Management della fibrillazione_atriale

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Management della fibrillazione_atriale

  1. 1. REVIEWManagement of Atrial Fibrillation: Translating ClinicalTrial Data into Clinical PracticeKim A. Eagle, MD,a David S. Cannom, MD,b David A. Garcia, MDca Albion Walter Hewlett, University of Michigan Health System, Ann Arbor; bGood Samaritan Hospital, Los Angeles, Calif; cUniversityof New Mexico School of Medicine, Albuquerque. ABSTRACT Atrial fibrillation is a supraventricular tachyarrhythmia with significant consequences in terms of morbidity and mortality. In light of the limitations of available pharmacologic treatment options (suboptimal efficacy plus safety and tolerability issues), atrial fibrillation management should be individualized based on patient characteristics and comorbidities that could influence response to specific management approaches. The importance of adequate anticoagulation should not be overlooked. This review provides a practical guide for primary care physicians, internists, and cardiologists on current management strategies for atrial fibrillation, based on recent guidelines and current clinical data. © 2011 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2011) 124, 4-14 KEYWORDS: Atrial fibrillation; Management; TreatmentAtrial fibrillation is the most common cardiac rhythm dis- than 5.5 million people in the United States will have atrialturbance encountered by physicians in clinical practice.1 fibrillation.1Atrial fibrillation is characterized by uncoordinated atrial Atrial fibrillation presents in specific patterns and can beactivation, and if not managed appropriately, may be asso- classified as paroxysmal (self-terminating and lasting 7ciated with significant morbidity and mortality and a reduc- days), persistent (not self-terminating and lasting 7 days),tion in quality of life.2 It is estimated that 2.3 million and permanent (lasting 1 year and/or refractory to cardio-Americans and 4.5 million Europeans are affected by atrial version).3 Paroxysmal atrial fibrillation and persistent atrialfibrillation, which predominantly impacts persons 65 fibrillation are not mutually exclusive, and individuals mayyears of age.2 By the year 2050 it is estimated that more experience both at different times. A patient’s atrial fibril- lation often is characterized based on the most frequent or most sustained presentation. Well-known risk factors for Funding: The authors received editorial support in the preparation of atrial fibrillation include coronary artery disease (CAD),this manuscript. The editorial assistance was provided by Mary Tom, diabetes, heart failure, hypertension, hyperthyroidism, andPharmD, and funded by sanofi-aventis US. The authors, however, were myocardial infarction.4fully responsible for all content and editorial decisions and received no In animal models, atrial fibrillation has been shownfinancial support or other form of compensation related to the developmentof the article. to cause electrophysiologic changes in the atrium, includ- Conflicts of Interest: Dr Eagle has had research grants from sanofi- ing marked shortening of the atrial effective refractoryaventis, the Hewlett Foundation, Mardigan Foundation, and Gore. period.5,6 With continued atrial fibrillation, contractile andDr Cannom has acted as Chair for Medtronic Physician Advisory Group, structural remodeling occurs, and atrial fibrillation can be-and has been a speaker for Boston Scientific and sanofi-aventis. Dr Garcia come self-sustained, no longer requiring a trigger.5,7,8 Elec-has received research grants and/or consulting honoraria from Bristol-Myers Squibb and Boehringer Ingelheim. trical, contractile, and structural changes also have been Authorship: All authors participated in the preparation and review of observed in humans, and it has been noted that the durationthe manuscript, had access to the data, and had a role in writing the of atrial fibrillation tends to correlate well with the progres-manuscript. sion of these changes.9-12 In addition to shortening of the Reprint requests should be addressed to Kim A. Eagle, MD, Universityof Michigan Cardiovascular Center, 1500 East Medical Center Drive, Suite atrial effective refractory period, several other factors have2131, SPC 5852, Ann Arbor, MI 48109-5852. been associated with structural remodeling in atrial fibrilla- E-mail address: keagle@umich.edu tion. These include aging, alcohol consumption, autonomic0002-9343/$ -see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.amjmed.2010.05.016
  2. 2. 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-
  3. 3. 6 The American Journal of Medicine, Vol 124, No 1, January 2011creased mortality risk.26 Older patients and patients withprior stroke or transient ischemic attack (TIA), or those withhypertension, heart failure, or diabetes seem to be particu-larly susceptible to stroke.27 Atrial fibrillation also reducesquality of life relative to healthy controls, the general pop-ulation, and patients with other cardiovascular disease.15Reduced quality of life is generally attributed to the dis-comfort associated with atrial fibrillation symptoms, re-duced exercise tolerance, and chronic fatigue.2 Recent stud-ies aimed at objectively quantifying the reduction in qualityof life in patients with atrial fibrillation, demonstrated thatthe scores on all domains of the short-form health survey(SF-36) among patients with intermittent atrial fibrillationwere significantly (P .05) worse than those of published Figure 1 Cumulative mortality from any cause in thecontrols with significant coronary heart disease and no atrial rhythm-control group and the rate-control group.29 These data,fibrillation (eg, those who had recently undergone percuta- from the Atrial Fibrillation Follow-Up Investigation of Rhythmneous transluminal coronary angioplasty or suffered a myo- Management (AFFIRM) trial, show that there is a mortalitycardial infarction).28 difference between rhythm and rate control and that patients in whom a rhythm-control strategy is attempted have increased mortality compared with patients who received rate controlGOALS OF THERAPY alone. Time zero is the day of randomization. Data have beenPractical goals of atrial fibrillation therapy are to reduce truncated at 5 years. Reprinted from: Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythmmorbidity and mortality and improve quality of life. More control in patients with atrial fibrilation. N Engl J Med 2002;specific goals are control of heart rate, correction of the 347:1825-1833. Copyright © 2002 Massachusetts Medical So-rhythm disturbance, and prophylaxis against thromboembo- ciety. All rights reserved.lism.3 Despite the availability of both rate-control andrhythm-control options, the fundamental issue of which ofthese treatment goals to pursue has been a source of debate.2 example, in the AFFIRM study, the rates for noncardiovascu-The restoration and maintenance of sinus rhythm should, lar death were 12% in the rhythm-control group versus 8% intheoretically, be a more favorable approach compared to a the rate-control group (P .0008).35rate-control strategy, given that the reduction in ventricular These results have led, in part, to the fact that currentfilling occurring during atrial fibrillation would be reversed treatment guidelines generally recommend rhythm-controlby the restoration of regular rhythm, which would result in therapy only for patients with persistent or recurrent parox-normalization of heart rate, gain of atrial contraction, and ysmal atrial fibrillation if they are associated with disablingrestoration of AV synchrony. The restoration and mainte- symptoms.2 It is, therefore, reasonable to assume that thenance of sinus rhythm has been shown to be associated with use of safer, more effective rhythm-control strategies couldreduced atrial remodeling, improved left ventricular func- improve the rate of attainment and maintenance of normaltion, reduced symptoms, greater exercise tolerance, in- sinus rhythm and subsequently lead to significantly im-creased ability to perform activities of daily living, and proved clinical outcomes.improved quality of life. Of course, the theoretical benefit ofrhythm control relies on the availability of safe, tolerable, andeffective rhythm-control methods. However, rates of attain- GUIDELINESment and maintenance of sinus rhythm have been suboptimal Several guidelines for the management of atrial fibrillationin comparative studies such as Atrial Fibrillation Follow-Up and the associated risk for thromboembolism have beenInvestigation of Rhythm Management (AFFIRM),29 Polish published. The authoritative American College of Cardiol-How to Treat Chronic Atrial Fibrillation,30 Pharmacological ogy (ACC)/American Heart Association (AHA)/EuropeanIntervention in Atrial Fibrillation,31 Rate Control vs Elec- Society of Cardiology (ESC) guidelines3 advocate more oftrical Cardioversion,32 Strategies of Treatment in Atrial an individualized approach based on symptoms, durationFibrillation,33 and Atrial Fibrillation and Congestive Heart and pattern of atrial fibrillation, comorbidities, and short-termFailure,34 all of which failed to demonstrate a survival and long-term treatment goals. The ACC/AHA/ESC guide-benefit for rhythm-control over rate-control therapy (for ex- lines recommend that, when rhythm control is desired, theample, as outlined in Figure 1 from the AFFIRM Study).29 selection of therapy includes consideration of whether treat-This is probably because the anti-arrhythmic therapies studied ment is for newly discovered atrial fibrillation, recurrent par-had limited efficacy, poor tolerability, and the potential to oxysmal atrial fibrillation, recurrent persistent atrial fibrillation,trigger new arrhythmias. Moreover, several of the anti-arrhyth- or permanent atrial fibrillation, and whether there are con-mics used for rhythm control in these studies were associated comitant conditions such as hypertension, CAD, and heartwith a significant increase in noncardiovascular deaths. For failure (Figure 2).3 These guidelines allow for individual-
  4. 4. 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
  5. 5. 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.
  6. 6. 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
  7. 7. 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.
  8. 8. 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. 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