculopathy was absent angiographically in 17 patients, was mild in four patients and advanced in 22. Nine of the 16 deaths in this patient population were caused by allograft vasculopathy. Seventeen (28.3%) of the long-term survivors did not undergo coronary angiography and/or intravascular ultrasound for vasculopathy workup for at least 10 years because of lack of clinical suspicion or marginal renal function. Discussion Figure 4: The infection-free overall survival and the infectionfree 1-year survival (inset) for the long-term survivors is presented. of the pre-csa era with reported follow-ups, a calcineurin inhibitor (CsA in three cases and tacrolimus in one) was added to the regimen over the years, whereas, seven patients remained on azathioprine and prednisone. Seven (17.1%) of 41 patients of the CsA era were switched to tacrolimus for CsA-side effects or rejection and 34 patients (82.9%) remained on CsA. No patient was switched from a CsA-based to a calcineurin inhibitor-free regimen. Azathioprine was still used in 13 patients. MMF and sirolimus were used as second immunosuppressive agents in 17 and 5 patients, respectively, mainly if allograft vasculopathy was present. Twenty-eight patients (68.3%) remained on low-dose steroids of less than 5 mg/day, most of these because of prolonged complaints of generalized, possibly Addisonian, weakness after complete withdrawal of corticosteroids that resolved when small doses were reintroduced. Malignancy Twenty-two patients (36.7%) developed some kind of malignancy over the years. The most common type was skin cancer (n = 15), which was diagnosed a mean of 7.8 ± 7.6 years after transplantation and was the cause of death in one patient after 20.5 years. The second most common malignancy was lymphoma (n = 3). All three patients were diagnosed early (2.0 ± 2.9 years after transplant) and one patient died of lymphoma after 21.5 years. One of the two patients diagnosed with posttransplant colorectal cancer died after 22.4 years. Prostate and parotid cancer were the cause of death after 20.2 and 22.4 years in one patient each. The era of human heart transplantation now spans a period of 4 decades, over which newly gained immunologic knowledge and the implementation of more selective immunosuppressive strategies have made clinical heart transplantation an established curative treatment for end stage heart disease, and the work is still in progress. Management of heart transplant patients before 1988 During the early phase of the program at Stanford, immunosuppressive regimens included azathioprine and steroids, drugs that were already in use for kidney transplantation at that time (9). However, reliable diagnostic tools for cellular rejection were unavailable, which made the dosing of immunosuppression a challenge. The inevitable overand underimmunosuppression led to relatively high incidences of death from infection and rejection (10). The first heart transplant recipient at Stanford lived for 15 days and died of bacterial pneumonia and sepsis (11). A total of 19 more heart transplant procedures were performed in 18 patients within the following 2 years. A total of 29 serious and 5 minor infectious episodes occurred in these patients, four eventuating in death (12). The first recipients that lived longer than 1, 3 or 5 years after transplant were patient no. 4, 7 and 14 and the 19th patient already lived more than 21 years and was the first long-term survivor. Major advances in the field of heart transplantation occurred in the 1970s. The implementation of EMB in July 1972 established an objective method for studying cardiac histopathology and diagnosing cellular rejection in living patients (7). The 45th transplant recipient was the first to undergo EMB and histology confirmed the clinical suspicion of severe acute rejection. EMB was applied routinely thereafter. A major step forward in providing an increased number of donors was the introduction of distant heart procurement, which was first performed in 1973 for the 62nd heart transplant recipient and became routine in mid (13). Equine antithymocyte globulin, available since 1970, was replaced by the more potent RATG in 1973, starting with the 65th Stanford transplant recipient (14). Introduction of RATG significantly reduced hospital stay, decreased the frequency of rejection and improved 1-year survival from 41% to 66% (14). The 75th patient was the first pediatric heart transplant at Stanford. He received his 1772 American Journal of Transplantation 2008; 8:

5 Twenty-Year Survivors of Heart Transplantation transplant in August 1974 and lived for more than 11 years (15). Brain death was legally defined in California in 1974 and minimized legal problems with organ procurement (13). A total of 219 heart transplants in 200 patients had been performed before the first patient received a CsAbased immunosuppression in December Fifteen patients (7.5%) transplanted in the pre-csa era became longterm survivors and lived for more than 20 years. The 1-year survival for patients transplanted within the first 2 years after introduction of CsA significantly improved from 62.5% to 81.6% compared to patients who received their transplanted up to 2 years earlier. The monoclonal anti-cd3 antibody OKT3 was initiated in mid-1987 in the 450th recipient and significantly reduced hospital stay and rejection rates in the following year (16). Predictors and patient characteristics of long-term survivors The overall adult patient population between 1968 and 1987 was significantly different from our current patients in terms of age. Whereas the 2007 ISHLT report presented a mean recipient age of 50.7 ± 12.5 years between 2004 and 2006 (1), the early patients at Stanford were younger (42.2 ± 9.9 years). The donors were also younger in the first 2 decades (24.1 ± 7.4 years) compared to today (33.5 ± 13.0 years) (1). However, the diagnoses leading to heart transplantation now and then were similar, with CAD and cardiomyopathy each accounting for 40 45% (1). Age and diagnosis have been identified by the ISHLT as risk factors for mortality within 15 years (1). Accordingly, the adult 20-year survivors at our institution were significantly younger and more frequently transplanted for cardiomyopathy than recipients that died within 20 years. However, donor age and the percentage of female donors for male recipients, although found to be further risk factors (1), were equally distributed among long-term and non-longterm survivors in this study. Importantly, the risk stratification reported by the ISHLT includes only patients who were transplanted after 1987 and may therefore not be accurate for previous eras. The 20-year survivors reported today have been transplanted before 1987 and 15 of these patients were even transplanted in the pre-csa era. These patients were not screened for antibody sensitization preoperatively and received immunosuppression with azathioprine and steroids only and these had to be dosed according to the clinical picture given the lack of immune assays or drug levels. They did not get CMV prophylaxis with ganciclovir (introduced in 1989 (17)), nor diltiazem (used since 1990 (18)) or lipidlowering agents to reduce allograft vasculopathy (started in 1993 (19)), nor fungal prophylaxis with inhaled amphotericin B during inpatient stays (introduced mid-1993 (20). Hence, the infection-free 1-year survival rates of all heart transplant patients at Stanford in the pre-csa and CsA eras, until 1987, were as low as 16% and 21%, respectively (21). The rejection-free 1-year survival rates during these periods were 11% and 10% (21). Among the patients who became long-term survivors, only 18.3% did not get an infection and only 13.3% did not have a rejection episode within the first year after transplantation. The long-term success in these patients would therefore not have been obvious in the early posttransplantat period. An increasing number of HLA mismatches between donor and recipient has been shown to impair recipient survival (22). However, although HLA typing was only incompletely reported in this series, our data show that the number of HLA matches in our long-term survivors were not higher than average (1). Morbidity Long-term survival is accompanied by long-term exposure to immunosuppressants and associated with considerable morbidity. Hypertension is among the most common side effects of calcineurin inhibitors (23). Hypertension is reported in 98.5% of CsA-treated patients in the ISHLT database (1) and 83.8% of heart transplant recipients at Stanford (24) after 10 years. The rate of hypertension in 20- year survivors in this report is 86.6%, and thus, similar to the 10-year data at our institution. This lack of increase may be because this report also includes patients who were on a calcineurin inhibitor-free regimen with azathioprin and steroids, which is associated with a lower rate of drugrelated hypertension (25). The rate for chronic renal dysfunction in our long-term survivors after 20 years (45.0%) is higher than that reported by the ISHLT for 10-year survivors (38.7%) (1). Although less stringent immunosuppression is used after 5 10 years, an ongoing nephrotoxic effect must be assumed. Interestingly, all patients in this study who were on hemodialysis or status post kidney transplantation at their last follow-up were in the de novo CsA treatment group and no patient was from the pre-csa era. Malignancies account for significant morbidity and mortality in long-term heart transplant survivors, and they seem to be more frequent than in other solid organ transplant recipients (26). Since the mean age at transplant is rising, more malignancies may be expected in older patients in the future. However, evidence for anticancer effects of mammalian Target of Rapamycin (mtor) inhibitors raise the possibility for new therapeutic strategies for the prevention and treatment of malignancies in clinical practice (27). Pediatric patients Fifteen (34.9%) of the 43 pediatric transplant recipients before 1988 became long-term survivors >20 years and 12 of these patients are still alive. These outcome data are encouraging and reflect the current ISHLT estimates for pediatric 20-year survival of 36.9% (28). Although allograft vasculopathy has been reported to be less prevalent in pediatric patients (29), we did not find a relevant difference between long-term survivors who were 18 years (five patients with severe and one with mild vasculopathy of American Journal of Transplantation 2008; 8:

6 Deuse et al. 15 pediatric transplants) compared to >18 years of age at transplant (17 patients with severe and 3 with mild vasculopathy of 45 adult transplants). Conclusion Entering the fifth decade of heart transplantation, our single-center outcome data show that survival rates have improved with every successive 5-year interval and that the slopes for 5-, 10- and 20-year survival over time continue to improve. Due to significantly improved immunosuppressive regimens and infectious prophylaxis and other treatment options in the past decade, the long-term survival rates are expected to rise in the future as the patients transplanted in the 2000s reach their 10- or 20-year anniversaries. Current research is dedicated to better understand the molecular and immunologic mechanisms of host-graftadaption which may offer better predictors of long-term survival and help to individualize treatment regimens. References 1. Taylor DO, Edwards LB, Boucek MM et al. 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Is there a role for proliferation signal/mtor inhibitors in the prevention and treatment of de novo malignancies after heart transplantation? Lessons learned from renal transplantation and oncology. J Heart Lung Transpl 2007; 26: Boucek MM, Aurora P, Edwards LB et al. Registry of the international society for heart and lung transplantation: Tenth official pediatric heart transplantation report J Heart Lung Transpl 2007; 26: Minami K, von Knyphausen E, Niino T et al. Long-term results of pediatric heart transplantation. Ann Thorac Cardiovasc Surg 2005; 11: American Journal of Transplantation 2008; 8: