Q:Atrial fibrillation:When is rate control enough?

EDUARDO B. SAAD, MDThe Center for Atrial Fibrillation, Section of Electrophysiologyand Pacing, Department of Cardiovascular Medicine,The Cleveland Clinic Foundation

ROBERT A. SCHWEIKERT, MDThe Center for Atrial Fibrillation, Section of Electrophysiologyand Pacing, Department of Cardiovascular Medicine,The Cleveland Clinic Foundation

This may seem like a straightforwardquestion, but it is not.

The quick answer is that older patientswho tolerate atrial fibrillation with minimalor no symptoms after the ventricular rate isbrought under control may not benefit from arhythm control strategy.

However, the full answer is by no meansso simple, and the benefit of ventricular ratecontrol vs rhythm control for the manage-ment of atrial fibrillation remains controver-sial.

In the following discussion, “ventricularrate control” refers to control of the ventric-ular response to atrial fibrillation (most com-monly with the use of atrioventricular [AV]nodal-blocking drugs), and “rhythm control”refers to restoration and maintenance ofsinus rhythm (most commonly with the useof antiarrhythmic drugs, with or withoutelectrical cardioversion). Our commentsapply only to patients who are candidates foreither treatment strategy: ie, they have norelative or absolute contraindications to car-dioversion, such as lack of appropriate anti-coagulation.

■ THE CHOICE IS NOT SOSTRAIGHTFORWARD

The choice may be relatively easy for apatient with symptomatic atrial fibrillationdespite adequate ventricular rate control.Such a patient needs a rhythm control strat-egy to restore and maintain sinus rhythm to

alleviate symptoms. One could also arguethat every patient with an initial episode ofatrial fibrillation should be offered at leastone chance to restore sinus rhythm withelectrical cardioversion without long-termantiarrhythmic drug therapy.

But what about patients who tolerate atri-al fibrillation with minimal or no symptoms?Several recent randomized studies wouldappear to support continuing ventricular ratecontrol alone with appropriate anticoagula-tion for such patients who tolerate atrial fib-rillation after ventricular rate control isachieved (see below).

However, these studies had importantlimitations, and unfortunately, their resultshave already been misunderstood and improp-erly generalized, causing confusion and misin-formation. As with any study, we must be cau-tious in interpreting the results and keep inmind what type of patients were studied,which treatment options were studied (andwhich options were not), and to whichpatients in your practice the results are applic-able.

■ OLD ASSUMPTIONS ABOUTTHE BENEFITS OF RHYTHM CONTROL

For many years we assumed that rhythmcontrol would be the better treatmentapproach for patients with atrial fibrilla-tion.

Presumed benefits of rhythm control• Better relief of symptoms. Certainly this

strategy alleviates symptoms for manypatients (therefore justifying the risks ofantiarrhythmic drugs), but there was con-troversy about patients who tolerated atri-al fibrillation once ventricular rate con-trol was achieved.

ONEONE MINUTE MINUTECONSULTCONSULT

BRIEF ANSWERS

TO SPECIFIC

CLINICAL

QUESTIONS

Rate vs rhythmcontrol foratrialfibrillationis stillcontroversial

A:

1-MINUTE CONSULT

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CREDITCME

In trials inolder patients,rhythm controlwas not betterthan ratecontrol

ATRIAL FIBRILLATION SAAD AND SCHWEIKERT

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• Less risk of stroke and perhaps evendeath.1–3 Often this approach was usedwith the idea that if sinus rhythm weremaintained, the patient might not needlong-term anticoagulation and there-fore could avoid its potential complica-tions.

• “Cosmetic appeal.” Seeing sinus rhythmrather than atrial fibrillation on the elec-trocardiogram is reassuring for bothpatients and physicians.

Presumed risks of rate controlIn contrast, ventricular rate control had beenused more often as a secondary strategy whensinus rhythm could not be restored and main-tained despite the use of multiple antiar-rhythmic drugs and cardioversions. Thisapproach generally involves the use of drugsthat block the AV node, such as beta-block-ers, calcium channel blockers, and digoxin.For refractory cases, radiofrequency catheterablation of the AV node and implantation ofa permanent pacemaker were sometimesrequired.

Concerns about the rate control approachparticularly involved the perceived risks ofallowing atrial fibrillation to continue, eg,thromboembolism and stroke, hemorrhagiccomplications from anticoagulation, atrialmyopathy from long-standing atrial fibrilla-tion, and increased mortality.

Concerns about antiarrhythmic drugsThe dilemma for patients with asymptomaticor minimally symptomatic atrial fibrillationbecame magnified as data began to emergeabout the risks of antiarrhythmic drugs, partic-ularly for patients with structural heart dis-ease. For example, the Cardiac ArrhythmiaSuppression Trial (CAST)4 demonstratedincreased mortality with the use of certainclass IC antiarrhythmic drugs to suppress ven-tricular ectopy in patients with ischemic heartdisease. Other trials showed increased mortal-ity for patients with atrial fibrillation treatedwith class I antiarrhythmic drugs.5–7

These observations led to concern thatthe potential beneficial effects of restoringand maintaining sinus rhythm may be offsetby the adverse effects of the treatmentitself.

■ STUDIES OF RATE CONTROLVS RHYTHM CONTROL STRATEGIES

Several recent randomized controlled trialshave provided important information that isrelevant to this decision-making process(nicely reviewed by Dr. Mina Chung8 in thisjournal).

The Atrial Fibrillation Follow-upInvestigation of Rhythm Management(AFFIRM),9 the largest of these studies,directly compared the two strategies, withtotal mortality as the primary end point. Atotal of 4,060 patients who were at least 65years old or who had other risk factors forstroke were randomized to a strategy ofrhythm control or rate control.

The rhythm control group received antiar-rhythmic drugs and cardioversion as necessaryto maintain sinus rhythm. Continuous antico-agulation was encouraged but could be stoppedif sinus rhythm had apparently been main-tained for at least 4 weeks.

The rate control group received AVnodal-blocking agents and continuous antico-agulation, with the goal of a heart rate nothigher than 80 beats per minute at rest and110 beats per minute during a 6-minute walk-ing test. Catheter ablation of the AV nodewith pacemaker implantation could be used ifventricular rate control was not achieved witha combination of drugs.

After 5 years of follow-up (mean 3.5years), more patients had died in the rhythmcontrol group (24% vs 21%), but the differ-ence was not statistically significant. The ratesof a composite end point of death, disablingstroke, disabling anoxic encephalopathy,major bleeding, or cardiac arrest were also sim-ilar in the two groups. More rhythm controlpatients were hospitalized or had adverse drugeffects; the same was true for the crossoverrate, consistent with the fact that antiarrhyth-mic drugs are often ineffective or poorly toler-ated. Ischemic stroke occurred in about 1% ofpatients per year in each group, mostly inpatients in whom warfarin had been stoppedor whose international normalized ratio (INR)was subtherapeutic.

Other studies comparing rate control vsrhythm control treatment strategies2,10,11

showed similar results.8,12,13

Results ofcatheterablation foratrialfibrillation havebeen good

■ IMPLICATIONS FOR CLINICAL PRACTICE

These studies showed that a strategy ofrhythm control was not superior to a strategyof ventricular rate control for older patientswith atrial fibrillation. There were no signifi-cant differences in mortality or quality of life.The incidence of ischemic stroke was notreduced by attempts to maintain sinusrhythm. In fact, the overall incidence was dis-turbingly high: 7.1% in the AFFIRM trial9and 7.9% in the Rate Control vs ElectricalCardioversion for Persistent Atrial Fibril-lation (RACE) trial.10

Also, many patients with stroke (about50% in the AFFIRM trial and 30% in theRACE trial) were in sinus rhythm at the timeof the event. Some of the strokes in therhythm control groups may have been due tosubclinical episodes of atrial fibrillation, rais-ing concern about the practice of stoppingwarfarin after a patient is presumed to bemaintaining sinus rhythm by symptom report-ing. In fact, previous studies showed that theincidence of asymptomatic episodes of parox-ysmal atrial fibrillation are indeed more com-mon than symptomatic ones,14,15 and theseepisodes could be responsible for the higherrisk of cerebrovascular events when sinusrhythm is presumed to be maintained. This,along with the potential side effects of antiar-rhythmic drugs,5–7,16,17 could have negatedthe potential advantages of rhythm control.

Possible inclusion biasesThe patient population in both studies wasreasonably representative of patients withatrial fibrillation seen in clinical practice.However, there were two sources of possibleinclusion bias.• Only patients who were able and willingto tolerate atrial fibrillation after ventricularrate control had been achieved were included.Those with continued symptoms despite ven-tricular rate control were therefore unlikely tobe included in these trials.• Patients were relatively older (the averageage was about 60 to 70 years in these trials).The conclusions of these studies may there-fore not apply to younger patients.

Furthermore, follow-up was relativelyshort. The effects of ongoing atrial fibrillation

over very long periods of time remain unclear.The progression of atrial myopathy in suchpatients may have long-term consequencesnot discovered by the relatively shorter fol-low-up period in the older patient populationsincluded in these studies.

Newer treatments are availableAnother important limitation of these studiesis that they did not assess other, potentiallycurative treatments. One could argue thatthese trials compared two suboptimal treat-ment strategies, and the more appropriateconclusion may be that a rhythm controlstrategy using antiarrhythmic drugs is just asbad or worse than a ventricular rate controlstrategy.

Of interest, the AFFIRM trial investiga-tors recently reported that sinus rhythm isassociated with a lower risk of death.18

For these reasons, we cannot yet concludethat restoring sinus rhythm has been eliminat-ed as a management strategy for many patientswith atrial fibrillation. Further studies arerequired to determine the best strategy foryounger patients and to investigate alterna-tive treatment strategies.

Percutaneous catheter ablation is a verypromising newer treatment that can cure atri-al fibrillation. This procedure targets theectopic foci around or within the pulmonaryveins, which have been recognized as the trig-gers for atrial fibrillation in most patients.19

The topic has been reviewed elsewhere byFinta and Haines.20

Over the past few years the ablation pro-cedure has evolved substantially. The initialstrategy was to find and ablate the triggeringfoci themselves. However, this strategy wasineffective, posed technical difficulties, andwas associated with unacceptably high rates ofcomplications, particularly pulmonary veinstenosis. Now the strategy is to isolate thesefoci electrically so that the impulses cannotexit the pulmonary veins. For this reason, theprocedure is now often called “pulmonaryvein isolation.”

Results of this procedure have been good,and it has become an option for manypatients. At The Cleveland Clinic Foun-dation, the procedure is associated with a curerate of 80% to 90% and low rates of serious

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complications.21,22 Of note, it has been shownto be safe and effective for older patients andthose with structural heart disease.23,24 In anonrandomized, long-term study, Pappone etal reported that catheter ablation of atrial fib-rillation may result in improved outcomes interms of freedom from atrial fibrillation, qual-ity of life, cardiovascular morbidity, and evenmortality.25

We must emphasize that catheter ablationhas not yet become a first-line therapy for atri-al fibrillation. At present, appropriate candi-dates are patients with symptomatic atrial fib-rillation refractory to antiarrhythmic drugtherapy.

Surgical treatments for rhythm manage-ment of atrial fibrillation include the Cox mazeprocedure and minimally invasive surgicalapproaches to pulmonary vein isolation.26,27

These strategies are more invasive but may begood options for appropriate patients.

Pacemaker strategies using various sys-tems and modes have had variable results, butoverall have only demonstrated modest effec-tiveness for suppressing or terminating atrial

fibrillation.28 A very good review of the vari-ous strategies for restoring and maintainingsinus rhythm was published recently byMartin et al in this journal.29

These rhythm management strategies arealternatives or adjuncts to the use of antiar-rhythmic medications, and were not studiedin the rate-vs-rhythm-control studies men-tioned above. Randomized clinical trials com-paring rate control and curative rhythm con-trol strategies such as catheter ablation arebeing considered.

Thus, the available evidence, particularlyfrom recent clinical trials, has provided valu-able guidance for many patients, but there isstill much to learn about the types of patientsand treatment approaches that were notincluded in these studies.

■ RECOMMENDATIONS

Many patients with atrial fibrillation continueto have symptoms even after the ventricularrate has been brought under control, and theyshould be considered for a rhythm control

Therapeutic approach to atrial fibrillation

Atrial fibrillation

Ventricular rate control*

Asymptomatic or minimal symptoms

First arrhythmia episode

Rhythm control

Recurrent atrial fibrillation

Rhythm or rate controlon individual basis

Ventricular rate control

Older patient(> approximately65 years)

Young or middle-aged patient

Symptomatic

Rhythm control†

FIGURE 1

*Rate control may include one or more of the following: AV nodal blocking medications (beta-blockers, calciumchannel blockers, digoxin), AV nodal ablation/modification, pacemaker algorithms.

†Rhythm control may include one or more of the following: electrical or pharmacologic cardioversion, antiarrhythmicdrugs, percutaneous catheter ablation, pacemaker algorithms, surgical approaches. Long-term anticoagulationshould be strongly considered irrespective of the treatment strategy used.

ATRIAL FIBRILLATION SAAD AND SCHWEIKERT

Considerlong-termanticoagulationeven if sinusrhythm ismaintained

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■ REFERENCES1. Waldo AL. Management of atrial fibrillation: the need for

AFFIRMative action. AFFIRM investigators. Atrial Fibrillation Follow-up Investigation of Rhythm Management. Am J Cardiol 1999;84:698–700.

2. Hohnloser SH, Kuck KH, Lilienthal J. Rhythm or rate control in atrialfibrillation—Pharmacological Intervention in Atrial Fibrillation(PIAF): a randomised trial. Lancet 2000; 356:1789–1794.

3. Van Gelder IC, Crijns HJ, Tieleman RG, et al. Chronic atrial fibrilla-tion. Success of serial cardioversion therapy and safety of oral anti-coagulation. Arch Intern Med 1996; 156:2585–2592.

4. Echt DS, Liebson PR, Mitchell LB, et al. Mortality and morbidity inpatients receiving encainide, flecainide, or placebo. The CardiacArrhythmia Suppression Trial. N Engl J Med 1991; 324:781–788.

5. Flaker GC, Blackshear JL, McBride R, Kronmal RA, Halperin JL, HartRG. Antiarrhythmic drug therapy and cardiac mortality in atrial fib-rillation. The Stroke Prevention in Atrial Fibrillation Investigators. JAm Coll Cardiol 1992; 20:527–532.

6. Reimold SC, Chalmers TC, Berlin JA, Antman EM. Assessment of theefficacy and safety of antiarrhythmic therapy for chronic atrial fibril-lation: observations on the role of trial design and implications ofdrug-related mortality. Am Heart J 1992; 124:924–932.

7. Coplen SE, Antman EM, Berlin JA, Hewitt P, Chalmers TC. Efficacyand safety of quinidine therapy for maintenance of sinus rhythmafter cardioversion. A meta-analysis of randomized control trials.Circulation 1990; 82:1106–1116.

8. Chung MK. Atrial fibrillation: rate control is as good as rhythm con-trol for some, but not all. Cleve Clin J Med 2003; 70:567–573.

9. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate controland rhythm control in patients with atrial fibrillation. N Engl J Med

2002; 347:1825–1833.10. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate

control and rhythm control in patients with recurrent persistent atri-al fibrillation. N Engl J Med 2002; 347:1834–1840.

11. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-con-trol versus rhythm-control in persistent atrial fibrillation: theStrategies of Treatment of Atrial Fibrillation (STAF) study. J Am CollCardiol 2003; 41:1690–1696.

12. Chung MK. Randomized trials of rate vs. rhythm control for atrialfibrillation. J Interv Cardiol Electrophysiol 2004; 10(suppl 1):45–53.

13. Wijffels MC, Crijns HJ. Rate versus rhythm control in atrial fibrilla-tion. Cardiol Clin 2004; 22:63–69.

14. Page RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett EL.Asymptomatic arrhythmias in patients with symptomatic paroxysmalatrial fibrillation and paroxysmal supraventricular tachycardia.Circulation 1994; 89:224–227.

15. Page RL, Tilsch TW, Connolly SJ, et al. Asymptomatic or “silent” atri-al fibrillation: frequency in untreated patients and patients receivingazimilide. Circulation 2003; 107:1141–1145.

16. Hohnloser SH, Singh BN. Proarrhythmia with class III antiarrhythmicdrugs: definition, electrophysiologic mechanisms, incidence, predis-posing factors, and clinical implications. J Cardiovasc Electrophysiol1995; 6:920–936.

17. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortal-ity in patients with left ventricular dysfunction after recent andremote myocardial infarction. The SWORD Investigators. SurvivalWith Oral d-Sotalol. Lancet 1996; 348:7–12.

18. Corley SD, Epstein AE, DiMarco JP, et al. Relationships between sinusrhythm, treatment, and survival in the Atrial Fibrillation Follow-Up

strategy. But controversy still exists forpatients who tolerate atrial fibrillation.

For an initial episode of atrial fibrillation,it may be appropriate to try to restore sinusrhythm, preferably without the long-term useof an antiarrhythmic drug, ie, with electricalcardioversion (FIGURE 1). There is no specific“window of opportunity” for attempting this,but the chance of successful restoration ofsinus rhythm is higher the earlier the car-dioversion is performed.

In an older patient with asymptomatic orminimally symptomatic recurrent atrial fibril-lation, a strategy of ventricular rate controlalone may be appropriate and does not appearto be inferior to a rhythm control strategyusing antiarrhythmic medications.

For younger patients and for other rhythmcontrol strategies there will still be controver-sy. One may be reluctant to leave a 35-year-old patient in atrial fibrillation forever, even ifthere are no symptoms whatsoever.

The decision is more difficult for middle-aged patients. Such patients should be evalu-ated carefully and a decision made after suffi-cient education and counseling is providedregarding the pros and cons of the varioustreatment strategies. The potential benefit of

restoring sinus rhythm may become evidentwith the development of a treatment strategythat does not have harmful effects to negatesuch benefit.

Regardless of the strategy, in light of theimportant risk of stroke even in those patientswith apparent maintenance of sinus rhythm,appropriate anticoagulation should be usedand a low threshold set for long-term therapy.This is particularly important for patients withrisk factors for stroke. As mentioned above,many episodes of atrial fibrillation may beasymptomatic, and this should be consideredvery carefully when planning the duration ofanticoagulation after restoration of sinusrhythm. The guidelines support a minimum of4 weeks for everyone.30 The target INR is gen-erally 2.0 to 3.0.

The management of atrial fibrillation willcontinue to evolve as more is learned.Guidelines for the management of patientswith atrial fibrillation have been publishedfrom a task force assembled by the AmericanCollege of Cardiology (ACC), AmericanHeart Association (AHA) and EuropeanSociety of Cardiology (ESC),30 although suchguidelines may not reflect the latest informa-tion from recent trials.

Investigation of Rhythm Management (AFFIRM) Study.Circulation 2004; 109:1509–1513.

19. Haissaguerre M, Jais P, Shah DC, et al. Spontaneous initia-tion of atrial fibrillation by ectopic beats originating inthe pulmonary veins. N Engl J Med 1998; 339:659–666.

20. Finta B, Haines DE. Catheter ablation therapy for atrialfibrillation. Cardiol Clin 2004; 22:127–145.

21. Marrouche NF, Martin DO, Wazni O, et al. Phased-arrayintracardiac echocardiography monitoring during pul-monary vein isolation in patients with atrial fibrillation:impact on outcome and complications. Circulation 2003;107:2710–2716.

22. Marrouche NF, Dresing T, Cole C, et al. Circular mappingand ablation of the pulmonary vein for treatment of atri-al fibrillation: impact of different catheter technologies. JAm Coll Cardiol 2002; 40:464–474.

23. Bhargava M, Marrouche NF, Martin DO, et al. Impact ofage on the outcome of pulmonary vein isolation for atrialfibrillation using circular mapping technique and cooled-tip ablation catheter. J Cardiovasc Electrophysiol 2004;15:8–13.

24. Chen MS, Marrouche NF, Khaykin Y, et al. Pulmonary veinisolation for the treatment of atrial fibrillation in patientswith impaired systolic function. J Am Coll Cardiol 2004;43:1004–1009.

25. Pappone C, Rosanio S, Augello G, et al. Mortality, mor-bidity, and quality of life after circumferential pulmonaryvein ablation for atrial fibrillation: outcomes from a con-trolled nonrandomized long-term study. J Am Coll Cardiol2003; 42:185–197.

26. McCarthy PM, Gillinov AM, Castle L, Chung M, CosgroveD 3rd. The Cox-Maze procedure: the Cleveland Clinicexperience. Semin Thorac Cardiovasc Surg 2000; 12:25–29.

27. Gillinov AM, McCarthy PM. Advances in the surgicaltreatment of atrial fibrillation. Cardiol Clin 2004;22:147–157.

28. Gillis AM. Clinical trials of pacing for maintenance ofsinus rhythm. J Interv Card Electrophysiol 2004; 10(suppl1):55–62.

29. Martin DO, Saliba W, McCarthy PM, et al. Approaches torestoring and maintaining normal sinus rhythm. CleveClin J Med 2003; 70(suppl 3):S12–S29.

30. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESCGuidelines for the Management of Patients With AtrialFibrillation: Executive Summary. A Report of theAmerican College of Cardiology/American HeartAssociation Task Force on Practice Guidelines and theEuropean Society of Cardiology Committee for PracticeGuidelines and Policy Conferences (Committee toDevelop Guidelines for the Management of Patients WithAtrial Fibrillation) Developed in Collaboration With theNorth American Society of Pacing and Electrophysiology.Circulation 2001; 104:2118–2150.

ADDRESS: Robert A. Schweikert, MD, Section ofElectrophysiology and Pacing, Department of CardiovascularMedicine, F15, The Cleveland Clinic Foundation, 9500 EuclidAvenue, Cleveland, OH 44195; e-mail schweir@ccf.org

718 CLEVELAND CL IN IC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 9 SEPTEMBER 2004

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