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Everolimus With Reduced Calcineurin Inhibitor in Thoracic Transplant Recipients With Renal Dysfunction: A Multicenter, Randomized Trial

Gullestad, Lars1,14; Iversen, Martin2; Mortensen, Svend-Aage3; Eiskjær, Hans4; Riise, Gerdt C.5; Mared, Lena6; Bjørtuft, Øystein7; Ekmehag, Björn8; Jansson, Kjell9; Simonsen, Svein10; Gude, Einar10; Rundqvist, Bengt11; Fagertun, Hans E.12; Solbu, Dag13; Bergh, Claes-Håkan11

doi: 10.1097/TP.0b013e3181cbac2d
Clinical and Translational Research
Free
SDC

Background. The proliferation signal inhibitor everolimus offers the potential to reduce calcineurin inhibitor (CNI) exposure and alleviate CNI-related nephrotoxicity. Randomized trials in maintenance thoracic transplant patients are lacking.

Methods. In a 12-month, open-labeled, multicenter study, maintenance thoracic transplant patients (glomerular filtration rate ≥20 mL/min/1.73m2 and <90 mL/min/1.73 m2) >1 year posttransplant were randomized to continue their current CNI-based immunosuppression or start everolimus with predefined CNI exposure reduction.

Results. Two hundred eighty-two patients were randomized (140 everolimus, 142 controls; 190 heart, 92 lung transplants). From baseline to month 12, mean cyclosporine and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. The primary endpoint, mean change in measured glomerular filtration rate from baseline to month 12, was 4.6 mL/min with everolimus and −0.5 mL/min in controls (P<0.0001). Everolimus-treated heart and lung transplant patients in the lowest tertile for time posttransplant exhibited mean increases of 7.8 mL/min and 4.9 mL/min, respectively. Biopsy-proven treated acute rejection occurred in six everolimus and four control heart transplant patients (P=0.54). In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002). Serious adverse events occurred in 66 everolimus patients (46.8%) and 44 controls (31.0%) (P=0.02).

Conclusion. Introduction of everolimus with CNI reduction offers a significant improvement in renal function in maintenance heart and lung transplant recipients. The greatest benefit is observed in patients with a shorter time since transplantation.

1 Department of Cardiology, Oslo University Hospital, Rikshospitalet, and Faculty of Medicine, University of Oslo, Oslo, Norway.

2 Division of Lung Transplantation, Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.

3 Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.

4 Department of Cardiology B, Aarhus University Hospital, Skejby, Aarhus, Denmark.

5 Department of Respiratory Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.

6 Department of Respiratory Medicine, Lund University Hospital, Lund, Sweden.

7 Department of Respiratory Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

8 Department of Cardiology, Lund University Hospital, Lund, Sweden.

9 Department of Cardiology, Heart Center, University Hospital, Linköping, Sweden.

10 Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

11 Department of Cardiology, Sahlgrenska University Hospital, University of Göteborg, Göteborg, Sweden.

12 Capturo AS (statistics) Kjeller, Norway.

13 Novartis Norge AS, Oslo, Norway.

This work was supported by Novartis Scandinavia.

H.F. was funded by Novartis Scandinavia to undertake the statistical analysis, and D.S. is an employee of Novartis Scandinavia. All other authors declare no conflicts of interest.

14 Address correspondence to: Lars Gullestad, M.D., Ph.D., Department of Cardiology, Rikshospitalet University Hospital, Oslo 0027, Norway.

E-mail: lars.gullestad@medisin.uio.no

L.G., M.I., H.E., G.C.R., D.S., and C.-H.B. designed the study. L.G., M.I., S.-A.M., H.E., G.C.R., L.M., Ø.B., B.E., K.J., S.S., E.G., B.R., and C.-H.B. undertook the study and collected data. L.G., M.I., H.E., G.C.R., and D.S. developed the manuscript, following which it was reviewed and approved by all authors. H.E.F. undertook the statistical analysis of data. All authors approved the final version and had full access to the data. L.G., M.I., H.E., and G.C.R. had the final responsibility for the decision to submit this manuscript for publication.

Received 28 September 2009. Revision requested 28 September 2009.

Accepted 30 September 2009.

As attention shifts toward improving long-term outcomes in thoracic transplant recipients, there is a growing emphasis on maintenance immunosuppressive regimens that minimize exposure to calcineurin inhibitors (CNIs) (1). CNI-related renal toxicity (2) is of particular concern in view of the high rate of chronic renal failure observed in heart and lung transplant recipients (3), but other CNI-related complications such as diabetes mellitus, hyperlipidemia, hypertension, and infections can also adversely affect outcomes. Importantly, progressive renal disease, metabolic abnormalities, and infections contribute to the risk of cardiac allograft vasculopathy (4), the leading cause of death after the first year after heart transplantation (5).

The introduction of proliferation signal inhibitors (PSIs) has created a novel opportunity to limit CNI exposure without loss of efficacy. The PSI everolimus inhibits growth factor-driven T-cell and B-cell proliferation (6, 7), offering a complementary mode of action to CNIs, and because of side effects related to CNI treatment, there has been considerable interest in the use of everolimus to achieve CNI-sparing immunosuppression in heart or lung transplant recipients (8, 9). In addition, everolimus suppresses the proliferation of vascular smooth muscle cells (6, 7) that characterizes the intimal thickening observed in cardiac allograft vasculopathy (10). Intravascular ultrasound measurements obtained during a randomized, double-blinded study of everolimus versus azathioprine in 634 de novo heart transplant recipients demonstrated a significant inhibition of intimal thickening in everolimus-treated patients at month 12 (11). In lung transplantation, the first randomized, double-blinded study with everolimus compared with azathioprine in 213 maintenance lung patients also suggested delayed progression of bronchiolitis obliterans with everolimus compared with azathioprine (12), but this could not be evaluated because of a high dropout rate in the everolimus arm after many patients developed significant increases in serum creatinine. It was realized that in future trials the concentrations of everolimus and cyclosporine (CsA) would have to be lowered.

Consistent with experience in renal transplantation (13–15), the available evidence relating to PSI therapy with complete CNI avoidance in de novo heart transplant patients (16) suggests that high rates of acute rejection and intolerance limit the value of this strategy. Conversion of maintenance thoracic transplant patients with deteriorating renal function to a PSI with CNI withdrawal may be effective (17–20), but concerns about the risk of rejection mean that introduction of PSI therapy with continued but reduced CNI exposure may be the most attractive approach. However, to date, data relating to the efficacy and safety of everolimus with CNI minimization in maintenance thoracic transplant recipients are restricted to a single-arm pilot study (21) and a nonrandomized, single-center trial (22).

We report here the results of a multicenter, open- labeled trial in which 282 maintenance heart and lung transplant patients with renal impairment were randomized to remain on standard CNI-based therapy or switch to low-dose everolimus with low-exposure CNI. The primary objective was to investigate whether initiation of everolimus in this setting resulted in an improvement in renal function.

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METHODS

Study Design and Conduct

NOrdic Certican Trial in HEart and lung Transplantation was a 12-month, open-labeled, multicenter, randomized, controlled study undertaken at transplant centers in Scandinavia in which maintenance heart and lung transplant patients were randomized to continue their current immunosuppressive regimen or start everolimus therapy with a predefined reduction in CNI exposure. Written informed consent was obtained from all patients after institutional review board approval, and the study was carried out in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice, applicable local regulations and the Declaration of Helsinki.

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Patient Population

Patients who had undergone a heart or lung transplant ≥1 year previously were eligible if they were older than 18 years, were receiving CsA or tacrolimus, and had a measured or calculated glomerular filtration rate (GFR) ≥20 mL/min/1.73 m2 and <90 mL/min/1.73 m2. For patients with GFR ≥60 mL/min/1.73 m2 and <90 mL/min/1.73 m2, at least one posttransplant GFR value >10% below baseline GFR was required to confirm deteriorating renal function. Recipients of multiorgan transplants were excluded, as were those who had experienced acute rejection within the preceding 3 months. Other exclusion criteria included current or previous treatment with a PSI, platelet count <50,000/mm3, white blood cell count ≤2500/mm3, hemoglobin <8 g/dL, severe hypercholesterolemia (≥8.0 mmol/L) or hypertriglyceridemia (≥6.0 mmol/L) despite conventional optimal treatment, planned coronary revascularization, or a major cardiac event within the preceding 3 months.

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Immunosuppression and Concomitant Medication

Randomization was performed centrally by a computer-based automated system. For patients randomized to everolimus therapy, everolimus was initiated on the morning of day 1 at a dose of 0.75 to 1.5 mg two times per day. At the week 1 visit and thereafter, the dose was adjusted to target blood concentration in the range 3 to 8 ng/mL, measured centrally at Rikshospitalet University Hospital, Oslo, using a fluorescence polarization immunoassay (TDX Abbott-Seradyn Innofluor Assay, Seradyn Inc., Indianapolis, IN). The protocol specified that the dose of CsA or tacrolimus be reduced by at least 20% on day 1. As soon as the everolimus trough concentration was in the range 3 to 8 ng/mL, the CNI dose was reduced further to achieve a CNI trough level reduction of 30% to 70% compared with baseline, with the target of achieving a CsA trough level <75 ng/mL or a tacrolimus trough level <4 ng/mL. For patients in the everolimus group who were receiving CsA and mycophenolic acid (MPA), a 25% to 50% reduction in MPA dose was recommended 1 week after introduction of everolimus with further MPA dose reductions as required, to avoid an inadvertent increase in MPA exposure after CsA dose reduction and the corresponding reduction in CsA-related suppression of MPA levels for a given dose (23, 24). For everolimus-treated patients receiving tacrolimus, MPA treatment was to continue unchanged unless medically necessitated. Concomitant azathioprine was to continue unchanged. Because the CNI levels would be reduced to low values with no previous experience, it was decided to maintain patients on MPA or azathioprine to maintain the overall level of immunosuppression.

In the standard CNI arm, all immunosuppression including MPA and azathioprine was continued unchanged as per local practice.

Corticosteroid therapy, where used, was to continue unaltered in both treatment groups unless a change was required due to medical reasons.

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Evaluation

After screening, study visits took place at baseline (day 0), weeks 1, 2, 3, 4, and 6, and months 3, 6, 9, and 12. GFR was measured at baseline (i.e., within 2 weeks before randomization) and at month 12 using Cr-ethylenediamine tetraacetic acid clearance or an equivalent method. Estimated creatinine clearance values are reported based on the MDRD formula (25). Echocardiography was performed at baseline and month 12 in heart transplant recipients. Lung function (forced expiratory volume in 1 second [FEV1] and forced vital capacity) was measured at baseline, week 6, and month 12 in lung transplant recipients (26). A protocol myocardial biopsy was performed in all heart transplant recipients at week 6, or if clinically indicated, and evaluated locally. Some centers performed additional routine myocardial biopsies. Biopsies in lung transplant recipients were performed only if clinically indicated.

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Statistical Analysis

The primary efficacy variable was change in measured GFR (mGFR) from baseline to month 12. The sample size calculation showed that a population of 150 patients per treatment arm (using a 2:1 ratio, this would comprise 100 heart transplant patients and 50 lung transplant patients) was required for 80% power to detect a mean difference of 6 mL/min/1.73 m2 between treatment groups assuming a two-sided, unpaired t test, a significance level of 0.05, a standard deviation of 16 in each case and a dropout rate of approximately 10%. All analyses of both primary and secondary endpoints were two sided at a significance level of 0.05.

Analysis of covariance (ANCOVA) was used to compare the primary endpoint between treatment groups. The Proc SAS GLM ANCOVA procedure was used (25), with treatment group, type of transplant (heart or lung), center, adjunctive therapy at baseline (MPA or azathioprine), time from transplantation (below/above median), baseline mGFR (below/above median) as fixed effects and patient as random effect, age as a covariate, and the following interaction terms: treatment*mGFR, treatment*time since transplantation, type of transplant*time since transplantation, and treatment*time since transplantation*type of transplant. Between-group comparisons of secondary endpoints used the ANCOVA model with treatment and center as factors and baseline value as covariates, the Wilcoxon Rank-Sum test (for continuous variables) or Fisher's exact test (for categorical variables).

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RESULTS

Study Population

In total, 282 patients were enrolled and randomized (140 everolimus and 142 controls), comprising 190 heart transplant recipients (94 everolimus and 96 controls) and 92 lung transplant recipients (46 in each group). The first patient visit took place during December 2005, with the final visit in March 2009. Two hundred forty-five patients completed the study, with a higher proportion of patients completing in the control arm (93.7% vs. 80.0% in the everolimus group; P<0.001) (Fig. 1). The most frequent reason for study discontinuation was adverse events (everolimus 18, controls 2; P<0.001).

FIGURE 1.

FIGURE 1.

In the heart and lung transplant cohorts, mean time posttransplant was 76±54 months and 52±37 months, respectively. mGFR was higher in the heart transplant cohort at baseline (mean 49.8±14.1 mL/min) compared with lung transplant recipients (43.1±13.3 mL/min). Baseline characteristics, including graft function, were similar between treatment groups with the exception of recipient age and time posttransplant (Table 1). In both cases, the between-group difference was accounted for by the heart transplant subpopulation (mean age: everolimus 60.2±9.3 years, controls 55.3±12 years [P=0.002]; mean time posttransplant: everolimus 68.4±48.2 months, controls 83.1±57.7 months [P=0.06]). There were no significant differences in baseline characteristics between groups in the lung transplant recipients.

TABLE 1

TABLE 1

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Immunosuppression and Concomitant Medication

Mean everolimus dose at baseline and months 3, 6, and 12 was 1.6±0.4 mg/day, 1.3±0.6 mg/day, 1.2±0.6 mg/day, and 1.2±0.6 mg/day, respectively. Everolimus trough level remained within target range (3–8 ng/mL) throughout the study. The proportion of patients receiving CsA or tacrolimus was similar in both groups (Table 1). Mean CsA trough level was consistently within target range after introduction of everolimus (Fig. 2a), but tacrolimus trough level remained above the target maximum of 4 ng/mL (Fig. 2b). From baseline to month 12, mean CsA and tacrolimus trough levels in the everolimus cohort decreased by 57% and 56%, respectively. In the control arm, the decrease in mean CsA dose (from 200±61 mg/day to 182±59 mg/day) and mean trough level (from 140±62 ng/mL to 112±47 ng/mL) from baseline to month 12 were significant (both P<0.001), whereas for tacrolimus, neither the change in dose nor the change in trough level was significant (P=0.79 and P=0.77, respectively). Use of MPA, azathioprine, and corticosteroids was similar between groups (Table 1). The mean dose of mycophenolate mofetil was 2000±711 mg at baseline and 1932±722 mg after 1 month, after which it remained stable.

FIGURE 2.

FIGURE 2.

Approximately three quarters of patients were receiving statin therapy at study entry (89% of heart transplant recipients). No differences were observed between treatment groups for use of statins, beta blockers, calcium channel blockers, or angiotensin converting enzyme inhibitors either at baseline (Table 1) or during the study (data not shown).

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Renal Function

At baseline, mean mGFR was approximately 7 mL/min higher in the heart transplant cohort compared with lung transplant patients. Mean mGFR was similar between treatment groups at baseline, both overall, and within the heart and lung transplant cohorts (Table 2). From baseline to month 12, mGFR increased by a mean of 4.6 mL/min in the everolimus cohort but decreased by 0.5 mL/min in controls. The between-group difference was statistically significant (P<0.0001), such that the primary endpoint was met. Similar findings were observed when patients were analyzed according to whether they were receiving CsA or tacrolimus (Table 2). Heart transplant recipients showed a greater benefit in mGFR after conversion to everolimus (mean increase 5.8 mL/min) compared with lung transplant patients (2.3 mL/min) (Table 2).

TABLE 2

TABLE 2

Covariance analysis showed that patients with a shorter time posttransplant experienced the greatest improvement in mGFR after conversion to everolimus (Fig. 3). Heart and lung transplant patients who were in the lowest tertile for time posttransplant had a mean increase of 7.8 mL/min and 4.9 mL/min, respectively, in mGFR at 12 months after conversion to everolimus, whereas patients in the highest tertile showed no improvement during the 12-month study. The results of an ANCOVA analysis of change in mGFR for different patient subpopulations are presented in Figure 4. These confirmed the finding that the benefit of conversion to everolimus-based immunosuppression was not only greatest in patients with a shorter (≤median) time posttransplant and in heart transplant recipients but also demonstrated a preferential benefit in male recipients, those receiving concomitant MPA therapy and in patients with lower baseline mGFR (≤median [48.5 mL/min]). The mean between-group difference between change in mGFR from baseline to month 12 was 7.9 (95% confidence interval: 4.9–10.9) in patients with baseline mGFR ≤median and 2.2 in patients with baseline mGFR >median (95% confidence interval: −1.5 to 6.0).

FIGURE 3.

FIGURE 3.

FIGURE 4.

FIGURE 4.

Changes observed in estimated GFR (eGFR and modification of diet in renal disease study group [MDRD]) and serum creatinine confirmed the differences between treatment groups observed for mGFR, with improvements in renal function becoming apparent within the first few weeks after introduction of everolimus. At weeks 6 and 12, eGFR had increased by 4.4 mL/min and 4.9 mL/min, whereas serum creatinine had decreased by 6.8 mmol/L by week 6, remaining unchanged at 12 months. Values for serum creatinine at baseline were 130±34 μmol/L and 133±35 μmol/L in the everolimus and control arms, when compared with 125.5±51 μmol/L and 136.5±50 μmol/L at month 12.

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Efficacy

Biopsy-proven acute rejection (BPAR) that received treatment occurred in six everolimus patients and four control patients by month 12 (P=0.54). By month 12, 42 patients had experienced 59 episodes of rejection of any type, that is, treated or untreated (22 everolimus patients and 20 controls, P=0.74). The total number of rejection episodes observed on clinically indicated or protocol biopsies by month 12 was 29 in the everolimus arm (heart transplants: 14 grade IA, 4 grade IB, 2 grade 2 and 5 grade 3A; lung transplants 3 grade AI and 1 grade A2) and 30 in the control arm (heart transplants: 19 grade IA, 4 grade IB, 2 grade 2, and 5 grade 3A; no episodes in lung transplants).

Three patients died in the everolimus group, due to sudden death, cardiac arrest and, heart failure in one case each. There were no other cases of graft loss during the study.

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Safety

In total, 138 everolimus patients (98.6%) and 127 control patients (89.4%) experienced one or more adverse event (P=0.002) (668 adverse events in the everolimus group and 414 in controls). The most frequently reported adverse events in the everolimus cohort were edema (29.3% of patients), nasopharyngitis (20.7%, mostly common cold), diarrhea (17.1%), pneumonia (13.6%), and leukopenia (11.4%). In the control arm, the most frequent adverse events were nasopharyngitis (19.0%), edema (8.5%), pneumonia (7.7%), hypertension (7.0%), and headache (6.3%). The incidence of edema (29.3% vs. 8.5%; P<0.001), diarrhea (17.1% vs. 5.6%; P=0.003), and leukopenia (11.4% vs. 0%; P<0.001) was significantly more frequent in the everolimus cohort.

There were 81 serious adverse events reported in 66 everolimus patients (46.8%) and 60 serious adverse events in 44 control patients (31.0%) (P=0.02), of which the most frequent were infections (32 everolimus, 19 controls, P<0.001), neoplasms (eight in each group), and thromboembolic/vascular events (eight everolimus and six controls). Infections included 20 and 10 cases of pneumonia, respectively. Other than the rate of infections, there were no marked differences in the incidence of any serious adverse event between treatment groups. One case of bone marrow toxicity occurred as a serious adverse event, in an everolimus-treated patient. Adverse events led to study discontinuation in 18 everolimus patients (recurrent rejection and pulmonary embolism (2), pneumonia (4), obliterative bronchiolitis, alveolar proteinosis, leg edema, leg edema/abdominal pain, gout, arthritis/increasing muscular pain, nausea/diarrhea/weight loss/muscle atrophy, mouth ulcers, mouth ulcers/abscess below breast, swollen throat, increased creatine kinase/shivering/elevated blood glucose/vomiting/fatigue), and two control patients (subarachnoid bleeding and respiratory failure). Mean everolimus trough level was numerically, but not significantly, higher during the first 3 weeks after conversion in the 18 everolimus patients who discontinued the study.

Immunosuppression levels were investigated in the 20 everolimus-treated patients in whom pneumonia was reported as a serious adverse event. During the first 3 months postconversion, mean everolimus trough concentration tended to be higher among those with pneumonia (n=20, 6.6±2.1 ng/mL) than pneumonia-free patients (n=120, 5.9±1.9 ng/mL; P=0.11). CsA concentration during the same period did not differ (77±16 ng/mL among those with pneumonia vs. 82±25 ng/mL for pneumonia-free patients, P=0.27).

The change in lipid levels from baseline to month 12 was significantly greater in the everolimus cohort versus controls (total cholesterol, 0.6±0.8 mmol/L vs. 0.1±0.9 mmol/L, P<0.001; LDL-cholesterol, 0.4±0.8 mmol/L vs. 0.1±0.7 mmol/L, P<0.001; HDL-cholesterol, 0.0±0.5 mmol/L vs. −0.1±0.3 mmol/L, P=0.09; LDL/HDL ratio, 0.3±0.6 vs. 0.2±0.5, P=0.22; triglycerides, 0.3±0.9 mmol/L vs. 0.0±0.6 mmol/L, P=0.001). Changes in liver function markers during the 12-month study also showed a significant difference between groups, but these were considered clinically unimportant. Between-group differences in the change from baseline to month 12 in serum potassium (everolimus −0.2±0.4 mmol/L, controls −0.1±0.4 mmol/L, P<0.001) and heart rate (everolimus 2±12 bpm, controls −2±14 bpm, P=0.004) were not considered to be clinically significant. There was no evidence of bone marrow toxicity, with no change in hemoglobin levels, white blood cell count, and platelet count.

Left ventricular end diastolic dimension and ejection fraction remained stable in both groups in the heart transplant cohort, with a mean change in left ventricular end diastolic dimension from baseline of 0.0±0.5 cm and −0.1±0.4 cm and in ejection fraction from baseline of −1±10% and 0±8% in the everolimus and control groups, respectively. Forced vital capacity decreased in the everolimus cohort from baseline to month 12 (−0.17±0.31 L) but not the controls (0±0.24 L), a difference that was significant (P=0.02). The mean change in FEV1 during the 12-month study did not differ between groups (everolimus −0.17±0.28 L/s, controls −0.10±0.18 L/s).

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DISCUSSION

Results from this multicenter, randomized trial show that introduction of everolimus with a concurrent large reduction in CNI exposure in thoracic transplant recipients leads to a significant improvement in renal function at 1 year without loss of immunosuppression efficacy. The change in mGFR from baseline to month 12 was approximately 5 mL/min higher in the everolimus cohort versus controls, a difference that was statistically significant, such that the primary endpoint was achieved.

Patients with the shortest time posttransplant showed the greatest benefit after conversion to everolimus, with mGFR increasing by approximately 8 mL/min 1 year after conversion in heart transplant patients who were in the lowest tertile of time since transplantation. Notably, heart transplant patients >96 months or lung transplant patients >56 months posttransplant obtained no benefit from conversion to everolimus. This time dependency of renal function improvement is not unexpected, because CNI-related arteriolar lesions have been shown to increase progressively after kidney transplantation and are generally irreversible once established despite CNI dose reductions (28). It would seem that the most effective approach is to introduce everolimus early after transplantation, acting preemptively before extensive, irreversible CNI-related renal damage has occurred. Another group that showed most benefit was those with the lowest baseline GFR. Thus, those patients with the lowest GFR and shortest exposure to CNI were best placed to show an improvement in renal function after CNI reduction. The results of this study are at variance with a recent randomized study in heart transplant recipients reported by Groetzner et al. (29) in which renal function improved only after CNI withdrawal and not after CNI reduction, as observed in our trial. Although their population was similar in age and mean time posttransplant (66 months) to that of our heart transplant cohort (61 months), their study was smaller (with only 63 patients compared with 282 in this study), and baseline creatinine clearance was approximately 10 mL/min lower in their trial. These differences and the smaller reduction in CNI exposure (∼40% compared with ∼57% here) are likely to account for the absence of renal function improvement in their CNI reduction arm.

There was a higher baseline mGFR and a greater increase in mGFR in the heart transplant patients after conversion to everolimus compared with lung transplant patients, despite the longer average time posttransplant among the heart cohort. This is likely to reflect the more rapid decline in renal function observed after lung transplantation that has previously been documented (3, 30).

After introduction of everolimus, CsA trough level was decreased by 57%, achieving a mean of 56 ng/mL in accordance with the study protocol. To our knowledge, this is the most extensive reduction in CsA exposure achieved in thoracic transplant recipients with everolimus therapy. In the single-arm CADENCE pilot study (31), conducted in heart transplant recipients ≥1 year posttransplant, a reduction of approximately 50% in CsA trough levels after introduction of everolimus was associated with a significant improvement in eGFR (∼7 mL/min) at 1 year without increased risk of BPAR. In a single-center retrospective analysis of 37 heart transplant patients an average of 5.7 years posttransplant, Schweiger et al. (22) reported a mean CsA trough level reduction of 34% and stable renal function after conversion. Our experience suggests that a more profound reduction in CsA exposure is beneficial and can be undertaken without jeopardizing immunosuppressive potency. Although mean tacrolimus exposure (C0) decreased by 56%, it did not reach the target of 4 ng/mL or below, largely due to the minimum capsule size of 0.5 mg, which meant that the dose could not be reduced further. Interestingly, the decrease in GFR observed in the control arm during the study (0.5 mL/min, i.e., 1%) was smaller than expected (29), most likely due to the significant reduction in CsA exposure among control patients. Thus, if the CsA exposure had been kept constant, the difference between the two groups might have been even greater.

There was no evidence that conversion to everolimus with CNI reduction impaired immunosuppressive efficacy. Although there were numerically more BPAR events in the everolimus group, the incidence of BPAR ≥3A was low and similar in both arms, as was the mean severity of all BPAR events. The changes in FEV1 were small and within the expected range (32), and there was no difference between treatment groups.

The overall rate of adverse events, and the incidence of edema, diarrhea, and leukopenia, were higher in the everolimus cohort. Additionally, the rate of serious adverse events was higher in the everolimus arm and more everolimus-treated patients discontinued due to adverse events compared with controls. This was partly due to a greater number of infections reported as serious adverse events in the everolimus- treated patients, most notably pneumonia. The open-labeled nature of the study may have made a contribution to this difference: for example, of the 20 everolimus patients who developed pneumonia as a serious adverse event, four discontinued compared with none of the control patients with pneumonia. It is possible that quadruple therapy including everolimus led to overimmunosuppression. In accordance with this, the patients who developed pneumonia tended to have higher everolimus trough concentrations the first 3 months after conversion and somewhat lower CsA during the same period compared with those without pneumonia (the difference was nonsignificant, but there were only 20 everolimus-treated patients with pneumonia). It seems probable that the CsA dose was reduced in response to overimmunosuppression, whereas it may have been more appropriate to lower everolimus dose. It could be speculated that such an approach might have reduced the rate of pneumonia in the everolimus arm, but this cannot be confirmed. The independent Data Monitoring Committee found a possible relationship between the higher incidence of serious adverse events in the everolimus group and everolimus blood concentration levels in the upper part of the recommended target range of 3 to 8 ng/mL. As a consequence, the everolimus levels were reduced during the study and we subsequently observed a reduced frequency of pneumonia.

The study benefited from direct measurement of GFR, and from good adherence to immunosuppressive protocol, and was adequately powered. In study design, we recognize that a double-blinded approach is ideal, but this was not realistic in this setting due to the need to titrate everolimus and CNI doses in the conversion arm. The randomization process resulted in a shorter mean time posttransplant in the everolimus cohort, accounted for by fewer transplant patients who were more than 5 years since transplantation. Although this is a potentially confounding factor for the change in mGFR, the subanalysis of patients <36 months posttransplant (i.e., excluding any difference in time posttransplant) demonstrated an even more marked benefit with everolimus, so differences cannot solely be attributed to the longer time posttransplant in the control group. Randomization also resulted in a small but significant difference in recipient age between treatment arms (∼3 years), but this was not considered to have exerted a relevant effect on outcomes.

In conclusion, introduction of everolimus with CNI reduction achieves a significant improvement in renal function in maintenance heart and lung transplant recipients up to 8 years after transplantation. The greatest benefit is observed when everolimus is initiated relatively soon after transplantation, although an improvement in renal function is still observed up to 8 years posttransplant in heart transplant recipients and up to 5 years for lung transplant patients. Relatively profound reduction of CNI exposure is feasible in this setting without loss of efficacy. However, further investigation is required to develop conversion protocols that minimize withdrawal of everolimus due to adverse events.

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ACKNOWLEDGMENTS

The authors gratefully recognize the leading contribution made to this study by Claes-Håkan Bergh, who sadly died recently. The authors also express their gratitude to all other NOCTET investigators, coinvestigators, and study nurses: Copenhagen, Charlotte Just Poulsen; Ida Steffensen (study investigator); Göteborg, Bengt Rundqvist (study investigator), Katarina Karlson and Ulla Nyström; Lund, Björn Kornhall, Öyvind Reitan (study investigators), Liselotte Persson (study coordinator); Oslo, Anne Relbo, Ingelin Grov, Anne Toril Klette, Hege Merethe Hagen and Dag Bergli (all nursing team members). The authors are also grateful to members of the Data Monitoring Committee: Prof. Karl Swedberg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden (Chairman, cardiologist), Prof. Anders Hartmann, Oslo University Hospital (nephrologist), Prof. Asgeir Dirksen, Gentofte University Hospital, Copenhagen, Denmark (pneumunologist) and Prof. Hans Wedel, Nordic School of Public Health, Gothenburg, Sweden (statistician), and to Stein Bergan at the Central Laboratory, Rikshospitalet University Hospital, Oslo, Norway (everolimus blood concentration measurements). Caroline Dunstall provided editorial support.

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REFERENCES

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    Keywords:

    Everolimus; Certican; CNI; Cyclosporine; Tacrolimus; Renal Impairment

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