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

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.

Circulating delta-like Notch ligand 1 is correlated with cardiac allograft vasculopathy and suppressed in heart transplant recipients on everolimus-based immunosuppression

“…Similar to the original report, 31 there was a trend association between biopsy-proven acute rejection (BPAR) and the use of EVR (32% vs 13%, P = .056), and the use of CNI, respectively. As depicted in Table S1, we observed, however, no difference in change in DLL1 between …”

“…31 A total of 70 patients (CNI, n = 34; EVR, n = 36) with plasma collected at ≥3 timepoints: 7-11 weeks (i.e., baseline), 6 months, 1 year, and 3 years post-HTx, were included in the present follow-up substudy. The 2 regimens were initiated no later than the fifth postoperative day.…”

Everolimus and Malignancy after Solid Organ Transplantation: A Clinical Update

“…Observational studies of everolimus with reduced-exposure CNI from time of liver transplant, one strategy that could be advantageous for risk of HCC, have also shown good efficacy [94, 95] but more robust data are awaited. Randomized studies in which kidney [38, 96, 97], liver [76–78], or heart [45] transplant patients were converted early from a CNI-based regimen to CNI-free everolimus therapy have either maintained efficacy or been associated with an increase in mild episodes of biopsy-proven acute rejection. When considering introduction of everolimus to minimize risk for malignancy, the patient's immunological risk status thus must be carefully considered.…”

Hyaluronic Acid-Decorated Chitosan Nanoparticles for CD44-Targeted Delivery of Everolimus

“…EVE is successfully used in combination with cyclosporine and corticosteroids both in adult and paediatric population of renal- and cardiac-transplant recipients, but far less often for lung-transplant recipients [4,5,6,7]. Particularly for these patients, survival continues to be challenged by chronic allograft dysfunctions, such as obliterative bronchiolitis or its clinical correlate bronchiolitis obliterans syndrome (BOS), a fibrous obliteration of small airways caused by mesenchymal cells (MSc) abnormal proliferation, and extracellular matrix deposition causing bronchiolar occlusion and organ rejection [8,9,10,11].…”