Randomized Controlled Trial of Sirolimus Conversion in Cardiac Transplant Recipients With Renal Insufficiency

Abstract

Clinical Trials. gov identifier number: NCT00369382This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73m 2 were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. −1.4 mL/min/1.73 m 2 , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

Sirolimus Conversion After Heart Transplant: Risk Factors for Acute Rejection and Predictors of Renal Function Response

“…Sirolimus has not been associated with nephrotoxic effects similar to those of CNIs (13)(14)(15). In a recent multinational, randomized, openlabel study, cardiac transplant patients who experienced mild-to-moderate renal insufficiency while receiving CNI therapy exhibited significantly better renal function at 1 year following conversion to sirolimus compared with continuation on a CNI (16). However, conversion was associated with an attendant risk of biopsy-confirmed acute rejection (BCAR) and a higher discontinuation rate attributable to adverse events.…”

“…Patient disposition and characteristics of the 116 patients randomized correctly to study treatment and included in the ITT population have been previously reported (16). In total, 57 patients were randomized to conversion to sirolimus, and 59 patients were randomized to continue on CNIs ( Figure 1).…”

“…Protocol-mandated biopsies were performed at 2-6 weeks following completion of conversion (16). BCAR included all rejections of Grade 3A (per the International Society for Heart and Lung Transplantation [ISHLT] 1990)/2R (per ISHLT 2004) or higher, and those below Grade 3A/2R accompanied by hemodynamic compromise or who required treatment.…”

Effects of Immunosuppressive agents on neutrophils inflammatory response in humans: An inflammatory perspective on coronary allograft vasculopathy

“…SIR is a macrocyclic immunosuppressive agent that was originally investigated for its anti-fungal properties [75] . The use of sirolimus (SIR) has been proposed as a substitute for CNIs in cardiac transplant patient based on its role in renal function preservation and prevention of chronic allograft vasculopathy [76][77][78] . In fact, SIR, can prevent vascular remodeling and neointimal proliferation, two key components of CAV, by inhibiting smooth muscle cell (SMC) and fibroblast proliferation [7,28,[79][80][81][82][83][84][85][86] .…”

In Pursuit of Renal Preservation After Heart Transplantation: Inching Closer?

“…In a multi-center, prospective randomized, open-label comparative study of 116 heart transplant recipients who had already developed mild to moderate renal insufficiency, conversion from CNI to sirolimus at a mean 3.9 years after transplant revealed clinically modest but statistically significant improvement in creatinine clearance at 1 year (þ3.0 with sirolimus substitution vs. À1.4 mL/min/1.73 m 2 CNI continuation, p ¼ 0.004) (2). In this study, protocol biopsies were mandated only in the sirolimus group but again an increased risk of rejection in the CNI-free cohort was observed with an 18% rate occurring within 2 months of conversion.…”