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.
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.
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).
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.
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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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
Everolimus; Certican; CNI; Cyclosporine; Tacrolimus; Renal Impairment