Emerging Agents for Treating Atrial Fibrillation

Atrial fibrillation is the most common arrhythmia disorder in clinical practice. Management focuses on the choice of rhythm or rate control and the need for thromboembolic prophylaxis.

A series of trials of a rate-control strategy compared with a rhythm-control strategy failed to establish a mortality benefit of one approach over the other.^1-4 The morbidity associated with the rhythm-control strategy in these trials resulted from the toxicity of conventionally used antiarrhythmic drugs and the excess stroke rate with warfarin discontinuation in patients randomized to the rhythm-control strategy. The trials established the first principal of AF management: A strategy to maintain sinus rhythm does not preclude the need to maintain anticoagulation in patients at AF-related risk for stroke.

Unfortunately, warfarin remains a difficult drug to manage both for the patient and the physician, and rates of appropriate use are far below expectations.¹ After a period of relative quiescence in the development of pharmacologic options for managing AF, the last 2 years have welcomed new antiarrhythmic and anticoagulant drugs. Additional antiarrhythmic and anticoagulant drugs are in various stages of development and are likely to be available for clinical use in the coming decade.

Rhythm Agents

Amiodarone Analogues

Dronedarone is the first in a series of so-called amiodarone analogues hoped to have the rhythm-control benefits of amiodarone without the toxicity. The agent is a non-iodinated benzofuran derivative with a methyl substitution and a half-life of 13 to 24 hours. A study evaluating its effect on total mortality in a population with advanced congestive heart failure found it to be associated with excess mortality compared with placebo.² Two subsequent trials of efficacy for the maintenance of sinus rhythm in patients with AF without congestive heart failure found it to be a safe therapy with an efficacy of approximately 35%.³

The ATHENA study evaluated the safety of dronedarone in 4,300 AF patients without advanced congestive heart failure.⁴ A reduction in arrhythmic mortality and cardiovascular hospitalizations was associated with dronedarone use, with no effect on all cause mortality. A post hoc analysis of ATHENA demonstrated a 36% reduction in the incidence of stroke in the dronedarone-treated group, though the mechanism of this stroke reduction has not been determined.⁵

Dronedarone also has a modest effect on rate control, with an average reduction in ventricular response of 10 to 12 bpm.⁶ A mixed-treatment analysis of direct and indirect comparisons between antiarrhythmic drugs, including 30 randomized, controlled trials with 6,000 patients, found dronedarone to be slightly less effective than the other available antiarrhythmic drugs, but better tolerated from the standpoint of adverse effects.⁷

Dronedarone has not demonstrated thyroid or pulmonary toxicity, but has been associated with two reported cases of hepatic failure within 6 months of drug initation. The medication was approved for the reduction of cardiovascular hospitalizations in the United States in 2009 and is recommended as first-line therapy for rhythm control in all groups of patients except those with decompensated congestive heart failure.

Budiodarone, another amiodarone analogue, is not yet approved for clinical use. This agent is an iodinated benzofuran with a much shorter half-life than amiodarone. The Paroxysmal Atrial Fibrillation Study with Continuous Atrial Fibrillation Logging (PASCAL) evaluated budiodarone in a population of 72 patients with dual-chamber pacemakers. This protocol allowed the most comprehensive arrhythmic surveillance possible and demonstrated a 75% reduction in the frequency and duration of AF recurrences (In press). No cases of hepatic or pulmonary toxicity were reported in this small clinical experience, but budiodarone does appear to have thyroid effects similar to amiodarone.

Vernakalant

Vernakalant is a novel antiarrhythmic drug that blocks the Ikur and Ikach currents in the atria, in addition to the late sodium current. The drug has demonstrated efficacy in a series of clinical trials for the conversion of AF to sinus rhythm^8,9 but has proven to be relatively ineffective for atrial flutter. Vernakalant’s efficacy for AF is superior when the arrhythmia has been less than 7 days in duration.

A recent study compared intravenous vernakalant with intravenous amiodarone and demonstrated a 50% rate of conversion of AF at 90 minutes with vernakalant compared with a 5% conversion rate with amiodarone.¹⁰ The intravenous formulation is available in Europe for the conversion of AF, and the oral formulation is under clinical investigation.

Ranolazine

Ranolazine is currently approved as an antianginal drug that blocks the late sodium current and has been demonstrated to have some efficacy as an antiarrhythmic drug for supraventricular arrhythmias.¹¹ Some intriguing early-stage work in animals has demonstrated a synergistic effect whens used in combination with amiodarone or dronedarone.¹² In addition, ranolazine may increase patient safety in light of reports that late sodium channel blockade can reduce the risk of torsade de pointes associated with drugs that block Ikur.

Anticoagulants

Dabigatran

Stroke represents the most serious consequence of AF. Warfarin has been the standard for thromboembolic prophylaxis for decades but remains a complex drug to use due to individual differences in metabolism, drug and food interactions, and the requirement to monitor INR levels. A recent analysis of rates of anticoagulation in an ambulatory care Medicare population demonstrated a 40% utilization of warfarin regardless of the patient’s CHADS2 score.¹ Furthermore, patients must maintain a time in therapeutic INR range (TTR) of at least 60% to derive the full therapeutic potential of warfarin.¹⁴ In the ATHENA trial, patients taking warfarin were in the TTR only 50% of the time.

Dabigatran is the first of a group of novel anticoagulants designed to facilitate patient adherence through eliminating the need to monitor INR and minimizing food-drug interactions. Dabigatran is a direct thrombin inhibitor with a 14-hour half-life and twice-daily dosing. The RELY study compared dabigatran in two dosages (110 mg twice daily and 150 mg twice daily) with warfarin in a population of 18,000 patients with AF.¹⁵ The 150-mg dose was found to be superior to both the 110-mg dose and to warfarin. The risk of significant bleeding requiring transfusion was lower with the lower dose than with either warfarin or the 150-mg dabigatran dose. The risk of intracranial hemorrhage was 50% and 60% lower with the 150-mg and 110-mg doses, respectively, compared with warfarin.

The FDA chose to approve only the higher-dose regimen of dabigatran because of its superior effect on reducing stroke risk with comparable bleeding risk compared with warfarin.¹⁶ This approval restricted the use of dabigatran in the setting of renal insufficiency and recommended a dose of 75 mg twice a day in patients with a creatinine clearance of 15 to 30 ml/min. The designation of a 75-mg twice-daily dosage was based on pharmacodynamic predictions rather than clinical testing.

The recommendations differ in Canada, where the 110-mg dose is available and recommended as an option for patients 80 years of age or older and patients with multiple bleeding-risk factors. In Canada, dabigatran is not recommended for patients with a creatinine clearance below 30 ml/min.

Analysis of bleeding risk associated with dabigatran and stratified by age has found that the risk of intracranial bleeding is lower for both the 110-mg and 150-mg doses, compared with warfarin, below or above the age of 75. The risk for extracranial bleeding was lower for the 110-mg dose regardless of age, but slightly higher for gastrointestinal bleeding compared with warfarin for the 150-mg dabigatran dose in patients 75 or older.¹⁷

In the RELY study, 1,983 cardioversions were performed in 1,270 subjects taking either dabigatran or warfarin for a minumum of 3 weeks.¹⁸ Investigators found no difference in the risk of pericardioversion stroke, and dabigatran is considered safe as a pericardioversion anticoagulant.

In patients being switched from warfarin, dabigatran should be initiated once the INR is below 2. This medication should be discontinued 24 hours before procedures with a standard bleeding risk in patients with relatively normal renal function (creatinine clearance >50 mL/min) (Table). In patients with more-impaired renal function or those undergoing surgical procedures with a high risk of severe complication should bleeding occur (e.g., neurosurgery), dabigatran should be held for 2 to 4 days. Bleeding should be managed with fresh frozen plasma, and in severe cases, recombinant factor VIIa or prothrombin complex concentrates can be administered. Anticoagulation should dissipate within 24 hours of drug discontinuation, a duration similar to the time course for vitamin K reversal of warfarin-induced anticoagulation.

Table. Recommendations for Withholding Dabigatran for Reversal of Anticoagulation

*For example, abdominal and neurosurgery and procedures using spinal anesthesia, and for patients with major liver disease.
Source: Peter Zimetbaum, MD

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Factor Xa Inhibitors

Rivaroxaban is a direct factor Xa inhibitor that has also been evaluated as a new anticoagulant for thromboembolic prophylaxis in patients with non-valvular AF. The ROCKET AF study of 14,000 patients who had non-valvular AF showed that a single, once-daily dose of 10 mg of rivaroxaban resulted in equivalent thromboembolic prophylaxis with a lower rate of significant intracranial and extracranial hemorrhage compared with warfarin.

Apixaban is another factor Xa inhibitor that is awaiting approval from the FDA. Dosed twice daily, apixaban has the least renal-dependent clearance of this group of new anticoagulants. In AVERROES, a trial of 5,599 patients ages 50 and older with non-valvular AF and a relative contraindication to warfarin use, apixaban was significantly more effective than aspirin for reduction of stroke risk and risk of systemic embolism without increasing the risk of intracranial hemorrhage or major bleeding.¹⁸

ARISTOTLE, a larger noninferiority trial of 18,201 patients with AF from more than 1,000 international centers, compared 5 mg of apixaban twice daily with dose-adjusted warfarin. Primary endpoints for noninferiority were stroke (ischemic, hemorrhagic or unspecified type) and systemic embolism.

Full study results are expected to be reported at the European Society of Cardiology meeting in August.¹⁹

References

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