FTY720, A SPHINGOSINE 1-PHOSPHATE RECEPTOR AGONIST, HAS NO ADVERSE EFFECTS ON CARDIAC CONDUCTION OR RHYTHM IN MAINTENANCE RENAL TRANSPLANT PATIENTS

Abstract

O359* Aims: In clinical trials, the first doses of FTY720 were associated with a mild, transient, reversible reduction in heart rate. This study investigated the cardiac rhythm in renal transplant recipients treated with FTY720 or MMF for at least 12 months. Methods: A total of 421 recipients (FTY720, n=94; MMF, n=327) pooled from phase II studies underwent ECG and 24-hour Holter monitoring. Results were compared between pooled FTY720, MMF groups and the two FTY720 dosing groups (2.5 and 5.0mg). Results: Patient demographics were comparable between groups except for a higher percentage of patients >60 yrs in the MMF group vs. FTY720 (18% vs. 9%, respectively). Analysis of mean hourly HR over 24 hours and during day or night yielded no significant difference between groups. Circadian HR rhythm was maintained and was similar across treatment groups. Analyses based on cardiac medical history, concomitant use of β-blockers, gender or age revealed no differences. The incidence of bradycardia (HR <50bpm); either sustained (for >1min), severe (<35bpm) and sustained and severe (HR <35bpm for >1min) were observed more frequently with MMF. A percentage of patients were maintained on β blockers in the FTY720 and MMF groups (23% vs. 52% respectively). The incidence of bradycardia in these patients was comparable between FTY720 and MMF groups. Serious Holter findings were observed only with MMF (sustained ventricular tachycardia [n=1], Torsade des Pointes [n=1] and second-degree atrioventricular block [n=2]), with no serious findings in the FTY720 group. Autonomic cardiovascular responsiveness (changes between supine and standing systolic and diastolic BP, and HR) was comparable between groups. ECG parameters did not differ significantly between FTY720 and MMF groups for mean PR (155.1 vs 158.0msec) and QTc interval (Bazett 409.7 vs 404.1msec; Frederica 401.9 vs 395.8msec), respectively. No significant differences in these parameters were noted between FTY720 groups supporting the absence of a dose-dependent effect. Conclusions: This study demonstrates the lack of any clinically significant effect of FTY720 on cardiac rhythm or conduction in patients on chronic therapy, thus confirming that the transient reduction in HR observed after the first dose of FTY720 does not persist in the maintenance phase.Figure