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  • 1. Review Article Management Strategies in Atrial Fibrillation in Patients With Heart Failure Amir Y. Shaikh, MD,* Abhishek Maan, MD,* E. Kevin Heist, MD, PhD,† Dennis A. Tighe, MD,‡ Gerard P. Aurigemma, MD,‡ and David D. McManus, MD, FACC, FHRS‡ Abstract: Atrial fibrillation (AF) and heart failure (HF) frequently occur current evidence-based pharmacologic and invasive therapeutic together, and their coexistence is associated with a poor prognosis. AF and options for managing AF in patients with coexistent HF. HF share risk factors, but their relationship involves complex hemodynamic, neurohormonal, inflammatory, ultrastructural, and electrophysiologic pro- EPIDEMIOLOGY AND RISK FACTORS: ATRIAL cesses that extend beyond epidemiological associations. The shared mecha- FIBRILLATION AND HEART FAILURE nisms underlying AF and HF have important implications for the treatment of HF and AF share several common risk factors such as coro- AF in patients with HF. This article focuses on reviewing contemporary data nary artery disease, valvular heart disease, diabetes mellitus, hyper- as it pertains to AF management in patients with HF and provides insight into tension, obesity, and obstructive sleep apnea. AF and HF have investigational therapies currently under development. inextricably linked complex ultrastructural, electrophysiologic, and Key Words: atrial fibrillation, heart failure, rate control, rhythm control, neurohormonal processes that promote their coexistence.6 AF is thus catheter ablation, antiarrhythmic drugs exceedingly common in HF, affecting 30% of all individuals with (Cardiology in Review 2012;20: 288–296) HF.7 Men and women with AF have a threefold and 11-fold increased risk, respectively, of the combined end point of HF and all-cause mortality when compared with those in sinus rhythm.1,8 Conversely, the development of HF is associated with a 4.5- to 5.9-fold increased risk of future AF.7,8 There is a direct relationship between the preva- A trial fibrillation (AF) is the most common sustained arrhythmia in industrialized nations, with a lifetime risk of approximately 25% for individuals over 40 years of age. The incidence of AF and lence of AF and worsening HF class (Fig. 2). Although data on this topic are limited, patients with HF and preserved systolic function are also vulnerable to AF at alarmingly high rates. As in patients with heart failure (HF) increases markedly with advancing age. The HF and reduced systolic function, development of AF among those prevalence of both these disorders has increased over the last few with normal left ventricular (LV) systolic function may represent a decades related in part to increasing survival of patients with other precipitant and/or consequence of diastolic HF.12–15 forms of cardiovascular disease. The growing burden of AF has pro- found impact on public health because it is associated with increased morbidity, mortality, and health-care expenditure.1,2 The prevalence TREATMENT OF ATRIAL FIBRILLATION AND HEART of AF is highest in those with clinical cardiovascular disease and FAILURE occurs most commonly in older age groups.1,3 Like AF, chronic HF Rate vs Rhythm Control of Atrial Fibrillation is highly prevalent, predominantly affecting the elderly, and exerts a A rhythm control strategy for asymptomatic patients with AF profoundly negative influence on the public health.1,4–8 and HF has long been presumed to be advantageous based on the The adverse hemodynamic consequences of AF, including known deleterious effects of AF with respect to cardiovascular hemo- elevated cardiac filling pressures, chronically increased heart rates, dynamics, thromboembolic risk, and quality of life. Investigators irregular ventricular intervals, lack of effective atrial contraction, have also hypothesized that restoration of sinus rhythm may reverse and loss of atrioventricular (AV) synchrony, can impair ventricular the progression of HF.16 However, since 2000, 5 studies have com- function and contribute to HF.9 Similarly, ventricular dysfunction pared rhythm to rate control strategies, yet no study to date has dem- can create a substrate predisposed to AF through its effect on atrial onstrated superiority of a rhythm control in patients with AF with size, conduction properties, and fibrosis (Fig. 1).10 Patients with HF respect to major clinical end points. Several of these studies included therefore may have atrial structural, mechanical, and electrical char- patients with AF and HF (Table 1).17–21 acteristics distinct from those without HF. The pathophysiological Not surprisingly, in light of the relatively small number of mechanisms underlying AF likely differ between patients with AF patients with AF and HF included in many of the landmark rhythm and HF when compared with AF alone.11 In this article, we discuss vs rate control trials, there remains controversy with respect to the optimal treatment strategy for the patient with AF and HF.18,19 A sub- group analysis involving Atrial Fibrillation Follow-up Investigation of Rhythm Management participants suggested that patients with HF From the *Department of Medicine, University of Massachusetts Medical School, and AF had an increased risk of death when assigned to rhythm as Worcester, MA; †Cardiac Arrhythmia Service, Massachusetts General Hospi- compared with rate control, whereas the findings of the Rate Con- tal and Harvard Medical School, Boston, MA; and ‡Division of Cardiology, trol Efficacy in Permanent Atrial Fibrillation study suggested that University of Massachusetts Medical School, Worcester, MA. Disclosure: The authors have no conflicts of interest to report. patients with AF and HF had improved survival if sinus rhythm was Correspondence: David D. McManus, MD, Department of Medicine, Cardiology maintained.18,22 In the Congestive Heart Failure: Survival Trial of Division, Electrophysiology Section, University of Massachusetts Medical Antiarrhythmic Therapy (CHF-STAT)23 and Danish Investigations Center, 55 Lake Avenue North, Worcester, MA 01655. E-mail: mcmanusd@ of Arrhythmia and Mortality on Dofetilide (DIAMOND)24 stud- ummhc.org. Copyright © 2012 by Lippincott Williams & Wilkins ies, participants with HF and AF who achieved conversion to sinus ISSN: 1061-5377/12/288-296 rhythm had improved survival when compared with HF patients who DOI: 10.1097/CRD.0b013e31825dcf9b remained in AF. 288  |  www.cardiologyinreview.com Cardiology in Review  •  Volume 20, Number 6, November/December 2012CRD_v20n6.indb 288 10/1/2012 10:38:49 AM
  • 2. Cardiology in Review  •  Volume 20, Number 6, November/December 2012 AF in HF Patients Risk factors Electrical atrial remodeling Structural atrial remodeling Atrial electrical and mechanical dysfunction AF - RVR Neurohormonal Dysregulation of Increased - Irregular rate Decreased Fibrosis activation intra-cellular filling pressure - Loss of atrial kick cardiac output calcium - Increased MR, TR HF Tachycardia LV dilatation and hypertrophy mediated cardiomyopathy MI LVH Risk factors Figure 1.  Pathophysiological interactions of AF and HF. AF indicates atrial fibrillation; HF, heart failure; LV, left ventricle; LVH, left ventricular hypertrophy; MI, myocardial infarction; MR, mitral regurgitation; RVR, rapid ventricular rate; TR, tricuspid regurgitation. major study end points, the study authors concluded that rhythm con- trol should not be routinely recommended for asymptomatic patients with AF and HF.21 One of the major and notable limitations of rhythm control among patients with AF and HF included in the aforemen- tioned studies was the limited long-term efficacy of antiarrhythmic drug (AAD) therapy in these patients (only 44% of participants remaining in sinus rhythm in DIAMOND, 51% in CHF-STAT, and 58% in Atrial Fibrillation in Congestive Heart Failure).21,23,24 These findings suggest that although conversion to sinus rhythm is a posi- tive prognostic sign in patients with HF and AF, the limited efficacy and toxicities of contemporary AADs in such patients limits the over- all impact of the rhythm control strategy. The adequacy of ventricular rate control in patients with AF and HF has not been studied extensively,25 but the Rate Control Effi- Figure 2. Prevalence of AF in several major HF trials. Adapt- cacy in Permanent Atrial Fibrillation II trial26 evaluated the potential ed from Eur Heart J.10 AF indicates atrial fibrillation; HF, heart benefits of strict (resting heart rate <80 bpm, heart rate <100 bpm failure; NYHA, New York Heart Association. during a 6-minute walk) vs lenient (resting heart rate <110 bpm) rate control in patients with permanent AF. Lenient rate control was found to be noninferior to strict rate control in terms of 3-year esti- The issue of rate vs rhythm control in patients with AF and HF mated cumulative incidence of death from cardiovascular causes, was further addressed in the landmark Atrial Fibrillation in Conges- hospitalization for HF, thromboembolic events, bleeding, and life- tive Heart Failure trial,21 which is the largest study to-date designed threatening arrhythmias. However, in this study, the mean ejection specifically to investigate whether rhythm control pharmacologic fraction (EF) was 52%, while the patients who had EF <40% were strategies impact mortality over rate control therapy in patients with only 15% of the total subjects. Thus, no conclusions can be drawn HF. On the basis of their observation that patients with AF and HF regarding lenient or strict rate control in HF patients with permanent randomized to rhythm control were at equivalent risk for all of the AF. In addition, the long-term effects of a rapid heart rate response © 2012 Lippincott Williams & Wilkins www.cardiologyinreview.com  |  289CRD_v20n6.indb 289 10/1/2012 10:38:50 AM
  • 3. Shaikh et al Cardiology in Review  •  Volume 20, Number 6, November/December 2012 TABLE 1.  Clinical Trials Comparing Rate vs Rhythm Control Strategy in AF and HF Mortality, Ischemic Stroke, History of Rate Control Rhythm Control Rate/Rhythm Rate/Rhythm Hospitalization, Rate/ Trials Patients FU (yr) CHF (%) (SR, %) (SR, %) Control (%) Control (%) Rhythm Control (%) STAF17 200 1.6 55.5 BB, NCCB, Class I or III AADs 8/4 1/5 26/54, P = 0.001 DIG, or (23) AVNA (0) RACE18 522 2.3 50 BB, NCCB, Class I or III AADs 7/6.8*, NS 5.5/7.9†, NS 5.4/3.8 DIG (26) (39) AFFIRM19 4060 3.5 23.1 BB, NCCB, Class I or III AADs 25.9/26.7, 5.5/7.1, P = 0.79 73/80.1, P < 0.001 DIG (34.6) (62.6) P = 0.08 HOT-CAFE20 205 1.7 62 BB, NCCB, Sotalol or Class I 1/3, NS 0/3, NS 5/100, P = 0.001 DIG (N.A.) AADs (63.5) AF-CHF21 1376 3.1 100 BB, Digoxin, Amiodarone, 25/27, NS 2/1, NS 59/64, P = 0.06 NCCB Sotalol (58%) (30%) AFFIRM indicates Atrial Fibrillation Follow-up Investigation of Rhythm Management; AF-CHF, Atrial Fibrillation in Congestive Heart Failure; FU, follow-up; AADs, antiarrhythmic drugs; AVNA, atrioventricular nodal ablation or modification; BB, β-blockers; DIG, digoxin; HOT-CAFÉ, How to Treat Chronic Atrial Fibrillation; NA, no data available; NCCB, nondihydropyridine calcium channel antagonists; NS, not statistically significant or P values not available; RACE, Rate Control Efficacy in Permanent Atrial Fibrillation; SR, patients in sinus rhythm at study end or latest follow-up; STAF, Strategies of Treatment of Atrial Fibrillation. *Cardiovascular mortality. †Thromboembolic complications. to AF on ventricular function were not studied and the study was Pharmacologic Agents for Rhythm Control in Atrial inadequately powered to provide conclusive data on all clinically rel- Fibrillation and Heart Failure evant differences in clinical outcomes between the 2 groups.26 The Amiodarone is a class III AAD having functional overlap most recent American College of Cardiology Foundation/American with class I AADs, β-blockers, and calcium channel blocker drugs. Heart Association/Heart Rhythm Society guidelines state that strict Despite the fact that it is not Food and Drug Administration approved rate control is not more beneficial than lenient rate control in patients for the conversion of AF or maintenance of sinus rhythm in patients with persistent AF and stable LV function, although uncontrolled with AF, amiodarone is one of the most widely used rhythm con- tachycardia may over time be associated with a reversible decline in trol agents. Amiodarone is an effective agent for acute cardioversion, ventricular performance.25 although the time from drug administration to conversion of AF may be slower with amiodarone than class Ic agents. Amiodarone appears Pharmacologic Agents for Rate Control in Atrial to be the most effective agent for long-term maintenance of normal Fibrillation and Heart Failure sinus rhythm in patients with AF with or without HF.37–42 In a sub- β-blockers are first-line agents for achieving rate control in AF study of the CHF-STAT trial, the long-term effects of amiodarone on and for reducing long-term morbidity and mortality in HF, especially morbidity and mortality in patients with HF and AF were evaluated among patients with severely reduced systolic function.27 Carvedilol during a 4-year period.43 It showed that in patients with HF, amioda- therapy significantly improved the LVEF and showed a trend toward rone has a significant potential to spontaneously convert patients in a reduction in the combined end point of death or HF hospitalization AF to sinus rhythm, with patients who convert having a lower mortal- in patients with concomitant AF and HF in a retrospective analy- ity rate than those who do not. Amiodarone also prevented the devel- sis of “US Carvedilol Heart Failure Trial.”28 However, carvedilol is opment of new-onset AF and significantly reduced the ventricular not a β1-selective blocker and might not result in optimal rate con- rate in those with persistent AF.43 On the basis of these and other trol. Bisoprolol and metoprolol succinate have also been shown to findings, amiodarone remains a first-line agent for the acute conver- improve mortality among patients with HF,29 and labetalol has also sion and maintenance of sinus rhythm in patients with AF and HF. demonstrated effectiveness for ventricular rate control in patients However, the benefit of amiodarone must be weighed against its well- with AF.30 Nebivolol, a highly β1-selective blocker has been shown as documented potential long-term adverse effects.44 an effective and well-tolerated treatment for HF in elderly patients.31 Dronedarone is a multiclass AAD that has a superior safety Nondihydropyridine calcium channel blockers (verapamil profile and shorter half-life than amiodarone. Dronedarone has been and diltiazem) are effective rate controlling agents in AF, but their shown to reduce the rate of hospitalization and death in patients with negative inotropic properties can worsen systolic HF.10 Some stud- AF.45 However, the Antiarrhythmic Trial with Dronedarone in Mod- ies suggest that the short-term use of intravenous diltiazem in AF erate to Severe CHF Evaluating Morbidity Decrease (ANDROM- and moderate-to-severe HF may be safe and effective; however, EDA) study demonstrated increased cardiovascular mortality among their safety in chronic heart rate control in patients with coexisting patients with advanced and recently decompensated HF.46 In contrast, HF remains to be proven, and these agents are generally avoided in a post hoc analysis of ATHENA (A Placebo-Controlled, Double- patients with severe HF.32,33 Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 Digoxin as monotherapy for AF rate control is ineffective and not mg bid for the Prevention of Cardiovascular Hospitalization or Death recommended.34,35 A small study in patients with AF and HF suggested from any Cause in Patients with Atrial Fibrillation/Atrial Flutter) that the combination of digoxin and a β-blocker (carvedilol), however, study patients with AF and stable HF demonstrated that dronedar- reduces symptoms, improves ventricular function, and leads to a bet- one did not increase mortality and showed a reduction of cardiovas- ter rate control than either agent alone.36 It remains unclear whether cular hospitalization or death similar to the overall population.47,48 digoxin affects mortality in patients with AF and HF.10 In addition, Dronedarone is therefore contraindicated in patients with New York digoxin is not effective for heart rate reduction during exercise. Thus, Heart Association (NYHA) class IV or unstable NYHA classes II digoxin is often a helpful adjunctive agent for patients with AF and HF and III HF.48 The most recently published PALLAS (Permanent Atrial in whom rate control is not adequately achieved with β-blockers alone. Fibrillation Outcome Study Using Dronedarone on Top of Standard 290  |  www.cardiologyinreview.com © 2012 Lippincott Williams & WilkinsCRD_v20n6.indb 290 10/1/2012 10:38:50 AM
  • 4. Cardiology in Review  •  Volume 20, Number 6, November/December 2012 AF in HF Patients Therapy)69 study, which was prematurely terminated, demonstrated mechanisms that promote atrial structural or electrophysiological that dronedarone increased the rates of HF, stroke, and death from remodeling. None of these agents have specific approval for AF pre- cardiovascular causes in patients with permanent AF who were at vention, but they are available for clinical use and their present indi- risk for major vascular events, thus raising serious concerns about cations (hypertension, coronary artery disease, and heart failure) are dronedarone’s clinical utility in the future.49 some of the most frequent associations of AF.63 Dofetilide, a class III AAD, has substantial evidence support- Several epidemiological and experimental studies suggest ing its use in patients with AF and HF.24,50–52 A substudy of the DIA- that n-3 polyunsaturated fatty acids (PUFA) may exert antiar- MOND trial showed that although all-cause mortality was unaffected rhythmogenic or antifibrillatory effects.64 The Gruppo Italiano per by dofetilide treatment, use of this AAD led to a significant reduction lo Studio della Sopravvivenzanell’Infarto Miocardico-Heart Fail- of hospitalization for HF.24 Torsades de pointes is a known complica- ure trial demonstrated a small benefit of n-3 PUFA administration tion of dofetilide use and this life-threatening arrhythmia developed with respect to reducing cardiovascular mortality in patients with in <1% of patients in the dofetilide treatment arm of the DIAMOND HF (of whom 20% had concomitant AF).64 However, a recent meta- study. However, there was no significant difference in the total analysis of 10 randomized controlled trials evaluating the role of arrhythmic mortality between the dofetilide and placebo groups in n-3 PUFA for AF demonstrated that there were no significant ben- patients with AF and severe LV dysfunction.51 When patients are efits of n-3 PUFA supplementation for AF prevention.65 Due to their dosed appropriately and monitored for QTc prolongation, patients anti-inflammatory effects, statin drugs are also theorized to be of with AF and HF can be treated with dofetilide without any detectable benefit with respect to the primary prevention of AF. However, a increase in mortality risk.51 recent meta-analysis evaluating 22 trials of statin agents showed no Ibutilide is an intravenous class III AAD shown to have mod- significant reduction in the rates of AF among individuals random- est-to-high conversion rates with AF, particularly when administered ized to receive statin agents.66 within a few weeks of AF onset.53–55 However, ibutilide infusion car- Several large randomized studies have suggested that renin- ries a 2–4% risk of precipitating polymorphic ventricular tachycar- angiotensin-aldosterone system blockade with angiotensin- convert- dia. Given the propensity for ventricular arrhythmias among patients ing enzyme inhibitors or angiotensin I receptor blockers may reduce with LV dysfunction, ibutilide should be used cautiously among the incidence or recurrence of AF.67,68 However, the recently pub- patients with AF and HF with decreased systolic function.56 lished Atrial Fibrillation Clopidogrel Trial with Irbesartan for Pre- Sotalol is a class III AAD with strong β-blocking effects. The vention of Vascular Events (ACTIVE I) study, which evaluated the Survival With Oral d-Sotalol trial, which involved prophylactic admin- effect of irbesartan on cardiovascular outcomes in 9016 patients with istration of d-sotalol (an investigational agent which contains class III AF, demonstrated that the irbesartan treatment among patients with but not β-blocking properties) to patients with severe LV dysfunction intermittent AF who were in sinus rhythm at enrollment had no effect after myocardial infarction, was prematurely terminated as it dem- on rates of AF recurrence.69 Similarly, the Gruppo Italiano per lo Stu- onstrated an increased cardiovascular mortality among those treated dio della Sopravvivenzanell’Infarto Miocardico-Heart Failure study with sotalol.57 In a retrospective analysis derived from 22 clinical trials did not demonstrate a significant reduction in the occurrence of new- involving 3135 adult patients who received oral d,l-sotalol for AF, a onset or recurrent AF events in patients with HF or LV hypertrophy history of HF was one of the factors most predictive of torsades de randomized to receive valsartan.70 pointes ventricular tachyarrhythmia.58 The Sotalol Amiodarone Atrial The ACTIVE I trial did show a significant reduction in HF hos- Fibrillation Efficacy Trial demonstrated that as compared to amioda- pitalization rate with the addition of irbesartan in patients with AF.69 rone, sotalol has similar efficacy in converting persistent AF to sinus These findings are consistent with the results of a trial of angiotensin rhythm.37 Amiodarone was superior to sotalol, however, with respect to receptor blockers in patients with a low EF71 and with the results of maintenance of sinus rhythm, although this difference was not signifi- the Candesartan in Heart Failure: Assessment of Reduction in Mor- cant among the subgroup of patients with ischemic heart disease. How- tality and Morbidity Preserved trial (NCT00634712),72 involving ever, Sotalol Amiodarone Atrial Fibrillation Efficacy Trial excluded patients with a normal EF and HF. However, ACTIVE I results differ patients with NYHA class III or IV HF. On the basis of available from those of the Telmisartan Randomized Assessment Study in ACE data suggesting that HF patients treated with sotalol are vulnerable to Intolerant Subjects with Cardiovascular Disease (NCT00153101)73; increased rates of potentially life-threatening ventricular arrhythmias, Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes sotalol is generally avoided in patients with AF and severe HF.59 Research (NCT00097786)74; and Irbesartan in Heart Failure with Flecainide and Propafenone are type Ic AADs, which have a Preserved Ejection Fraction (NCT00095238) study75; all of which class I recommendation for the acute cardioversion of AF. These drugs showed no benefit of additional angiotensin receptor blockers with also are effective in the long-term maintenance of sinus rhythm, often respect to HF. used as a “pill-in-the-pocket” approach.60,61 The Cardiac Arrhythmia Suppression Trial, which involved administration of encainide or Device-Based and Ablative Therapies for Atrial flecainide for the suppression of ventricular ectopy after myocardial Fibrillation and Heart Failure infarction, showed an increased rate of death from arrhythmia and An implantable cardiac defibrillator (ICD) is indicated for the shock in patients treated with encainide or flecainide.62 Therefore, prevention of sudden death from ventricular tachycardia and ven- type Ic AADs are generally avoided in patients with ischemic cardio- tricular fibrillation in high-risk populations.11 Cardiac resynchroniza- myopathy, coronary heart disease, and HF. These agents should also tion therapy (CRT), or biventricular pacing, is another device-based be avoided in patients with nonischemic cardiomyopathy because of therapy known to improve symptoms and reduce mortality in patients their negative inotropic action. with HF and left bundle branch block.76–82 CRT, through its saluta- tory benefits on hemodynamic function and cardiac remodeling, has also been theorized to reduce the incidence of AF. However, in the PHARMACOLOGIC AGENTS FOR THE PREVENTION Cardiac Resynchronization in Heart Failure trial, randomization to OF ATRIAL FIBRILLATION AND HEART FAILURE CRT did not result in any reduction in the incidence rates of AF at It has been hypothesized that drugs such as renin-angiotensin- 30 months of follow-up.76,83 Of note, however, approximately 10% aldosterone system inhibitors, 3-hydroxy-3-methyl-glutaryl-CoA of patients enrolled in Cardiac Resynchronization in Heart Failure reductase inhibitors (statins), and omega-3 fatty acids can prevent Study who had been characterized as having “permanent” AF con- the incidence of new or recurrent AF by targeting pathophysiological verted to sinus rhythm after implantation with CRT.84 © 2012 Lippincott Williams & Wilkins www.cardiologyinreview.com  |  291CRD_v20n6.indb 291 10/1/2012 10:38:50 AM
  • 5. Shaikh et al Cardiology in Review  •  Volume 20, Number 6, November/December 2012 Patients with AF and HF who undergo biventricular pacemaker the 2011 American College of Cardiology Foundation/American Heart or ICD implantation remain less likely to respond to CRT, perhaps due to Association/Heart Rhythm Society guidelines now recommend con- low rates of biventricular pacing.85 A recent meta-analysis of 23 observa- sidering catheter-based AF ablation for the treatment of symptomatic, tional studies demonstrated that AF was associated with an increased risk paroxysmal AF in patients with significant left atrial dilatation or with of nonresponse to CRT (Relative Risk = 1.32; P = 0.001) and all-cause significant LV dysfunction.25 mortality (Relative Risk = 1.50; P = 0.015). The presence of AF was The Cox-maze surgical procedure involves placing multiple also associated with less improvement in quality of life, 6-minute walk incisions within the left and right atrial myocardium, with the inten- distance, and LV end-systolic volume, but not LVEF. The hypothesis that tion of interrupting potential reentry and isolating AF triggers. The poor CRT response among patients with AF and HF is explained by low Cox-maze procedure has excellent long-term efficacy, with nearly rates of biventricular pacing is supported by a recent analysis, showing 90% of treated patients remaining in sinus rhythm at 10 years. that AF patients who underwent AV node ablation and CRT implanta- Although it is usually avoided in patients with HF, the Cox-maze tion had significantly improved EFs, exercise tolerance, and decreased operation has been shown to be safe and effective for rhythm con- hospitalizations as compared to patients with AF and HF who underwent trol of AF.105,106 Although the full “cut and sew” Cox-maze procedure biventricular ICD implantation alone.86–89 In addition, there is a possible (with lesions created by surgical incision) is now rarely performed risk of increased inappropriate ICD shocks due to rapid conduction of due to its complexity, variants of this procedure are in widespread AF to the ventricles in patients who undergo ICD implantation without use, typically using either cryo- or radiofrequency energy to create AV nodal ablation. ablative lesions. These procedures are most commonly performed Catheter-based AF ablation has been shown to be safe and effec- via thorascopic access as a stand-alone procedure for AF or via ster- tive for rhythm control among patients with symptomatic AF, includ- notomy or thoracotomy when combined with other cardiac surgical ing those with HF (Fig. 3).90–93 Five studies have specifically focused procedures requiring more complete surgical access. on the benefit of catheter-based AF ablation among patients with AF and HF. These studies have shown that Catheter-based AF ablation significantly improved the cardiac function, symptom burden, exercise FUTURE DIRECTIONS IN THE MANAGEMENT OF capacity, and quality of life of patients with AF and HF.94–98 The Pulmo- ATRIAL FIBRILLATION AND HEART FAILURE nary Vein Antral Isolation vs AV Node Ablation with Biventricular Pac- Because ventricular proarrhythmia is one of the most com- ing for the Treatment of AF in Patients with CHF trial99 demonstrated mon and life-threatening complications of the available AADs used that pulmonary vein isolation resulted in significant improvement in in AF, much attention has been focused on developing atrial-selective EF and 6-minute walk distance as compared to AV nodal ablation and AADs for AF. Atrial selectivity could be achieved by targeting ion biventricular pacemaker implantation. Catheter ablation for AF was channels that are selectively expressed in the atria or by achievement also shown to be superior to AAD therapy for maintaining normal of atrial-selective Na+ channel blockade via state-selective block- sinus rhythm at a 1-year follow-up.100–104 On the basis of these data, ing properties that produce more block for atrial than for ventricular Figure 3. Catheter-based radiofrequency AF ablation. View of the posterior left atrium. It shows antral pulmonary vein isola- tion (a.) and isolation of the posterior left atrium (b.). The multispline mapping catheter (c.) is positioned over the posterior left atrium showing lack of potentials after isolation (shaded arrow); whereas the potentials are still present (empty arrow) on the coronary sinus catheter (d.). AF indicates atrial fibrillation; LIPV, left inferior pulmonary vein; LSPV, left superior pulmonary vein; RSPV, right superior pulmonary vein; RIPV, right inferior pulmonary vein. 292  |  www.cardiologyinreview.com © 2012 Lippincott Williams & Wilkins05_CRD_200337.indd 292 10/1/2012 12:47:22 PM
  • 6. Cardiology in Review  •  Volume 20, Number 6, November/December 2012 AF in HF Patients Maintenance of sinus rhythm in AF with co-existent HF Avoid: Flecaninide, Propafenone, lbutilide NYHA Class I – II HF HTN with significant LVH NYHA Class III – IV HF Avoid: Dronedarone Dofetilide Amiodarone Sotalol Inpatient initiation, monitor Monitor for effects on thyroid, creatinine clearance and QTc lungs and liver Dofetilide Inpatient initiation, monitor creatinine clearance and QTc Amiodarone Radiofrequency catheter Monitor for effects on thyroid, ablation/Pulmonary vein lungs and liver isolation Amiodarone Monitor for effects on thyroid, lungs and liver May consider Dronedarone or Sotalol if HF is mild and clinically stable Cox – Maze surgical ablation if concurrent valvular/cardiac surgery Figure 4. An algorithmic approach to maintenance of sinus rhythm in patients with AF and coexistent stable HF. AF indicates atrial fibrillation; HF, heart failure; NYHA, New York Heart Association. action potentials, or that are highly selective for rapid rhythms like Ranolazine, an antianginal drug, has atrial-selective antiar- AF.63 Nowhere is the importance of atrial selectivity more important rhythmic properties. Two recent nonrandomized studies showed than in the patient with AF and HF because such patients are espe- that ranolazine safely converts new-onset or paroxysmal AF and cially susceptible to serious ventricular arrhythmias such as ventricu- promotes maintenance of sinus rhythm.115,116 Large prospective stud- lar tachycardia and fibrillation. ies of ranolazine in suppression of AF are currently ongoing.117 A Vernakalant is an atrial-selective AAD that affects cardiac recently published, nonrandomized, single-center study of patients Na+ and several K+ channels, including the atrial-selective currents undergoing bypass surgery demonstrated that ranolazine signifi- IKur and IKACh.107 Vernakalant has been studied primarily in the cantly reduced rates of AF as compared to amiodarone, with no dif- setting of acute conversion of recent-onset AF, but a longer-acting ference in the incidence of adverse events.118 Animal studies suggest oral preparation is in development.108 Randomized, double-blind, pla- that ranolazine may be particularly effective for the treatment of AF cebo-controlled studies demonstrated an efficacy of approximately when combined with dronedarone,119 but there are no conclusive data 50% for the acute conversion of AF to sinus rhythm, with very few regarding the use of this drug combination in humans. side effects.109–111 ATI-2042 (budiodarone) is a chemical analog of amiodarone The recently published A Phase III Superiority Study of Ver- with a half-life of 7 hours. Electrophysiology similar to amiodarone, nakalant vs Amiodarone in Subjects With Recent Onset AF (AVRO) the drug may have fewer side effects, drug-drug interactions, and trial112 concluded that vernakalant demonstrated superior efficacy toxicity. A recent small phase II study showed that it reduces AF bur- when compared with amiodarone for acute conversion of recent- den.120 SSR149744C (celivarone) is another amiodarone analog in onset AF, resulted in rapid conversion (median time of 11 minutes development for the treatment of AF.121 in responders), and was associated with a higher rate of symptom relief compared with amiodarone. However, a major limitation of this study was the short follow-up period (90 minutes) and short infusion CONCLUSIONS period (24 hours) for amiodarone. Preliminary results from a double- Patients with AF and HF are unique with respect to their under- blind, placebo-controlled, randomized dose-ranging phase 2 study lying pathophysiology, treatment response, and long-term outcome. showed that high-dose oral vernakalant prevented recurrence of AF Although patients with AF and HF are at high risk for increased mor- without detectable proarrhythmia.113 However, patients with decom- bidity and mortality, a variety of therapies, including drugs, devices, pensated HF, EF <35% and NYHA class III–IV HF were excluded, and ablation procedures, are available to aid in the management of and thus the generalizability of this study’s findings to those with AF symptomatic and asymptomatic patients with both AF and HF. We and severe HF is unknown. A recently published phase III random- recommend a sequential approach for maintenance of sinus rhythm ized controlled trial of vernakalant demonstrated that at a dose of 500 in patients with AF and coexistent HF (Fig. 4). Based on the available mg twice daily, oral vernakalant appears to be reasonably effective therapies outlined above, we believe that an individualized approach and safe for the prevention of AF recurrence after cardioversion.114 can improve symptoms and prognosis for patients with AF and HF. © 2012 Lippincott Williams & Wilkins www.cardiologyinreview.com  |  293CRD_v20n6.indb 293 10/1/2012 10:38:51 AM
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