Cardiac Electrophysiology Review 2003;7:208–210C© 2003 Kluwer Academic Publishers. Manufactured in The Netherlands.

Rationale for the Atrial Fibrillation and Congestive HeartFailure (AF-CHF) Trial

Denis RoyResearch Center, Montreal Heart Institute, Montreal,Quebec, Canada

Abstract. Congestive heart failure and atrial fibrilla-tion (AF) are two important and growing problems inmedicine and cardiology. Both conditions often coexistand complicate each other’s management. Two thera-peutic strategies are available for patients with AF andcongestive heart failure: the first aims at restoring andmaintaining sinus rhythm, whereas the second focusesexclusively on optimizing ventricular rate. Prior stud-ies of AF and congestive heart failure were not random-ized and most were retrospective. Although some stud-ies suggested that AF had no effect on survival, in mostrecent large congestive heart failure trials, AF was re-ported to be an independent risk factor for mortalityor major morbidity. The primary objective of the AtrialFibrillation in Congestive Heart Failure (AF-CHF) trialis to compare the two widely used treatment strate-gies with respect to cardiovascular mortality. AF-CHFis a prospective, multicenter trial that will randomize1450 CHF patients with left ventricular ejection fraction(LVEF) ≤35% and a documented recent episode of atrialfibrillation to either a rhythm control or a rate con-trol strategy. From recent trial data, we anticipate an18.75% 2-year cardiovascular mortality in the rate con-trol arm and a 25% event reduction in the rhythm con-trol group. As of December 2003, 960 patients have beenrandomized. Enrollment is expected to be completed inSeptember 2004 with a minimum follow-up of 2 years.

Key Words. atrial fibrillation, congestive heart failure,rhythm control, rate control

Introduction

The incidence of atrial fibrillation (AF) in patientswith congestive heart failure (CHF) ranges from 10to 50%, with the highest incidence in those with themost severe symptoms [1–3]. Excessive ventricularrate, irregularity of ventricular response, and lossof atrial contraction associated with AF may resultin adverse hemodynamic consequences and influenceprognosis in patients with CHF [4–15]. Restorationof sinus rhythm has been associated with improve-ment in cardiac output, exercise capacity, and maxi-mal oxygen consumption [5–11]. However, the impactof AF on survival remains controversial. Prior stud-ies of AF and CHF were all nonrandomized compar-isons and most were retrospective [1,2,16–21]. Threestudies suggested that AF had no effect on survival[2,20,21], but five studies reported that AF is an in-dependent risk factor for mortality or major morbid-

ity [1,16–19]. Furthermore AF was found to be anindependent risk factor (RR 1.20; 95% CI 1.03-1.40,p = 0.02) for increased mortality among the patientsin the registry of the antiarrhythmic vs implantabledefibrillator (AVID) study [22], and a very recentreport from the Framingham Heart Study showedthat participants with either AF or CHF who sub-sequently developed the other condition had a poorprognosis [23].

The recently published AFFIRM trial which com-pared the relative benefits of rhythm and rate con-trol in the management of AF did not demonstrateany significant differences between the two groupsin terms of overall mortality, morbidity and symp-toms [24]. However, the AFFIRM trial was not de-signed and did not have the power to establish opti-mal management of AF in patients with CHF. Thisspecific subset of patients, underrepresented in AF-FIRM, are often felt by clinicians to require the addi-tional contribution to cardiac output afforded by theatrial kick and despite the adverse effects related toantiarrhythmic therapy there exists a certain biasfavouring rhythm control. Among the available an-tiarrhythmic medication, only amiodarone has beenreported to have a probable beneficial impact on sur-vival in CHF patients [25] and this drug has beenfound more effective than other agents for the strat-egy of maintenance of sinus rhythm [26,27]. Thequestion of rate versus rhythm strategy in patientswith heart failure has never been compared with therhythm strategy in an adequately powered random-ized trial.

The primary objective of the AF and AF-CHF trialis to determine whether restoring and maintainingsinus rhythm significantly reduces cardiovascularmortality compared with a rate control strategy inpatients with AF and CHF [28]. AF-CHF is a prospec-tive multicenter trial (130 centers in Canada, UnitedStates, South America, Europe and Israel), thatwill randomize 1450 patients with New York Heart

Supported by an operating grant from the Canadian Institutesof Health Research, Ottawa, Ontario, Canada.

Address correspondence to: Dr. Denis Roy, Montreal HeartInstitute, Research Center, 5000 Belanger East, Montreal,Quebec H1T 1C8. Canada. E-mail: roy@icm.umontreal.ca

208

CEPR 2003; Vol. 7, No. 3 Rationale for the AF-CHF Trial 209

Association (NYHA) class II to IV CHF and LVEF≤35% (NYHA class I patients with prior hospitaliza-tion for heart failure or ejection fraction ≤25% arealso eligible) and a documented clinically significantepisode of AF within the past 6 months to one of twotreatment strategies:

1. Rhythm control with the use of electrical car-dioversion combined with antiarrhythmic drugs(amiodarone, dofetilide), and additional nonphar-macological therapy in resistant patients.

2. Rate control with the use of beta-blockers, digoxinor pacemaker and AV node ablation if necessary.

Cardiovascular mortality is the primary endpointand the intention-to-treat approach is the primarymethod of analysis. We anticipate an 18.75% 2-yearcardiovascular mortality in the rate control arm witha 25% mortality reduction in the rhythm control.

As of December 2003, 960 patients have beenenrolled. Eighty-one percent are male and the aver-age age is 66 years. The predominant cardiovasculardisease is coronary artery disease in 47% and pri-mary cardiomyopathy in 37% of patients. The meanLVEF measured prior to randomization is 27 ± 6%.Seventy-eight percent of patients are treated withbeta-blockers and 86% are receiving ACE inhibitors.Currently, over 90% of patients are maintained inthe treatment strategy to which they were assignedat randomization. Enrollment is expected to be com-pleted in May 2004 with a minimum follow-up of 2years.

The results of this trial should provide definiteinformation concerning two widely applicable treat-ment strategies of AF in a large cohort of patientswith CHF. If the study hypothesis is borne out,the data will support a compelling indication foragressive treatment of AF with prompt cardiover-sion and long-term antiarrhythmic therapy. Giventhe frequent occurrence of CHF and AF and thehigh mortality and hospitalization rates associatedwith them, we postulate that even a modest improve-ment could prevent thousands of hospitalizationsand deaths each year. It would also provide a strongincentive to search for new and improved methodsto maintain sinus rhythm. On the other hand, if thetrial yields negative results, it will indicate that ade-quate rate control is sufficient therapy and will elim-inate the need for cardioversion and hospitalizationin otherwise stable patients.

Data from this study and other ongoing controlledtrials evaluating new pharmacologic (such as atrialspecific antiarrhythmic drugs, ionic remodellingagents, ACE inhibitors) and non-pharmacologic(curative catheter ablation, biatrial/biventricularpacing, etc.) treatments should provide therapeuticopportunities for the management of AF in patientswith CHF.

References

1. Bourassa MG, Gurne O, Bangdiwala SI, Ghali JK, YoungJB, Rousseau M, Johnstone DE, Yusuf S, for the Stud-ies of Left Ventricular Dysfunction (SOLVD) investigators:Natural history and patterns of current practice in heartfailure. J Am Coll Cardiol 1993;22(Suppl A):14A–19A.

2. Carson PE, Johnson GR, Dunkman WB, Fletcher RD,Farrell L, Cohn JN, for the V-HeFT VA Cooperative Stud-ies Group. The influence of atrial fibrillation on prognosisin mild to moderate heart failure. The V-HeFT Studies.Circulation 1993;87(Suppl VI):VI-102–VI-110.

3. Deedwania PC, Singh BN, Ellenbogen K, Fisher S, FletcherR, Singh SN, for the Department of Veterans Affairs CHF-STAT Investigators. Spontaneous conversion and mainte-nance of sinus rhythm by amiodarone in patients withheart failure and atrial fibrillation. Observations fromthe Veterans Affairs Congestive Heart Failure SurvivalTrial of Antiarrhythmic Therapy (CHF-STAT). Circulation1998;98:2574–2579.

4. Stevenson WG, Stevenson LW. Atrial fibrillation in heartfailure [editorial]. N Engl J Med 1999;341:910–911.

5. Waktare JE, Camm AJ. Acute treatment of atrial fibril-lation: Why and when to maintain sinus rhythm. Am JCardiol 1998;81:3C–15C.

6. Lemery R, Brugada P, Cheriex E, Wellens HJ. Reversibil-ity of tachycardia-induced left ventricular dysfunction af-ter closed-chest catheter ablation of the atrioventricularjunction for intractable atrial fibrillation. Am J Cardiol1987;60:1406–1408.

7. Peters KG, Kienzle MG. Severe cardiomyopathy dueto chronic rapidly conducted atrial fibrillation: Com-plete recovery after restoration of sinus rhythm.Am J Med 1988;85;242–244.

8. Grogan M, Smith HC, Gersh BJ, Wood DL. Left ventric-ular dysfunction due to atrial fibrillation in patients ini-tially believed to have idiopathic dilated cardiomyopathy.Am J Cardiol 1992;69:1570–1573.

9. Kieny JR, Sacrez A, Facello A, Arbogast R, Bareiss P, RoulG, Demangeat J-L, Brunot B, Constantinesco A. Increasein radionuclide left ventricular ejection fraction after car-dioversion of chronic atrial fibrillation in idiopathic dilatedcardiomyopathy. Eur Heart J 1992;13:1290–1295.

10. Rodriguez LM, Smeets JL, Xie B, de Chillou C, Cheriex E,Pieters F, Metzger J, den Dulk K, Wellens HJ. Improve-ment in left ventricular function by ablation of atrioven-tricular nodal conduction in selected patients with loneatrial fibrillation. Am J Cardiol 1993;72:1137–1141.

11. Gosselink AT, Crijns HJ, van den Berg MP, van den BroekSA, Hillige H, Landsman ML, Lie KI. Functional capac-ity before and after cardioversion of atrial fibrillation: Acontrolled study. Br Heart J 1994;72:161–166.

12. Clark DM, Plumb VJ, Epstein AE, Kay GN. Hemodynamiceffects of an irregular sequence of ventricular cycle lengthsduring atrial fibrillation. J Am Coll Cardiol 1997;30:1039–1045.

13. Daoud EG, Weiss R, Bahu M, Knight BP, Bogun F, GoyalR, Harvey M, Strickberger SA, Man KC, Morady F. Ef-fect of an irregular ventricular rhythm on cardiac output.Am J Cardiol 1996;78:1433–1436.

14. Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA,Fitzpatrick AP, Sheinmann MM. Tachycardia-induced car-diomyopathy: A review of animal models and clinical stud-ies. J Am Coll Cardiol 1997;29:709–715.

210 Roy CEPR 2003; Vol. 7, No. 3

15. Pozzoli M, Cioffi G, Traversi E, Pinna GD, Cobelli F,Tavazzi L. Predictors of primary atrial fibrillation and con-comitant clinical and hemodynamic changes in patientswith chronic heart failure: A prospective study in 344patients with baseline sinus rhythm. J Am Coll Cardiol1998;32:197–204.

16. Middlekauf HR, Stevenson WG, Stevenson LW. Prognosticsignificance of atrial fibrillation in advanced heart failure.A study of 390 patients. Circulation 1991;84:40–48.

17. Dries DL, Exner DV, Gersh BJ, Domanski MJ, WaclawiwMA, Stevenson LW. Atrial fibrillation is associated withan increased risk for mortality and heart failure progres-sion in patients with asymptomatic and symptomatic leftventricular systolic dysfunction: A retrospective analysisof the SOLVD trials. Studies of Left Ventricular Dysfunc-tion. J Am Coll Cardiol 1998;32:695–703.

18. Maggioni AP, Di Gregorio L, Gorini M, Midi P, Lucci D,Tavazzi L, on behalf of IN-CHF Investigators. Predictorsof 1 year mortality in 2086 outpatients with congestiveheart failure: Data from Italian network on congestiveheart failure. J Am Coll Cardiol 1998:34(Suppl A):218A(Abstract).

19. Matthew J, Hunsberger S, Fleg J, Mc Sherry F, Williford W,Yusuf S, for the Digitalis Investigation Group. Incidence,predictive factors and prognostic significance of supraven-tricular tachy-arrhythmias in congestive heart failure.J Am Coll Cardiol 1998;34(Suppl A):218A (Abstract).

20. Mahoney P, Kimmel S, De Nofrio D, Wohl P, Loh E. Prog-nostic significance of atrial fibrillation in patients at a ter-tiary medical center referred for heart transplantation be-cause of severe heart failure. Am J Cardiol 1999;83:1544–1547.

21. Crijns HJGM, Tjeerdsma G, de Kam PJ, Boomsma F, vanGelder IC, van den Berg MP, van Veldhuisen DJ. Prognosticvalue of the presence and development of atrial fibrillationin patients with advanced chronic heart failure. Eur HeartJ 2000;21:1238–1245.

22. Wyse DG, Love JC, Yao Q, Carlson MD, Cassidy P, GreeneLH, Martin JB, Ocampo C, Raitt MH, Schron E, StamatoNJ, Olarte A. Atrial fibrillation: A risk factor for increasedmortality—an AVID registry analysis. J Interv Card Elec-trophysiol 2001;5:267–273.

23. Wang TJ, Larson MG, Levy D, Vasan RS, Leip EP, WolfPA, D’Agostino RB, Murabito JM, Kannel WB, BenjaminEJ. Temporal relations of atrial fibrillation and congestiveheart failure and their joint influence on mortality. TheFramingham Heart Study. Circulation 2003;107:2920–2925.

24. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosen-berg Y, Schron EB, Kellen JC, Greene HL, Mickel MC,Dalquist JE, Corley SD; Atrial Fibrillation Follow-up In-vestigation of Rhythm Management (AFFIRM) Investi-gators. A comparison of rate control and rhythm con-trol in patients with atrial fibrillation. N Engl J Med2002;347:1825–1833.

25. Amiodarone Trials Meta-Analysis Investigators. Effect ofprophylactic amiodarone on mortality after acute my-ocardial infarction and in congestive heart failure: Meta-analysis of individual data from 6500 patients in ran-domised trials. Lancet 1997;350:1417–1424.

26. Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ,Green M, Kus T, Lambert J, Dubuc M, Gagne P, NattelS, Thibault B. Amiodarone to prevent recurrence of atrialfibrillation. Canadian Trial of Atrial Fibrillation Investi-gators. N Engl J Med 2000;342:913–920.

27. The AFFIRM First Antiarrhythmic Drug Substudy Inves-tigators. Maintenance of sinus rhythm in patients withatrial fibrillation. An AFFIRM substudy of the first an-tiarrhythmic drug. J Am Coll Cardiol 2003;43:20–29.

28. The AF-CHF trial investigators. Rationale and design ofa study assessing treatment strategies of atrial fibrilla-tion in patients with heart failure: The atrial fibrillationand congestive heart failure (AF-CHF) trial. Am Heart J2002;144:597–607.