Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.703282
Title: If inhibition with ivabradine : electrophysiological effects and cardiac safety
Author: Savelieva, I
ISNI:       0000 0004 6061 0097
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2014
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Abstract:
Ivabradine belongs to a new pharmaceutical entity of specific heart rate reducing agents, which inhibit spontaneous pacemaker activity of the sinus node by selectively and specifically blocking the If current, thus allowing heart rate reduction without affecting major haemodynamic parameters. Ivabradine is currently recommended for treatment of patients with coronary artery disease and stable angina, and patients with congestive heart failure and potentially patients with inappropriate sinus tachycardia or postural orthostatic tachycardia syndrome. Because of its highly selective action, ivabradine deems to be devoid of significant adverse effects. However, bradycardia and bradycardia-related ventricular proarrhythmia is possible with ivabradine. This dissertation was set to explore the effects of ivabradine on cardiac electrophysiology and function and to highlight potential safety considerations in respect to ventricular repolarisation and proarrhythmias, namely: 1) to explore the electrophysiological effects of intravenous ivabradine in acute electrophysiological testing in patients with normal electrophysiological properties undergoing electro physiological assessment for paroxysmal supraventricular tachycardias; 2) to study the electrophysiological effects of oral ivabradine in patients with dual chamber pacemakers with a non-invasive programmed stimulation (NIPS) facility; 3) to assess the effects of ivabradine on the aT interval compared with atenolol in patients with coronary artery disease using a specific population-derived formula for rate correction; 4) to evaluate the direct effects of ivabradine on the QT interval compared with placebo when the influence of the heart rate was controlled by atrial pacing; and 5) to study the influence of It inhibition on autonomic nervous system by measuring heart rate variability in patients with coronary artery disease treated with ivabradine or an active comparator amlodipine. All these objectives have been accomplished and the results are briefly described below. I demonstrated that intravenous ivabradine lengthened the sinus cycle length, but had no effect on atrioventricular nodal properties. The sinus node conduction time and the sinus node recovery time were both prolonged after the administration of ivabradine. There was no effect on ventricular refractoriness at the same paced cycle lengths before and after ivabradine. Therefore, ivabradine appears unlikely to significantly alter the electrophysiological properties of the heart after chronic oral administration, other than to slow the sinus cycle length and increase the ventricular refractory period. Therapy with ivabradine is not associated with QT prolongation when the QT interval is appropriately corrected for heart rate (using a rate correction formula designed for a specific population) or when the influence of heart rate changes was controlled by atrial pacing at a series of identical rates. In the process, I demonstrated the feasibility of using NIPS incorporated in implantable devices as a method for assessing the electrophysiological effects of oral agents and developed and validated a new model for assessing the effects of oral agents on ventricular repolarisation. I found that the heart rate lowering effect of ivabradine is determined by heart rate at baseline - the property which accounts for a low incidence of severe bradycardia with ivabradine. Finally, I established that ivabradine is associated with a significant improvement in the cardiac autonomic status. In summary, this dissertation provides a comprehensive invasive electrophysiological evaluation, and non-invasive assessment of the effects of cardiac electrophysiology and safety of ivabradine and substantially complements existing evidence for the safe and effective use of this agent in clinical practice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.703282  DOI: Not available
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