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edi tor ial s

T h e n e w e n g l a n d j o u r n a l o f medicine

Rate Control in Atrial FibrillationPaul Dorian, M.D.

Untreated atrial fibrillation is usually associated with a rapid, irregular ventricular response and isoften accompanied by symptoms including palpi-tations, fatigue, dyspnea, and dizziness. It is wide-ly accepted that slowing the ventricular response,

both at rest and during activity, with the use ofdrugs that prolong the refractory period of theatrioventricular (AV) node (so-called rate-controlagents) will result in an improvement in symp-toms and most likely reduce the future risk of adverse cardiovascular events. The strategy of ratecontrol is preferred by most physicians to the strat-egy of rhythm control as initial therapy for pa-tients with atrial fibrillation,1 given the failure toshow that rhythm-control strategies result in low-er rates of death, stroke, or hospitalizations or bet-ter quality of life in large, well-conducted, random-ized clinical trials.2

When choosing to administer a rate-controlagent to a patient, it seems reasonable to attemptto achieve ventricular rates similar to those pres-ent during sinus rhythm in patients with a simi-lar degree of heart disease. These targets arebased on the belief that lower heart rates will re-sult in fewer symptoms, are likely to be associat-ed with better cardiovascular function because oflonger diastolic filling times and more satisfac-tory

hemodynamics, and are associated with a

lower risk of tachycardia-related cardiomyopathy.Extrapolation from epidemiologic studies show-ing that faster heart rates in sinus rhythm areassociated with increasing mortality from cardiovascular causes, and the documented clinical andquality-of-life benefits of the “pace and ablate”approach to ventricular rate control,3 also implythat the more closely ventricular rates duringatrial fibrillation approximate those during nor-mal sinus rhythm, the better the outcome.

These considerations have led to widely adopt-ed guidelines for the ventricular rate targets inpatients with atrial fibrillation,4 which recom-mend resting heart-rate targets of less than 80beats per minute and targets during moderate

physical activity of less than 110 beats per min-ute. These admittedly arbitrary targets, measured with the use of electrocardiography, are basedon the expectation that the benefits of more in-tensive rate control outweigh its disadvantagesand risks.

A number of previous lines of evidence, how-ever, suggest possible flaws in the concept of tar-geting heart rates to near-normal levels. First, therelation between the achieved heart rate and thequality of life or symptoms is inconsistent, andthe degree of symptoms during atrial fibrillationis more strongly related to severity of the under-lying cardiac disease, age, and sex than it is toheart rate itself.5,6 In retrospective substudies ofAFFIRM (the Atrial Fibrillation Follow-up Investi-gation of Rhythm Management) trial7 and theRACE (Rate Control versus Electrical Cardiover-sion for Persistent Atrial Fibrillation) trial,2 in which patients were randomly assigned to under-go a rate-control strategy or a rhythm-controlstrategy, there was no evidence of a reduction inmorbidity or mortality or improved quality of life

in patients with “tight” versus “less tight” ratecontrol.6,8 In patients with heart failure, in whomthe potential deleterious effects of a high ventric-ular rate might be particularly prominent, thereis no evidence that bisoprolol, as compared withplacebo, reduced the rates of death or hospital-ization in a subgroup of patients who had atrialfibrillation at baseline.9

In this issue of the Journal, Van Gelder and col-leagues report on the RACE II (Rate Control Ef-

The New England Journal of Medicine

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T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 362;15 nejm.org april 15, 20101440

ficacy in Permanent Atrial Fibrillation: a Compari-son between Lenient versus Strict Rate Control II)trial (ClinicalTrials.gov number, NCT00392613).10 They have made an important contribution to ourunderstanding of the potential benefits and risksof the current guideline-recommended approachto ventricular rate control in patients with per-

sistent atrial fibrillation.By means of a variety of AV nodal blocking

agents, which included beta-blocker therapy in79% and calcium-blocker therapy in 37% of pa-tients, a resting heart rate of less than 80 beatsper minute at rest was achieved in 67% of pa-tients who were randomly assigned to this strictrate-control target. In this group, the average(±SD) heart rate measured with the use of 24-hour Holter monitoring was 78±11 beats perminute, and 88% of patients had resting heartrates of 90 beats per minute or less after the

dose-adjustment phase. Conversely, in the lenient-control group, in which the resting heart-rate tar-get was less than 110 beats per minute, 98% ofpatients achieved this target; resting heart rates were faster than 80 beats per minute in 98% andfaster than 100 beats per minute in 23%. Thisless stringent rate-control target was achieved with the use of lower doses of beta-blockers, andbeta-blockers were required in only 65% of pa-tients; a combination of AV nodal blockers wasnecessary in 30% of patients, in contrast to 69%in the strict-control group.

Although the confidence intervals around thehazard ratios for the composite primary outcomeand the components of the primary outcome are wide, there is no indication that there was anyclinical benefit to strict rate control with respect tothe risk of death, serious adverse outcomes (in-cluding heart failure), or symptoms. It is instruc-tive to speculate that symptomatic adverse effectsof rate-control drugs could offset the potentialsymptomatic benefits of strict rate control, giventhe minority of patients in both groups (24%) who

had palpitation as a recorded symptom. In thestrict-control group, the reason the target wasnot achieved was because of drug-related adverseevents in 25% of patients. These results suggestthat the potential clinical benefits of a “conven-tional” approach to ventricular rate control, evenif present, may be offset by the potential adverseeffects of drugs used for this purpose.

A number of limitations of the RACE II studyneed to be borne in mind. First, it is possible

that rapid ventricular rates may take many yearsto result in cardiac deterioration and illness ordeath, and thus there may be a benefit of more“strict” ventricular rate control over a period ofdecades or more. Patients with atrial f ibrillation who also have very rapid ventricular responses,present with heart failure, and appear to have

tachycardia-related cardiomyopathy may haveparticular benefit from strict rate control; thissubgroup may have been underrepresented ornot enrolled in the RACE II trial. The data onsymptoms and quality of life collected in thestudy were somewhat limited, such that subtlebenefits in this regard from stricter rate controlmay not have been easily ascertained. As in allrandomized, clinical trials, selection bias mostlikely limited the enrollment of patients to those who were relatively clinically well, were somewhat younger than the average age for patients

with atrial f ibrillation, and had some degree ofrate control at study entry (mean heart rate inboth groups at baseline, 96 beats per minute).Two thirds of the patients were men; women areknown to have more severe symptoms than menduring atrial fibrillation, possibly in association with more rapid ventricular rates on average.11

What clinical inferences can be drawn fromthe RACE II study, given the previous state ofknowledge regarding rate control? First, a heart-rate target of less than 110 beats per minute atrest, although it may make physicians feel un-comfortable, is probably as useful as the currentguideline-recommended target heart rates at restand during exercise, at least in the medium term.Many patients will continue to be symptomaticunder the rate-control approach, whether a strictor more lenient target heart rate is used. TheRACE II study does not suggest that ventricularrate control is not needed, only that the conven-tional therapeutic target needs to be reassessed.At a minimum, the study indicates that reflexive,“recipe-based” adherence to a rate-control target

does not seem sensible and that an approach em-phasizing the adjustment of therapy on the basisof symptoms and general well-being can be safelyrecommended.

As in many other clinical situations, in pa-tients with atrial fibrillation, treating a labora-tory test is not a good substitute for targetingovert clinical outcomes. This important studyserves as a reminder that it is better to treat thepatient and not the electrocardiogram.






editorials

n engl j med 362;15 nejm.org april 15, 2010 1441

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

From the Division of Cardiology, St. Michael’s Hospital, Toronto.

This article (10.1056/NEJMe1002301) was published on March15, 2010, at NEJM.org

Nieuwlaat R, Capucci A, Camm AJ, et al. Atrial fibrillation1.

management: a prospective survey in ESC member countries: the

Euro Heart Survey on Atrial Fibrillation. Eur Heart J 2005;26:2422-34.Van Gelder IC, Van Veldhuisen DJ, Crijns HJ, et a l. RAte Con-2.

trol Efficacy in permanent atrial fibrillation: a comparison be-tween lenient versus strict rate control in pat ients with and with-out heart fai lure: background, aims, and design of RACE II. AmHeart J 2006;152:420-6.

Wood MA, Brown-Mahoney C, Kay GN, Ellenbogen KA. Clin-3.

ical outcomes after ablation and pacing therapy for atrial fibril-lation: a meta-analysis. Circulation 2000;101:1138-44.

Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 20064.

guidelines for the management of patients with atrial fibrilla-tion: a report of the American College of Cardiology/AmericanHeart Association Task Force on Practice Guidelines and theEuropean Society of Cardiology Committee for Practice Guide-lines (writing committee to revise the 2001 guidelines for the

management of patients with atrial fibrillation) developed incollaboration with the European Heart Rhythm Association andthe Heart Rhythm Society. J Am Coll Cardiol 2006;48(4):e149-e246.

Reynolds MR, Lavelle T, Essebag V, Cohen DJ, Zimetbaum P.5.

Influence of age, sex, and atrial fibrillation recurrence on qual-ity of life outcomes in a population of patients with new-onsetatrial f ibrillation: the Fibrillation Registry Assessing Costs, Ther-apies, Adverse events and Lifestyle (FRACTAL) study. Am Heart J 2006;152:1097-103.

Cooper HA, Bloomfield DA, Bush DE, et al. Relation between6.

achieved heart rate and outcomes in patients with atrial f ibrilla-tion (from the Atrial Fibrillation Follow-up Investigation of

Rhythm Management [AFFIRM] Study). Am J Cardiol 2004;93:1247-53.The Atrial Fibrillation Follow-up Investigation of Rhythm7.

Management (AFFIRM) Investigators. A comparison of rate con-trol and rhythm control in patients with atrial f ibrillation. N Engl J Med 2002;347:1825-33.

Groenveld HF, Crijins HJGM, Rienstra M, Van den Berg MP,8.

Van Veldhuisen DJ, Van Gelder IC. Does intensity of rate controlinfluence outcome in persistent atrial fibrillation? Data of theRACE study. Am Heart J 2009;158:785-91.

Lechat P, Hulot JS, Escolano S, et al. Heart rate and cardiac9.

rhythm relationships with bisoprolol benefit in chronic heartfailure in CIBIS II Trial. Circulation 2001;103:1428-33.

Van Gelder IC, Groenveld HF, Crijns HJGM, et al. Lenient10.

versus strict rate control in patients with atrial fibril lation.N Engl J Med 2010;362:1363-73.

Paquette M, Roy D, Talajic M, et al. Role of gender and per-11.sonality on quality-of-life impairment in intermittent atrial fi-brillat ion. Am J Cardiol 2000;86:764-8.Copyright © 2010 Massachusetts Medical Society.

Optimal Duration of Clopidogrel Use after Implantationof Drug-Eluting Stents — Still in Doubt

Peter B. Berger, M.D.

As compared with bare-metal stents, drug-elutingstents reduce restenosis in every clinical situationand every type of lesion studied. Why, then, dosome cardiologists use drug-eluting stents in 90%of patients and other cardiologists in 10%? Theexplanation relates primarily to two questions.First, are drug-eluting stents associated with agreater risk of “very late” (>1 year after implan-tation) stent thrombosis than bare-metal stents?And second, what is the required duration of dualantiplatelet therapy after implantation of drug-eluting stents? Incredibly, the answers to these

questions are still unknown.Definitions of stent thrombosis are either in-sufficiently sensitive or insufficiently specific.Since nearly all stent thromboses causes a largemyocardial infarction or death, assessing the fre-quency of death and infarction rather than stentthrombosis ought to be sufficient. However, doingso might result in small infarctions due to reste-nosis and repeat procedures,

the risks of whichare reduced by drug-eluting stents, “counterbal-

ancing” large infarctions due to stent thrombosis,the rates of which might be increased by drug-eluting stents. Whether such counterbalancing hasin fact clouded the interpretation of analyses isunknown. A meta-analysis of 22 randomized tri-als comparing drug-eluting stents and bare-metalstents showed no evidence of an increase in therisk of death, myocardial infarction, or stentthrombosis with drug-eluting stents.1 But the me-dian duration of follow-up in this analysis wasonly 2.9 years.1 Concern arises from observationalstudies indicating absolute rates of very late stent

thrombosis of 0.5% per year and higher that per-sists for years in association with drug-elutingstents but not bare-metal stents.2,3

The second question relates to the requisite du-ration of dual antiplatelet therapy after implan-tation of drug-eluting stents. This question is ad-dressed in this issue of the Journal by Park andcolleagues in their report 4 on two trials, calledREAL-LATE (Correlation of Clopidogrel TherapyDiscontinuation in Real-World Patients Treated




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