Atrial Fibrillation: How Best to Use Rate Control and Anticoagulation

Atrial fibrillation (AF) is the most commonsustained cardiac arrhythmia; itaffects about 2.2 million Americans.The prevalence of AF, which increaseswith age,¹ is approximately 5.9% in personsolder than 65 years² and greaterthan 10% in those older than 75 years.³

Framingham data revealed a morethan 2-fold increase in the incidence ofAF for each decade of life in personsolder than 55 years.⁴ Thus, more thantwo thirds of patients with AF are between65 and 85 years of age.⁴

Men are approximately 1.5 timesmore likely to have chronic AF thanwomen of the same age. However, becauseelderly women outnumber elderlymen, the absolute number ofwomen with AF is greater.²

Here, we discuss the most commonpresentations of AF and describetreatment strategies for rate controland prevention of thromboembolism.In a second article, beginning on page539, we will address the benefits andrisks of conversion to sinus rhythm.

OVERVIEW

Classification.

AF may be classifiedas:

• Acute (less than a few days).
• Paroxysmal (episodic with spontaneousconversion to normal sinusrhythm or requiring intervention forconversion).
• Chronic and/or permanent (refractoryto conversion).⁵

Paroxysmal AF ultimately becomeschronic in 25% of cases.⁶

Lone AF has no known precipitatingcause, and patients with this conditionhave no clinical or echocardiographicevidence of cardiopulmonarydisease. Patients with lone AF who areyounger than 60 to 65 years and do nothave hypertension are at low risk forthromboembolism.

Comorbid conditions. Althoughisolated AF can occur, the arrhythmiais usually associated with other conditions(Table 1). The FraminghamStudy revealed several independentrisk factors for AF, including age, congestiveheart failure, systemic hypertension,coronary artery disease, anddiabetes mellitus.⁴ A history of valvularheart disease and increased left atrialdimensions are among the strongestpredictors of AF.⁷ A study of echocardiographicpredictors of AF suggestedthat increased left atrial dimensions,left ventricular wall thickness, and reducedleft ventricular fractional shorteningsignificantly heighten the risk ofnonrheumatic AF.⁸

Pathophysiology. AF is thoughtto result from the continuous electricalactivity of multiple wavelets ofreentry that arc around the atrium.⁹For propagation of AF to occur, a criticalmass of excitable tissue must bepresent, and reentrant wavelets mustnot encounter refractory tissue remainingfrom a previous wavelet.Therefore, a short refractory periodfor the atrial myocardium or slow conductiontime (which allows atrial myocardialtissue to recover) enhancesthe propagation of AF.¹⁰

The atrial enlargement that occurswith valvular heart disease, ischemicheart disease, cardiomyopathy,and AF itself promotes persistence ofAF by accommodating more wavelengths.¹¹ Atrial refractory periods mayshorten in the case of increased vagalor sympathetic tone, thyrotoxicosis, orelectrical remodeling that is further enhancedby persistence of this arrhythmia.Myocardial ischemia, fibrosis orinflammation, electrolyte abnormalities,and increased vagal tone may alsoenhance AF propagation by decreasingconduction velocity in atrial myocardialtissue.¹⁰

Associated risks. AF is associatedwith significant morbidity¹² andmortality¹³-even in patients who donot have organic heart disease--principallybecause of the increased incidenceof thromboembolic events.These events are thought to result primarilyfrom stasis of blood within theatria (caused by loss of atrial contractility)and subsequent thrombus formation.Left heart emboli may result instroke, myocardial infarction (MI), orother systemic embolic phenomena.Moreover, AF may itself confer a hypercoagulablestate, as indicated by elevatedplasma concentrations of fibrin,D-dimer, and β-thromboglobulin.¹⁴

Framingham data show that nonrheumaticAF increases the overall riskof stroke from 1% to approximately 5%per year. Additional risk factors forstroke include transient ischemic attack(TIA) or previous stroke, hypertension,diabetes, and advancing age.¹⁵Patients with mitral stenosis and AFhave a 17-fold risk of stroke comparedwith the general population.¹⁶ In the Framingham cohort, not only didstroke occur more commonly in patientswith AF, but AF-associated strokewas twice as likely to be fatal and survivorsexperienced more recurrencesand greater functional deficits.¹⁷

Morbidity may also result fromthe hemodynamic compromise associatedwith AF. Loss of "atrial kick" mayreduce cardiac output by up to 30%. Inaddition, the rapid heart rates that areoften associated with new-onset AFshorten the period of diastolic fillingand further reduce cardiac output.¹⁸

Thus, patients with a history ofcardiac disease, such as MI or left ventriculardysfunction (systolic or diastolic),are at particular risk for hemodynamicdecompensation if subsequentAF develops.¹⁹ Morbidity mayalso result from a persistently rapidheart rate, which can lead to tachycardia-induced cardiomyopathy²⁰ and atrialenlargement.^21,22 These conditionsmay further predispose to the persistenceof AF through electrical remodelingand fibrosis. Finally, morbiditymay result from pharmacologic treatmentof AF.

CLINICALPRESENTATION
The initial presentation of AFvaries considerably according to theventricular rate and severity of anyconcomitant cardiovascular or pulmonarydisease. Patients may haveminimal or no symptoms, or nonspecificmanifestations such as palpitations,decreased exercise tolerance, orfatigue of recent onset.

A study of paroxysmal AFshowed that patients were generallyasymptomatic during these episodes.²³Patients with underlying coronaryartery disease may experience new oraccelerated anginal symptoms, andthose with heart failure may havesymptoms of fluid overload or frankpulmonary edema. Stroke may sometimesbe the initial presentation in anotherwise asymptomatic patient. Onestudy of hospitalized patients with AFfound that among those with symptoms,52% had dyspnea, 34% had chestpain, 26% had palpitations, and 19% haddizziness or syncope.²⁴ In the unusualscenario of Wolff-Parkinson-White syndromewith AF, the accessory pathwayis likely to transmit the rapid atrial signalsto the ventricle, which may resultin exceedingly rapid ventricular ratesand risk of deterioration to ventricularfibrillation.

ACHIEVINGRATE CONTROLImmediate. The initial approachto AF is similar to that of any otheracute cardiac arrhythmia. Patientswho are hemodynamically unstable(eg, who have low blood pressure or adecreased level of consciousness) as aresult of a rapid ventricular responseto AF should undergo immediate cardioversion,initially with a 200-J synchronizedshock. Most patients whopresent with AF are hemodynamicallystable; rate control is therefore theprimary short-term treatment objective.²⁵ Once hemodynamic stability isassured, the goals of management areto determine the underlying or precipitatingcauses (see Table 1), relievesymptoms, and prevent thromboemboliccomplications.

Long-term.

Two strategies are appropriatefor long-term treatment ofAF:

• Ventricular rate control plus anticoagulationtherapy.
• Restoration and maintenance of normalsinus rhythm.

Although the second optionseems preferable, the drugs that maybe necessary to accomplish this goalall have the potential for significantmorbidity and even mortality.

Three multicenter randomized trialsnow under way will compare ratecontrol with rhythm control: Atrial FibrillationFollow-up Investigation ofRhythm Management (AFFIRM),Rate Control Versus Electrical Cardioversion(RATE), and PharmacologicIntervention in Atrial Fibrillation(PIAF).^26,27 Results of these studiesshould provide guidance in choosingbetween the 2 strategies. Until then,the choice must be made on an individualbasis.

Pharmacologic therapy. The rapid,irregular ventricular rate usually associatedwith new-onset AF is responsiblefor many of its symptoms. Thiscondition may also aggravate ventriculardysfunction or cause a tachycardiainducedcardiomyopathy.^15,28

Digoxin, calcium channel antagonists,and β-blockers--which all workby slowing atrioventricular (AV) nodalconduction--can be used for immediateand long-term rate control. Until recently,digoxin had been consideredstandard first-line therapy for the treatmentof new-onset rapid AF. This drugworks primarily through a vagotonicmechanism to slow the ventricular response.Digoxin is likely to be most effectivefor patients with AF and heartfailure.

Digoxin has a relatively slow onsetof action (30 minutes to 2 hours),and it is often clinically ineffective forrate control in settings in which vagaltone is low and/or endogenous catecholaminelevels are high, such as inexercise-induced AF, thyrotoxicosis, oracute illness.²⁹ Contrary to a previouslyheld belief, digoxin does not convertAF to sinus rhythm more effectivelythan placebo.³⁰ Given these drawbacks,many clinicians now select alternativeagents for initial rate control.

The calcium channel antagonistsdiltiazem and verapamil are both veryeffective for overall rate control at restand during exercise. In patients whodo not have underlying sick sinus syndrome,these drugs usually do notcause significant bradycardia at rest.They have a rapid onset of action (usually2 to 3 minutes) when given intravenously.Diltiazem is less likely tocause hypotension than verapamil andhas a less negative inotropic effect. Inaddition, it can be carefully titratedwith a continuous intravenous infusion.

Despite its negative inotropic effect,diltiazem is effective and has agood safety profile even when administeredto patients with mild to moderateheart failure.³¹ Verapamil, and to alesser extent diltiazem, raises serumdigoxin levels, so levels should bemonitored closely when these agentsare used in combination with digoxin.

Some clinicians favor β-blockersas first-line therapy for initial rate control.Use of these agents makes physiologicsense, because they not onlyblock AV nodal conduction but alsocounteract increased sympathetic activity.Like calcium channel antagonists,they are highly effective and featurerapid onset of action (usually within5 minutes) and easy titratabilitywhen given as continuous intravenousinfusions. They may be particularlyuseful for patients whose heart rate increasessubstantially with activity orstress.³²

Use β-blockers cautiously in patientswith reactive airways disease, diabetes,hypotension, or systolic heartfailure, because these agents may aggravateor mask these conditions. Allβ-blockers are equally effective for ratecontrol, but certain ones may offer advantagesin specific clinical settings.For example, β-blockers with intrinsicsympathomimetic activity, such as pindololor acebutolol, may be desirablefor patients in whom adequate ratecontrol cannot otherwise be achievedwithout excessive bradycardia.³³

β-Blockers and calcium channelantagonists may also be used in combinationwith digoxin if either agent isineffective alone. Although the combi-nation of β-blockers and calcium channelantagonists is usually safe in patientswho do not have sick sinus syndrome,caution is warranted becauseof the potential risk of excessive bradycardia.Avoid concomitant use of intravenousβ-blockers and calcium channelantagonists because of the risk ofsevere bradycardia, heart block, oreven asystole.

If rate control is not achievedafter usual therapy, several otheragents may be considered. Magnesiumsulfate (1 to 4 g infused over severalhours) may enhance the effect ofother drugs.^34,35 Candidates for magnesiuminfusion include patients at riskfor magnesium depletion, such asthose with other electrolyte abnormalities(hypokalemia, hyponatremia,hypocalcemia, or hypophosphatemia),those undergoing cancer chemotherapywith cisplatin or similar agents,those undergoing diuretic therapy, andthose with a history of alcoholism oracute MI. Intravenous amiodaronemay also be considered, because itprolongs AV nodal refractory time.

Radiofrequency ablation. If ratecontrol is not achieved despitemaximum medical therapy, considerreferral to a cardiac electrophysiologistfor more invasive alternative treatments.Both AV node modificationand AV node ablation with permanentpacemaker implantation can achievelong-term rate control.^36-38 These procedures,which use radiofrequencyenergy, are performed with the patientunder conscious sedation inthe electrophysiology laboratory.Major complication rates of lessthan 3% have been reported.³⁶ Asmall risk of torsades de pointes existswith these procedures; hospital monitoringfor 48 to 72 hours is thereforerecommended.^36,39

Many patients who undergo AVnode ablation with pacemaker implantationfeel much better after the procedure.Although long-term anticoagulationis still needed (because theatria are still fibrillating), left ventricularfunction often improves significantlybecause heart rate can now becontrolled.

ANTICOAGULATION
Rate control through pharmacologicor nonpharmacologic treatmentusually improves symptoms and mayprevent or at least partially reversetachycardia-induced cardiomyopathy.Unfortunately, it does not prevent ischemicstroke; hence the necessity forlong-term anticoagulation with warfarinin patients for whom the benefitsof this therapy outweigh the risks.

Warfarin. In 5 randomized, controlledprimary prevention trials, warfarinreduced the risk of stroke by 37%to 86%.^40-44 Pooled data from these trialsyielded an average stroke risk reductionof 68%; the reduction was greaterin women than in men (84% vs 60%).¹²Risk reduction was noted across allage groups studied and was independentof such risk factors as MI, con-gestive heart failure, hypertension, diabetes,and previous TIA or stroke.Risk reduction was not seen in patientswith lone AF; however, very fewstrokes occurred in this group. Warfarinalso reduced overall mortality by31%.^41,43,44 Warfarin may be even moreeffective for secondary prevention ofstroke in patients with AF and a previouscerebral ischemic event.⁴⁵

The target INR in the randomizedtrials ranged from 1.4 to 4.5; most embolicevents occurred with INRs lowerthan 2, and most hemorrhagic eventsoccurred with INRs higher than 4.⁴⁶ Intracranialhemorrhage occurred at anaverage rate of 1.3% per year.

Aspirin. The role of aspirin in preventingstroke related to nonrheumaticAF is less clear. Aspirin was comparedwith both placebo and warfarinin several of the large anticoagulationtrials.^40,43,46,47 Pooled data from 3 studiesshow a 21% risk reduction with aspirintherapy--much lower than thatassociated with warfarin. However, inthe Stroke Prevention in Atrial FibrillationII study, the incidence of intracerebralhemorrhage was significantlyhigher in patients older than 75 yearswho received warfarin than in thosewho received aspirin.⁴⁸

The combination of low-dose warfarin(INR, 1.2 to 1.5) and aspirin (325mg) has not proved effective for reducingischemic stroke or intracerebralhemorrhage.⁴⁹

Recommendations. Warfarin isclearly more effective than aspirin forstroke risk reduction and should bestrongly considered for all patients (ifno contraindication exists) at high riskfor embolic stroke from AF. Recentmeta-analyses confirm that warfarinprovides greatest benefit for those athighest risk for stroke and that thisbenefit is not offset by the occurrenceof major hemorrhage.^50,51

Those at low risk for stroke mayderive sufficient protection from aspirin.⁵⁰ (The slightly greater preventionbenefit provided by warfarin is offsetby the greater risk of hemorrhage inthis low-risk population.) Practicallyspeaking, patients at low risk forstroke are those who have true loneAF (as defined by the absence of anyevidence of heart disease--includinghypertension--in patients youngerthan 60 to 65 years).

The American College of ChestPhysicians⁵² and the American HeartAssociation⁵³ have developed guidelinesfor the use of warfarin and aspirinto prevent stroke in patients with nonrheumaticAF. These guidelines arebased on anticoagulation trials and expertopinion; the major recommendationsare listed in Table 2.

References:

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