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Ann Thorac Surg 2001;72:440-449
© 2001 The Society of Thoracic Surgeons
a Department of Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA
b Department of Cardiology, Columbia University College of Physicians and Surgeons, New York, New York, USA
Address reprint requests to Dr John, Division of Cardiothoracic Surgery, Milstein Hospital Building 7-435, 177 Fort Washington Ave, New York, NY 10032
Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, San Marco Island, FL, Nov 9–11, 2000.
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Abstract |
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Methods. A retrospective review of 1,086 consecutive cardiac allograft recipients who underwent transplantation between 1977 to 1999 was performed. Patients were divided into four eras based on type of immunosuppressive therapy: era 1 = steroids, azathioprine (n = 26, February 1977 to March 1983), era II = steroids, cyclosporine (n = 43, April 1983 to April 1985), era III = cyclosporine, steroids, azathioprine (n = 752, April 1985 to December 1995), era IV = cyclosporine, steroids, mycophenolate mofetil (n = 315, January 1996 to October 1999).
Results. The actuarial survival of the entire cohort of 1,086 patients undergoing cardiac transplantation was 79%, 66%, and 49% at 1, 5, and 10 years, respectively. There were significant trends in recipient age and gender distribution among the four eras with increasing proportion of older age (> 60 years) and female recipients in eras III and IV (p = 0.001 and 0.02). Early mortality and long-term survival improved significantly over all eras (p < 0.001). Rejection as a cause of death decreased over time (era I, 24%; era II, 21%; era III, 15%; era IV, 9%; p = 0.02), whereas the contribution of transplant coronary artery disease as a cause of death remained unchanged.
Conclusions. Cardiac transplantation provides satisfactory long-term survival for patients with end-stage heart failure. The improving outcomes in survival correlate with improved immunosuppressive therapy in each era. Although the reasons for improvement in survival over time are multifactorial, we believe that changes in immunosuppressive therapy have had a major impact on survival as evidenced by the decreasing number of deaths due to rejection.
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Introduction |
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Numerous reports on survival have demonstrated excellent short- to medium-term outcomes after cardiac transplantation. However, only a few reports of long-term follow-up (> 10 years) have been reported [5, 6]. The objective of this study was to determine trends in cardiac transplantation over time and to correlate both long-term outcomes and causes of death with different eras of immunosuppressive therapy after cardiac transplantation at a single center during a two-decade period.
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Material and methods |
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Donor acceptance criteria
Donors and recipients were matched for ABO blood type compatibility and size (generally within 20% of body weight). Prospective HLA matching was not used; however, recipients with high levels of panel reactive anti-HLA antibodies (> 20%) underwent a prospective crossmatch. Donor men less than 40 years of age and women less than 45 years of age met criteria as suitable donors provided there is no evidence of preexisting heart disease or impaired myocardial function by echocardiography. Older individuals also met criteria as suitable donors provided coronary atherosclerotic lesions could be excluded, optimally by cardiac catheterization. Individuals with serologies positive for HIV, hepatitis B (hepatitis B sAg) and C, and nonprimary brain cancers were not used as donors.
Operative techniques
Donor hearts were harvested from beating heart brain-dead individuals. Graft procurement and preservation with cold cardioplegic arrest using Euro-Collin’s solution (Baxter Healthcare Corporation, Deerfield, IL) and later the University of Wisconsin solution (Viaspan; DuPont Pharmaceuticals, Wilmington, DE) and topical hypothermia. From 1977 to 1996, orthotopic cardiac transplantation was performed using the biatrial technique described by Lower and Shumway [7]. Since 1996 we have performed almost all transplants using the bicaval anastomosis technique.
Immunosuppressive regimen
Four eras were identified during which patients received specific immunosuppressive therapy. Era I was between Febuary 1977 and March 1983, when patients received steroids and azathioprine (n = 26). Era II was between April 1, 1983 and April 3, 1985, when patients received cyclosporine and steroid therapy (n = 43). Era III was between April 3, 1985 and December 1995, when all patients received cyclosporine, steroids and azathioprine (n = 752). Era IV was from January 1996 to October 1999, when mycophenolate mofetil (MMF) has replaced azathioprine as part of cyclosporine-based triple therapy (n = 315).
Immunosuppressive therapy dosing
Dosing for immunosuppressive therapy consists of (1) cyclosporine: a preoperative dose (3 to 6 mg/kg) followed by intravenous cyclosporine (1 to 2 mg/kg every 24 hours) until oral intake is tolerated. Daily oral doses (3 to 6 mg/kg) are adjusted so that serum levels are maintained at 300 to 350 mg/dL. After 6 to 12 months, cyclosporine dosing is reduced to maintain serum levels between 100 and 150 ng/mL. (2) Azathioprine is administered in a preoperative oral dose (4 mg/kg) followed by daily doses of 2 mg/kg with dosing adjusted according to the patient’s white blood cell count, platelet count, and hepatic function. Since 1996, MMF starting at a dose of 1,000 mg twice daily has replaced azathioprine. (3) Intravenous methylprednisolone (500 mg) is administered during the operation and followed in the postoperative period by 125 mg every 8 hours for three doses. Prednisone is then instituted at a daily oral dose of 1 mg/kg and gradually tapered during 4 months to 0.1 mg/kg per day. Intravenous murine monoclonal antibody OKT3 (5 mg/d) has been used instead of cyclosporine for the first 4 days after transplantation for patients who have severe renal dysfunction.
Management of rejection
Rejection was diagnosed by routine endomyocardial biopsy; weekly for the first 4 weeks, then every 2 weeks for the next 1 month, monthly for 4 months, every 2 months for the next 6 months, followed by every 3 months for the 6 months, and then every 6 to 12 months (current schedule). Routine treatment of grade 3A or greater rejection consisted of an increase in oral prednisone to 100 mg/d for 3 days followed by a taper for 1 week to the baseline dose. If rejection persisted, as seen on endomyocardial biopsy, after a course of oral prednisone therapy, or if rejection was accompanied by altered hemodynamics, intravenous methylprednisolone (1 g daily for 3 days) was used to reverse rejection. Intravenous OKT3 (5 mg/d) and antithymocyte globulin were used in hemodynamically unstable patients and in patients with rejection episodes refractory to intravenous steroid boost.
Angiography/diagnosis of transplant coronary disease
All patients undergo annual coronary angiography. The diagnosis of transplant-related coronary artery disease is based on the following: (1) discrete lesions resulting in more than 50% obstruction of the proximal or midportions of major graft vessels or (2) diffuse, concentric narrowing of the whole vessels, including their branches. If transplant-related coronary artery disease is identified, the frequency of angiography was increased to a biannual regimen. Patients are not given routine vasodilators before coronary injections. All angiograms are reviewed by a cardiologist and compared with the previous year’s films to detect the presence of luminal irregularities, discrete stenoses, loss of third order branches, or pruning of vessels. Explanted hearts and autopsy specimens were examined for evidence of vessel occlusion and irregularities, ischemic damage, and presence of acute cardiac rejection.
Statistical analysis
Data were examined univariately by the Student’s t test for continuous variables and Fisher’s exact test for discrete data. Actuarial survival of patients was estimated by Kaplan Meier analysis, with p values calculated by log-rank statistics [8]. For the multivariable survival analysis posttransplantation, variables with a univariate p value less than 0.25 were entered into a Cox proportional hazards model [9]. This model is a multiple regression analysis to examine the time to a dichotomous outcome and their potential associated risk factors by modeling a linearized function of a set of covariates. The interpretation of a risk factor allowed into the final model with a p value less than 0.05 is that it is an independent risk factor associated with the event, over and above other potential risk factors included in the equation. The risk ratio is the ratio of the estimated hazard for those with the characteristic variable in question to the estimated hazard for those without, controlling for other variables (or covariates). For all statistical analysis, data were analyzed using SAS System software (SAS Institute, Inc, Cary, NC).
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Results |
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The distribution of demographic variables among different eras of immunosuppressive therapy is shown in Table 1. Statistically significant trends in the distribution of age, gender, and pretransplant diagnosis among the different eras were noted. There is an increased proportion of older recipients (> 60 years) in the latter eras. Although no older recipients were seen in eras I and II, the proportion of older recipients in eras III and IV were 14% and 26%, respectively (p = 0.001). Furthermore, an increased proportion of female recipients was seen in eras III and IV (p = 0.02).
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Multivariable analysis
Multivariable analysis by Cox proportional hazards model revealed recipient age, female gender, a pretransplant diagnosis of congenital heart disease, and transplantation during eras I and II as statistically significant risk factors adversely affecting survival after cardiac transplantation (Table 3).
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Comment |
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Our study shows a significant improvement in survival with each subsequent era of immunosuppressive therapy. However, the improvements in survival are also seen when evaluated at 5-year intervals. It is clear that the reasons for the improvement in survival are multifactorial. Nevertheless, we believe that advancements in immunosuppressive therapy and immunologic monitoring have been one of the cornerstones for the superior survival outcomes achieved during the past two decades. This is supported by the marked decrease in the proportion of deaths from rejection, the result of improving immunosuppressive therapy. Cyclosporine-based triple therapy has not only been shown to favorably influence cardiac transplant recipients, but other solid transplanted organs as well [10]. The introduction of cyclosporine-based immunosuppressive regimens has allowed for a reduction and even complete tapering of steroids, thereby, reducing the adverse steroid-related complications. Both azathioprine and MMF act by inhibition of purine synthesis; however, MMF has a more specific action by its ability to block an enzyme in the de novo synthesis pathway that only lymphocytes depend on. This functional selectivity allows lymphocyte proliferation to be specifically targeted with less anticipated effect on erythropoiesis and neutrophil production than is seen with azathioprine. Thus, an agent such as MMF with a narrow range of target cells in the immune system would be predicted to provide more optimal balance in immunosuppressive therapy by inhibiting those cells involved in allograft rejection, yet allowing uninhibited cells to provide important defenses against infection. An earlier randomized double-blind, active-controlled trial in cardiac transplant patients showed that the use of MMF as part of triple immunosuppressicve therapy was associated with significant reduction in acute rejection and mortality after transplantation when compared to the use of azathioprine [11]. Previous studies have also shown that MMF can reverse recurrent and refractory rejection [12, 13]. Furthermore, animal studies have demonstrated that MMF can decrease intimal proliferation in transplant models of allograft arteriopathy [14]. However, it is important to note that we did not see a statistically significant difference in survival between eras III and IV by multivariable analysis.
The causes of death in cardiac transplant recipients differ based on the interval after transplant as well as the era of transplant. McGiffin and colleagues [15] reported that during the first posttransplantation year, patients were significantly more likely to die of rejection in an earlier era of transplant (1981 to 1986). Similar to our findings, the reduction in the contribution of rejection as a cause of death in the later era is reflective of the impact of triple immunosuppressive therapy, better immunologic and graft surveillance, as well as with the strategies available to treat acute rejection. That study also reported an increased, although not significant incidence of death due to early graft failure in the early eras [15].
In contrast to short-term heart transplant survivors where rejection and infection play a dominant role in mortality and morbidity, the predominant cause of death in long-term survivors is TCAD. Gallo and associates [16] reported graft vasculopathy as the single most common cause of death in long-term survivors. However, McGiffin and colleagues [15] reported a similar distribution of TCAD, malignancy, and infection as a late cause of death. Furthermore, there was no difference in the incidence of TCAD between an early and a more recent era of transplant experience. In this study, we were unable to define a trend in the number of deaths due to TCAD, especially because patients in the current era have a relatively shorter time of follow-up and many of the deaths attributed to other diseases may have been related to TCAD. There was an increasing trend in the proportion of deaths from cardiovascular causes, which includes deaths secondary to myocardial infarctions and arrhythmias. It is possible that a number of deaths from the cardiovascular category may represent undetected TCAD. It has been shown that hearts with cardiac allograft vasculopathy often display features such as hypertrophy with disarray of myocytes and substitution scarring that can account for sudden cardiac death in this subset of patients. Munoz and colleagues [17] has reported that sudden death in the late period is mostly a sequel of unrecognized myocardial infarction. It is important to note that a substantial proportion of patients with TCAD can have a cardiac-related event but may not manifest angiographic evidence of coronary artery disease [18]. Thus, death secondary to allograft failure of unknown etiology and sudden cardiac death may be a result of unrecognized TCAD. The increasing use of intravascular ultrasound in the current era may allow earlier and more accurate detection of TCAD. However, it is important to note that the introduction of cyclosporine has not reduced the incidence and prevalence of TCAD as seen in the observational studies of Gao [19] and Olivari [20] and their coworkers, although a beneficial effect of a higher dose of cyclosporine on the incidence of TCAD has been suggested [21].
The increased early mortality in those undergoing transplantation for congenital heart disease has been observed by other centers. Pediatric patients have been recognized as a group that has a poorer outcome in some multicenter studies, especially in infants and younger pediatric patients with congenital heart disease [22]. Gajarski and colleagues [23] reported excellent long-term survival in a nonneonatal pediatric population; however, a majority of these patients had idiopathic cardiomyopathy as opposed to surgically inoperable congenital heart disease. We have previously reported that a pretransplant diagnosis of congenital heart disease remains a risk factor for mortality after cardiac transplantation [3]. Possible explanations of this finding are that children with inoperable or previously attempted correction of congenital heart defects have an increased postoperative mortality as a result of irreversible changes in their pulmonary vasculature or an increased risk of bleeding secondary to multiple previous operations.
The trend toward improved survival exhibited by male recipients adds credibility to the previously reported role of donor–recipient gender matching in determining outcomes after cardiac transplantation [24, 25]. However, the influence of gender is certainly complex and results have not always been consistent in the transplant literature. Until this issue is more clearly defined, we do not believe that gender should be a criterion in the current allocation of donor hearts, especially in view of the present shortage of organs. However, there may be a role for closer immunologic monitoring and stronger immunosuppressive therapy in situations of donor–recipient gender mismatch.
In summary, this study shows that cardiac transplantation provides excellent long-term survival for patients with end-stage heart disease. During the past 23 years there have been numerous improvements in patient selection, surgical techniques, treatments for right ventricular dysfunction and pulmonary hypertension, as well as immunosuppressive therapy. And although these changes have all contributed to the improved survival with each subsequent era of transplantation, one of the major influences on survival appears to be the improvements in immune suppression. This is evidenced by the decrease in death secondary to rejection and the unchanged incidence of other causes of death during the different eras. We have earlier shown that in a more recent cohort of cardiac transplant recipients, previously identified risk factors such as pretransplant pulmonary hypertension, use of left ventricular assist devices, sensitization, and a prior cardiac allograft are no longer significant risk factors in the modern era [3].
Limitations
The limitations of this study include those related to a retrospectively performed study. There is also a possibility of underreporting of TCAD. Moreover, identification of risk factors for mortality was not the primary objective of this study. To perform a thorough analysis of the risk factors influencing survival after cardiac transplantation during a 20-year period is clearly beyond the scope of this study owing to many reasons including unavailability of complete data on certain variables as well as changing facets in the management of transplant patients both in the pre- and posttransplant period that cannot be objectively measured. Many risk factors affecting survival after cardiac transplantation has been identified in both single and multicenter studies including a recent study from our center [3, 26–28]. We did perform a multivariable analysis on a limited number of risk factors to mainly evaluate the influence of era of transplantation as a risk factor for survival after cardiac transplantation. Furthermore, several advances in the field of cardiac transplantation has significantly changed the overall management of these patients, which differ from that in use one to two decades ago.
In conclusion, this study clearly demonstrates that cardiac transplantation continues to evolve and mature, with simultaneous advances in several medical and surgical aspects, resulting in improved early and long-term survival. Cyclosporine-based triple therapy and the advent of MMF have contributed to the improved survival of cardiac transplant recipients. Despite an inability to show a direct causal relationship between immunosuppressive regimens and improved outcomes after transplantation, we do provide strong indirect evidence as shown by a marked reduction in deaths secondary to acute rejection, which clearly is related to immunosuppressive therapy. With newly emerging options for the treatment of end-stage heart failure, cardiac transplantation is a modality that has stood the test of time and currently remains the gold standard of treatment for these patients.
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Discussion |
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(Applause and Laughter)
I was hoping you would have some information about rejection data as well, since you are tying the immunosuppression information with survival data. In fact, do you have anything about the rejection rates of these patients using your three eras that were involved in this study?
DR RAJASINGHE: Right, yes. Unfortunately the data from the early portions of the experience are less well documented than the more recent portions of the experience, about if we were to look at it, even cursorily, acute rejection as a cause of death is certainly a lot less in the more recent era, 7% versus about 20% in the early part of the experience. And then other sources of death, infection, transplant coronary artery disease and graft failure, although there has been a substantial decline from the earlier eras, meaning era 1 to the more recent era, era 4, it is less clear in the intermediate eras, eras 2 and 3.
DR HUDDLESTON: What I meant was actual rejection rate in terms of episodes, not necessarily deaths being caused by an episode of acute rejection, episodes per patient year or something like that.
DR RAJASINGHE: No, I don’t have that data with me.
DR MITCHELL J. MAGEE (Dallas, TX): I too was interested in the incidence of acute and chronic rejection, and acute rejection episodes, early versus late. I also was interested to know if you had changed your patterns of steroid use over that period of time. Many programs have placed a higher emphasis on steroid tapering, and also I didn’t see any evidence of your instituting the use of FK506, particularly for recalcitrant rejection, and the impact of the use of FK on steroid taper. Also I was curious to know if you correlate any donor information with your long-term results, for instance, donor gender, donor age, and donor ischemic times. Many programs now are tending to have longer ischemic times and older donors.
DR RAJASINGHE: I will answer the latter questions first. The donor information is actually well recorded for the latter portion of the experience, and we have actually looked at our more recent cohort of patients who underwent cardiac transplantation and formed a multivariable analysis of those patients. We actually saw that donor age and donor ischemic time actually had an impact both on early and late mortality in the more contemporary experience. So we know that they actually play a role. In the earlier portion of the experience we can’t make that same conclusion.
With regard to the use of immunosuppression, we have actually radically tapered our steroids, especially since we introduced cyclosporine, but we have not necessarily observed a tremendous drop in our infection rates with that.
DR D. GLENN PENNINGTON (Johnson City, TN): This is really an outstanding series. You indicated that your use of assist devices was increasing, and in fact Columbia was somewhat of a late-comer to the use of devices, so you had a long period of time without them and now you have used them. But, as you know, UNOS and ISHLT still list VAD as a risk factor leading to decreased survival. Could you tell us, is the use of a device positive or negative in your experience?
DR RAJASINGHE: We actually just published this data, looking again at our more contemporary experience since 1993 of risk factors that influence survival after heart transplantation, and specifically the use of mechanical circulatory assistance does not actually adversely affect heart transplant survival as an independent risk factor. What does, though, is donor age, gender and the year of transplant. So, again, the people who are getting transplanted more recently are actually doing much better than the people who are in the earlier eras.
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