Steroid-Free Maintenance Immunosuppression After Heart Transplantation

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1 Steroid-Free Maintenance Immunosuppression After Heart Transplantation Timothy E. Oaks, MD, Thomas Wannenberg, MD, Sherry A. Close, BSN, Laura E. Tuttle, BSN, and Neal D. Kon, MD Departments of Cardiothoracic Surgery and Cardiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina Background. Steroids are routinely used in almost all immunosuppressive protocols after cardiac transplantation. The metabolic side effects of steroids are well known and could lead to significant morbidity and mortality in the posttransplant period. There is growing evidence to suggest that steroids may not be a requirement for adequate immunosuppression and that morbidity may be reduced by withdrawing steroids in select patients. We have reviewed our series of patients undergoing heart transplantation in whom steroids were weaned postoperatively. Methods. We retrospectively reviewed all adult patients undergoing heart transplantation at our institution between November 1993 and April 2000 treated with a triple-drug immunosuppressive regimen. Medications were recorded at discharge and at 6, 12, and 24 months posttransplant to determine the success of steroid weaning. Freedom from infection and rejection as well as overall survival was calculated using Kaplan-Meier methods. Results. By 24 months posttransplant, almost 70% of patients were receiving double-drug therapy. Survival for the entire group was excellent with 1-, 3-, and 5-year survival of 98% 2.0%, 93.2% 3.8%, and 88.3% 6.0%, respectively. Freedom from rejection at 6 months was 60.7% 6.5%, at 1 year was 60.7% 6.5%, and at 2 years was 58.5% 6.7%. Infectious complications were low with freedom from infection at 6 months of %, at 1 year of 76.5% 5.7%, and at 2 years of 72.0% 6.2%. Conclusions. Our data suggest that an immunosuppressive regimen without long-term steroid administration results in excellent survival rates without an apparent increase in rejection or infectious complications. (Ann Thorac Surg 2001;72:102 6) 2001 by The Society of Thoracic Surgeons The surgical procedure for orthotopic cardiac transplantation has changed very little over the last 30 years, with the exception of the bicaval technique favored by some centers. Therefore, the success of cardiac transplantation is primarily related to the immunosuppression agents administered postoperatively. The major causes of morbidity and mortality after transplantation continue to be related to immunosuppression with the goal to produce a balance of immunosuppression to prevent rejection and yet avoid infectious and other complications. In addition, patients may experience side effects from their immunosuppressive agents, such as hypertension, glucose intolerance, hyperlipidemia, renal dysfunction, obesity, osteoporosis, and cataracts. The complications of malignancy and graft vasculopathy may also be associated with immunosuppression. Therefore, it seems clear that further advances in cardiac transplantation will be limited by our understanding of immunosuppression agents and their long-term risk-to-benefit ratio. It also seems obvious that using the least amount of immunosuppression to prevent rejection would have long-term beneficial effects. However, this has not been absolutely proven. Yacoub and colleagues [1] was the first to suggest that immunosuppression after cardiac transplantation could exclude steroids. Since then many centers have developed protocols for steroid weaning after cardiac transplantation in select adult patients. Many, but not all, of these centers have reported a beneficial effect of steroid weaning. Despite these positive benefits of steroid withdrawal, the majority of patients continue to receive steroids for long-term immunosuppression. We believe that most patients should be considered candidates for steroid withdrawal, and the purpose of this study was to review our results with an immunosuppressive protocol stressing withdrawal of steroids after cardiac transplantation. Patients and Methods Between November 1993 and April 2000, 63 patients underwent cardiac transplantation at our institution. Six Presented at the Forty-seventh Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 9 11, Address reprint requests to Dr Oaks, Department of Cardiothoracic Surgery, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC ; toaks@wfubmc.edu. This article has been selected for the open discussion forum on the STS Web site: by The Society of Thoracic Surgeons /01/$20.00 Published by Elsevier Science Inc PII S (01)

2 Ann Thorac Surg OAKS ET AL 2001;72:102 6 STEROID-FREE IMMUNOSUPPRESSION AFTER HEART TRANSPLANTATION 103 patients were less than 18 years of age and were excluded from analysis. Of the 57 adult patients, all were treated with a polyclonal antithymocyte globulin (usually for 5 to 7 days) and then maintained on cyclosporine, azathioprine or mycophenolate mofetil and prednisone. Since mycophenolate mofetil was introduced into our practice in November 1995, it has been utilized in place of azathioprine in all patients. Cyclosporine was begun on postoperative days 2 or 3 with most patients. Cyclosporine levels were measured by radioimmunoassay with a whole blood target trough level of 350 to 400 ng/ml at 1 month and 150 to 200 ng/ml by 1 year. Mycophenolate mofetil was given at a dose of 1 gram twice daily. Azathioprine was initially given at a dose of 2 mg/kg/day and adjusted to maintain the white blood cell count greater than 5,000/mm 3. Prednisone was begun at 1 mg/kg/day and tapered by 5 mg/day to 0.2 mg/kg/day by 2 weeks. All patients received prophylactic trimethoprimsulfamethoxazole while on steroids. Patients who were seropositive for cytomegalovirus or received an organ from a seropositive donor, received prophylactic ganciclovir for 1 month followed by oral acyclovir for 5 months. Most patients also received diltiazem (to increase cyclosporine levels) and pravastatin within the first week after transplantation. Endomyocardial biopsies were performed weekly for the first month, twice a month for the second month, monthly until the sixth month, and also at months 9 and 12. Thereafter, endomyocardial biopsies were not routinely performed except during steroid weaning. Specifically, annual surveillance biopsies were not obtained and patients underwent biopsy only if symptoms suggested rejection. All biopsies were graded according to the International Society for Heart and Lung Transplantation (ISHLT) guidelines. Biopsy scores 3A or greater were treated with intravenous methylprednisolone, 1 gm/day, followed by prednisone 1 mg/kg/day rapidly tapered to the baseline of 0.2 mg/kg/day. Infectious complications were defined according to the Cardiac Transplant Research Database Group and included any infection requiring intravenous therapy (either as an outpatient or inpatient) or any infection considered life threatening that was treated with oral agents (eg, herpes simplex esophagitis). All patients were considered candidates for steroid withdrawal except for those experiencing two or more rejection episodes (ISHLT score 3A or greater) within the first 6 months, those with poor ventricular function, and those experiencing a rejection episode with hemodynamic instability. Beginning at 6 months posttransplant, the prednisone dose was decreased by 5 mg/day over 2 to 3 months and an endomyocardial biopsy was obtained. If an ISHLT biopsy score of less than 3A was obtained, the dose of prednisone was decreased by 5 mg/day over several months and another biopsy was obtained. This process was repeated until the patient was weaned off prednisone. If a rejection episode occurred during steroid weaning, the patient was treated and placed back on chronic maintenance steroids. If no rejection occurred, endomyocardial biopsies were performed 1 and 2 months off prednisone and were not specifically repeated unless the patient had symptoms to suggest rejection. All patients underwent coronary angiography at 1 year. Recently, we alternated annual dobutamine stress echocardiogram with cardiac catheterization to determine the presence of graft vasculopathy. Graft vasculopathy was defined as none or minimal (less than or equal to 50% stenosis in the left main, left anterior descending, circumflex, right or first order branch vessels); moderate (50% to 70% stenosis in the left anterior descending, circumflex, right or first order branch vessels); or severe (greater than 50% stenosis in the left main or greater than or equal to 70% stenosis of the left anterior descending, circumflex, right or first order branch vessels). We interpreted a normal dobutamine stress echocardiogram to represent none or minimal graft vasculopathy if the patient had a prior coronary angiogram that was interpreted as normal within the last year. Time to first-event for the two outcomes of interest (first infection and rejection) was calculated as the difference between the date of operation and the first date of observed infection or rejection. If a patient had not yet had an event occur, the patient was censored for that outcome on the last known event-free date. Infection-free and rejection-free rates and the corresponding standard errors were calculated using the Kaplan-Meier method; survival curves were generated using these same estimates of the survival distribution function. Data are presented as mean standard error. Results Between November 1993 and April 2000, 57 adult patients, including 6 patients supported with ventricular assist devices, underwent orthotopic cardiac transplantation at our institution. There was no operative mortality and follow-up was complete for all patients. Fifty-six patients (98%) were discharged on triple-drug immunosuppression and formed the basis for this article. Of these 56 patients, 14 patients (25%) were treated with cyclosporine, azathioprine, and prednisone, whereas 42 patients (75%) were treated with cyclosporine, mycophenolate mofetil, and prednisone. Six-month follow-up data were available on 50 patients. Forty-six patients (92%) were still receiving tripledrug therapy. Three patients (6%) with persistent white blood cell counts less than 5,000/mm 3 were receiving double-drug therapy with cyclosporine and prednisone, and 1 patient with a severe infection was receiving cyclosporine, alone. Twelve-month follow-up was available in 43 patients. Ten patients (23%) were receiving double-drug therapy (cyclosporine and prednisone, 5 patients; cyclosporine and azathioprine or mycophenolate mofetil, 5 patients). The remaining 33 patients (77%) were receiving triple-drug therapy. By 2 years after transplantation, 7 patients (19%) continued to receive triple-drug immunosuppression, whereas 28 patients (76%) received double-drug therapy (cyclosporine and prednisone, 2 patients; cyclosporine

3 104 OAKS ET AL Ann Thorac Surg STEROID-FREE IMMUNOSUPPRESSION AFTER HEART TRANSPLANTATION 2001;72:102 6 Table 1. Posttransplant Immunosuppression Medications Discharge (n 56) 12 Months (n 43) 24 Months (n 37) Cyclo/Aza or MMF/Pred 56 (100%) 33 (77%) 7 (19%) Cyclo/Aza or MMF 5 (12%) 26 (70%) Cyclo/Pred 5 (12%) 2 (5%) Cyclo 2 (5%) Cyclo Cyclosporine; Aza Azathioprine; MMF Mycophenolate Mofetil; Pred Prednisone and azathioprine or mycophenolate mofetil, 26 patients), and 2 patients (5%) received cyclosporine only. Therefore, by 2 years after transplantation more than 80% of the patients were not receiving triple-drug immunosuppression (Table 1). Rejection episodes were defined as an ISHLT score of 3A or greater. Thirty patients never experienced a rejection episode. Only 1 patient had a biopsy score of greater than 3A; this patient was noncompliant and had hemodynamic compromise requiring methylprednisolone and antithymocyte globulin for treatment. Only 1 noncomplaint patient died of acute rejection at 13 months. The actuarial freedom from a first rejection episode was 71.4% 6.1% at 1 month, 60.7% 6.5% at 6 months, 60.7% 6.5% at 12 months, 58.5% 6.7% at 24 months, and % at 36 months (Fig 1). Nineteen patients developed 50 infections after transplantation. Thirty-five infections were bacterial, 8 were caused by cytomegalovirus, 3 were caused by fungus, 2 were viral, and 2 were unknown. Two patients alone accounted for more than half of the infections. One patient, who experienced 17 infectious episodes, underwent an emergency coronary artery bypass operation and could not be weaned from cardiopulmonary bypass, requiring extracorporeal membrane oxygenation and a left ventricular assist device support. She developed mediastinitis, sepsis, pneumonia, and multiple catheter related infections prior to successful cardiac transplantation. The other patient accounted for 10 infections; this is the only patient to die from infection in our series. He Fig 1. Time to first rejection. Fig 2. Time to first infection. developed pulmonary mucormycosis and expired 7 months postoperatively. Overall, the freedom from infection was 85.7% 4.7% at 1 month, 78.5% 5.5% at 6 months, 76.5% 5.7% at 12 months, 72.0% 6.2% at 24 months, and 66.9% 6.7% at 36 months (Fig 2). The degree of coronary vasculopathy was graded as none or minimal, moderate or severe. On the basis of these definitions, 2.4% of patients developed moderate or severe graft vasculopathy within 1 year and 8.1% within 2 years. Survival was excellent in this series with 1-, 2-, 3-, 4-, and 5-year survival rates of 98.0% 2.0%, 93.2% 3.8%, 93.2% 3.8%, %, respectively. Four patients died during the study period: 2 from graft vasculopathy at 18 months and 43 months, 1 from infection at 7 months, and 1 from acute rejection at 13 months. Comment Triple-drug therapy with cyclosporine, azathioprine, and prednisone remains the gold standard for maintenance immunosuppression after cardiac transplantation. Several groups believe that mycophenolate mofetil should replace azathioprine in the triple-drug regimen because of its reported efficacy [2]. However, there is increasing evidence that steroids may not be required for long-term immunosuppression in heart transplantation. Yacoub and colleagues [1] were credited with the first report of the feasibility of steroid-free immunosuppression. Since then, many centers have reported their experience with steroid withdrawal either early or late after cardiac transplantation. Despite these excellent reports, almost 90% of patients continue to receive prednisone at 1-year posttransplant and 70% at three years posttransplant [3 4]. A recent review of over 1,800 patients from the combined ISHLT/United Network for Organ Sharing Thoracic Registry outlined the morbid complications that patients suffer within the first year after transplantation [4]. Many of these complications are known side effects of prednisone, including hypertension (61%), diabetes mellitus (16%), hyperlipidemia (26%), symptomatic bone

4 Ann Thorac Surg OAKS ET AL 2001;72:102 6 STEROID-FREE IMMUNOSUPPRESSION AFTER HEART TRANSPLANTATION 105 disease (5%), and cataracts (2%). Similar results were seen in the ISHLT database [3]. In addition, the development of graft vasculopathy may be related to the hypertension, diabetes, and hyperlipidemia. Clearly it would be desirable to avoid these complications, and perhaps a steroid-free maintenance immunosuppressive regimen would be beneficial. Several centers have reported their results with immunosuppressive regimen that did not include oral steroids in the immediate posttransplant period. In a series of nonrandomized patients, Katz and coworkers [5], found that 61% of patients could be treated without any steroids in the posttransplant period. These patients had similar survival, infection, and rejections rates, but a much lower incidence of diabetes mellitus, compared to triple-drug treated patients. Livi and colleagues [6], who found that 79% of patients could be treated without maintenance steroids, reported a similar group of patients. Keogh and associates [7], reported an elegant 5-year follow-up study on 112 patients prospectively randomized to triple-drug therapy or double-drug therapy with cyclosporine and azathioprine. Patients with significant renal dysfunction or who had three consecutive rejection episodes or four rejection episodes overall were converted to maintenance steroids. Only 47% of patients required conversion to triple-drug therapy. Actuarial survival was excellent in both groups of patients. Rejection in the first 3 months was lower with triple-drug therapy but did not differ between groups beyond 3 months. There was no difference in ventricular function, renal function, graft vasculopathy, diabetes mellitus, or bone disease. Patients receiving triple-drug therapy, however, had higher serum cholesterol and required more antihypertensive agents. These studies clearly demonstrate that steroid-free maintenance immunosuppression is possible in at least onehalf of patients, is as safe as triple-drug therapy, and may reduce some of the long-term complications of steroids. Others have taken a somewhat different approach to steroids after transplantation. These investigators used steroids in all patients in the early posttransplant period, but began to wean selected patients after several weeks or months. Using center-specific indications for steroid withdrawal, Taylor and coworkers [8], were able to successfully discontinue maintenance steroids in 30% of 374 patients. Mortality, both short-term and long-term, was significantly lower in patients in whom successful early withdrawal from steroids was achieved. The prevalence of late acute rejection was also lower in patients weaned from steroids. Graft vasculopathy was lower in patients weaned from steroids (4.5% versus 9.5%), although this difference did not reach statistical significance. The authors concluded that successful early corticosteroid withdrawal identifies a subgroup of immunologic-privileged patients with a low risk for long-term mortality, late rejection, or clinically significant graft vasculopathy. Prieto and colleagues [9] also found a beneficial effect of early steroid weaning as evidenced by a lower amount of hypercholesterolemia and hypertension but not survival. Several centers have reported their results with steroid weaning 6 months or more after transplantation. Olivari and associates [10] found that the degree of posttransplantation weight gain, lipid abnormalities, and incidence of hypertension were not modified by the fast tapering of steroids, whereas the incidence of cataracts, compression fracture, and the degree of bone loss were significantly reduced. Similar results were reported by Miller and coworkers [11]. However, Kobashigawa and colleagues [12] found that patients successfully weaned from steroids did have a significant weight reduction and significantly lower serum cholesterol. Our success with steroid weaning is similar to previously published articles. We believe that steroids should be administered during the time of greatest risk of rejection, namely the first 6 months. At that time, we assess the patient and begin to wean steroids slowly over a 6- to 9-month period. Using this approach, at 2 years posttransplant, only 19% of our patients were receiving triple-drug therapy. Only 1 patient experienced a rejection episode after successful steroid weaning and was placed back on chronic triple-drug therapy without further attempts to wean steroids. Although we did not specifically evaluate weight loss or lipid abnormalities, it has been our impression that weight reduction is easier after steroid withdrawal. Additionally, we cannot discuss the effect of steroid withdrawal on lipid abnormalities because almost all our patients received pravastatin within a few weeks after transplantation. We believe that pravastatin should be used in all patients if possible because it has been shown to lower cholesterol, reduce graft vasculopathy, and improve survival [13]. Rejection and infection rates using our immunosuppressive protocol have been low and comparable to other reported series. By definition, we treated all ISHLT biopsy scores of 3A or greater. Patients with biopsy scores of grade 2 were not treated, but closely monitored, and another biopsy was performed within 2 weeks. Although the definition of rejection is quite variable from institution to institution, and may even include clinical events not associated with a lymphocytic myocardial infiltrate, our results suggest that our rejection rates are comparable to previously published reports [14 16]. We could not attribute the low rejection rates to augmented immunosuppression because this would have resulted in higher infectious complications. In fact, our infection rates were lower than previously reported from the Cardiac Transplant Research Database [17]. Finally, a small number of patients in our series precludes comparison with other studies regarding the incidence of graft vasculopathy. Survival was excellent throughout this series with 1-, 3-, and 5-year survival rates of 98%, 93%, and 88%, respectively. These results compare very favorably to the ISHLT and Cardiac Transplant Research Databases. Four patients died during the study period. Two patients died from graft vasculopathy at 18 and 43 months, 1 patient died from infection at 7 months, and 1 noncompliant patient died of acute rejection at 13 months. In summary, our results lend further evidence to the excellent results that can be obtained using a steroid-free immunosuppressive protocol. Despite the small number of patients in our series, we believe that the rate of

5 106 OAKS ET AL Ann Thorac Surg STEROID-FREE IMMUNOSUPPRESSION AFTER HEART TRANSPLANTATION 2001;72:102 6 infection, rejection, and transplant vasculopathy was not increased using a protocol that stressed steroid withdrawal. We strongly believe that steroids can be safely withdrawn in select patients after cardiac transplantation. References 1. Yacoub M, Alivizatos P, Khaghani A, Mitchell A. The use of cyclosporine, azathioprine, and antithymocyte globulin with or without low-dose steroids for immunosuppression of cardiac transplant patients. Transplant Proc 1985;17: Kobashigawa J, Miller L, Renlund D, et al. A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 1998;66: Hosenpud JD, Bennett LE, Keck BM, et al. The registry of the international society for heart and lung transplantation: fifteenth official report J Heart Lung Transplant 1998; 17: Brann WM, Bennett LE, Keck BM, Hosenpud JD. Morbidity, functional status, and immunosuppressive therapy after heart transplantation: an analysis of the joint international society for heart and lung transplantation/united network for organ sharing thoracic registry. J Heart Lung Transplant 1998;17: Katz MR, Barnhart GR, Szentpetery S, et al. Are steroids essential for successful maintenance of immunosuppression in heart transplantation? J Heart Lung Transplant 1987;6: Livi U, Luciani GB, Boffa GM, et al. Clinical results of steroid-free induction immunosuppression after heart transplantation. Ann Thorac Surg 1993;55: Keogh A, Macdonald P, Mundy J, Chang V, Harvinson A, Spratt P. Five-year follow-up of a randomized double-drug versus triple-drug therapy immunosuppressive trial after heart transplantation. J Heart Lung Transplant 1992;11(3 Part 1): Taylor DO, Bristow MR, O Connell JB, et al. Improved long-term survival after heart transplantation predicted by successful early withdrawal from maintenance corticosteroid therapy. J Heart Lung Transplant 1996;15: Prieto M, Lake KD, Pritzker MR, et al. OKT3 induction and steroid-free maintenance immunosuppression for treatment of high-risk heart transplant recipients. J Heart Lung Transplant 1991;10: Olivari MT, Jessen ME, Baldwin BJ, et al. Triple-drug immunosuppression with steroid discontinuation by six months after heart transplantation. J Heart Lung Transplant 1995; 14(1 Part 1): Miller LW, Wolford T, McBride LR, Peigh P, Pennington G. Successful withdrawal of corticosteroids in heart transplantation. J Heart Lung Transplant 1992;11(2 Part 2): Kobashigawa JA, Stevenson LW, Brownfield ED, et al. Corticosteroid weaning late after heart transplantation: relation to HLA-DR mismatching and long-term metabolic benefits. J Heart Lung Transplant 1995;14: Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med 1995;333: Kubo SH, Naftel DC, Mills RM, et al. Risk factors for late recurrent rejection after heart transplantation: a multiinstitutional, multivaribale analysis. J Heart Lung Transplant 1995;14: Kobashigawa JA, Kirklin JK, Naftel DC, et al. Pretransplantation risk factors for acute rejection after heart transplantation: a multiinstitutional study. J Heart Lung Transplant 1993;12: Kirklin JK, Naftel DC, Bourge RC, et al. Rejection after cardiac transplantation. A time-related risk factor analysis. Circulation 1992;86(Supp II):II Smart FW, Naftel DC, Costanzo MR, et al. Risk factors for early, cumulative, and fatal infections after heart transplantation: a multiinstitutional study. J Heart Lung Transplant 1996;15: DISCUSSION DR MICHAEL C. MAXWELL (Charlotte, NC): Those are very good results, but one of the things I was struck by is the fact that there are probably as many different cocktails for immunosuppression as there are transplant centers, and I wondered if you know how your results would compare with centers or reports that use a similar protocol, with the only difference being the maintenance of steroid therapy postoperatively? DR OAKS: Well, there have been reports in the literature using cyclosporine and azathioprine. Those represent a relatively old series of patients, but recently there have been additional series of patients looking at cyclosporine and mycophenolate. Now, I have to admit that our group included both mycophenolate and azathioprine as a second drug, but about three-quarters of our patients were on mycophenolate. So it is difficult for me to compare our results of cyclosporine and mycophenolate to previously reported series with cyclosporine and azathioprine, and I am sure that there are other institutions with larger series of patients using double-drug therapy. But I think that our immunosuppressive protocol as we utilized it did allow us to remove about three-quarters of our patients off of prednisone, which I can only believe is going to be good for them in the long run. DR W. STEVES RING (Dallas, TX): As you probably know, we have also utilized a protocol of early steroid withdrawal, actually aiming to have patients off of all prednisone by six months rather than the 15 months in your series, and have noticed a very beneficial outcome in these particular patients and would agree with the aggressive attempt to wean patients from steroids. One of the questions I do have, in your particular study, what percentage of patients in whom there was an attempt to wean from steroids, did they ultimately have to go back and be placed on steroids? DR OAKS: We had only one patient in which we had discontinued steroids who then required reinstitution of chronic maintenance steroids, and that patient had a symptomatic rejection episode at about two years. We do not routinely perform endomyocardial biopsies once they are off steroids, other than the first two months. So we don t routinely screen them annually for rejection. But if a patient developed a rejection episode during their steroid wean, they were placed back on 0.2 mg/kg/ day, but only one patient required reinstitution of steroids once they were off completely.