Eagle et al Atrial Fibrillation Management 5activation, obesity, the use of stimulants, inﬂammation ﬁbrillation.8 Electrical remodeling, which begins soon aftercaused by pericarditis or other disorders, and pulmonary arrhythmia onset, is characterized by a shortening of the atrialdisease. refractory period. This process may be reversible upon resto- Hospitalizations for atrial ﬁbrillation have increased signif- ration of sinus rhythm. Structural remodeling, which is likelyicantly in recent years, primarily due to the increased avail- more permanent than electrical remodeling, occurs weeks toability and utilization of hospital- months after the onset of the ar-based therapeutic options including rhythmia and includes changes atdrugs and nonpharmacologic inter- both the cellular and tissue lev- CLINICAL SIGNIFICANCE STATEMENTventions (eg, cardioversion).13 The els.8,19,20 Together, these pro-escalating prevalence of atrial ﬁ- ● Many established options for the treat- cesses result in contractile remod-brillation and the need for re- ment of atrial ﬁbrillation have limited eling that may facilitate atrialpeated hospitalizations and long- efﬁcacy and safety/tolerability issues, ﬁbrillation persistence and the de-term pharmacologic treatment of velopment of negative sequelae but newer therapies attempt to addressthese patients make the condition (eg, thrombus formation and atrialcostly; one recent European sur- these issues and have promising out- dilation). Recovery of contractilityvey showed that the mean in- comes from clinical trials and postmar- after restoration of sinus rhythm iscreased annual cost of caring for a keting surveillance. typically slow.patient with atrial ﬁbrillation is ● Customized atrial ﬁbrillation manage- The pathophysiology of atrial ﬁ-approximately €3200 ($5000) ment, assessing individual patient char- brillation in patients with underly-compared with a matched popula- acteristics and comorbidities, should ing congestive heart failure seemstion without atrial ﬁbrillation.14 to be somewhat different. In con- guide the optimal treatment selection.Indeed, it has been estimated that gestive heart failure, interstitial ﬁ-the direct cost of managing atrial brosis is found to be increased in theﬁbrillation to the United Kingdom atria, leading to heterogeneity ofNational Health Service accounts for 2.4% of their annual atrial conduction and regions of slow electrical conduction,expenditure, amounting to more than £450 million.15 Atrial predisposing to the occurrence of atrial ﬁbrillation.21,22 Theﬁbrillation is associated with a signiﬁcant economic burden in atrial ﬁbrosis in congestive heart failure seems to be due tothe US as well. Several studies have shown that health care upregulation of the renin-angiotensin-aldosterone systemcosts in the US are approximately 5 times higher for patients and dysregulation of intracellular Ca2 homeostasis in cellswith atrial ﬁbrillation than for those without it, and hospital- of the atrial myocardium.23 14,16izations are a key contributor. Thorough clinical evaluation of patients who present Early detection and intervention potentially could de- with certain conditions (eg, hypertension/hypertensive heartcrease the burden of atrial ﬁbrillation on the individual and disease, congestive heart failure, CAD, ischemic cardiomy-society by preventing progression and related conse- opathy, valvular [rheumatic] heart disease, diabetes, hyper-quences. The purpose of this review was to brieﬂy describe thyroidism, obesity, and obstructive sleep apnea)9,24,25 canthe pathophysiology of atrial ﬁbrillation and associated se- facilitate early atrial ﬁbrillation detection and timely inter-quelas, review the goals of atrial ﬁbrillation therapy, and vention. Of course, clinicians should remain mindful thatprovide a practical management guide for internists based atrial ﬁbrillation can occur even in the absence of predis-on recent guidelines and current clinical data. posing factors. Typically, the term “lone atrial ﬁbrillation” is used to describe younger patients ( 60 years of age) who have atrial ﬁbrillation in the absence of underlying cardio-PATHOPHYSIOLOGY AND BURDEN OF pulmonary disease.3ATRIAL FIBRILLATION Up to 40% of patients in whom atrial ﬁbrillation is foundThe pathophysiology of atrial ﬁbrillation remains incom- on a baseline electrocardiogram (ECG) do not experience orpletely understood; however, it is clear that its occurrence recognize symptoms.1 Even among those that do manifestrequires a triggering factor and an appropriate substrate to symptoms, clinical presentation is highly variable. Whensustain re-entry.3,17 In the majority of patients, the under- present, symptoms can include palpitations, chest pain, dys-lying triggering mechanism is thought to involve the inter- pnea, fatigue, lightheadedness, syncope, and polyuria. Theaction of rapidly ﬁring ectopic foci in the pulmonary veins, hemodynamic consequences of loss of atrial contractioninto which the atrial muscle is known to extend.18 The with resultant loss of atrioventricular (AV) synchrony, heartmechanism for aberrant impulse origin in pulmonary veins rate irregularity, and rapid ventricular response that areis uncertain but may involve automaticity, triggered activ- typically found in atrial ﬁbrillation may each contribute inity, and/or re-entry.18 varying degrees to the manifestations of these symptoms.1 If atrial ﬁbrillation has been sustained for a period of Regardless of presentation, improperly managed atrialtime, physical and molecular changes in the electrical and ﬁbrillation is associated with signiﬁcant morbidity and mor-structural properties of the atria (“remodeling”) occur and tality, including a 5-fold increased risk of stroke (in thefacilitate the conversion from transient to persistent atrial absence of anticoagulation) and a 1.5-fold to 1.9-fold in-
Eagle et al Atrial Fibrillation Management 7 Figure 2 American College of Cardiology (ACC)/American Heart Association (AHA)/Euro- pean Society of Cardiology (ESC) algorithm for the selection of maintenance anti-arrhythmic drug therapy.3 It can be seen that catheter ablation for atrial ﬁbrillation is considered second-line therapy after failure of an anti-arrhythmic drug. For the clinician, the decision is made after careful consideration and discussion with the patient about the risks and beneﬁts of either approach. Reprinted from Fuster et al.,3 with permission from Oxford University Press.ization of therapy based on the speciﬁc clinical character- tions, the potential for drug-drug and drug-food interactions,istics of the patient. The guidelines recognize the impor- and the need for ongoing monitoring.41 Current guidelinestance of concomitant anticoagulation therapy in the advocate more liberal use of warfarin, while full-dose aspi-management of atrial ﬁbrillation. rin may be useful for patients at low risk for stroke.3,36,37 Data from recently completed and ongoing studies of Stroke risk and the identiﬁcation of atrial ﬁbrillationnewer atrial ﬁbrillation management therapies will likely patients who may beneﬁt most from antithrombotic therapyplay a major role in shaping future guidelines. Several can be assessed by the Congestive heart failure, Hyperten-studies are investigating important clinical endpoints that sion, Age, Diabetes, prior Stroke risk index by assigningmore closely reﬂect practical treatment goals, such as the numerical values to accepted risk factors (advanced age ofprevention of cardiovascular hospitalization and death. 75 years old; concomitant congestive heart failure, hyper- tension, or diabetes; and history of stroke or TIA).27 Bleed-BENEFITS/RISKS OF MANAGEMENT OPTIONS ing risk should also be determined and weighed against the potential beneﬁt before anticoagulant initiation. Factors thatAntithrombotic Treatment may inﬂuence risk include patient characteristics (eg, in-Current guidelines recommend long-term anticoagulation in creased age, history of bleeding, presence of treated hyper-patients with atrial ﬁbrillation and risk factors for thrombo- tension, cerebrovascular disease, ischemic stroke, seriousembolism, regardless of atrial ﬁbrillation management ap- heart disease, diabetes, renal insufﬁciency, alcoholism, liverproach.3,36,37 Even patients who seem to be in normal sinus disease, or malignancy; or genetic factors affecting drugrhythm after atrial ﬁbrillation remain at considerable risk for metabolism), concomitant medications (eg, antiplateletstroke. For this reason, longer-term risk-based anticoagula- drugs), and proposed intensity and length of therapy.42tion should be prescribed even in patients receiving anti- The protective effects of anticoagulants have been dem-arrhythmic drug therapy and also in patients who have onstrated repeatedly and are generally greater than thoseundergone electrical cardioversion or radiofrequency (RF) associated with antiplatelet therapy.43 Results of the Atrialablation.26,38 Fibrillation Clopidogrel Trial with Irbesartan for Prevention Despite a strong body of evidence supportive of the of Vascular Events44 and Birmingham Atrial Fibrillationbeneﬁts of antithrombotic therapy, it is widely underutilized Treatment of the Aged45 studies provide evidence of thein the atrial ﬁbrillation population.39,40 The reluctance of protective effects of warfarin therapy over clopidogrel plusclinicians to prescribe, and patients to use, warfarin likely aspirin, and aspirin alone, respectively. However, for pa-arises from fear of increased risk for bleeding complica- tients unable or unwilling to assume the risks of warfarin
8 The American Journal of Medicine, Vol 124, No 1, January 2011therapy, clopidogrel plus aspirin may reduce the risk of except amiodarone and propafenone, were associated withmajor vascular events over aspirin alone.46 signiﬁcant pro-arrhythmia risk.52 Rates of withdrawal due Other alternatives for reducing thromboembolism risk to adverse effects ranged from 9% to 23% and rates of(eg, direct thrombin inhibitors) are in various stages of withdrawal due to pro-arrhythmia ranged from 1% to 7%.clinical evaluation. The direct thrombin inhibitor ximelagat- Withdrawals due to both pro-arrhythmia and adverse eventsran was shown to be at least as effective as adjusted-dose were lower with amiodarone than with sodium channelwarfarin therapy for stroke/TIA prevention in noninferiority blockers.trials (Stroke Prophylaxis Using an Oral Thrombin Inhibitor Because of the pro-arrhythmia risk, maintenance therapyin Atrial Fibrillation III and V)47,48 but was not approved in with any of these agents generally should be initiated atthe United States because of concern about hepatotoxicity. relatively low doses and while the patient is hospitalized.Another direct thrombin inhibitor, dabigatran, has been Clinicians should seek to identify at-risk patients via com-shown to be at least as safe and effective as warfarin therapy plete medical history, physical examination, and/or electro-in a large-scale, international, multicenter trial (Randomized cardiographic monitoring (Table provides typical doses ofEvaluation of Long-Term Anticoagulant Therapy).49 Al- anti-arrhythmic drugs used to maintain normal sinus rhythmthough this was an open-label study, its other methodologic in atrial ﬁbrillation).3 Established predisposing factors in-strengths were signiﬁcant; application for regulatory ap- clude QT interval 440 msec for men and 460 msec forproval in the United States, Canada, and Europe is antici- women, left ventricular ejection fraction (LVEF) 40%,pated soon. Two direct factor Xa inhibitors (apixaban and hypokalemia/hypomagnesemia, female sex, renal dysfunc-rivaroxaban) are currently listed at clinicaltrials.gov in tion, bradycardia, concomitant drugs that prolong the QTphase III trials designed to determine noninferiority to war- interval (eg, antifungals) or drugs associated with torsadesfarin as a stroke prevention strategy. Although vitamin K de pointes, previous pro-arrhythmic response to anti-ar-antagonists present challenges, such as a narrow therapeutic rhythmics, and concomitant ventricular tachycardia or rapidindex and numerous drug/dietary interactions, the conve- ventricular response rate.53nience and safety of warfarin therapy can be increased with Generally, doses of anti-arrhythmic drugs are titrated toaccess to a dedicated anticoagulation management service heart rate and electrocardiographic response. Changes inand or both patient home measurement of international patient status also should be monitored, as changes in car-normalized ratio values.50,51 diac function, plasma electrolytes, or renal function could affect drug response and pro-arrhythmia risk. PatientsMaintenance of Normal Sinus Rhythm should be counseled regarding potential signs of arrhythmia(Pharmacologic Therapies) such as syncope, angina, or dyspnea.A number of agents are effective for the maintenance of Potential drug-drug interactions need to be considered asnormal sinus rhythm in patients with atrial ﬁbrillation. a number of anti-arrhythmics are cytochrome P enzymeACC/AHA/ESC guidelines describe amiodarone, disopyr- substrates (eg, quinidine, disopyramide, lidocaine, mexil-amide, ﬂecainide, propafenone, and sotalol as agents with etine, ﬂecainide, and propafenone) or inhibitors (amioda-proven efﬁcacy for this use (Table).3 However, meta-anal- rone). Others undergo active tubular secretion (procain-ysis of data from 44 clinical trials revealed high rates of amide), and are, therefore, inﬂuenced by inhibitors of thisatrial ﬁbrillation recurrence (55% to 67%) with maintenance route of elimination (eg, cimetidine, trimethoprim).54 Inanti-arrhythmic therapy, and all atrial ﬁbrillation therapies, some instances, dose adjustment for concomitant medica-Table Anti-arrhythmic agents used to maintain sinus rhythm in patients with atrial ﬁbrillation.Drug* Daily Dose Potential Adverse EffectsAmiodarone† 100-400 mg Photosensitivity, pulmonary toxicity, polyneuropathy, gastrointestinal upset, bradycardia, torsades de pointes (rare), hepatic toxicity, thyroid dysfunction, eye complicationsDisopyramide 400-750 mg Torsades de pointes, heart failure, glaucoma, urinary retention, dry mouthDofetilide‡ 500-1000 g Torsades de pointesFlecainide 200-300 mg Ventricular tachycardia, heart failure, conversion to atrial ﬂutter with rapid conduction through the atrioventricular nodePropafenone 450-900 mg Ventricular tachycardia, heart failure, conversion to atrial ﬂutter with rapid conduction through the atrioventricular nodeSotalol‡ 160-320 mg Torsades de pointes, heart failure, bradycardia, exacerbation of chronic obstructive or bronchospastic lung disease Modied from Fuster et al., with permission from Oxford University Press. *Drugs are listed alphabetically. †A loading dose of 600 mg/d is usually given for 1 month, or 1000 mg/d for 1 week. ‡Dosage should be adjusted for renal function and QT interval response during in-hospital initiation phase.
Eagle et al Atrial Fibrillation Management 9tions should be made before beginning anti-arrhythmics. mortality rate in the dronedarone-treated patients (16% riskFor example, doses of warfarin and digoxin should be reduction; P .18).58 Adverse event rates were higher inhalved before amiodarone administration in anticipation of the dronedarone group than in the placebo group, and moreamiodarone-associated cytochrome P enzyme inhibition. patients in the dronedarone group discontinued from the Despite amiodarone (Wyeth Pharmaceuticals Inc.,/ study prematurely due to adverse events (12.7% vs 8.1%;Pﬁzer, Philadelphia, Penn) being widely considered the P .001). Approximately one-fourth of patients (26.2%)most effective of the available anti-arrhythmic drugs for treated with dronedarone reported gastrointestinal eventsmaintenance of sinus rhythm in atrial ﬁbrillation pa- compared with 22% of patients who received a placebotients,55,56 it lacks the US Food and Drug Administration (P .001). Bradycardia (3.5% vs 1.2%), QT prolongation(FDA) approval for this indication. Additionally, its long- (1.7% vs 0.6%), and increased serum creatinine (4.7% vsterm use has been associated with serious adverse effects, 1.3%) were also more common in the dronedarone treat-including pulmonary and hepatic toxicity, thyroid dysfunc- ment group (all P .001 vs placebo). The results oftion, and eye complications.57 Therefore, there is a pressing ATHENA provide evidence of the morbidity and mortalityunmet need for maintenance therapies with improved efﬁ- beneﬁts of dronedarone in appropriate populations. Thecacy/safety proﬁles. early discontinuation of one nonatrial ﬁbrillation trial Anti- In contrast to these older agents, a newly approved ben- arrhythmic Trial with Dronedarone in Moderate to Severezofuran derivative, dronedarone (Multaq [dronedarone]; Congestive Heart Failure Evaluating Morbidity Decreasesanoﬁ-aventis US LLC, Bridgewater, NJ), was recently ap- (ANDROMEDA) conducted in high-risk patients with ad-proved (July 2009) by the FDA to reduce the risk of hos- vanced congestive heart failure and recent decompensationpitalization in patients with atrial ﬁbrillation or atrial ﬂutter leading to hospitalization (regardless of the absence or pres-and associated cardiovascular risk factors (ie, age 70 years ence of atrial ﬁbrillation), led to concern regarding the effectsold, hypertension, diabetes, prior cerebrovascular accident, of dronedarone on mortality in this high-risk group.62left atrial diameter 50 mm or LVEF 40%), who are in The ATHENA investigators suggested that the differencesinus rhythm or will be cardioverted. Its use is contraindi- in outcomes between ATHENA and ANDROMEDA maycated in patients with New York Heart Association (NYHA) be a reﬂection of the disparate populations studied (ie,class IV heart failure, or NYHA class II to III heart failure ANDROMEDA enrolled only patients with advanced heartwith a recent decompensation requiring hospitalization or failure and recent decompensation leading to hospitalization;specialist referral. Dronedarone has characteristics of all 4 ATHENA speciﬁcally excluded patients who had either hemo-Vaughan–Williams classes and a short half-life (of approx- dynamic instability or severe [NYHA class IV] heart failure).58imately 24 hours), which reduces its accumulation in tissue. A “pill-in-pocket” approach has been advocated forLacking an iodine moiety, dronedarone is expected to offer some patients with paroxysmal or persistent atrial ﬁbrilla-reduced risk of thyroid and pulmonary toxicity.58 tion.3 This approach, in which patients are instructed to In clinical studies,59,60 dronedarone 400 mg twice daily self-administer a single dose of a Vaughan–Williams Classwas effective for preventing the recurrence of atrial ﬁbril- IC agent, such as ﬂecainide or propafenone, upon the onsetlation or atrial ﬂutter (prolonged time to recurrence relative of atrial ﬁbrillation symptoms, may terminate the episode orto placebo) and was well tolerated (no serious side effects). prevent recurrence in patients with paroxysmal atrial ﬁbril-Perhaps even more importantly, it has demonstrated bene- lation and reduce the risk for toxicity associated with pro-ﬁcial effects with respect to cardiovascular morbidity and longed anti-arrhythmic therapy. This method is associatedmortality in the atrial ﬁbrillation population. Data from the with few adverse effects in patients with no structural heartrecent A Placebo-Controlled, Double-Blind, Parallel Arm disease. All patients using this method should receive on-Trial to Assess the Efﬁcacy of Dronedarone 400 mg twice a going beta-blockers or nondihydropyridine calcium channelday for the Prevention of Cardiovascular Hospitalization or blocker therapy for rate control to prevent rapid AV con-Death from Any Cause in Patients with Atrial Fibrillation/ duction. In addition to being rapidly effective and safe, theAtrial Flutter (ATHENA) trial in patients with moderate- pill-in-pocket approach has been associated with improvedrisk to high-risk paroxysmal or persistent atrial ﬁbrillation quality of life,63 reduced emergency department and hospi-or atrial ﬂutter (N 4628; 29% with history of class I, II, or tal admissions,63,64 and lower costs.63III heart failure and 12% with LVEF 45%) demonstratedsigniﬁcantly reduced cardiovascular morbidity and mortal- Rate Controlity in the dronedarone group.58 Compared with a placebo, Generally, beta-blockers and nondihydropyridine calciumtreatment with dronedarone in ATHENA reduced the com- channel blockers are appropriate for most patients withposite endpoint of “time to ﬁrst cardiovascular hospitaliza- persistent or permanent atrial ﬁbrillation for whom controltion or death from any cause” by 24% (P .001), time to of their ventricular rate is desired.3 (Digoxin or amiodaroneﬁrst cardiovascular hospitalization by 26% (P .001), car- should be considered in patients with heart failure and nodiovascular mortality by 29% (P .03), and stroke by 34% accessory pathway.) All of these agents can be administered(P .027).58,61 Unlike other rhythm-control agents which intravenously in the acute setting and orally for maintenancemay be associated with an increase in noncardiovascular therapy. For most patients, a target heart rate of 60 to 80mortality, there was a trend toward improvement in the total beats per minute at rest and 90 to 115 beats per minute
10 The American Journal of Medicine, Vol 124, No 1, January 2011during moderate exercise is appropriate. The selection of cess rates with single procedures are approximately 60% inappropriate rate-control therapy for each patient should in- patients with paroxysmal atrial ﬁbrillation and 30% include consideration of the drug’s potential impact on co- patients with persistent atrial ﬁbrillation, up to 70% andmorbid conditions such as hypertension, ischemic heart 50% with a second or third attempt, respectively.68 How-disease, and hypertrophic cardiomyopathy. ever, there are no large well-designed trials to support wide- Generally, beta-blockers and nondihydropyridine cal- spread use of RF ablation. RF ablation is associated with acium channel blockers are well tolerated; however, they are 6% risk of major complications69 and should not be used innot always effective at controlling heart rate nor always the presence of left atrial thrombus.68 This approach is besttitrated to suitable levels, possibly because up-titration is performed early in the course of the disease, as longerassociated with the increased occurrence of adverse durations are associated with poorer outcomes.70events.65 In at-risk patients, these agents may contribute to Surgical maze procedures are usually optional add-onthe development of decreased blood pressure, heart block, procedures in patients undergoing other open-heart surgicaland/or heart failure.3,66 Beta-blockers should be used with operations.71 Similarly, AV node ablation is not recom-caution in patients with asthma. Amiodarone may cause mended as a primary strategy, but is typically reserved forbradycardia, hypotension, visual disturbances, and gastroin- symptomatic patients who have a rapid ventricular rate andtestinal events (oral route), or phlebitis (peripheral intravenousroute).3 Long-term use of amiodarone may result in end-organ who are refractory to pharmacologic treatment.3 AV nodetoxicity (pulmonary, hepatic, thyroid, neurologic, and/or ablation is warranted in patients with a rapid ventricularskin).57 When digoxin is used, patients should be monitored response to atrial ﬁbrillation who cannot be controlled withfor signs of digoxin toxicity, especially in those with reduced medication. It is associated with improved symptoms andrenal function, advanced age, acute or chronic hypoxia, or quality of life and reduced health care resource utilization.72thyroid disease.67 Because this technique results in complete heart blockage, permanent pacing and long-term continuous anticoagulation are required.3CardioversionConversion to normal sinus rhythm may be attempted usingelectrical or pharmacologic measures and may be appropri- OTHER TREATMENT OPTIONSate for patients with persistent atrial ﬁbrillation, symptom-atic atrial ﬁbrillation, or atrial ﬁbrillation-induced acute Renin-angiotensin System Blockadeheart failure, hypotension, or worsening of angina pectoris Several lines of evidence suggest that angiotensin-convert-(in persons with CAD).3,36 Regardless of approach (electri- ing enzyme inhibitors and angiotensin receptor blockerscal or pharmacologic), appropriate anticoagulation prophy- (ARBs) can retard or reverse atrial ﬁbrosis and structurallaxis should be implemented before cardioversion whenever remodeling of the atria.73,74 These agents have been shownpossible. to decrease atrial pressure, reduce the frequency of prema- The efﬁcacy of direct-current cardioversion is widelyaccepted; however, limitations include the need for the ture atrial beats, reduce ﬁbrosis, and may lower atrial ﬁbril-patient to receive conscious sedation or anesthesia along lation relapse rates after cardioversion. These actions havewith risks of thromboembolism and proarrhythmia.3,36 promoted interest in their potential use for primary preven-Pharmacologic cardioversion does not require sedation or tion or treatment of recurrent episodes of atrial ﬁbrillation,anesthesia; however, it is likely less effective and still poses particularly when associated with hypertension, myocardialthromboembolic and pro-arrhythmia risks. The ACC/AHA/ infarction, congestive heart failure, or diabetes mellitus.3ESC guidelines identify dofetilide, ibutilide, and amioda- Renin-angiotensin system inhibitors also may be useful inrone as agents with efﬁcacy for pharmacologic cardiover- patients receiving maintenance anti-arrhythmic drug ther-sion of atrial ﬁbrillation of 7 days’ duration and apy. The combination of amiodarone plus an angiotensin-disopyramide, ﬂecainide, procainamide, propafenone, and converting enzyme inhibitor or ARB has been shown toquinidine as less effective or incompletely studied.3 result in better control of sinus rhythm in several studies.75-77Ablation Although the impact of renin-angiotensin system block-Patients failing ﬁrst-line anti-arrhythmic treatment should ers on morbidity and mortality in patients with atrial ﬁbril-be considered candidates for amiodarone or RF ablation, lation has not been well studied, ARB therapy was associ-which is considered to be a second-line option for paroxys- ated with a reduction in the risk of the primary compositemal or persistent atrial ﬁbrillation, or may be useful in endpoint (cardiovascular mortality, stroke, and myocardialpatients with highly symptomatic lone atrial ﬁbrillation.3 infarction), stroke, and cardiovascular death relative to beta-Good candidates for RF ablation include individuals who blocker therapy in patients with hypertension, left ventric-are 70 years of age, with highly symptomatic paroxysmal ular hypertrophy, and atrial ﬁbrillation in the Losartan In-atrial ﬁbrillation, who have never cardioverted, and have a tervention For Endpoint study.78 Additional studies areleft atrial size 5 cm and ejection fraction 40%.68 Suc- needed to conﬁrm these ﬁndings.
Eagle et al Atrial Fibrillation Management 11Statins, Steroids, and Polyunsaturated early reversible neutropenia86 have been identiﬁed andFatty Acids complicated the clinical development of this agent.Cardiac inﬂammation seems to play a role in the pathogen- Tedisamil is an anti-ischemic agent currently being eval-esis of atrial ﬁbrillation in some patients, and evidence uated for use in patients with atrial ﬁbrillation. In patients with recent-onset symptomatic atrial ﬁbrillation or atrialsuggests that statins, steroids, and polyunsaturated fatty ﬂutter, intravenous tedisamil has demonstrated rapid (withinacids may have beneﬁcial anti-inﬂammatory and anti-ar- 30-40 minutes), dose-related effects (cardioversion); how-rhythmic properties.73 The prevalence of atrial ﬁbrillation is ever, pro-arrhythmic effects were evident in the high-dosereportedly lower among patients with reduced LVEF taking group (1 case each of torsades de pointes and monomorphiclipid-lowering drugs (ﬁbric-acid derivatives, bile-acid se- ventricular tachycardia).87questrants, statins, ezetimibe, or niacin) than among patients Vernakalant has demonstrated consistent conversionwith similar levels of ventricular function who are not rates (as high as 61% with intravenous administration) andtaking these drugs.79 low pro-arrhythmia risk.88-90 Orally administered ver- nakalant reduced short-term recurrence (39%) relative toManagement of Concomitant Conditions placebo (57%) in a phase II clinical trial.91 Adverse eventsHypertension,80 heart failure,9,81 and diabetes82 all com- that occurred more frequently in the active treatment groupsmonly coexist with atrial ﬁbrillation and may contribute to than with placebo were bradycardia, sinus bradycardia, andits development and progression. Therefore, strategies for ﬁrst-degree AV block (rates not provided). Torsades dethe management of these conditions should be part of the pointes did not occur.overall treatment plan. The ACC/AHA/ESC guidelines pro- Additional studies are needed to determine if thesevide speciﬁc recommendations for maintenance of sinus agents will have a role in the management of atrial ﬁbril-rhythm in patients with recurrent paroxysmal or persistent lation in the future.atrial ﬁbrillation plus hypertension, CAD, or heart failure(Figure 2).3 When no (or minimal) heart disease or uncom-plicated hypertension is present, ﬂecainide, propafenone, or SUMMARYsotalol are recommended as ﬁrst-line agents. However, fur- Atrial ﬁbrillation is an increasingly common supraventric- ular arrhythmia which, if not managed appropriately, resultsther clinical assessments should be made as, for example, in signiﬁcant consequences in terms of patient morbiditythe choice of sotalol would not be recommended if the and mortality. The primary goals of atrial ﬁbrillation ther-patient has underlying bradycardia or a prior sensitivity to apy should be to reduce such consequences and minimizebeta-blockers. If hypertension is complicated with substan- symptoms (if present). To ensure the best possible outcome,tial left ventricular hypertrophy, amiodarone or catheter atrial ﬁbrillation management should be individualizedablation is recommended. In patients with CAD, it is rec- based on patient characteristics and comorbidities that couldommended that treatment be initiated using dofetilide or inﬂuence response to speciﬁc management approaches. Thesotalol, followed by amiodarone or ablation. In the case of importance of adequate anticoagulation concomitant withheart failure, amiodarone or dofetilide are ﬁrst-choice anti-arrhythmic therapy should not be overlooked. Histori-agents, followed by catheter ablation if pharmacologic- cally, anti-arrhythmic drugs have provided suboptimal efﬁ-based treatment is not successful. Again, choosing between cacy and have had safety/tolerability issues, resulting in anamiodarone or catheter ablation also would need to take into unmet clinical need for atrial ﬁbrillation drug therapies withaccount the prospective patient’s age and comorbidities that improved beneﬁt/risk proﬁles and demonstrable beneﬁts oncould exclude drug therapy. clinically meaningful outcomes. Newer drugs, such as dronedarone and several other agents in later stages ofInvestigational Agents clinical development may potentially address this need byNew atrial ﬁbrillation therapies being investigated that show providing greater efﬁcacy, reduced cardiovascular morbid-particular promise include safer multi-ion channel blockers ity and mortality, and an improved safety proﬁle.or atrial-selective/preferential ion channel blockers such asazimilide, tedisamil, and vernakalant. Other agents in earlier Referencesstages of development include new rate-control agents (eg, 1. Rho RW, Page RL. Asymptomatic atrial ﬁbrillation. Prog Cardiovasctecadenoson, selodenoson), stretch-activated ion channel Dis. 2005;48:79-87.blockers (eg, GsMTx-4), and gap junction modiﬁers (eg, 2. Cohen M, Naccarelli GV. Pathophysiology and disease progression of atrial ﬁbrillation: importance of achieving and maintaining sinusrotigaptide, AAP10). rhythm. J Cardiovasc Electrophysiol. 2008;19:885-890. The investigational agent azimilide has demonstrated 3. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guide-mixed results in clinical trials conducted in patients with lines for the management of patients with atrial ﬁbrillation-executiveatrial ﬁbrillation.83-85 Although its potential role remains to summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Europeanbe established, the beneﬁt of azimilide may be greater in Society of Cardiology Committee for Practice Guidelines (Writingpatients with a history of ischemic heart disease or heart Committee to Revise the 2001 Guidelines for the Management offailure. An increased risk of torsades de pointes and, rarely, Patients with Atrial Fibrillation). Eur Heart J. 2006;27:1979-2030.
12 The American Journal of Medicine, Vol 124, No 1, January 2011 4. Tsang TS, Miyasaka Y, Barnes ME, Gersh BJ. Epidemiological proﬁle 26. Crijns HJ. Rate versus rhythm control in patients with atrial ﬁbrilla- of atrial ﬁbrillation: a contemporary perspective. Prog Cardiovasc Dis. tion: what the trials really say. Drugs. 2005;65:1651-1667. 2005;48:1-8. 27. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical 5. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial ﬁbrillation classiﬁcation schemes for predicting stroke: results from the National begets atrial ﬁbrillation. A study in awake chronically instrumented Registry of Atrial Fibrillation. JAMA. 2001;285:2864-2870. goats. Circulation. 1995;92:1954-1968. 28. Dorian P, Jung W, Newman D, et al. The impairment of health-related 6. Morillo CA, Klein GJ, Jones DL, Guiraudon CM. Chronic rapid atrial quality of life in patients with intermittent atrial ﬁbrillation: implica- pacing. Structural, functional, and electrophysiological characteristics tions for the assessment of investigational therapy. J Am Coll Cardiol. of a new model of sustained atrial ﬁbrillation. Circulation. 1995;91: 2000;36:1303-1309. 1588-1595. 29. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control 7. Ausma J, Wijffels M, Thoné F, et al. Structural changes of atrial and rhythm control in patients with atrial ﬁbrillation. N Engl J Med. myocardium due to sustained atrial ﬁbrillation in the goat. Circulation. 2002;347:1825-1833. 1997;96:3157-3163. 30. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs rhythm 8. Allessie M, Ausma J, Schotten U. Electrical, contractile and structural control in patients with nonvalvular persistent atrial ﬁbrillation: the remodeling during atrial ﬁbrillation. Cardiovasc Res. 2002;54:230- results of the Polish How to Treat Chronic Atrial Fibrillation (HOT 246. CAFE) Study. Chest. 2004;126:476-486. 9. Schoonderwoerd BA, Van Gelder IC, Van Veldhuisen DJ, et al. 31. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrial Electrical and structural remodeling: role in the genesis and mainte- ﬁbrillation--Pharmacological Intervention in Atrial Fibrillation (PIAF): a nance of atrial ﬁbrillation. Prog Cardiovasc Dis. 2005;48:153-168. randomised trial. Lancet. 2000;356:1789-1794.10. Manning WJ, Silverman DI, Katz SE, et al. Impaired left atrial me- 32. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate chanical function after cardioversion: relation to the duration of atrial control and rhythm control in patients with recurrent persistent atrial ﬁbrillation. J Am Coll Cardiol. 1994;23:1535-1540. ﬁbrillation. N Engl J Med. 2002;347:1834-1840.11. Franz MR, Karasik PL, Li C, et al. Electrical remodeling of the human 33. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate- atrium: similar effects in patients with chronic atrial ﬁbrillation and control versus rhythm-control in persistent atrial ﬁbrillation: the Strat- atrial ﬂutter. J Am Coll Cardiol. 1997;30:1785-1792. egies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll12. Brundel BJ, Van Gelder IC, Henning RH, et al. Ion channel remod- Cardiol. 2003;41:1690-1696. eling is related to intraoperative atrial effective refractory periods in 34. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control patients with paroxysmal and persistent atrial ﬁbrillation. Circulation. for atrial ﬁbrillation and heart failure. N Engl J Med. 2008;358:2667- 2001;103:684-690. 2677.13. Miyasaka Y, Barnes ME, Gersh BJ, et al. Changing trends of hospital 35. Steinberg JS, Sadaniantz A, Kron J, et al. Analysis of cause-speciﬁc utilization in patients after their ﬁrst episode of atrial ﬁbrillation. Am J mortality in the Atrial Fibrillation Follow-up Investigation of Rhythm Cardiol. 2008;102:568-572. Management (AFFIRM) study. Circulation. 2004;109:1973-1980.14. Le Heuzey JY, Paziaud O, Piot O, et al. Cost of care distribution in 36. Snow V, Weiss KB, LeFevre M, et al. Management of newly detected atrial ﬁbrillation patients: the COCAF study. Am Heart J. 2004;147: atrial ﬁbrillation: a clinical practice guideline from the American 121-126. Academy of Family Physicians and the American College of Physi-15. Thrall G, Lane D, Carroll D, Lip GY. Quality of life in patients with cians. Ann Intern Med. 2003;139:1009-1017. atrial ﬁbrillation: a systematic review. Am J Med. 2006;119:448.e1- 37. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in 448.e19. atrial ﬁbrillation: American College of Chest Physicians Evidence-16. Wu EQ, Birnbaum HG, Mareva M, et al. Economic burden and Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 co-morbidities of atrial ﬁbrillation in a privately insured population. Suppl):546S-592S. Curr Med Res Opin. 2005;21:1693-1699.17. Shiroshita-Takeshita A, Brundel BJ, Nattel S. Atrial ﬁbrillation: basic 38. Calkins H, Brugada J, Packer DL, et al. HRS/EHRA/ECAS expert mechanisms, remodeling and triggers. J Interv Card Electrophysiol. consensus statement on catheter and surgical ablation of atrial ﬁbril- 2005;13:181-193. lation: recommendations for personnel, policy, procedures and follow-18. Wit AL, Boyden PA. Triggered activity and atrial ﬁbrillation. Heart up. A report of the Heart Rhythm Society (HRS) Task Force on Rhythm. 2007;4(3 Suppl):S17-S23. Catheter and Surgical Ablation of Atrial Fibrillation developed in19. Xu J, Cui G, Esmailian F, et al. Atrial extracellular matrix remodeling partnership with the European Heart Rhythm Association (EHRA) and and the maintenance of atrial ﬁbrillation. Circulation. 2004;109:363- the European Cardiac Arrhythmia Society (ECAS); in collaboration 368. with the American College of Cardiology (ACC), American Heart20. Nakano Y, Niida S, Dote K, et al. Matrix metalloproteinase-9 contrib- Association (AHA), and the Society of Thoracic Surgeons (STS). utes to human atrial remodeling during atrial ﬁbrillation. J Am Coll Endorsed and approved by the governing bodies of the American Cardiol. 2004;43:818-825. College of Cardiology, the American Heart Association, the European21. Wongcharoen W, Chen SA. Management of atrial ﬁbrillation in pa- Cardiac Arrhythmia Society, the European Heart Rhythm Association, tients with heart failure: from drug therapy to ablation. Expert Rev the Society of Thoracic Surgeons, and the Heart Rhythm Society. Cardiovasc Ther. 2009;7:311-322. Europace. 2007;9:335-379.22. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial ﬁbrillation by 39. Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambu- heart failure in dogs: atrial remodeling of a different sort. Circulation. latory patients with nonvalvular atrial ﬁbrillation: the anticoagulation 1999;100:87-95. and risk factors in atrial ﬁbrillation (ATRIA) study. Ann Intern Med.23. Ohkusa T, Ueyama T, Yamada J, et al. Alterations in cardiac sarco- 1999;131:927-934. plasmic reticulum Ca2 regulatory proteins in the atrial tissue of 40. Waldo AL, Becker RC, Tapson VF, Colgan KJ. Hospitalized patients patients with chronic atrial ﬁbrillation. J Am Coll Cardiol. 1999;34: with atrial ﬁbrillation and a high risk of stroke are not being provided 255-263. with adequate anticoagulation. J Am Coll Cardiol. 2005;46:1729-24. Lévy S, Maarek M, Coumel P, et al. Characterization of different 1736. subsets of atrial ﬁbrillation in general practice in France: the ALFA 41. Mitchell AR. Will this be the end of the anticoagulation clinic for study. The College of French Cardiologists. Circulation. 1999;99: patients with atrial ﬁbrillation? Curr Drug Targets Cardiovasc 3028-3035. Haematol Disord. 2005;5:405-408.25. Kannel WB, Benjamin EJ. Current perceptions of the epidemiology of 42. Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic compli- atrial ﬁbrillation. Cardiol Clin. 2009;27:13-24. cations of anticoagulant and thrombolytic treatment: American Col-
Eagle et al Atrial Fibrillation Management 13 lege of Chest Physicians Evidence-Based Clinical Practice Guidelines 62. Køber L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality (8th Edition). Chest. 2008;133(6 Suppl):257S-298S. after dronedarone therapy for severe heart failure. N Engl J Med.43. Aguilar MI, Hart R, Pearce LA. Oral anticoagulants versus antiplatelet 2008;358:2678-2687. therapy for preventing stroke in patients with non-valvular atrial ﬁ- 63. Capucci A, Villani GQ, Piepoli MF, Aschieri D. The role of oral 1C brillation and no history of stroke or transient ischemic attacks. Co- antiarrhythmic drugs in terminating atrial ﬁbrillation. Curr Opin Car- chrane Database Syst Rev. 2007;Issue 3. Art. No.: CD006186. DOI: diol. 1999;14:4-8. 10.1002/14651858.CD006186.pub2. 64. Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-44. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, onset atrial ﬁbrillation with the “pill-in-the-pocket” approach. N Engl Pogue J, et al. Clopidogrel plus aspirin versus oral anticoagulation for J Med. 2004;351:2384-2391. atrial ﬁbrillation in the Atrial ﬁbrillation Clopidogrel Trial with Irbe- 65. Van Gelder IC, Wyse DG, Chandler ML, et al. Does intensity of sartan for prevention of Vascular Events (ACTIVE W): a randomised rate-control inﬂuence outcome in atrial ﬁbrillation? An analysis of controlled trial. Lancet. 2006;367:1903-1912. pooled data from the RACE and AFFIRM studies. Europace. 2006;8:45. Mant J, Hobbs FD, Fletcher K, et al. Warfarin versus aspirin for stroke 935-942. prevention in an elderly community population with atrial ﬁbrillation 66. Singh BN. -blockers and calcium channel blockers as antiarrhythmic (the Birmingham Atrial Fibrillation Treatment of the Aged Study, drugs. In: Zipes DP, Jalife J, editors. Cardiac Electrophysiology: From BAFTA): a randomised controlled trial. Lancet. 2007;370:493-503. Cell to Bedside, 4th edition. Philadelphia: W.B. Saunders, 2004 p46. ACTIVE Investigators, Connolly SJ, Pogue J, et al. Effect of clopi- 918-931. dogrel added to aspirin in patients with atrial ﬁbrillation. N Engl 67. DiMarco JP. Adenosine and digoxin. In: Zipes DPJalife J, editors J Med. 2009;360:2066-2078. Cardiac Electrophysiology: From Cell to Bedside, 4th edition. Phila-47. Olsson SB; Executive Steering Committee of the SPORTIF III Inves- delphia: W.B. Saunders, 2004 p 942-949. tigators. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular 68. Calkins H. New ACC/AHA/ESC guidelines for the management of atrial ﬁbrillation (SPORTIF III): randomised controlled trial. Lancet. atrial ﬁbrillation: highlighting stroke prevention and catheter ablation. 2003;362:1691-1698. 2006. Available at: http://cme.medscape.com/viewarticle/543645_48. Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for print. Accessed April 2009. stroke prevention in patients with nonvalvular atrial ﬁbrillation: a 69. Cappato R, Calkins H, Chen SA, et al. Worldwide survey on the randomized trial. JAMA. 2005;293:690-698. methods, efﬁcacy, and safety of catheter ablation for human atrial49. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus war- ﬁbrillation. Circulation. 2005;111:1100-1105. farin in patients with atrial ﬁbrillation. N Engl J Med. 2009;361:1139- 70. Kobza R, Hindricks G, Tanner H, et al. Late recurrent arrhythmias 1151. after ablation of atrial ﬁbrillation: incidence, mechanisms, and treat-50. Ansell J, Jacobson A, Levy J, et al. Guidelines for implementation of ment. Heart Rhythm. 2004;1:676-683. patient self-testing and patient self-management of oral anticoagula- 71. Padanilam BJ, Prystowsky EN. Atrial ﬁbrillation: goals of therapy and tion. International consensus guidelines prepared by International Self- management strategies to achieve the goals. Med Clin North Am. Monitoring Association for Oral Anticoagulation. Int J Cardiol. 2005; 2008;92:217-235. 99:37-45. 72. Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clinical51. Garcia DA, Witt DM, Hylek E, et al. Delivery of optimized antico- outcomes after ablation and pacing therapy for atrial ﬁbrillation: a agulant therapy: consensus statement from the Anticoagulation Forum. meta-analysis. Circulation. 2000;101:1138-1144. Ann Pharmacother. 2008;42:979-988. 73. Goldstein RN, Stambler BS. New antiarrhythmic drugs for prevention52. Lafuente-Lafuente C, Mouly S, Longás-Tejero MA, et al. Antiarrhyth- of atrial ﬁbrillation. Prog Cardiovasc Dis. 2005;48:193-208. mic drugs for maintaining sinus rhythm after cardioversion of atrial 74. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial ﬁbril- ﬁbrillation: a systematic review of randomized controlled trials. Arch lation with angiotensin-converting enzyme inhibitors and angiotensin Intern Med. 2006;166:719-728. receptor blockers: a meta-analysis. J Am Coll Cardiol. 2005;45:1832-53. Roden DM, Anderson ME. Proarrhythmia. Handb Exp Pharmacol. 1839. 2006;73-97. 75. Madrid AH, Bueno MG, Rebollo JM, et al. Use of irbesartan to54. Trujillo TC, Nolan PE. Antiarrhythmic agents: drug interactions of maintain sinus rhythm in patients with long-lasting persistent atrial clinical signiﬁcance. Drug Saf. 2000;23:509-532. ﬁbrillation: a prospective and randomized study. Circulation. 2002;55. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Mainte- 106:331-336. nance of sinus rhythm in patients with atrial ﬁbrillation: an AFFIRM 76. Ueng KC, Tsai TP, Yu WC, et al. Use of enalapril to facilitate sinus substudy of the ﬁrst antiarrhythmic drug. J Am Coll Cardiol. 2003;42: rhythm maintenance after external cardioversion of long-standing per- 20-29. sistent atrial ﬁbrillation. Results of a prospective and controlled study.56. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for Eur Heart J. 2003;24:2090-2098. atrial ﬁbrillation. N Engl J Med. 2005;352:1861-1872. 77. Yin Y, Dalal D, Liu Z, et al. Prospective randomized study comparing57. Vorperian VR, Havighurst TC, Miller S, January CT. Adverse effects amiodarone vs. amiodarone plus losartan vs. amiodarone plus perin- of low dose amiodarone: a meta-analysis. J Am Coll Cardiol. 1997; 30:791-798. dopril for the prevention of atrial ﬁbrillation recurrence in patients with58. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone lone paroxysmal atrial ﬁbrillation. Eur Heart J. 2006;27:1841-1846. on cardiovascular events in atrial ﬁbrillation. N Engl J Med. 2009;360: 78. Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity 668-678. and mortality in hypertensive patients with a history of atrial ﬁbrilla-59. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of tion: The Losartan Intervention For End Point Reduction in Hyperten- atrial ﬁbrillation: a dose-ranging study. Eur Heart J. 2003;24:1481- sion (LIFE) study. J Am Coll Cardiol. 2005;45:705-711. 1487. 79. Hanna IR, Heeke B, Bush H, et al. Lipid-lowering drug use is asso-60. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance ciated with reduced prevalence of atrial ﬁbrillation in patients with left of sinus rhythm in atrial ﬁbrillation or ﬂutter. N Engl J Med. 2007; ventricular systolic dysfunction. Heart Rhythm. 2006;3:881-886. 357:987-999. 80. Lombardi F, Terranova P. Hypertension and concurrent arrhythmias.61. Connolly SJ. ATHENA: the effect of dronedarone on cardiovascular Curr Pharm Des. 2003;9:1703-1713. outcomes and stroke in patients with atrial ﬁbrillation. Presented at the 81. Savelieva I, John Camm A. Atrial ﬁbrillation and heart failure: natural European Society of Cardiology Congress 2008, Munich, Germany, history and pharmacological treatment. Europace. 2004;5(Suppl 1): August 30-September 3, 2008. S5-S19.
14 The American Journal of Medicine, Vol 124, No 1, January 201182. Movahed MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a 87. Hohnloser SH, Dorian P, Straub M, et al. Safety and efﬁcacy of intrave- strong, independent risk for atrial ﬁbrillation and ﬂutter in addition to nously administered tedisamil for rapid conversion of recent-onset atrial other cardiovascular disease. Int J Cardiol. 2005;105:315-318. ﬁbrillation or atrial ﬂutter. J Am Coll Cardiol. 2004;44:99-104.83. Pritchett EL, Kowey P, Connolly S, et al. Antiarrhythmic efﬁcacy of 88. Roy D, Rowe BH, Stiell IG, et al. A randomized, controlled trial azimilide in patients with atrial ﬁbrillation. Maintenance of sinus rhythm of RSD1235, a novel anti-arrhythmic agent, in the treatment of after conversion to sinus rhythm. Am Heart J. 2006;151:1043-1049. recent onset atrial ﬁbrillation. J Am Coll Cardiol. 2004;44:2355-84. Pratt CM, Singh SN, Al-Khalidi HR, et al. The efﬁcacy of azimilide in 2361. the treatment of atrial ﬁbrillation in the presence of left ventricular 89. Roy D, Pratt C, Wyse G, et al. RSD1235 for conversion of atrial systolic dysfunction: results from the Azimilide Postinfarct Survival ﬁbrillation, the phase III atrial arrhythmia conversion trial. Heart Evaluation (ALIVE) trial. J Am Coll Cardiol. 2004;43:1211-1216. Rhythm. 2005;2:1035. Abstract LBA– 6098.85. Lombardi F, Borggrefe M, Ruzyllo W, Lüderitz B. Azimilide vs. 90. Pratt C, Roy D, Juul-Moller S, et al. Efﬁcacy and tolerance of placebo and sotalol for persistent atrial ﬁbrillation: the A-COMET-II RSD1235 in the treatment of atrial ﬁbrillation or atrial ﬂutter: results (Azimilide-CardiOversion MaintEnance Trial-II) trial. Eur Heart J. of a phase III, randomized, placebo-controlled, multicenter trial. J Am 2006;27:2224-2231. Coll Cardiol. 2006;47:10A. Abstract 804-803.86. VerNooy RA, Mangrum JM. Azimilide, a novel oral class III antiar- 91. Pratt CM, Navratil J, Nagy A, et al. Oral vernakalant (RSD1235-SR) rhythmic for both supraventricular and ventricular arrhythmias. Curr prevents recurrence of atrial ﬁbrillation following cardioversion. Heart Drug Targets Cardiovasc Haematol Disord. 2005;5:75-84. Rhythm. 2007;4(Suppl):S176. Abstract PO2-92.