Everolimus Initiation With Early Calcineurin Inhibitor Withdrawal in De Novo Heart Transplant Recipients: Three-Year Results From the Randomized SCHEDULE Study

Am J Transplant. 2016 Apr;16(4):1238-47 doi: 10.1111/ajt.13588.
Abstract

In a randomized, open-label trial, de novo heart transplant recipients were randomized to everolimus (3-6 ng/mL) with reduced-exposure calcineurin inhibitor (CNI; cyclosporine) to weeks 7-11 after transplant, followed by increased everolimus exposure (target 6-10 ng/mL) with cyclosporine withdrawal or standard-exposure cyclosporine. All patients received mycophenolate mofetil and corticosteroids. A total of 110 of 115 patients completed the 12-month study, and 102 attended a follow-up visit at month 36. Mean measured GFR (mGFR) at month 36 was 77.4 mL/min (standard deviation [SD] 20.2 mL/min) versus 59.2 mL/min (SD 17.4 mL/min) in the everolimus and CNI groups, respectively, a difference of 18.3 mL/min (95% CI 11.1-25.6 mL/min; p < 0.001) in the intention to treat population. Multivariate analysis showed treatment to be an independent determinant of mGFR at month 36. Coronary intravascular ultrasound at 36 months revealed significantly reduced progression of allograft vasculopathy in the everolimus group compared with the CNI group. Biopsy-proven acute rejection grade ≥2R occurred in 10.2% and 5.9% of everolimus- and CNI-treated patients, respectively, during months 12-36. Serious adverse events occurred in 37.3% and 19.6% of everolimus- and CNI-treated patients, respectively (p = 0.078). These results suggest that early CNI withdrawal after heart transplantation supported by everolimus, mycophenolic acid and steroids with lymphocyte-depleting induction is safe at intermediate follow-up. This regimen, used selectively, may offer adequate immunosuppressive potency with a sustained renal advantage.

CET Conclusion
Reviewer: Mr Simon Knight, Centre for Evidence in Transplantation, The Royal College of Surgeons of England.
Conclusion: This manuscript reports medium-term (36 month) outcomes from the SCHEDULE study, in which de novo cardiac transplant recipients were randomised to a gradual early switch from CNI to everolimus, or continuation of CNI. At 36 months, there was a significantly higher measured GFR in the everolimus group, along with reduced progression of allograft vasculopathy on IVUS in intention-to-treat analysis. These benefits are seen despite the earlier report of higher rates of acute rejection in the everolimus arm. The study also demonstrated a higher incidence of adverse events during months 12-36 in the everolimus arm. In particular diarrhoea, acne and respiratory tract infections were higher in everolimus-treated recipients. It should also be noted that only around 75% of patients underwent IVUS. Whilst the increased risk of early acute rejection does not appear to affect 3-year allograft vasculopathy or survival, longer-term follow-up will be required to confirm the safety of this regimen.
Expert Review
Reviewer: Dr Christina S. Jenkins, Dr Erin M. Schumer and Dr Mark S. Slaughter, .Department of Cardiovascular and Thoracic Surgery, University of Louisville, USA
Conflicts of Interest: No
Clinical Impact Rating 3
Review: Andreassen, et. al. report three year outcomes from the SCHEDULE study, comparing outcomes of de novo cardiac transplant recipients randomized to two separate immunosuppression regimens: everolimus with early calcineurin inhibitor withdrawal (CNI) versus standard CNI therapy. Patients receiving treatment with everolimus had significantly higher mGFR at three years compared to patients undergoing standard CNI therapy, and multivariate analysis demonstrated that choice of immunosuppression regimen was an independent predictor of mGFR at 3 years. The coronary artery maximal intimal thickness determined by IVUS was also significantly less in the everolimus group, although no significant differences in cardiac allograft vasculopathy were found. Despite these benefits, patients in the everolimus group reported more serious adverse events during the study period and, as previously reported, had higher rates of biopsy-proven acute rejection in the first year after transplant. This study had strict inclusion and exclusion criteria, limiting the generalizability of the study; however, the results suggest that everolimus could benefit patients at high risk for renal compromise following cardiac transplant by limiting progressive renal dysfunction seen with standard immunosuppression with CNI. Use of everolimus may also offer reduction in coronary intimal thickness over time, but the clinical significance of this reduction is unknown. With the higher rate of adverse events in the everolimus arm of the study, long term analysis is needed to determine if the benefit of preserved renal function is maintained beyond three years, and if so, if this benefit outweighs the risk of adverse events in these selected patients
Methodological quality
Jadad score 2
Allocation concealment YES
Data analysis AVAILABLE CASE ANALYSIS
Score based on Andreassen AK, et al. SCHEDULE Investigators. Everolimus initiation and early calcineurin inhibitor withdrawal in heart transplant recipients: A randomized trial. American Journal of Transplantation,14: 1828-1838, 2014.
Study Details
Aims: To provide long term results of the effect of early everolimus initiation with calcineurin inhibitor (CNI) withdrawal on renal function and the rate of cardiac allograft vasculopathy (CAV) progression compared to a conventional CNI-based regimen.
Interventions: Participants were randomized to either, everolimus, low-exposure cyclosporine, mycophenolate mofetil (MMF) and corticosteroids with cyclosporine withdrawal after 7 weeks (everolimus group), versus cyclosporine, MMF and corticosteroids (cyclosporine group).
Participants: 115 de novo heart transplant recipients aged 18-70 years
Outcomes: The primary outcome was mean measured glomerular filtration rate (GFR). Other measured outcomes included GFR, estimated GFR, left ventricular function, coronary intravascular ultrasound (IVUS), blood pressure, laboratory data, trough concentrations of everolimus and cyclosporine, concomitant medication and adverse events.
Follow Up: 36 months
Metadata
Funding: Industry funding
Publication type: Multicenter Study, Randomized Controlled Trial, Randomised Controlled Trial
Trial registration: ClinicalTrials.gov - NCT01266148
Organ: Heart
Language: English
Author email: lars.gullestad@medisin.uio.no
MeSH terms: Adolescent; Adult; Aged; Allografts; Calcineurin Inhibitors; Cyclosporine; Everolimus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Heart Diseases; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Function Tests; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Risk Factors; Transplant Recipients; Vascular Diseases; Withholding Treatment; Young Adult; 0 (Calcineurin Inhibitors); 0 (Immunosuppressive Agents); 83HN0GTJ6D (Cyclosporine); 9HW64Q8G6G (Everolimus)