- Email: [email protected]
Calcineurin Inhibitor-free Immunosuppression Using Everolimus (Certican) after Heart Transplantation: 2 years' Follow-up from the University Hospital Münster
Calcineurin Inhibitor-free Immunosuppression Using Everolimus (Certican) after Heart Transplantation: 2 years’ Follow-up from the University Hospital Münster J. Stypmann, M.A. Engelen, S. Eckernkemper, S. Amler, S. Gunia, J.R. Sindermann, M. Rothenburger, A. Rukosujew, G. Drees, and H.A. Welp ABSTRACT Background. Everolimus is a proliferation-signal inhibitor which was introduced for heart transplant recipients in 2004. To date, there are only sparse data about long-term calcineurin inhibitor (CNI)–free immunosuppression using everolimus. Methods. After heart transplantation, patients receiving everolimus were consecutively enrolled. Reasons for switching to everolimus were side effects of CNI immunosuppression, such as deterioration of kidney function and recurrent rejection episodes. All 60 patients underwent standardized switching protocols, 42 patients completed 24-month follow-up. Blood was sampled for lipid status, renal function, routine controls, and levels of immunosuppressive agents. On days 0, 14, and 28, and then every 3 months, echocardiography and physical examination were performed. Results. After switching to everolimus, most patients recovered from the side effects. Renal function improved significantly after 24 months (creatinine, 2.1 ⫾ 0.6 vs 1.8 ⫾ 1 mg/dL; P ⬍ .001; creatinine clearance, 41.8 ⫾ 22 vs 48.6 ⫾ 21.8 mL/min; P ⬍ .001). Median blood pressure increased from 120.0/75.0 mm Hg at baseline to 123.8/80.0 mm Hg at month 24 (P values .008 and .003 for systolic and diastolic pressures, respectively). Tremor, peripheral edema, hirsutism, and gingival hyperplasia markedly improved. Levels of interleukin-6 were stable between baseline and 24-month levels. Temporary adverse events occurred in 8 patients [13.3%: interstitial pneumonia (n ⫽ 2), skin disorders (n ⫽ 2); reactivated hepatitis B (n ⫽ 1), and fever of unknown origin (n ⫽ 3)]. Conclusion. CNI-free immunosuppression using everolimus is safe, with excellent efficacy in maintenance of heart transplant recipients. Arterial hypertension and renal function significantly improved. CNI-induced side effects, such as tremor, peripheral edema, hirsutism, and gingival hyperplasia, markedly improved in most patients.
C
alcineurin inhibitor (CNI) immunosuppression was introduced for the prevention of rejection after heart transplantation more than 30 years ago,1 resulting in a
dramatic improvement in efficacy. This led to a marked improvement in survival rates,2 but the side effects of CNI therapy—particularly impairment of renal function— became
From the Department of Cardiology and Angiology (J.S., M.A.E., S.E., S.G.), University Hospital Münster, Germany; Department of Medical Informatics and Biomathematics (S.A.), University of Münster, Germany; and Department of Thoracic and Cardiovascular Surgery (J.R.S., M.R., A.R., G.D., H.A.W.), University Hospital Münster, Germany. The first two authors contributed equally to this work.
This study was supported by Novartis Pharma, Basel, Switzerland. Based in part on the doctoral thesis of S.E. Address correspondence to Dr. med. Henryk A. Welp, University Hospital Münster, Department of Thoracic and Cardiovascular Surgery Albert-Schweitzer-Str. 33, D-48149 Münster, Germany. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2010.12.062
Transplantation Proceedings, 43, 1847–1852 (2011)
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increasingly apparent.3 In addition to their nephrotoxic effect, CNI agents increase the risk of arterial hypertension that requires medical intervention; this, in turn, causes further adverse events and reduces adherence.3 Moreover, the incidence of tremor and cosmetic side effects, such as gingival hyperplasia and hirsutism, are common with CNI-based immunosuppression.3 In 2004, the new immunosuppressive drug everolimus (Certican; Novartis Pharma, Basel, Switzerland) became available. Everolimus, a novel inhibitor of p70 S6 kinase, binds to tacrolimus-binding protein 12 and creates an active moiety that effectively blocks the mammalian target of rapamycin (mTOR) and thereby arrests the cell cycle of lymphocytes and vascular smooth muscle cells in the G1 phase.4 Additionally, it exerts immunosuppressive effects via inhibition of interleukin (IL) 2 and IL-15-mediated Tand B-cell proliferation.4 First used clinically in kidney transplant recipients, everolimus was later adopted in maintenance heart transplant recipients.5–7 Patients given everolimus experience superior tolerability and fewer cytomegalovirus infections compared to other regimens.5–7 Previously, CNI-free immunosuppression with an mTOR inhibitor in heart transplantation was focused on sirolimus (Rapamune; Wyeth Pharmaceuticals, Collegeville, PA, USA) in combination with mycophenolate mofetil (MMF; CellCept; Roche, Basel, Switzerland).8,9 After CNI withdrawal, the majority of patients experienced an improvement in renal function.8,9 More recently, promising data for everolimus with low-dose CNI protocols have become available,10 –12 but there are still few reports regarding heart transplant recipients receiving everolimus-based CNI-free immunosuppression.13 We have undertaken a prospective study to evaluate the effect of switching maintenance heart transplant patients experiencing CNI-related adverse events or rejection to everolimus with CNI discontinuation. Patients were monitored for 2 years after switching to everolimus, and to our knowledge this is the first report of such extended follow-up with everolimus-based CNI-free immunosuppression in a large cohort of maintenance heart transplant recipients.
METHODS Study Design This was a prospective, single-arm, single-center study in which maintenance heart transplant patients were switched from CNI therapy (cyclosporine [CsA]) to everolimus. Patients receiving CsA with a clinical indication for switching immunosuppression were eligible to take part in the study unless they had severe preterminal chronic kidney insufficiency or were already receiving hemodialysis. Recruitment took place at a transplant outpatient clinic during the period of April 2005 to April 2007, and patients were followed for 2 years. The study was conducted in accordance with the Declaration of Helsinki and US Food and Drug Administration guidelines for good clinical practice following approval by the local Medical Ethics Committee.
STYPMANN, ENGELEN, ECKERNKEMPER ET AL
Immunosuppression Using a standardized protocol, everolimus was introduced at a fixed dose of 0.75 mg twice daily (1.5 mg/d) with the dose of CsA remaining unchanged for 1 week. In the second week, the baseline CsA dose was reduced to 70%, targeting a trough concentration of 50 ng/mL. The dose of everolimus remained unchanged for a further 2 weeks, at which point CsA was stopped and everolimus dose was adjusted as necessary to target a trough concentration of 4 – 8 ng/mL. Doses of MMF (1,000 mg twice daily) and prednisone (5 mg/d) were unchanged.14,15 All patients received antihypertensive therapy (beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers); doses could be adjusted as required. In the minority of patients who were not receiving statins at baseline, statin therapy could be initiated as necessary after introduction of everolimus.
Evaluation Study visits took place at baseline and every subsequent 3 months until 24 months after the switch. At each visit, a physical examination was performed, blood biochemistry was analyzed, and the trough concentration of everolimus was measured. Everolimus concentration was determined by liquid chromatography with mass spectrometry.16 A standard echocardiographic examination and Doppler echocardiography was performed at each study visit. Right ventricular biopsy was performed only in the event of suspected rejection and before and after larger operations with deep surgical wounds, because patients were temporarily returned to CNI-based protocols for such operations. Patient questionnaires were used to assess hirsutism and gingival hyperplasia.
Statistical Analyses Renal function and blood pressure after 6 months were taken as the combined endpoint in the previous study.1 In the present follow-up study, we continued to observe the primary endpoints up to 2 years from baseline. Secondary endpoints were changes in CNI-related adverse events (tremor, hirsutism, gingival hyperplasia, and peripheral edema), changes in lipid status, the occurrence of adverse events and hospital readmissions and rejections following the switch to everolimus. Patients’ characteristics are reported as mean ⫾ standard deviation in case of a normal distribution or as median (25%–75% percentiles) for nonparametric data. Univariate comparisons for continuous variables were made using the t test and Wilcoxon signed rank test, for paired samples data. McNemar and marginal homogeneity tests were performed to compare frequencies within nominal or ordinal data. Additionally, Kaplan-Meier curves were created for the time of first side effect and cessation of everolimus treatment. Statistical significance was assumed when the P value was ⬍.05.
RESULTS
The results of the first 6 months after switching to everolimus, including side effects, have been previously published.15 Herein we present the results from month 7 to month 24. Patient Population
A total of 60 patients were recruited, of whom 49 patients were followed for 12 months and 42 were followed for 24
EVEROLIMUS AFTER HEART TRANSPLANTATION
1849
months. Thirteen patients (21.7%) discontinued owing to adverse events, and 3 patients (5.0%) died of irreversible cardiac decompensation unrelated to the switch to everolimus. There were no signs for rejection in these 3 patients. Two patients (3.3%) withdrew consent. The study population included 53 men and seven women, with an overall mean age of 56.6 ⫾ 13.5 years. At baseline, the mean time after transplantation was 5.7 ⫾ 3.7 years. All patients had undergone orthotopic heart transplantation ⱖ1 year before. In all but 1 case, the indication for switching to everolimus was CNI-related adverse events, comprising renal impairment (n ⫽ 55 [91.7%]), allograft vasculopathy (n ⫽ 8 [13.3%]), peripheral artery occlusive disease (n ⫽ 4 [6.7%]), and malignancy (n ⫽ 2 [3.3%]). One patient was switched due to recurrent grade 3A/B rejection episodes despite several different immunosuppressive regimens. Twelve patients had previously experienced 1 rejection episode of either grade 2 or 3A within the first year after transplantation, and an additional 2 patients had had ⱖ2 rejection episodes of grade 2 or 3A/B. Tremor (n ⫽ 5), gingival hyperplasia (n ⫽ 2), hirsutism (n ⫽ 3), rheumatic disorders (n ⫽ 4), acne (n ⫽ 4), and lipometabolic disorders (n ⫽ 2) had been reported as CNI-related adverse events before conversion. Immunosuppression
At study entry, all patients were receiving CsA and steroids, 56 patients were receiving MMF, and 4 patients were receiving other immunosuppressive regimes. After introduction of everolimus, all patients achieved the target everolimus trough concentration range (4 – 8 ng/mL), although in 2 patients this was attained only after addition of diltiazem as a competitive substrate for cytochrome P450. The mean everolimus trough level was 6.1 ⫾ 1.6 ng/mL at 12 months and 6.0 ⫾ 1.7 ng/mL at 24 months. All patients discontinued CNI, but in 15 cases CNI therapy was reintroduced at a mean of 295 (range, 31– 684 days) days after baseline owing to adverse events (n ⫽ 13) or withdrawal of consent (n ⫽ 2). Renal Function
Mean serum creatinine at baseline was 1.8 (1.4 –2.4) mg/dL, decreasing to 1.4 (1.1–1.9) mg/dL at month 12 (P ⬍ .001 vs baseline), and stabilizing at 1.4 (1.2–2.0) mg/dL at 24 months (P ⫽ .002 vs baseline; Fig 1A). Median serum creatinine values are presented in Table 1. Creatinine clearance (Cockcroft-Gault formula17 also improved significantly from baseline to month 12, a difference that was sustained up to month 24 (Fig 1B; Table 1).
Fig 1. (A) Box-and-whisker plots of serum creatinine at baseline and 12 months and 24 months after conversion from CNI to everolimus. P ⬍ .001 for baseline versus 12 months; P ⫽ .003 for baseline versus 24 months. (B) Box-and-whisker plot of creatinine clearance (Cockcroft-Gault formula17) at baseline and 12 months and 24 months after conversion from CNI to everolimus. P ⬍ .001 for baseline versus 12 months; P ⫽ .017 for baseline versus 24 months. Circles represent outliers.
(ns). Mean total cholesterol increased temporarily during year 1, but did not differ significantly from baseline at month 12 or month 24 (Table 1). Serum concentrations of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides did not change significantly from baseline at either month 12 or month 24 (Table 1). CNI-Related Adverse Events
As reported previously,15 the incidence of CNI-related tremor, hirsutism, gingival hyperplasia, and peripheral edema decreased within the first few weeks after switching to everolimus. This effect was sustained up to month 24, with no de novo cases of CNI-related side effects reported and no deterioration of those adverse events that had not resolved.
Blood Pressure and Lipid Profile
Both systolic and diastolic blood pressure increased modestly but significantly during the 24-month study, although remaining within normal range (Table 1; Fig 2). At baseline, 48 patients (80.0%) were receiving statin therapy compared with 40 patients (66.7%) at month 24
Safety and Tolerability
The majority of everolimus-related adverse events developed shortly after switching.15 Adverse events reported for the first time after month 6 included skin problems (n ⫽ 11), most of which were acne and easily treated; peripheral
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STYPMANN, ENGELEN, ECKERNKEMPER ET AL Table 1. Laboratory and Echocardiography Values at Baseline, Month 12, and Month 24 Month 12 n
Serum creatinine (mg/dL) Creatinine clearance (mL/ min) Systolic blood pressure (mm Hg)* Diastolic blood pressure (mm Hg)* Total cholesterol (mg/dL)† LDL cholesterol (mg/dL)† HDL cholesterol (mg/dL)† Triglycerides (mg/dL)* Ejection fraction (%)* Shortening fraction (%)* LVEDD (mm)† LVESD (mm)†
50 50
Baseline
1.8 (1.5–2.2) 42.0 (22.2)
Month 24 Month 12
1.5 (1.1–2.0) 50.3 (24.1)
P Value
n
⬍.001 ⬍.001
43 43
Baseline
Month 24
1.8 (1.5–2.2) 42.7 (21.6)
P Value
1.5 (1.2–2.1) 48.6 (21.8)
.003 .017
50
120.0 (110.0–125.0)
120.0 (110.0–120.0)
.649
44
120.0 (110.0–120.0)
123.8 (115.6–136.9)
.008
50
70.0 (70.0–80.0)
80.0 (70.0–80.0)
.048
44
75.0 (70.0–80.0)
80.0 (73.1–85.0)
.003
49 15 15 49 38 41 42 42
218.4 (69.8) 103.6 (22.1) 79.8 (33.1) 184.0 (128.0–257.5) 61.0 (56.0–70.3) 34.0 (26.5–42.5) 47.3 (6.1) 31.1 (6.6)
229.0 (66.7) 103.9 (40.8) 79.2 (35.1) 192.5 (131.8–164.5) 63.5 (55.0–70.0) 30.0 (24.0–36.4) 47.3 (8.7) 33.0 (7.6)
.249 .974 .954 .838 .786 .088 .997 .139
43 13 13 43 32 33 37 35
220.6 (72.9) 106.5 (21.4) 77.9 (36.1) 185.0 (129.0–262.0) 60.0 (56.0–69.8) 34.0 (26.5–39.5) 47.4 (6.0) 31.3 (6.5)
220.4 (57.5) 109.3 (39.5) 68.7 (27.0) 200.0 (156.0–263.5) 61.0 (53.3–67.8) 35.7 (27.9–41.1) 47.8 (5.3) 30.7 (6.3)
.987 .800 .289 .195 .883 .193 .558 .564
LDL, HDL, low- and high-density lipoprotein, respectively; LVEDD, LVESD, left ventricular end-diastolic and -systolic diameter, respectively. *Nonnormal distribution: values shown as median (range), compared using Wilcoxon signed rank test. † Normal distribution: values shown as mean (SD), compared using paired t test.
edema (n ⫽ 7) that could not be explained by deteriorating cardiac function; infectious pneumonia (n ⫽ 7); influenza (n ⫽ 2); and tricuspid valve endocarditis (n ⫽ 1; Table 2). Two cases of interstitial pneumonia occurred, both requiring termination of everolimus und reswitching to a regime with CNIs. Both cases occurred during the first 6 months after switching, both in older patients ⬎65 years, of whom one patient had already been re-transplanted.15 Most adverse effects occurred during the beginning of everolimus treatment, but there were also some adverse effects in the later course. Only 4 cases of rejection occurred after month 6: 1 low-grade rejection episode in 1 patient and 3 rejection episodes in the patient who was switched after recurrent
rejection episodes under different immunosuppressive regimes. Eight patients had to be switched back to CNI therapy after month 6, mainly because of bacterial infections. During the whole study period, 15 patients were reswitched, and the mean time from switching to reswitching was 295 days (range, 31– 684 days). Eight patients required unscheduled readmission to hospital between months 7 and 24. Cardiac Function
There were no significant changes in any echocardiographic parameter from baseline to month 24. DISCUSSION
In this large cohort of maintenance heart transplant patients with CNI-related adverse events, conversion from CNI- to everolimus-based immunosuppression resulted in a significant improvement in renal function that was sustained throughout the 2-year follow-up period. Most other Table 2. Occurrence and Severity of Adverse Events Occurring de Novo After Month 6
Fig 2. Box-and-whisker plot of systolic and diastolic blood pressure at baseline and at 12 and 24 months after conversion from CNI to everolimus. Systolic blood pressure: P ⫽ ns for baseline versus 12 months; P ⫽ .048 for baseline versus 24 months. Diastolic blood pressure: P ⫽ .008 for baseline versus 12 months; P ⫽ .003 for baseline versus 24 months. Circles and asterisk represent outliers.
Adverse Event (AE)
n
Severity
AE Related to Everolimus
Skin problems (acne) Muscle cramp Peripheral edema Anemia/leucopenia Pneumonia infection Influenza infection Severe weight loss Tricuspid valve endocarditis
11 1 7 1 7 2 1 1
Mild, easy to treat Mild Mild-moderate Moderate Severe Severe Severe Severe
Probably yes Unclear Probably yes Unclear Probably yes Unclear Unclear Unclear
EVEROLIMUS AFTER HEART TRANSPLANTATION
CNI-related adverse events resolved, including tremor, peripheral edema, hirsutism, and gingival hyperplasia. Severe adverse events under medication with everolimus were infrequent, although it had to be discontinued in some cases. Our finding that renal function improved after switching from CNI to everolimus is consistent with the results of studies in kidney transplantation18 –20 and other data from heart transplantation,13,21 although an extended delay after transplantation22 or high baseline creatinine levels23 before conversion can obviate any benefit. In our experience, not the duration of exposure to CNIs, but the extent of renal impairment is the key factor for elimination of CNIs. Pathophysiologically, it seems logical that switching should be performed at an early stage of renal dysfunction, before irreparable structural changes occur. Blood pressure increased slightly but significantly over the 24 months after conversion from CNI to everolimus. There was an initial decrease in both systolic and diastolic pressure at month 6 after switching,15 presumably due to CNI withdrawal, and the subsequent rise may have been caused by deterioration of the underlying cardiac disease that led to transplantation and/or progression of earlier structural damage induced by CNI therapy. We observed no clinically relevant changes in lipid status, despite a numeric decrease in the proportion of patients receiving statin therapy. Other trials have shown mixed results regarding lipid parameters after conversion from CNI to everolimus therapy.23–27 The frequency of all CNI-related side effects improved early and significantly after switching to everolimus, suggesting lower neurologic toxicity and less induction of cellular hyperplasia. Once resolved, adverse events did not recur. The rate of adverse events reported during everolimus therapy was within the normal range observed with other immunosuppressive drugs. Most side effects occurred early after conversion and were mild and temporary, usually resolving spontaneously within a few weeks or after a minor reduction to everolimus exposure within the 4 – 8 ng/mL trough level target range.14,15 However, a small number of adverse effects of all severity grades occurred for the first time after month 6. Notably, 13 patients (⬃22%) were converted back from everolimus to a CNI-based regimen owing to adverse events over the course of the 24-month follow-up. The rate of CNI reintroduction may be reduced by refining patient selection for everolimus therapy, particularly by excluding patients after retransplantation and patients ⬎65 years old. In conclusion, the present results suggest that CNI-free immunosuppression using everolimus is an effective and safe option in maintenance of heart transplant patients with stable function in whom elimination of CNI would be desirable because of renal impairment or other complications. Conversion to everolimus before kidney function begins to deteriorate may be beneficial, but this was not explored in this study. Most adverse effects under everolimus occurred early after conversion and generally resolved
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within a few weeks without intervention. The significant improvement in renal function, and resolution of CNIrelated adverse effects, justifies conversion to everolimus in this setting. ACKNOWLEDGMENTS The authors specially thank Caroline Dunstall for editorial assistance. Ms. Dunstall was funded by Novartis.
REFERENCES 1. Keogh A: Calcineurin inhibitors in heart transplantation. J Heart Lung Transplant s23(5 Suppl):S202, 2004 2. Organ Procurement and Transplantation Network reports 1996 –2001. Available at: http://www.optn.org 3. Lindenfeld J, Miller GG, Shakar SF, et al: Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs. Circulation 110:3858, 2004 4. Chapman TM, Perry CM: Everolimus. Drugs 64:861, discussion 873, 2004 5. Eisen HJ, Tuzcu EM, Dorent R, et al: Everolimus for the prevention of allograft rejection and vasculopathy in cardiactransplant recipients. N Engl J Med 349:847, 2003 6. Leet AS, Bergin PJ, Richardson M, et al: Outcomes following de novo CNI-free immunosuppression after heart transplantation: a single-center experience. Am J Transplant 9:140, 2009 7. Kobashigawa J, Miller L, Renlund D, et al, Mycophenolate Mofetil Investigators: A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Transplantation 66:507, 1998 8. Lyster H, Panicker G, Leaver N, Banner NR: Initial experience with sirolimus and mycophenolate mofetil for renal rescue from cyclosporine nephrotoxicity after heart transplantation. Transplant Proc 36:3167, 2004 9. Groetzner J, Kaczmarek I, Meiser B, et al: Sirolimus and mycophenolate mofetil as calcineurin inhibitor–free immunosuppression in a cardiac transplant patient with chronic renal failure. J Heart Lung Transplant 23:770, 2004 10. Valantine H: Prevention of cardiac allograft vasculopathy with Certican (everolimus): the Stanford University experience within the Certican phase III clinical trial. J Heart Lung Transplant 24(4 Suppl):S191, 2005 11. Lehmkuhl H, Hetzer R: Clinical experience with Certican (everolimus) in de novo heart transplant patients at the Deutsches Herzzentrum Berlin. J Heart Lung Transplant 24(4 Suppl):S201, 2005 12. Ross H, Flugfelder P, Haddad H, et al: Cyclosporine reduction in the presence of everolimus: 3-month data from a Canadian pilot study of maintenance cardiac allograft recipients. J Heart Lung Transplant 27:197, 2008 13. Zuckermann A: Clinical experience with Certican (everolimus) in maintenance heart transplant patients at the Medical University of Vienna. J Heart Lung Transplant 24(4 Suppl):S206, 2005 14. Rothenburger M, Stypmann J, Welp H, et al: Calcineurin inhibitor–free immunosuppression using everolimus in long term heart transplant recipients—procedures of switching protocols and side effects. J Heart Lung Transplant 25:S166. [abstract 356], 2006 15. Rothenburger M, Teerling E, Bruch C, et al: Calcineurin inhibitor–free immunosuppression using everolimus (Certican) in maintenance heart transplant recipients: 6 months’ follow-up. J Heart Lung Transplant 26:250, 2007 16. Brignol N, McMahon LM, Luo S, Tse FL: High-throughput semi-automated 96-well liquid/liquid extraction and liquid chromatography/mass spectrometric analysis of everolimus (RAD 001) and cyclosporin a (CsA) in whole blood. Rapid Commun Mass Spectrom 15:898, 2001
1852 17. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31, 1976 18. Lebranchu Y, Thierry A, Toupance O, et al: Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: CONCEPT study. Am J Transplant 9:1115, 2009 19. Weir M, Mulgaonkar S, Pearson T, et al: Mycophenolate mofetil/sirolimus maintenance therapy after calcineurin inhibitor withdrawal in renal transplant recipients: 2-year outcomes of the Spare-the-Nephron (STN) trial. Am J Transplant 9:200, 2009 [abstract 33] 20. Budde K, Becker T, Sommerer C, et al: Analysis of renal function in everolimus/enteric-coated mycophenolate sodium treated de novo renal transplant recipients after calcineurin inhibitor withdrawal: the Zeus Study. Am J Transplant 9:259, 2009 [abstract 237] 21. Gleissner CA, Doesch A, Ehlermann P, et al: Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy. Am J Transplant 6:2750, 2006 22. Schena FP, Pascoe MD, Alberu J, et al: Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal
STYPMANN, ENGELEN, ECKERNKEMPER ET AL allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 87:233, 2009 23. Moro J, Almenar L, Martínez-Dolz L, et al: mTOR inhibitors and their secondary effects in cardiac transplant recipients: a descriptive study. Transplant Proc 39:2365, 2007 24. Vitko S, Margreiter R, Weimar W, et al: Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 5:2521, 2005 25. Ayala M, Morales J, Fierro A, et al: Metabolic changes following conversion from an anticalcineurin-based therapy to an everolimus-based one: a single-center experience. Transplant Proc 40:3265, 2008 26. Tenderich G, Fuchs U, Zittermann A, et al: Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients. Clin Transplant 21:536, 2007 27. Moro JA, Almenar L, Martínez-Dolz L, et al: Tolerance profile of the proliferation signal inhibitors everolimus and sirolimus in heart transplantation. Transplant Proc 40:3034, 2008
C
alcineurin inhibitor (CNI) immunosuppression was introduced for the prevention of rejection after heart transplantation more than 30 years ago,1 resulting in a
dramatic improvement in efficacy. This led to a marked improvement in survival rates,2 but the side effects of CNI therapy—particularly impairment of renal function— became
From the Department of Cardiology and Angiology (J.S., M.A.E., S.E., S.G.), University Hospital Münster, Germany; Department of Medical Informatics and Biomathematics (S.A.), University of Münster, Germany; and Department of Thoracic and Cardiovascular Surgery (J.R.S., M.R., A.R., G.D., H.A.W.), University Hospital Münster, Germany. The first two authors contributed equally to this work.
This study was supported by Novartis Pharma, Basel, Switzerland. Based in part on the doctoral thesis of S.E. Address correspondence to Dr. med. Henryk A. Welp, University Hospital Münster, Department of Thoracic and Cardiovascular Surgery Albert-Schweitzer-Str. 33, D-48149 Münster, Germany. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2010.12.062
Transplantation Proceedings, 43, 1847–1852 (2011)
1847
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increasingly apparent.3 In addition to their nephrotoxic effect, CNI agents increase the risk of arterial hypertension that requires medical intervention; this, in turn, causes further adverse events and reduces adherence.3 Moreover, the incidence of tremor and cosmetic side effects, such as gingival hyperplasia and hirsutism, are common with CNI-based immunosuppression.3 In 2004, the new immunosuppressive drug everolimus (Certican; Novartis Pharma, Basel, Switzerland) became available. Everolimus, a novel inhibitor of p70 S6 kinase, binds to tacrolimus-binding protein 12 and creates an active moiety that effectively blocks the mammalian target of rapamycin (mTOR) and thereby arrests the cell cycle of lymphocytes and vascular smooth muscle cells in the G1 phase.4 Additionally, it exerts immunosuppressive effects via inhibition of interleukin (IL) 2 and IL-15-mediated Tand B-cell proliferation.4 First used clinically in kidney transplant recipients, everolimus was later adopted in maintenance heart transplant recipients.5–7 Patients given everolimus experience superior tolerability and fewer cytomegalovirus infections compared to other regimens.5–7 Previously, CNI-free immunosuppression with an mTOR inhibitor in heart transplantation was focused on sirolimus (Rapamune; Wyeth Pharmaceuticals, Collegeville, PA, USA) in combination with mycophenolate mofetil (MMF; CellCept; Roche, Basel, Switzerland).8,9 After CNI withdrawal, the majority of patients experienced an improvement in renal function.8,9 More recently, promising data for everolimus with low-dose CNI protocols have become available,10 –12 but there are still few reports regarding heart transplant recipients receiving everolimus-based CNI-free immunosuppression.13 We have undertaken a prospective study to evaluate the effect of switching maintenance heart transplant patients experiencing CNI-related adverse events or rejection to everolimus with CNI discontinuation. Patients were monitored for 2 years after switching to everolimus, and to our knowledge this is the first report of such extended follow-up with everolimus-based CNI-free immunosuppression in a large cohort of maintenance heart transplant recipients.
METHODS Study Design This was a prospective, single-arm, single-center study in which maintenance heart transplant patients were switched from CNI therapy (cyclosporine [CsA]) to everolimus. Patients receiving CsA with a clinical indication for switching immunosuppression were eligible to take part in the study unless they had severe preterminal chronic kidney insufficiency or were already receiving hemodialysis. Recruitment took place at a transplant outpatient clinic during the period of April 2005 to April 2007, and patients were followed for 2 years. The study was conducted in accordance with the Declaration of Helsinki and US Food and Drug Administration guidelines for good clinical practice following approval by the local Medical Ethics Committee.
STYPMANN, ENGELEN, ECKERNKEMPER ET AL
Immunosuppression Using a standardized protocol, everolimus was introduced at a fixed dose of 0.75 mg twice daily (1.5 mg/d) with the dose of CsA remaining unchanged for 1 week. In the second week, the baseline CsA dose was reduced to 70%, targeting a trough concentration of 50 ng/mL. The dose of everolimus remained unchanged for a further 2 weeks, at which point CsA was stopped and everolimus dose was adjusted as necessary to target a trough concentration of 4 – 8 ng/mL. Doses of MMF (1,000 mg twice daily) and prednisone (5 mg/d) were unchanged.14,15 All patients received antihypertensive therapy (beta-blockers, calcium antagonists, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers); doses could be adjusted as required. In the minority of patients who were not receiving statins at baseline, statin therapy could be initiated as necessary after introduction of everolimus.
Evaluation Study visits took place at baseline and every subsequent 3 months until 24 months after the switch. At each visit, a physical examination was performed, blood biochemistry was analyzed, and the trough concentration of everolimus was measured. Everolimus concentration was determined by liquid chromatography with mass spectrometry.16 A standard echocardiographic examination and Doppler echocardiography was performed at each study visit. Right ventricular biopsy was performed only in the event of suspected rejection and before and after larger operations with deep surgical wounds, because patients were temporarily returned to CNI-based protocols for such operations. Patient questionnaires were used to assess hirsutism and gingival hyperplasia.
Statistical Analyses Renal function and blood pressure after 6 months were taken as the combined endpoint in the previous study.1 In the present follow-up study, we continued to observe the primary endpoints up to 2 years from baseline. Secondary endpoints were changes in CNI-related adverse events (tremor, hirsutism, gingival hyperplasia, and peripheral edema), changes in lipid status, the occurrence of adverse events and hospital readmissions and rejections following the switch to everolimus. Patients’ characteristics are reported as mean ⫾ standard deviation in case of a normal distribution or as median (25%–75% percentiles) for nonparametric data. Univariate comparisons for continuous variables were made using the t test and Wilcoxon signed rank test, for paired samples data. McNemar and marginal homogeneity tests were performed to compare frequencies within nominal or ordinal data. Additionally, Kaplan-Meier curves were created for the time of first side effect and cessation of everolimus treatment. Statistical significance was assumed when the P value was ⬍.05.
RESULTS
The results of the first 6 months after switching to everolimus, including side effects, have been previously published.15 Herein we present the results from month 7 to month 24. Patient Population
A total of 60 patients were recruited, of whom 49 patients were followed for 12 months and 42 were followed for 24
EVEROLIMUS AFTER HEART TRANSPLANTATION
1849
months. Thirteen patients (21.7%) discontinued owing to adverse events, and 3 patients (5.0%) died of irreversible cardiac decompensation unrelated to the switch to everolimus. There were no signs for rejection in these 3 patients. Two patients (3.3%) withdrew consent. The study population included 53 men and seven women, with an overall mean age of 56.6 ⫾ 13.5 years. At baseline, the mean time after transplantation was 5.7 ⫾ 3.7 years. All patients had undergone orthotopic heart transplantation ⱖ1 year before. In all but 1 case, the indication for switching to everolimus was CNI-related adverse events, comprising renal impairment (n ⫽ 55 [91.7%]), allograft vasculopathy (n ⫽ 8 [13.3%]), peripheral artery occlusive disease (n ⫽ 4 [6.7%]), and malignancy (n ⫽ 2 [3.3%]). One patient was switched due to recurrent grade 3A/B rejection episodes despite several different immunosuppressive regimens. Twelve patients had previously experienced 1 rejection episode of either grade 2 or 3A within the first year after transplantation, and an additional 2 patients had had ⱖ2 rejection episodes of grade 2 or 3A/B. Tremor (n ⫽ 5), gingival hyperplasia (n ⫽ 2), hirsutism (n ⫽ 3), rheumatic disorders (n ⫽ 4), acne (n ⫽ 4), and lipometabolic disorders (n ⫽ 2) had been reported as CNI-related adverse events before conversion. Immunosuppression
At study entry, all patients were receiving CsA and steroids, 56 patients were receiving MMF, and 4 patients were receiving other immunosuppressive regimes. After introduction of everolimus, all patients achieved the target everolimus trough concentration range (4 – 8 ng/mL), although in 2 patients this was attained only after addition of diltiazem as a competitive substrate for cytochrome P450. The mean everolimus trough level was 6.1 ⫾ 1.6 ng/mL at 12 months and 6.0 ⫾ 1.7 ng/mL at 24 months. All patients discontinued CNI, but in 15 cases CNI therapy was reintroduced at a mean of 295 (range, 31– 684 days) days after baseline owing to adverse events (n ⫽ 13) or withdrawal of consent (n ⫽ 2). Renal Function
Mean serum creatinine at baseline was 1.8 (1.4 –2.4) mg/dL, decreasing to 1.4 (1.1–1.9) mg/dL at month 12 (P ⬍ .001 vs baseline), and stabilizing at 1.4 (1.2–2.0) mg/dL at 24 months (P ⫽ .002 vs baseline; Fig 1A). Median serum creatinine values are presented in Table 1. Creatinine clearance (Cockcroft-Gault formula17 also improved significantly from baseline to month 12, a difference that was sustained up to month 24 (Fig 1B; Table 1).
Fig 1. (A) Box-and-whisker plots of serum creatinine at baseline and 12 months and 24 months after conversion from CNI to everolimus. P ⬍ .001 for baseline versus 12 months; P ⫽ .003 for baseline versus 24 months. (B) Box-and-whisker plot of creatinine clearance (Cockcroft-Gault formula17) at baseline and 12 months and 24 months after conversion from CNI to everolimus. P ⬍ .001 for baseline versus 12 months; P ⫽ .017 for baseline versus 24 months. Circles represent outliers.
(ns). Mean total cholesterol increased temporarily during year 1, but did not differ significantly from baseline at month 12 or month 24 (Table 1). Serum concentrations of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides did not change significantly from baseline at either month 12 or month 24 (Table 1). CNI-Related Adverse Events
As reported previously,15 the incidence of CNI-related tremor, hirsutism, gingival hyperplasia, and peripheral edema decreased within the first few weeks after switching to everolimus. This effect was sustained up to month 24, with no de novo cases of CNI-related side effects reported and no deterioration of those adverse events that had not resolved.
Blood Pressure and Lipid Profile
Both systolic and diastolic blood pressure increased modestly but significantly during the 24-month study, although remaining within normal range (Table 1; Fig 2). At baseline, 48 patients (80.0%) were receiving statin therapy compared with 40 patients (66.7%) at month 24
Safety and Tolerability
The majority of everolimus-related adverse events developed shortly after switching.15 Adverse events reported for the first time after month 6 included skin problems (n ⫽ 11), most of which were acne and easily treated; peripheral
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STYPMANN, ENGELEN, ECKERNKEMPER ET AL Table 1. Laboratory and Echocardiography Values at Baseline, Month 12, and Month 24 Month 12 n
Serum creatinine (mg/dL) Creatinine clearance (mL/ min) Systolic blood pressure (mm Hg)* Diastolic blood pressure (mm Hg)* Total cholesterol (mg/dL)† LDL cholesterol (mg/dL)† HDL cholesterol (mg/dL)† Triglycerides (mg/dL)* Ejection fraction (%)* Shortening fraction (%)* LVEDD (mm)† LVESD (mm)†
50 50
Baseline
1.8 (1.5–2.2) 42.0 (22.2)
Month 24 Month 12
1.5 (1.1–2.0) 50.3 (24.1)
P Value
n
⬍.001 ⬍.001
43 43
Baseline
Month 24
1.8 (1.5–2.2) 42.7 (21.6)
P Value
1.5 (1.2–2.1) 48.6 (21.8)
.003 .017
50
120.0 (110.0–125.0)
120.0 (110.0–120.0)
.649
44
120.0 (110.0–120.0)
123.8 (115.6–136.9)
.008
50
70.0 (70.0–80.0)
80.0 (70.0–80.0)
.048
44
75.0 (70.0–80.0)
80.0 (73.1–85.0)
.003
49 15 15 49 38 41 42 42
218.4 (69.8) 103.6 (22.1) 79.8 (33.1) 184.0 (128.0–257.5) 61.0 (56.0–70.3) 34.0 (26.5–42.5) 47.3 (6.1) 31.1 (6.6)
229.0 (66.7) 103.9 (40.8) 79.2 (35.1) 192.5 (131.8–164.5) 63.5 (55.0–70.0) 30.0 (24.0–36.4) 47.3 (8.7) 33.0 (7.6)
.249 .974 .954 .838 .786 .088 .997 .139
43 13 13 43 32 33 37 35
220.6 (72.9) 106.5 (21.4) 77.9 (36.1) 185.0 (129.0–262.0) 60.0 (56.0–69.8) 34.0 (26.5–39.5) 47.4 (6.0) 31.3 (6.5)
220.4 (57.5) 109.3 (39.5) 68.7 (27.0) 200.0 (156.0–263.5) 61.0 (53.3–67.8) 35.7 (27.9–41.1) 47.8 (5.3) 30.7 (6.3)
.987 .800 .289 .195 .883 .193 .558 .564
LDL, HDL, low- and high-density lipoprotein, respectively; LVEDD, LVESD, left ventricular end-diastolic and -systolic diameter, respectively. *Nonnormal distribution: values shown as median (range), compared using Wilcoxon signed rank test. † Normal distribution: values shown as mean (SD), compared using paired t test.
edema (n ⫽ 7) that could not be explained by deteriorating cardiac function; infectious pneumonia (n ⫽ 7); influenza (n ⫽ 2); and tricuspid valve endocarditis (n ⫽ 1; Table 2). Two cases of interstitial pneumonia occurred, both requiring termination of everolimus und reswitching to a regime with CNIs. Both cases occurred during the first 6 months after switching, both in older patients ⬎65 years, of whom one patient had already been re-transplanted.15 Most adverse effects occurred during the beginning of everolimus treatment, but there were also some adverse effects in the later course. Only 4 cases of rejection occurred after month 6: 1 low-grade rejection episode in 1 patient and 3 rejection episodes in the patient who was switched after recurrent
rejection episodes under different immunosuppressive regimes. Eight patients had to be switched back to CNI therapy after month 6, mainly because of bacterial infections. During the whole study period, 15 patients were reswitched, and the mean time from switching to reswitching was 295 days (range, 31– 684 days). Eight patients required unscheduled readmission to hospital between months 7 and 24. Cardiac Function
There were no significant changes in any echocardiographic parameter from baseline to month 24. DISCUSSION
In this large cohort of maintenance heart transplant patients with CNI-related adverse events, conversion from CNI- to everolimus-based immunosuppression resulted in a significant improvement in renal function that was sustained throughout the 2-year follow-up period. Most other Table 2. Occurrence and Severity of Adverse Events Occurring de Novo After Month 6
Fig 2. Box-and-whisker plot of systolic and diastolic blood pressure at baseline and at 12 and 24 months after conversion from CNI to everolimus. Systolic blood pressure: P ⫽ ns for baseline versus 12 months; P ⫽ .048 for baseline versus 24 months. Diastolic blood pressure: P ⫽ .008 for baseline versus 12 months; P ⫽ .003 for baseline versus 24 months. Circles and asterisk represent outliers.
Adverse Event (AE)
n
Severity
AE Related to Everolimus
Skin problems (acne) Muscle cramp Peripheral edema Anemia/leucopenia Pneumonia infection Influenza infection Severe weight loss Tricuspid valve endocarditis
11 1 7 1 7 2 1 1
Mild, easy to treat Mild Mild-moderate Moderate Severe Severe Severe Severe
Probably yes Unclear Probably yes Unclear Probably yes Unclear Unclear Unclear
EVEROLIMUS AFTER HEART TRANSPLANTATION
CNI-related adverse events resolved, including tremor, peripheral edema, hirsutism, and gingival hyperplasia. Severe adverse events under medication with everolimus were infrequent, although it had to be discontinued in some cases. Our finding that renal function improved after switching from CNI to everolimus is consistent with the results of studies in kidney transplantation18 –20 and other data from heart transplantation,13,21 although an extended delay after transplantation22 or high baseline creatinine levels23 before conversion can obviate any benefit. In our experience, not the duration of exposure to CNIs, but the extent of renal impairment is the key factor for elimination of CNIs. Pathophysiologically, it seems logical that switching should be performed at an early stage of renal dysfunction, before irreparable structural changes occur. Blood pressure increased slightly but significantly over the 24 months after conversion from CNI to everolimus. There was an initial decrease in both systolic and diastolic pressure at month 6 after switching,15 presumably due to CNI withdrawal, and the subsequent rise may have been caused by deterioration of the underlying cardiac disease that led to transplantation and/or progression of earlier structural damage induced by CNI therapy. We observed no clinically relevant changes in lipid status, despite a numeric decrease in the proportion of patients receiving statin therapy. Other trials have shown mixed results regarding lipid parameters after conversion from CNI to everolimus therapy.23–27 The frequency of all CNI-related side effects improved early and significantly after switching to everolimus, suggesting lower neurologic toxicity and less induction of cellular hyperplasia. Once resolved, adverse events did not recur. The rate of adverse events reported during everolimus therapy was within the normal range observed with other immunosuppressive drugs. Most side effects occurred early after conversion and were mild and temporary, usually resolving spontaneously within a few weeks or after a minor reduction to everolimus exposure within the 4 – 8 ng/mL trough level target range.14,15 However, a small number of adverse effects of all severity grades occurred for the first time after month 6. Notably, 13 patients (⬃22%) were converted back from everolimus to a CNI-based regimen owing to adverse events over the course of the 24-month follow-up. The rate of CNI reintroduction may be reduced by refining patient selection for everolimus therapy, particularly by excluding patients after retransplantation and patients ⬎65 years old. In conclusion, the present results suggest that CNI-free immunosuppression using everolimus is an effective and safe option in maintenance of heart transplant patients with stable function in whom elimination of CNI would be desirable because of renal impairment or other complications. Conversion to everolimus before kidney function begins to deteriorate may be beneficial, but this was not explored in this study. Most adverse effects under everolimus occurred early after conversion and generally resolved
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within a few weeks without intervention. The significant improvement in renal function, and resolution of CNIrelated adverse effects, justifies conversion to everolimus in this setting. ACKNOWLEDGMENTS The authors specially thank Caroline Dunstall for editorial assistance. Ms. Dunstall was funded by Novartis.
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1852 17. Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 16:31, 1976 18. Lebranchu Y, Thierry A, Toupance O, et al: Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: CONCEPT study. Am J Transplant 9:1115, 2009 19. Weir M, Mulgaonkar S, Pearson T, et al: Mycophenolate mofetil/sirolimus maintenance therapy after calcineurin inhibitor withdrawal in renal transplant recipients: 2-year outcomes of the Spare-the-Nephron (STN) trial. Am J Transplant 9:200, 2009 [abstract 33] 20. Budde K, Becker T, Sommerer C, et al: Analysis of renal function in everolimus/enteric-coated mycophenolate sodium treated de novo renal transplant recipients after calcineurin inhibitor withdrawal: the Zeus Study. Am J Transplant 9:259, 2009 [abstract 237] 21. Gleissner CA, Doesch A, Ehlermann P, et al: Cyclosporine withdrawal improves renal function in heart transplant patients on reduced-dose cyclosporine therapy. Am J Transplant 6:2750, 2006 22. Schena FP, Pascoe MD, Alberu J, et al: Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal
STYPMANN, ENGELEN, ECKERNKEMPER ET AL allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 87:233, 2009 23. Moro J, Almenar L, Martínez-Dolz L, et al: mTOR inhibitors and their secondary effects in cardiac transplant recipients: a descriptive study. Transplant Proc 39:2365, 2007 24. Vitko S, Margreiter R, Weimar W, et al: Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 5:2521, 2005 25. Ayala M, Morales J, Fierro A, et al: Metabolic changes following conversion from an anticalcineurin-based therapy to an everolimus-based one: a single-center experience. Transplant Proc 40:3265, 2008 26. Tenderich G, Fuchs U, Zittermann A, et al: Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients. Clin Transplant 21:536, 2007 27. Moro JA, Almenar L, Martínez-Dolz L, et al: Tolerance profile of the proliferation signal inhibitors everolimus and sirolimus in heart transplantation. Transplant Proc 40:3034, 2008