A dolus of i.v. amiodarone

This editorial refers to ‘Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study’†, by M. Ortiz et al., on page 1329. Clinical guidelines often make recommendations based on the consensus of the authors alone, with little supporting evidence. An area of medicine where it is very difficult to perform clinical trials is in the setting of emergency treatment of cardiac arrhythmia. As a result, there are few data informing us of the optimal strategy for the drug management of haemodynamically tolerated ventricular tachycardia (VT). Current guidelines acknowledge the potential advantages of pharmacological cardioversion, which may avoid the logistical issues of organizing an anaesthetic with the necessary additional staff.1 When considering pharmacological cardioversion, reasonable choices of agent include i.v. beta-blockers (e.g. metoprolol), class I agents (e.g. procainamide and lignocaine), a class III agent (e.g. sotalol), or amiodarone with mixed ion channel and beta-blocking action. To date, the complement of randomized controlled trials comparing these drugs is limited, though lignocaine appears to be the least effective,2 and current European guidelines advise either procainamide or amiodarone, with an emphasis on amiodarone use in patients with structural heart disease due to negative inotropic effects of class I agents.1,3,4 Both procainamide and amiodarone are widely, but not universally, available. For example, in the UK, i.v. procainamide is difficult to obtain; i.v. an beta-blocker (e.g. metoprolol) ± amiodarone is commonly used. The best drug to use for pharmacological cardioversion of monomorphic ventricular tachycardia is often unclear. Amiodarone and procainamide have differing effects on the action potential, with more marked effects on activation and repolarization by procainamide. Procainamide converted approximately two-thirds of patients to sinus rhythm, vs. one-third. However, this still left a large proportion of patients requiring DC cardioversion. The authors highlight discrepancies between these new data, and previously reported retrospective cohort studies, which assessed the use of i.v. amiodarone.7 Notably in older studies, severe hypotension occurred in fewer than half the proportion seen (41%) in this study. Further, the definition of major adverse event in retrospective trials was by the need for electrical cardioversion, rather than the discrete and specific definitions set in this study. Procainamide is a class IA agent working as a voltage-dependent, open-state sodium channel-blocking drug, with wider effects on delayed rectifier potassium currents and inward rectifier currents (e.g. the ATP-sensitive potassium channel, activated during metabolic challenges such as ischaemia).8,9 Procainamide is fast acting and slows phases 4 and 0 depolarization and prolongs the action potential and ventricular refractoriness (Figure 1). Its rapid, use-dependent electrophysiological effects lend itself towards terminating re-entrant arrhythmias. Why should amiodarone be less effective and seemingly more dangerous? Amiodarone has been shown to have antagonistic effects on pretty much the full repertoire of cardiac myocyte currents in the context of chronic oral therapy (INa, ICaL, IKur, Ito, IKr, IKs, IKACh, IKATP, and IK1).10–12 Yet after a bolus intravenous dose, the sodium channel class I, and potassium channel-blocking class III effects may not be evident,13 and ventricular refractoriness would be less affected. Rather, after a bolus dose, acute phase adrenoceptor and L-type calcium channel antagonism will predominate. Other off-target effects can reduce vascular tone and cause hypotension.11,14 Interestingly, the solvent used in most European preparations (Polysorbate 80 and benzyl alcohol) may exacerbate these vascular effects via histamine release, and a formulation of i.v. amiodarone (PM101) that does not contain this solvent is reported to avoid vasodilatory side effects.15 Although the findings might be unexpected, it could be argued that they are explainable. The major criticism that can be levied is the small study size; the study terminated after enrolment of only 74 patients out of the planned 300. The decision to cease recruitment and report must ultimately be seen as the sensible one as, despite the low numbers, this study presents compelling evidence that i.v. procainamide is safer and more effective than i.v. amiodarone for the medical treatment of monomorphic VT (Figure 1). These data point to the utility of procainamide as a suitable antiarrhythmic across VT, and to a clinical superiority over amiodarone in acute treatment of ventricular arrhythmias. Should this be enough to change guidelines? The trial could be seen as setting the scene for studying the efficacy and safety of procainamide across the emergency treatment of ventricular arrhythmia, where amiodarone dominates. However, as the perception that amiodarone is safe exists across the medical community, the establishment of such a trial would be incredibly challenging regardless of its potential value. Therefore we should base our practice on the data already in existence, which show amiodarone to be not as effective as other agents, and no safer. Yet, despite logistical difficulties, electrical cardioversion is generally safe and effective, and is ideal if your patient is one of the third that does not revert to sinus rhythm. Perhaps the best recommendation for stable VT might be to call your anaesthetist colleague, just as the procainamide infusion is being drawn up.