Drug Therapy for the Management of Atrial Fibrillation: An Update

Andrew RJ Mitchell

Disclosures

Br J Cardiol. 2003;10(5) 

In This Article

New Drugs for Atrial Fibrillation

Dofetilide is an anti-arrhythmic drug that has relatively pure class III properties. It exhibits reverse use dependence, with rate-related reductions in its capacity to prolong action potential duration and effective refractory period.[59] Dofetilide has a narrow therapeutic range and doses need to be adjusted on the basis of the renal function and effect on QT interval. In the Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) study, 325 patients with AF or atrial flutter were randomised to 125, 250 or 500 µg of dofetilide twice-daily versus placebo.[60] The 500 µg dose achieved 30% cardioversion within 36 hours and 58% remained in sinus rhythm at one year. There were two cases of 'torsades de pointes' and one sudden cardiac death. It has a 28% efficacy in terminating AF and a 66% efficacy for atrial flutter when given intravenously, with a mean time to conversion of between 20–50 minutes.[61] 'Torsades de pointes' arrhythmias were reported in 4% of cases when dofetilide was given intravenously.

Ibutilide is a pure class III agent approved in the United States for intravenous use in the acute termination of atrial flutter and fibrillation. Like dofetilide it is more effective at terminating atrial flutter (mean success rate 64%) than AF (33%) with an incidence of 'torsades de pointes' of 2.4%.[61] It also has effects on improving the success rate of cardioversion, primarily by lowering energy requirements for defibrillation by 30%.[32]

Azimilide is a class III anti-arrhythmic drug that has been shown to be more effective at terminating AF than dofetilide when given intravenously (success rate 93% versus 50%).[62] It may also have clinical effects in paroxysmal AF and flutter. In a dose-ranging trial of 384 patients with paroxysmal atrial arrhythmias, the drug was more effective than placebo at preventing AF recurrence.[63] It is extremely well tolerated with the incidence of adverse effects and mortality similar to placebo.[61]

Adenosine Agonists

Adenosine is a naturally occurring substance that is used for a number of electrophysiological tests and treatments. The main limitations of adenosine are that it has an ultra-short half-life (10 seconds), has to be given intravenously and that it has significant vasodilator effects. The adenosine receptor agonist CVT-510 has been developed in an attempt to circumvent these problems. In a comparison study with diltiazem in guinea pigs, it slowed atrioventricular nodal conduction but without the negative inotropic, vasodilator and hypotensive effects seen with diltiazem.[64] There were no reported pro-arrhythmic effects. Should this drug reach clinical use there may be the potential for its use as a rate-controlling agent in AF without major adverse side effects.

Dronedarone is a non-iodinated derivative of amiodarone that has actions in all four of the Vaughan-William's classes. It is currently under development for oral and intravenous use in the treatment of AF.[65] Ambasilide, almokalant, sematilide and tedisamil are compounds with effects on the delayed rectifier potassium current that are also under clinical investigation for AF management.[66,67,68,69]

Direct thrombin inhibitors are under development as a potential alternative to warfarin for the prevention of thrombo-embolic disease.[70] Ximelagatran, a prodrug of melagatran, is an orally active thrombin inhibitor under investigation for the prevention of stroke in AF.[71] It has a rapid onset of action and is administered on a weight-adjusted basis. Results from the SPORTIF III study are due to be published soon. This study showed a non-inferiority of ximelagatran compared with warfarin for the prevention of stroke (both ischaemic and haemorrhagic) and systemic thrombo-embolism (2.2% per year for warfarin and 1.3% per year for ximelagatran). The SPORTIF V data (randomising patients with AF to warfarin or ximelagatran) are eagerly awaited and are expected to be presented later this year.

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