Identification of the intermittent nature of trace mitral and/or aortic regurgitation: long-term longitudinal echocardiogram study in children with Dravet syndrome treated with fenfluramine

Abstract

Abstract Background Previous studies have identified the presence of trace valvular regurgitation; however, these studies are typically cross-sectional assessments at a single point in time and provide no information regarding the natural history of trace aortic or mitral regurgitation (AR, MR). To our knowledge no study has assessed valve function in growing children with longitudinal echocardiogram (ECHO) assessments. Purpose To monitor cardiac valve function with regular, standardized ECHOs in patients with Dravet syndrome (DS) treated with fenfluramine for up to 3 years. Methods Patients with DS who completed either of two double-blind Phase 3 clinical trials were eligible to enroll in the open label extension (OLE) study. Patients were to be excluded from entry into the double-blind trials if they exhibited any degree of AR or MR, including trace; or pulmonary artery hypertension (PAH). However, trace MR or AR were not exclusion criteria for continuation into the OLE study. All patients had an ECHO prior to initiation of treatment in the double-blind study, after 6 to 8 weeks of treatment, and at the end of that study. In the OLE study, ECHOs were performed at study week 4, 5, or 6, and every 3 months thereafter. Valve morphology was also examined. Results As of September 1, 2019 a total of 330 patients had enrolled in the OLE study and received at least one dose of fenfluramine. The average age of patients at enrollment was 9.0±4.6 years, 27.6% were <6 years old, and 54.5% were male. The median duration of treatment with fenfluramine in the OLE study was 631 days (min, max; 7, 1086 days), and a total of 2,691 ECHOs had been performed. The point prevalence of trace MR was 10.6% at OLE study entry and ranged from 2.8% to 12.9% thereafter. All instances of trace MR were transient events that reverted to absent or oscillated between trace and absent at later study visits. Four patients demonstrated trace AR at one or more visits and all had reverted to absent at their most recent examination. No changes in valve morphology were observed. Conclusions In this long-term longitudinal ECHO study in DS children treated with fenfluramine, we identified that trace MR and AR were intermittent and not predictive of future valve disease. In all cases trace reverted to absent regurgitation at subsequent ECHOs. No valve morphological changes were seen. The intermittent and transient nature of trace regurgitation observed in this study is consistent with current ECHO guidelines, which consider trace regurgitation to be a normal physiologic phenomenon. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Zogenix, Inc.