A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation

Anti-arrhythmic drugs (AAD) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current IKur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects.A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1-70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective IKur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients.The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the 4 treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up.DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective IKur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.A. John Camm, Paul Dorian, Stefan H. Hohnloser, Peter R. Kowey, Benoît Tyl, Yongbin Ni, Victoria Vandzhura, Pierre Maison-Blanche, Mirko de Melis, and Prashanthan Sanders, for the DIAGRAF-IKUR study investigator

Differences in clinical and functional outcomes of atrial fibrillation in women and men: two-year results from the ORBIT-AF Registry

IMPORTANCE:Despite the frequency of atrial fibrillation (AF) in clinical practice, relatively little is known about sex differences in symptoms and quality of life and how they may affect treatment and outcomes. OBJECTIVE:To determine whether symptoms, quality of life, treatment, and outcomes differ between women and men with AF. DESIGN, SETTING, AND PARTICIPANTS:This observational cohort study included 10 135 patients with AF. The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation is a prospective, nationwide, multicenter outpatient registry of patients with incident and prevalent AF enrolled at 176 sites between June 2010 and August 2011. MAIN OUTCOMES AND MEASURES:Symptoms, quality of life as measured by Atrial Fibrillation Effects on Quality of Life scores, AF treatment, cardiovascular outcomes, stroke or non-central nervous system embolism, and all-cause mortality. RESULTS:Overall, 4293 of the cohort (42%) were female. Compared with men, women were older (77 years; interquartile range [IQR], 69-83, vs 73 years; IQR, 65-80; P < .001) and had higher median CHA2DS2-VASc scores (5; IQR, 4-6, vs 3; IQR, 2-5; P < .001), but less sleep apnea (578 [13.5%] vs 1264 [21.6%]; P < .001). Only 32.1% of women (n = 1378) were asymptomatic (European Heart Rhythm Association class I) compared with 42.5% of men (n = 2483) in unadjusted analyses (P < .001). Women had lower (more severe) unadjusted baseline overall Atrial Fibrillation Effects on Quality of Life scores (n = 2007; 80; IQR, 62-92 vs 83; IQR, 69-94; P < .001). Women had similar rates of anticoagulation and similar time in therapeutic range. In follow-up, women experienced lower risk-adjusted all-cause mortality (adjusted hazard ratio, 0.57; 95% CI, 0.49-0.67) and cardiovascular death (adjusted hazard ratio, 0.56; 95% CI, 0.44-0.72); however, they had a higher risk for stroke or non-central nervous system embolism (adjusted hazard ratio, 1.39; 95% CI, 1.05-1.84; P = .02) compared with men. CONCLUSIONS AND RELEVANCE:Women with AF have more symptoms and worse quality of life. Despite higher risk, women have lower risk-adjusted all-cause and cardiovascular death compared with men, but higher stroke rates. Future studies should focus on how treatment and interventions specifically affect AF-related quality of life and cardiovascular outcomes in women. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT01165710.Jonathan P. Piccini, DaJuanicia N. Simon, Benjamin A. Steinberg, Laine Thomas, Larry A. Allen, Gregg C. Fonarow ... et al

General Principles for the Validation of Proarrhythmia Risk Prediction Models: An Extension of the CiPA In Silico Strategy

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration\u2013sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evaluate the progress in the development of a new cardiac safety paradigm, the Comprehensive in Vitro Proarrhythmia Assay (CiPA). The opinions regarding these principles reflect the collective views of those who participated in the discussion of this topic both at and after the breakout session. Although primarily discussed in the context of in silico models, these principles describe the interface between experimental input and model-based interpretation and are intended to be general enough to be applied to other types of nonclinical models for proarrhythmia assessment. This document was developed with the intention of providing a foundation for more consistency and harmonization in developing and validating different models for proarrhythmia risk prediction using the example of the CiPA paradigm