Everolimus in Different Combinations as Maintenance Immunosuppressive Therapy in Heart Transplant Recipients
Objectives: We examined the experiences of heart transplant recipients receiving everolimus as maintenance therapy in different combinations over a long time.
Materials and Methods: Between 2004 and 2009, forty patients (29 men, 11 women; mean age, 51.6 y) were switched from a routine immunosuppressive regimen to everolimus. Indications were other (2), renal insufficiency (17), cardiac allograft vasculopathy (14), and ongoing cellular rejection (7). Combinations were either along with cyclosporine (24), mycophenolate mofetil (14), or others (2). Indications for the introduction of everolimus including safety, efficacy, different combinations of everolimus, biopsy-proven acute rejections, renal function, and infections were evaluated retrospectively.
Results: Five patients died, 4 of them were still on everolimus at the time of death; they died from intracerebral hemorrhage (1), embolism (1), cardiac arrest (2), and unknown (1). Everolimus was discontinued in 6 patients owing to severe adverse effects: Edema (2), gastrointestinal adverse effects (3), and dermal adverse effects (1). Mean everolimus trough levels were 5.8 µmol/L at 6 months and 4.9 at 60 months. Mean cyclosporine levels were 67.62 µmol/L at 6 months and 47.3 µmol/L at 60 months. Mean serum creatinine levels were stable (147.9 µmol/L after 60 months). Four life-threatening infections (all pneumonia) occurred but resulted in complete recovery.
Conclusions: Everolimus is safe with different immunosuppressive combinations after receiving a heart transplant.
Key words: Renal failure, Proliferation inhibitors, Calcineurin inhibitor-free protocols, Midterm follow-up
The development of new immunosuppressive agents has resulted in good long-term survival rates in the majority of heart transplant recipients. Adverse effects of immunosuppressives (mainly steroids and calcineurin inhibitors) are some of the limiting factors affecting patient survival and quality-of-life, aside from cardiac allograft vasculopathy and malignancy. Proliferation signal inhibitors, such as rapamycin and everolimus (EvA) as alternative immunosuppressive regimens may increase long-term survival after one has a heart transplant.
Eisen and associates showed the efficacy and safety of de novo EvA compared with azathioprine in adult heart transplant recipients.1 Their study reported a delay in development and progression of cardiac allograft vasculopathy but found a worsening in renal function when EvA was combined with fixed-dosage cyclosporine. For that reason, Food and Drug Administration (FDA) approval was refused; however, the European Medicine Agency approved EvA for further studies in 2004.2 In a prospective, multicenter study, Lehmkuhl and associates demonstrated the possibility of dosage reduction of cyclosporine combined with EvA that resulted in stable renal function without loss of efficacy.3 Further studies have confirmed these results and additional favorable effects of EvA.4-6
This study sought to present EvA as maintenance therapy for different indications and combinations over 5 years in heart transplant recipients.
Materials and Methods
Intravenous administration of cyclosporine was given at a dosage of 1.5 mg to 2 per 1000 grams per day. Within 2 to 5 days, intravenous cyclosporine therapy was switched to oral administration (4 mg to 8mg per 1000 g per day), if necessary, by nasogastric tube. Targeted cyclosporine trough levels were 166 to 208 µmol/L (months 1 to 3), 124 to 166 µmol/L (months 3 to 6), 104 to 124 µmol/L (months 6 to 12), and above 83 µmol/L thereafter. When cyclosporine was combined with EvA, targeted trough levels were 100 to 150 (months 3 to 6), and after 6 months, 41 to 83 µmol/L.
Mycophenolate mofetil was started at a dosage of 1000 mg twice a day without trough level controls. Mycophenolate mofetil was reduced if gastrointestinal adverse effects occurred or blood count dropped. Prednisolone was started at 15 mg/d and tapered to 5 mg/d over 6 months.
Everolimus was introduced at 1.0 mg to 1.5 mg daily administered in 2 equal dosages orally. Drug administration was adapted to trough levels between 3.1 µmol/L and 8.3 µmol/L. The immunosuppressive drug to be replaced (mycophenolate mofetil, cyclosporine, or other) was withdrawn within 4 days, beginning with a dosage reduction at day 2 after switching to EvA.
Everolimus, cyclosporine trough levels, blood count, and routine laboratory values were controlled after 1 week and thereafter at routine ambulatory visits when clinically indicated, but at least monthly.
Safety, rejection surveillance
Five patients (3 men and 2 women) died, 4 of them were still receiving EvA treatment at the time of death. Reasons for death are available in Table 2. None of the deaths could be correlated to EvA. Everolimus had to be discontinued in 6 patients (14.6%; 5 men and 1 woman) owning to severe adverse effects (see Table 2). The patient on tacrolimus was switched to cyclosporine without problems after 6 months of EvA conversion; this was due to greater experience of the physician team with EvA and cyclosporine combination. This patient had no immunosuppressive adverse effects for 6 months or thereafter. Tacrolimus through levels were between 5 to 9 ng/mL. No renal impairment was observed. Follow-up of the patients after 60 months, by indication, is shown in Table 2.
In the collective 7 patients that were converted to EvA owing to ongoing rejection, acute cellular rejection was diagnosed at a median of 4.1 ± 2.8 years (range, 0.3 to 8 y) after orthotopic heart transplant. Immunosuppressive trough levels in these patients were within the target area. All patients switched to EvA owing to ongoing cellular rejection were combined with cyclosporine and showed no further rejection episodes greater 1R. For baseline cyclosporine trough levels, as well as 60-month follow-up, cyclosporine and EvA trough levels in these patients are shown in Tables 1 and 3.
Mean serum creatinine levels increased slightly from 151.64 ± 67.184 µmol/L before conversion to 171.496 ± 82.212 µmol/L after 5 years. Within 60 months, 4 patients were placed on hemodialysis: 2 on cyclosporine (creatinine levels before the switch, 159.12 µmol/L, 307.632 µmol/L) and 2 on mycophenolate mofetil (creatinine levels before the switch, 244.868 µmol/L and 353.6 µmol/L). One patient received kidney transplant.
Hemoglobin, cholesterol, triglycerides, leucocytes, and platelet counts for baseline and after 60 months are shown in Tables 1 and 2. Only triglyceride levels were above normal during follow-up, and rose from a mean of 2.16395 mmol/L to 2.71652 mmol/L over 5 years.
So far, EvA has been used mainly with cyclosporine, and results to 5 years are limited. In this observational study, no patient was lost owing to conversion to EvA. Most of the adverse effects were controllable. There seems to be some good arguments for converting to EvA. The best documented is cardiac allograft vasculopathy, already reported in 2003 by Eisen and colleagues.1, 8 Owing to its antiproliferative effect, EvA is also used in oncologic patients with renal carcinoma, pancreatic cancer, and neuroendocrine tumors.9-11 Mycophenolate mofetil has been reported to have antiproliferative effects. Everolimus and mycophenolate mofetil combined might hinder too fast the spread of malignancy and become an interesting combination.9-12 In our observation, during these 5 years, we did not see any de novo malignancy in these patients. One patient converted to EvA owing to a malignancy had to discontinue EvA owing to severe adverse effects.
In heart transplant recipients at risk of developing end-stage renal failure caused by nephrotoxic adverse effects, EvA may be combined with reduced cyclosporine trough levels; or even more-promising, combined with mycophenolate mofetil. In this study, patients with higher creatinine value before conversion were more likely to receive EvA combined with mycophenolate mofetil (158.6 ± 80 µmol/L) than they were with EvA and cyclosporine (122.7 ± 39.6 µmol/L). When combined with cyclosporine, creatinine values rose to 160.1 ± 81.5 µmol/L after 5 years; whereas in combination with mycophenolate mofetil, creatinine values declined to 129.6 ± 18.3 µmol/L (see Figure 2). The results are strengthened by the findings of Rothenburger and colleagues.13 These results led to a new internal policy at our center: Heart transplant recipients with renal impairment are switched to EvA combined with mycophenolate mofetil.
The effectiveness of EvA combined with reduced cyclosporine trough levels for acute cellular rejection has been reported.1, 3, 6, 14 In this study, 7 patients with ongoing cellular rejection episodes ranging from 3 months to 8 years after a heart transplant received EvA. Most of the patients were 2 years post-heart transplant; only two were 7 and 8 years after a heart transplant. It is unusual to have such late rejections episodes, and we do not have a comprehensive explanation for this. All rejection episodes were controlled by EvA in combination with cyclosporine. Careful attention must be paid to avoid over-immunosuppression mainly when EvA is combined with cyclosporine, as these drugs may enhance toxicity. In this study, 2 patients had interstitial pneumonia, which was linked to EvA treatment.15, 16 After pausing EvA during acute infection, EvA was continued in all patients without any recurrence of life-threatening infections.
Everolimus has been approved by the FDA to prevent organ rejection in adult kidney transplant recipients, but it is still under investigation for its use in heart transplants. Everolimus is increasingly used in combination with cyclosporine in European countries. Even in different combinations, EvA may be an alternative immunosuppressive drug in maintenance therapy with good results over 5 years.
Volume : 10
From the Medical University Graz, Department for Surgery, Division for
Transplantation Surgery, Auenbruggerplatz 29, 8036 Graz, Austria
Table 1. Baseline and follow-up data for patients switched to everolimus owing to different indications.
Table 2. Reasons for death and for discontinuation of everolimus.
Figure 1. Showing mean everolimus (EvA, triangle) and cyclosporine ( CsA, rectangle) trough levels (µmol/L) over 5 years.
Table 3. Sixty-month follow-up in patients receiving everolimus separated by indication.
Figure 2. Mean creatinine (Crea) values (µmol/L) (line) over the follow-up and divided by either combination of everolimus and cyclosporine (rectangle) or mycophenolate mofetil (triangle).
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