Atrial Fibrillation—Facing the Challenges

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Atrial fibrillation (AF) continues to be the most common arrhythmic disorder that is admitted to the hospital in the Medicare population. Over the next five years, the worldwide AF market potential will grow to in excess of 8.5 million people. This growth is predominantly fueled by the aging of the worldwide population and the fact that AF is an affliction of the aged with up to 6% of octogenarians having the disease.

Treatment for AF has concentrated on rate control strategies, maintenance of sinus rhythm with antiarrhythmics drugs and catheter ablation and anti-embolic therapy.

Multiple comparative trials have showed that rate control therapy, with proper anticoagulation in high-risk patients, is equally effective in long-term survival and morbidity compared with a more aggressive maintenance of sinus rhythm approach. Rate control therapy is routinely achieved using drugs such as digoxin, beta-blockers, and calcium channel blockers. In refractory patients with rapid AF, antrioventricular (AV) junction ablation with a permanent rate responsive pacemaker has been show to improve quality of life and improve left ventricular ejection fraction (LVEF) in patients who have tachycardia-induced cardiomyopathy.

Class IC and class III antiarrhythmic drugs are effective in about 50% of patients in maintaining sinus rhythm. If one includes partial efficacy rates, class IC and III agents are effective in about 70% of patients over the first year of therapy. Amiodarone is the most effective antiarrhythmic agent, achieving complete efficacy in about 65% of patients. Although amiodarone is more effective than other currently available antiarrhythmic drugs, the long-term cost of follow-up side effects and discontinuation rates for end organ toxicity, such as hypothyroidism or pulmonary fibrosis, is of concern and limits widespread use.

The recent American College of Cardiology (ACC)/European Society of Cardiology (ESC)/ American Heart Association (AHA) Guidelines have continued to suggest that antiarrhythmic drugs are first-line therapy for maintaining sinus rhythm in patients with recurrent paroxysmal or persistent AF. In those patients without structural heart disease, flecainide, propafenone, and sotalol are the preferred agents. In those with coronary artery disease (CAD), dofetilide and sotalol are the preferred agents, followed by amiodarone. In heart failure amiodarone and dofetilide are preferred agents.

There has been a major interest in developing new antiarrhythmic drugs with new possible mechanisms. Drugs such as carvedilol that have class I and class III effects have early data to suggest that they may be more effective than routine beta-blockers alone in preventing AF.The development of atrial selective antiar-rhythmic drugs specifically attacking the IKur and the IKach channels, which are atrial selective and not expressed in the ventricle, should minimize torsades de pointes.The drug that is furthest along in this regard is RSD-1235 (vernakolant), developed by Cardiome. Intravenously (IV), this drug has been shown to be effective in converting 52% of patients from persistent AF of less than seven days' duration to sinus rhythm compared with only a 4% conversion rate in the placebo group. Early phase IIa trials have shown that when taken orally this drug is effective in suppressing recurrences of AF over a 28-day period post-cardioversion compared with placebo.

Although there are multiple investigational antiarrhythmic drugs under development, the drug that has the most data is dronedarone, an amiodarone-like compound minus two iodine moieties. Because of this alteration of the molecule, no thyroid toxicity has been reported with dronedarone. Trials have demonstrated the drug to be effective in maintaining sinus rhythm in over 50% of patients with persistent and paroxysmal AF compared with placebo. Further trials to look at safety in patients with structural heart disease are on-going.

Other interesting data for the suppression of AF involves non-antiarrhythmic drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers, which appear to suppress the spontaneous occurrence of AF and help maintain sinus rhythm better when used in combination with amiodarone versus amiodarone alone. In one prospective trial of hypertensive patients with equal blood pressure control, losartan reduced new onset AF and associated risk of stroke by 33% compared with atenolol. Further studies may help define whether this benefit is from antagonizing the angiotensin II receptors in the left atrium, suppressing stretch activated channels or some other direct antiarrhythmic mechanism.

More recently statins and omega-3 fish oils have also been demonstrated to suppress AF in post-coronary artery bypass surgery (CABG) patients. Prospective trials of omega-3 fish oils in suppressing paroxysmal AF are planned. Statins have also been reported to suppress AF in several studies and prospectively decreased post-CABG AF. Statins and omega-3 fish oils may derive some of their benefit from a direct anti-inflammatory effect.

The largest interest of any treatment modality for AF has been with catheter ablation. This technique has evolved from focal ablation of the pulmonary veins to pulmonary vein isolation procedures with more complex ablation including left posterior atrial lines along the mitral valve isthmus and atrial flutter lines. Efficacy rates with one procedure have ranged from 60% to 90% with repeat procedures adding additional success.

Studies have demonstrated that this therapy can also be effective in patients with more advanced heart failure although the efficacy rates are not as high as in patients with less evidence of structural heart disease. Complications of these procedures including phrenic nerve injury and esophageal fistula have added some caution to this procedure. Although these results are very encouraging there are no US Food and Drug Administration (FDA)-approved catheter procedures at this time. However, there are plans for prospective randomized trials of regulatory quality data in the planning stages.

Finally, warfarin continues to be the most effective treatment in suppressing embolic strokes in patients with risk factors for AF. The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-W (ACTIVE-W) trial compared warfarin with aspirin plus clopidogrel but this trial was discontinued prematurely because of the 45% increase in the composite end-points of stroke, systemic embolism, myocardial infarction (MI) and vascular death in the aspirin and clopidogrel-treated group. It was disappointing the FDA did not approve ximelagatran, a direct thrombin inhibitor that was shown to be equally effective to warfarin. Dabigatran will undergo a large active controlled trial against warfarin in 15,000 patients in the future, to determine non-inferiority of this therapy to warfarin.

In 2006 there are limitations to the treatment of AF. Currently available antiarrhythmic drugs are only about 50-60% effective. The most effective therapy, amiodarone, has long-term end organ toxicity and cost of follow-up limiting the drug's use. Only three drugs, amiodarone, dofetilide, and sotalol, have guideline approval for use in structural heart disease. Currently available antiarrhythmic drugs have lower effectiveness in the remodeled atrium. Newer atrial selective drugs may get around this limitation and may also limit ventricular proarrhythmia in the future.

Catheter ablation often requires multiple procedures and the addition of antiarrhythmic drugs for complete efficacy. The results of catheter ablation are very encouraging but controlled prospective data establishing efficacy and safety are limited at this time. Device therapy appears to have a very limited efficacy in treating patients with AF and although warfarin is efficacious, drug interactions narrow the drug's therapeutic/toxic ratio and the evolution of drugs such as direct thrombin inhibitors will be a welcome addition to the armamentarium.