New Drug Therapies for Difficult-to-Control Atrial Fibrillation

Value-Based Care in Cardiometabolic Health May 2012, Vol 1, No 1
Wayne Kuznar

Chicago, IL—“Difficult” atrial fibrillation (AF), for which standard ratecontrol therapy or standard rhythmcontrol therapy has not been effective, or AF in the setting of sinus node or other conduction disease, has been shown to sometimes benefit from nonstandard or combination-drug treatment, according to James A. Reiffel, MD, Professor of Clinical Medicine, Columbia University Medical Center, New York City.

For patients in whom ventricular rate control cannot be attained with beta-blockers, calcium channel blockers, and/or digitalis, nonhepatically metabolized beta-blockers may be an option. Serum concentrations of metoprolol (Lopressor, Toprol) or propranolol (Inderal, Inderal LA, Innopran XL), for example, can vary up to 10-fold for the same dose, partially the result of high first-pass effects.

“I would avoid them,” Dr Reiffel cautioned. “I would use a renally cleared beta-blocker.”

For bradycardia-tachycardia syndrome, he suggests pindolol (Visken), which increases slow heart rates but blocks exercise rates. Digitalis is effective at slowing resting rates but not with exercise rates.

In patients with vagally induced AF, anticholinergic agents alone or in combination with traditional antiarrhythmic drugs may improve rhythm control.

Occasionally, AF is associated with stress, exercise, or stimulant intake. In these patients, beta-blockers alone or in combination with traditional antiarrhythmic drugs may improve rhythm control. “It has long been known that the electrophysiologic effects of antiarrhythmic drugs can be reversed by catecholamines,” Dr Reiffel noted.

This reversal of drug effects can be prevented by concomitant administration of beta-blockers and a drug such as verapamil (Calan, Covera, Isoptin, Verelan).

Evidence for the efficacy of combination treatment comes from several studies. In one trial of patients with persistent AF randomized to either amiodarone (Cordarone, Pacerone) alone or with verapamil and to flecainide (Tambocor) alone or with verapamil, at the 3-month follow-up, the verapamil groups had lower first-recurrence rates (20% vs 35%) and lower second-recurrence rates (68% vs 88%).

For rhythm control, novel antiarrhythmic drugs such as ranolazine (Ranexa) can be considered. Trials of ranolazine in patients with previous antiarrhythmic drug therapy for persistent AF showed good tolerance and a success rate of ≥75% in reducing the frequency or duration of persistent AF, said Dr Reiffel.

Combination Therapy: The Future?

Dr Reiffel is enthusiastic about the future of antiarrhythmic drug combinations in improving efficacy. In a retrospective chart review in his own practice from 1990 to 2010, Dr Reiffel found that he used antiarrhythmic drug combinations in highly symptomatic AF patients who were refractory to multiple antiarrhythmic drugs, including amiodarone. Combinations that provided clinically significant improvement included:

  • Amiodarone plus propafenone (Rhythmol)
  • Amiodarone plus disopyramide (Norpace)
  • Amiodarone plus ranolazine
  • Dronedarone (Mutlaq) plus ranolazine.

No proarrhythmia occurred in these patients, Dr Reiffel noted.

In reviewing charts from 1980 to 1995, he encountered 9 patients who had effective AF control with quinidine or disopyramide, with each dosed to efficacy. Gastrointestinal intolerance was ameliorated with a combination of these agents, each at half the previously effective dose.

A study of ibutilide (Corvert) and propafenone in combination had a success rate of 71.4%, and a study of amiodarone plus wenxin granules showed that at 6 months, normal sinus rhythm had been restored in 65.1% of patients.

For chronic maintenance of sinus rhythm, the combination of quinidine plus verapamil was studied. Patients randomized to digoxin or to verapamil were dosed until rate control had been achieved (<100 beats per minute). Conversion within 6 hours occurred in 84% of patients assigned to quinidine plus verapamil versus 45% of those assigned to quinidine plus digoxin, with no serious morbidity or mortality in either group.

As adjunctive therapy, Dr Reiffel says to consider improvement of concomitant disorders/underlying pathophysiologic alterations (“upstream therapies”), such as with angiotensinconverting enzyme inhibitors, angiotensin 2 receptor blockers, or their combination. Associated bradycardia should be treated and/or ablated and then the previous antiarrhythmic drugs retried. Consider having the patient enroll in a clinical trial of an investigational agent.

Dr Reiffel concluded by saying that the efficacy rate of an antiarrhythmic drug is lower when tried after a prior antiarrhythmic drug failure. “None - theless, drug therapy can be effective. Not all patients need to go to ablation. But just remember, as is true elsewhere, therapy is not perfect in all cases.”

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