Interim Results from an Open-Label Study of Planned Transition from Tacrolimus to Sirolimus vs Continued Tacrolimus in Renal Allograft Recipients: Cardiovascular Safety

Abstract

Introduction: Sirolimus (SRL) is used in renal transplant maintenance protocols to reduce nephrotoxicity resulting from prolonged use of calcineurin inhibitors. We present 1-year cardiovascular (CV) safety data from an ongoing study assessing renal function in kidney transplant patients transitioned from tacrolimus (TAC) to SRL, or continued on TAC. Methods: This 2-year, open-label, randomized, multicenter phase 4 study screened adult patients within 14 days of renal transplantation. Patients received TAC and inosine monophosphate dehydrogenase inhibitor from transplant and were randomized 90-150 days posttransplant to continue TAC or switch to SRL. CV safety data for patients who reached 1y posttransplant were assessed. Comparisons between treatments were made using 1-way analysis of covariance for continuous parameters and Fisher's exact test for categorical parameters. No multiplicity adjustments were made since analyses were considered exploratory. Results: In total, 137 patients (SRL, n=75; TAC, n=62) were randomized and evaluable for safety (mean age ±SD, 53±11y; male, 68%; white, 75%). Prior to randomization, 62% of patients used lipid-lowering drugs, 96% used antihypertensives, 49% used insulin, and 21% used noninsulin diabetes medications, with no differences between treatment groups. A significantly greater percentage of patients on SRL vs TAC reported adverse events (AEs; 89.3% vs 71.0%; P< .01) and discontinuations due to AEs (18.7% vs 1.6%; P=.002). No significant differences in CV-related AEs (Table 1) were noted for SRL vs TAC. Additional CV-related AEs with no differences between treatment groups were atrial fibrillation, bradycardia, left ventricular hypertrophy, myocardial infarction, tachycardia, palpitations, diabetes mellitus, and cerebral ischemia.Significant changes from baseline in total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and weight were observed at 1y for SRL vs TAC (Table 2). No significant changes in high-density lipoprotein cholesterol, glucose or insulin concentrations, blood pressure, or pulse were observed. Postrandomization, the percentage of patients started on lipid-lowering medication was significantly greater for SRL (30.7%) vs TAC (14.5%; P=.04); no significant differences were observed with regard to insulin. One death was reported in each of the treatment groups.Conclusion: Interim safety results show no significant differences between the 2 treatment groups with regard to CV-related events. Among potential CV risk factors, SRL was associated with increased plasma lipid levels compared with TAC.