| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 2006;82:637-644
© 2006 The Society of Thoracic Surgeons
a Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas
c Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
b Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina
Accepted for publication March 22, 2006.
* Address correspondence to Dr DiMaio, 5323 Harry Hines Blvd, Dallas, TX 75390-8879. (Email: michael.dimaio{at}utsouthwestern.edu).
Presented at the Fifty-second Annual Meeting of the Southern Thoracic Surgical Association, Orlando, FL, Nov 10–12, 2005.
| Dr Ring discloses a financial relationship with Novartis.
|
 |
Abstract |
|---|
 Top Abstract IntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
|---|
METHODS: We reviewed the records of 162 consecutive cardiac transplant recipients from our institution. Patients who underwent transplantation between 1988 and 1990 were treated with traditional triple-therapy immunosuppression (cyclosporine, azathioprine, and prednisone). Beginning June 1990, we instituted a protocol of early steroid taper with discontinuation by 6 months after transplant. The two groups were comparable with respect to age, sex, ethnicity, cause of heart failure, ischemic time, body mass index, and creatinine at the time of transplantation.
RESULTS: Fifty-seven percent of the patients in the early steroid taper group were successfully withdrawn from steroids at 6 months after transplantation. This group had a decreased freedom from and increased frequency of acute rejection (p < 0.01 for each) when compared with the traditional therapy group. There was, however, no difference in freedom from posttransplant coronary artery disease (p = 0.53). The early steroid taper group enjoyed an increased freedom from malignancy (p = 0.01) and trended toward a decreased frequency of infection (p = 0.10) and improved survival (p = 0.06).
CONCLUSIONS: Steroid withdrawal is possible in 57% of patients at 6 months after transplantation. The institution of an early steroid taper protocol improves the overall freedom from malignancies and may decrease the frequency of infection and prolong overall survival without increasing the risk of posttransplant coronary artery disease.
Advances in immunosuppressive therapy are a significant factor behind the success of heart transplantation. Successful immunosuppression, however, must balance the prevention of rejection with the well-documented side effects of immunosuppressive drugs, including those of long-term steroid therapy. To decrease the negative effects of prolonged steroid treatment, many transplant programs have investigated steroid-free or withdrawal protocols. In the mid 1980s, Yacoub and colleagues [1] demonstrated encouraging results with a steroid-free regimen. This pioneering work was quickly followed with several variations of this theme by other investigators. These included attempts at complete avoidance of steroids and early or late steroid taper after initial treatment with prednisone [2–17]. Although these protocols demonstrated the feasibility of steroid withdrawal with varying effects on rejection, steroid complications, and survival, 75% of today's heart transplant recipients are still treated with chronic steroid therapy [18].
Previously our institution reported that prednisone could be withdrawn in heart transplant recipients without jeopardizing survival and graft function. [11] Follow-up, however, was insufficient to assess the full impact of early withdrawal on long-term graft function, the incidence of coronary artery disease, and other complications. This report provides a reanalysis of this steroid withdrawal protocol to explore its long-term effects in heart transplant recipients.
|
Patients and Methods |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
|---|
The immunosuppressive protocol used by our program during this study period is outlined in detail elsewhere [11]. Briefly; both groups received cyclosporine and azathioprine during the entire study period according to an identical protocol. All patients received methylprednisolone on initiation of cardiopulmonary bypass and during the first postoperative day. On the second postoperative day, both groups were started on oral prednisone at a dose of 1 mg/kg per day. Subsequently, the steroid dose was tapered at different rates in the two groups and was completely withdrawn at 6 months after transplant in the CAPT group (Table 1). The CAPT patients were returned to the standard triple-drug regimen if they experienced two episodes of acute graft rejection, any hemodynamically compromised rejection, acute vascular rejection, leukopenia, renal insufficiency, or any other indication for steroid treatment. Data were analyzed according to intention-to-treat.
|
Follow-up was concluded on December 31, 2004. Serious infection was defined as any case that necessitated intravenous therapy or hospital admission. A solid malignancy was defined as any malignancy in which the primary lesion was not in the skin, including oropharyngeal cancers. Continuous variables were compared with Student's t tests, and categorical variables were analyzed with the 
2 statistic. Two-by-two tables were analyzed using Fisher's exact test. Patient survival and freedom from events were analyzed with Kaplan–Meier curves and compared with the log-rank statistic. The impact of immunosuppressive therapy on body mass index and serum creatinine values between the two groups was analyzed using a repeated-measure analysis of variance. All statistics were computed using SAS Version 9.1 (SAS Institute, Cary, NC), and p less than 0.05 determined significance. Data are expressed as mean ± standard deviation.
|
Results |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
|---|
|
|
|
|
|
|
Survival
Five patients died during the first 6 months after transplantation in the CAPT group. One died of infection, and 4 patients died of sudden cardiac death. Of those 4, 1 patient had been leukopenic from cytomegalovirus infection, and azathioprine had been held for almost a month. A second patient, who was known to be noncompliant with medications, was found deceased at home. A third patient suffered a cardiac arrest while in the hospital after his cyclosporine dosing had been decreased secondary to renal insufficiency. The fourth patient was also being treated with decreased dosing of cyclosporine when he died. All 4 patients' causes of death were classified as acute rejection; however, in each case the patient was on a nonstandard immunosuppression protocol owing to noncompliance or decreased dosing for the various previously stated reasons. Overall, the CAPT patients were found to have a very strong trend toward improved survival when compared with the CAP patients (Fig 5). There was no significant difference between the two groups in frequency of death because of acute rejection, chronic rejection, or malignancy (Table 4). The CAP group tended to be more likely to succumb to infection than the CAPT group (p = 0.06).
|
|
|
Comment |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
|---|
Some patient populations are less likely to be successfully weaned from steroids. Taylor and associates [12] reported that female patients have more treated rejection episodes during the first 3 months after transplantation and, therefore, are less likely to tolerate steroid withdrawal. African American patients have also been identified as a population that is less likely to be successfully weaned from steroids [17]. In our series, we noted a trend toward decreased success in steroid weaning in female patients at 6 months after transplant (p = 0.08), and a significant reduction in successful steroid weaning in African American patients (p = 0.03).
There is some debate as to whether or not steroid withdrawal leads to an increased incidence of acute rejection. Some studies demonstrate that acute rejection is lower in patients who are successfully tapered from steroids. These studies usually exclude patients who fail the steroid taper or place them in the steroid-requiring group for analysis. Price and coworkers [6] found that rejection was lower in patients who were tapered off steroids by four months and noted that successful steroid withdrawal may select for a group of patients with a decreased propensity for rejection during the following 32 months. Pritzker and associates [7] reported a similar incidence of acute rejection in both double-therapy and triple-therapy groups. Arnold and colleagues [15] found a higher incidence of acute rejection in the triple-therapy group, but this was after risk-stratifying patients who were at higher risk of rejection into the triple-drug group.
In contrast to the above studies, several reports describe an increased incidence of acute rejection after withdrawal of steroids. Keogh and coworkers [4] reported a higher incidence of rejection in a group of patients treated without steroids through the initial 3 months after transplantation. Previous data from our institution analyzed patients on an intent-to-treat basis (leaving those patients who failed steroid taper in the taper group for analysis) and found an increased incidence of acute rejection in the early withdrawal group [11]. Not surprisingly, our current results mirror this data.
This increased frequency of acute rejection may increase posttransplant coronary artery disease in our steroid withdrawal patients if immunologically mediated injury to the endothelium during acute rejection is an important etiologic factor in chronic rejection. Olivari and colleagues [19], however, reported that triple-drug therapy with cyclosporine, azathioprine, and prednisone, although effective in preventing acute rejection, does not alter the incidence of coronary lesions when compared with earlier and less effective immunosuppressive regimens [19]. In the current study, the frequency of acute rejection did not correlate with posttransplant coronary artery disease, a finding consistent with other reports [2, 6, 12].
Cardiac transplant recipients are at risk for developing malignancies, especially cutaneous neoplasms [20]. Immunosuppression is considered a possible etiologic factor in the increased incidence of cancer in this patient population. Our results suggest that steroid withdrawal improves the overall freedom from malignancy in our patient population. When individual types of malignancies were considered, however, only cutaneous malignancies were affected. These findings mirror other recently published data, which demonstrate that after multivariate analysis, immunosuppressive load (for cyclosporine, azathioprine, steroids, antithymocyte globulin, and OKT3) failed to emerge as independent risk factors for noncutaneous malignancy [21]. When considering cutaneous malignancies, however, the risk may be related to cumulative immunosuppressive dosage, and sunlight exposure may exert an additive immunosuppressive effect in these patients [22]. Certainly, the etiologic factors of cancer are multifactorial, and further study is needed.
Multiple reviews have examined the effects of steroid withdrawal on posttransplant infection. Several authors have reported that steroid withdrawal does not influence the incidence of infection [2–4, 23]. In contrast, Pritzker and colleagues [7] found an increased incidence of bacterial infection in patients who underwent early steroid taper. That study involved a group of patients who underwent induction therapy with OKT3. Previously published data from our institution described a decreased incidence of infection in patients who underwent steroid taper at 2-year follow-up [11]. Our current results suggest that this benefit may be lost during long-term follow-up (see Fig 4). Although freedom from infection is not different between our groups of patients, there is a trend toward decreased frequency of infection in the steroid-taper group.
Previous data from our institution demonstrated that at 1 year after transplantation, the incidence of diabetes was significantly higher in patients who remained on steroids [11]. Other series found no effect on posttransplant diabetes after steroid withdrawal [3, 17]. In the current study, we find no difference in freedom from diabetes in patients who undergo steroid withdrawal and also no significant difference in body mass index between the CAP and CAPT groups. Only one series demonstrated that those patients who are treated with triple therapy gain more weight [6]. Most authors have noted that cardiac transplant recipients regain their premorbid weight after surgery and that there is no difference in obesity between those patients managed with or without steroids [7, 9, 11, 16, 17]. Lake and associates [24] suggested that posttransplant weight gain is more dependent on genetic factors than immunosuppressive medications.
Survival tended to be improved in our CAPT patients. This is an interesting finding given the observed increased frequency of acute rejection and absence of any difference in posttransplant coronary artery disease and freedom from solid malignancy between the two groups. The improved survival could be attributed to the increased freedom from cutaneous malignancies, although malignancy as a cause of death is not significantly different between the two groups. The trend toward increased incidence of infective episodes may lead to decreased survival in the CAP group, a hypothesis supported by the observation that infection tended to more often be a cause of death in this group when compared with the CAPT group. Taylor and colleagues [12] also demonstrated improved survival in patients who could be weaned off of steroids. They suggested that those who are successfully tapered off steroids are "immunologically privileged" and have a low risk of long-term mortality.
In addition to the increased survival of the CAPT patients, there is evidence that these patients enjoy an improved quality of life as well. Jones and associates [25] reported that patients who are managed on double therapy (ie, without steroids) have a better sense of physical well being, are less anxious, more sexually satisfied, and financially more secure than their triple-therapy counterparts. In addition, double-therapy patients demonstrated a lower frequency of and less distress from therapeutic side effects [25].
We acknowledge the limitations inherent in this nonrandomized retrospective study. It is certainly possible that the decreased freedom from and increased frequency of acute rejection that is seen in the tapered patients is owing to the increased frequency of biopsies. However, when the steroid taper protocol was first instituted, it was thought that these patients must be closely monitored with increased biopsy frequency, and we still use this biopsy protocol today. It is difficult to assess the effects that a more frequent biopsy schedule during the first 2 years after transplant may have on long-term outcomes, but it is possible that it biases our results. Additionally, the improved survival that is seen in the steroid-taper patients could be related to the era in which these patients received their transplant. Unfortunately, we can only analyze variables that are available in the medical records. Subtle changes in surgical technique and postoperative care that evolve with time cannot always be captured. However, the years that define our CAP and CAPT patients (1988–1990 and 1990–1996) overlap three eras as defined by the latest registry of the International Society of Heart and Lung Transplantation (1982–1988, 1989–1993, and 1994–1998) [18]. Therefore, the increased survival of the CAPT patients cannot be explained exclusively by the era in which their transplantation was performed. Finally, it is difficult to assess the effects of steroid withdrawal on other important postoperative morbidities such as hypercholesterolemia and hypertension, when almost all heart transplant patients are routinely placed on lipid-lowering and antihypertensive therapies. Our study is strengthened, however, by its large size, long follow-up, and statistical analysis by intention-to-treat.
In conclusion, steroid withdrawal is possible in almost 60% of patients at 6 months after transplantation. Despite an increased frequency of acute rejection, early steroid withdrawal improves the freedom from malignancy and may decrease the frequency of infection and improve long-term survival in the cardiac transplant population without increasing the risk of posttransplant coronary artery disease.
|
Discussion |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
|---|
DR ROSENBAUM: If they were diagnosed with acute rejection, they were treated with 3 days of prednisone. If that resolved, then they were put back on a steroid taper and tapered off at 6 months. If they suffered another episode of rejection, they are placed back on long-term steroid treatment and remained on steroids but were left in the tapered group for analysis.
DR ANDREW J. LODGE (Durham, NC): Congratulations on a nice presentation. Can you comment on the definition of infection that was used, and also on the types of malignancies that you saw and what the breakdown of the different malignancy types was? You also mentioned that none of these patients got cytolytic induction therapy. Are you currently using any induction immunosuppression, and what is the current maintenance immunosuppression regimen that you are using?
DR ROSENBAUM: Definition of infection was any patient who required hospitalization or intravenous therapy. For breakdown of malignancies, I can actually show you a slide. I have one, anyway. When malignancies were broken down, there was actually no difference in freedom from solid malignancies or posttransplant lymphoproliferative disorder. There was increased freedom from cutaneous malignancies, which probably is what led to the increased freedom from overall malignancy. As I said, we did not use induction therapy during this treatment period. However, currently we are using induction with basiliximab on day 0 and 4, starting cyclosporine on day 5, and using mycophenolate mofetil and prednisone with a prednisone taper.
DR THOMAS M. EGAN (Chapel Hill, NC): Nice presentation. Two questions. One is, with the data that you have, are you considering delaying the onset of your steroid taper, because you have a pretty significant number that needed to go back on steroids and you might improve that by waiting to a year? The second question is, although you have demonstrated a nice difference in survival, have you analyzed causes of death to look at why the steroid patients are dying?
DR ROSENBAUM: Thank you for your comments. During this treatment period we had a 62% success rate in getting patients off steroids. With our current treatment protocol with mycophenolate mofetil, basiliximab induction, cyclosporine, and prednisone taper, we are actually getting people off at 6 months with an 85% success rate.
(Slide) In terms of our cause of death, as you can see by this, and I am sorry, I just didn't have time to include it in my talk, but infection and other as causes of death were significantly different between the two groups. So although there was an increase in freedom from malignancy, malignancy as a cause of a death was not significantly different, and that is probably, again, based on the fact that the main cause of that increased freedom from malignancy was cutaneous malignancies. Acute rejection, although increased in the tapered group, was not a cause of death difference, coronary artery disease was not a difference. So the patients who were left on steroids increased risk of dying from infection and those who were tapered off die from events like the rest of us.
DR JOHN H. CALHOON (San Antonio, TX): Doctor Rosenbaum, I have a question, and congratulations on presenting this very nicely and covering the data very nicely. To me, it almost seems as if you have defined two different groups and two different immune matches: those who are able to be weaned off of steroids or those who have a better match and are going to do better regardless of the steroids. Do you have any way or have you figured out a way to define whether that plays a major role or whether it is the steroids themselves that you are weaning off that are making them better? I can't tell whether the steroids are weaned off or whether it is just the patients have a better match that you weaned the steroids off.
DR ROSENBAUM: That is an interesting point and a good question, and it has been suggested before by some investigators that the patients who are able to be weaned off of steroids are inherently more immunologically adept at tolerating transplant and therefore are able to get off steroids and are therefore able to survive longer, which is a reasonable point and a consideration. However, we would expect that those patients therefore would at least potentially have an increased freedom from transplant coronary artery disease, and that was not seen with our patients. So we did not look at that specifically, but looking at transplant coronary vasculopathy as a potential end point difference in those types of patients, we did not see that.
|
Acknowledgments |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
|---|
|
References |
|---|
|
TopAbstractIntroductionPatients and MethodsResultsCommentDiscussionAcknowledgmentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  J. A. Kobashigawa Strategies in Immunosuppression After Heart Transplantation: Is Less Better? Circ Heart Fail, March 1, 2011; 4(2): 111 - 113. [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tanaka, T. Hasegawa, Z. Chen, Y. Okita, and K. Okada Renoprotective immunosuppression by pioglitazone with low-dose cyclosporine in rat heart transplantation J. Thorac. Cardiovasc. Surg., September 1, 2009; 138(3): 744 - 751. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Lam, N. Partovi, L. S. Ting, and M. H. Ensom Corticosteroid Interactions with Cyclosporine, Tacrolimus, Mycophenolate, and Sirolimus: Fact or Fiction? Ann. Pharmacother., July 1, 2008; 42(7): 1037 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Z. Sulemanjee, R. Merla, S. D. Lick, S. M. Aunon, M. Taylor, M. Manson, L. S.C. Czer, and E. R. Schwarz The First Year Post-Heart Transplantation: Use of Immunosuppressive Drugs and Early Complications Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2008; 13(1): 13 - 31. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
