Abstract
A six-month, multicenter, randomized, open-label study was undertaken to determine whether renal function is improved using reduced-exposure cyclosporine (CsA) versus standard-exposure CsA in 199 de novo heart transplant patients receiving everolimus and steroids ± induction therapy. Mean C2 levels were at the low end of the target range in standard-exposure patients (n = 100) and exceeded target range in reduced-exposure patients (n = 99) throughout the study. Mean serum creatinine at Month 6 (the primary endpoint) was 141.0 ± 53.1 μmol/L in standard-exposure patients versus 130.1 ± 53.7 μmol/L in reduced-exposure patients (P = 0.093). The incidence of biopsy-proven acute rejection ≥3A at Month 6 was 21.0% (21/100) in the standard-exposure group and 16.2% (16/99) in the reduced-exposure group (n.s.). Adverse events and infections were similar between treatment groups. Thus, everolimus with reduced-exposure CsA resulted in comparable efficacy compared to standard-exposure CsA. No renal function benefits were demonstrated; that is possibly related to poor adherence to reduced CsA exposure.
Highlights
One-year survival following cardiac transplantation has risen to approximately 85%, but long-term graft loss remains a significant problem with life expectancy 12 years after transplantation remaining at only 50% [1]
No trial has assessed CsA exposure in de novo everolimus-treated heart transplant recipients based on C2 monitoring, which has been shown to lead to clinical benefits versus conventional C0 monitoring [14,15,16,17,18,19,20]
The well-established nephrotoxicity associated with calcineurin inhibitors has prompted the exploration of immunosuppressive regimens that maintain low rejection rates while minimizing deterioration of renal function
Summary
One-year survival following cardiac transplantation has risen to approximately 85%, but long-term graft loss remains a significant problem with life expectancy 12 years after transplantation remaining at only 50% [1]. Journal of Transplantation [6], it can potentiate CsA-related nephrotoxicity by P450 inhibition of CsA metabolism [7], and serum creatinine levels were higher among patients receiving everolimus in this study. This was found to be due to the use of fixed-dose administration of everolimus, instead of concentration-controlled dosing, and because CsA was given at a standard level of exposure [4]. Everolimus dosing is based on blood concentration and reduced CsA dosing is recommended in the maintenance phase to preserve renal function in cardiac transplant recipients receiving everolimus [8]. No trial has assessed CsA exposure in de novo everolimus-treated heart transplant recipients based on C2 monitoring, which has been shown to lead to clinical benefits versus conventional C0 (trough level) monitoring [14,15,16,17,18,19,20]
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