to class III agents)

Quinidine sulfate (83%

quinidine; SR: Quinidex)

Quinidine gluconate (62%

quinidine; SR: Quinaglute)

t1/2 = 6.2 ± 1.8 hours (affected by age,

cirrhosis); Vd = 2.7 L/kg (↓ in HF);

liver metabolism, 80%; renal

clearance, 20%; Cp = 2–6 mcg/mL,

CYP3A4 substrate, CYP2D6

inhibitor, P-glycoprotein inhibitor

AF (conversion or

prophylaxis), WPW, PVCs,

VT

Diarrhea, hypotension, N/V,

cinchonism, fever,

thrombocytopenia, proarrhythmia

Procainamide (Pronestyl) t1/2 = 3 ± 0.6 hours; Vd = 1.9 ±

0.3 L/kg; liver metabolism 40%; renal

clearance (GFR + possible CTS)

60%; active metabolite (NAPA)a

Cp = 4–10 mcg/mL, possible CTS

substrate

AF (conversion or

prophylaxis), WPW, PVCs,

VT

Hypotension, fever, agranulocytosis,

SLE (joint/muscle pain, rash,

pericarditis), headache,

proarrhythmia

Disopyramide (Norpace; SR:

Norpace CR)

t1/2 = 6 ± 1 hours; Vd = 0.59 ±

0.15 L/kg; liver metabolism,

30%; renal clearance, 70%;

Cp = 3–6 mcg/mL

AF, WPW, PSVT, PVCs, VT Anticholinergic (dry mouth, blurred

vision, urinary retention), HF,

proarrhythmia

Class Ibb (cannot use to treat atrial arrhythmias)

Lidocaine (Xylocaine) t1/2 = 1.8 ± 0.4 hours; Vd = 1.1 ±

0.4 L/kg; liver metabolism, 100%;

Cp = 1.5–6 mcg/mL

PVCs, VT, VF Drowsiness, agitation, muscle

twitching, seizures, paresthesias,

proarrhythmia

Mexiletine (Mexitil) t1/2 = 10.4 ± 2.8 hours; Vd = 9.5 ±

3.4 L/kg; liver metabolism,

35%–80%; Cp = 0.5–2 mcg/mL

PVCs, VT, VF Drowsiness, agitation, muscle

twitching, seizures, paresthesias,

proarrhythmia, N/V, diarrhea

Class Ic (cannot be used in patients with structural heart disease)

Flecainide (Tambocor) t1/2 = 12–27 hours; CYP2D6 substrate,

75%; renal clearance, 25%;

Cp = 0.4–1 mcg/mL

AF, PSVT, severe ventricular

arrhythmias

Dizziness, tremor, lightheadedness,

flushing, blurred vision, metallic

taste, proarrhythmia

Propafenone (Rythmol) t1/2 = 2 hours (extensive metabolizer);

10 hours (poor metabolizer);

Vd = 2.5–4 L/kg, CYP2D6 substrate/

inhibitor, P-glycoprotein inhibitor

PAF, WPW, severe ventricular

arrhythmias

Dizziness, blurred vision, taste

disturbances, nausea, worsening of

asthma, proarrhythmia

Moricizine (Ethmozine) t1/2 = 1.3–3.5 hours; Vd >300 L Severe ventricular

arrhythmias

Nausea, dizziness, perioral numbness,

euphoria

Class III (can cause torsade de pointes similarly to class Ia agents, amiodarone and dronedarone have lower risk)

Amiodarone (Cordarone) t1/2 = 40–60 days; Vd = 60–100 L/kg;

erratic absorption; liver metabolism,

100%; oral F = 50%, Cp = 0.5–2.5

mcg/mL, CYP1A2, 2D6, 2C9, 3A4

inhibitor, P-glycoprotein inhibitor

AF, PAF, PSVT, severe

ventricular arrhythmias,

VF

Blurred vision, corneal microdeposits,

photophobia, skin discoloration,

constipation, pulmonary fibrosis,

ataxia, hypothyroid or hyperthyroid,

hypotension, N/V

Sotalolc (Betapace) t1/2 = 10–20 hours; Vd = 1.2–2.4 L/kg;

renal clearance, 100%

AF (prophylaxis), PSVT,

severe ventricular

arrhythmias

Fatigue, dizziness, dyspnea,

bradycardia, proarrhythmia

Dofetilide (Tikosyn) t1/2 = 7.5–10 hours; Vd = 3 L/kg; renal

elimination, 60% (GFR + CTS),

CYP3A4 substrate

AF or atrial flutter conversion

and prophylaxis

Chest pain, dizziness, headache,

proarrhythmia

Ibutilide (Corvert) t1/2 = 6 (2–12) hours; Vd = 11 L/kg,

Cp = undefined

AF or atrial flutter conversion Headache, nausea, proarrhythmia

Dronedarone (Multaq) t1/2 = 13–19 hours; Vd = 20 L/kg,

Tmax = 3–6 hours, CYP3A4

substrate, CYP 2D6, 3A4 inhibitor,

P-glycoprotein inhibitor, take with

food for maximal absorption

AF or atrial flutter

prophylaxis

Diarrhea, nausea, dermatitis or rash,

bradycardia, hepatotoxicity,

pregnancy category X

aNAPA is 100% renally eliminated and possesses class III antiarrhythmic activity.

b Phenytoin is classified as a class Ib antiarrhythmic.

c Possesses both class II and III antiarrhythmic activity.

AF, atrial fibrillation; Cp, steady-state plasma concentration; CR, controlled release; CTS, cation tubular secretion; CYP, cytochrome P-450; F, bioavailability; GFR,

glomerular filtration rate; HF, heart failure; NAPA, N-acetylprocainamide; N/V, nausea and vomiting; PAF, paroxysmal atrial fibrillation; PSVT, paroxysmal supraventricular

tachycardia; PVC, premature ventricular contraction; SLE, systemic lupus erythematosus; SR, sustained release; t1/2, half-life; Vd, volume of distribution; VF, ventricular

fibrillation; VT, ventricular tachycardia; WPW, Wolff-Parkinson-White syndrome.

495Cardiac Arrhythmias Chapter 20

Note undulating baseline with no discernable P waves.

R-R

0.64

R-R

0.48

R-R

0.32

FIGURE 20-4 Atrial fibrillation. Note the irregularly irregular R-R intervals, undulating baseline without definitive P waves, normal width of the

QRS complexes, and ventricular rate of 140 beats/minute.

The most common supraventricular arrhythmias are AF, atrial

flutter, and PSVT.

Atrial Fibrillation and Atrial Flutter

AF is usually initiated when a depolarization stimulus arising

from an ectopic focus or re-entrant circuit impacts the atria while

the tissue is in the vulnerable period. The vulnerable period in

the atria and ventricles occurs during the first half of the QRS

complex; this period is vulnerable because the net charge is near

normal but the ion concentrations of sodium, calcium, and potassium inside and outside the cells are radically different. Stimulation during the vulnerable period causes multiple ectopic foci

to arise and attempt to pace the atria with no single pacemaker

in control, eliminating discernable P waves on the ECG (Figure

20-4) and eliciting a rapid, ineffective writhing of the atrial muscle

with a classic “irregularly irregular” ventricular rate. In contrast,

atrial flutter (Fig. 20-5) is characterized by typical sawtooth atrial

waves, at a rate of 280 to 320 beats/minute, and a variable ventricular rate, depending on the nature of the AV block present

(e.g., 2, 3, or 4 atrial beats for each ventricular beat or 2:1, 3:1,

or 4:1 block). In most cases, the ventricular rate is approximately

150 beats/minute. Episodes of atrial flutter can progress to AF if

the ectopic atrial depolarization stimulus impacts the surrounding atrial tissue in the vulnerable period. When patients initially

experience AF, the episodes are usually short lived, and spontaneous conversion occurs. The pattern of erratic initiation and

termination of AF is termed paroxysmal atrial fibrillation (PAF),

and if enough AF events occur in close proximity to each other,

the duration of subsequent AF events increase in length and the

event degenerates into persistent AF. In persistent AF, the AF

episode will continue until the heart is electrically or chemically

converted out of the rhythm. With time, persistent AF degenerates into permanent AF, in which normal sinus rhythm cannot

be achieved and sustained. An example of PAF is presented in the

following section.

CLINICAL MANIFESTATION AND

UNDERLYING CAUSES

CASE 20-1

QUESTION 1: J.K., a 66-year-old man, presents for a routine checkup in the clinic. His medical history includes type 2

diabetes mellitus and systolic HF for the last 5 years, hypertension, and gout. There is no history of rheumatic heart

disease, MI, pulmonary embolism, or thyroid disease. Medications include glyburide 5 mg twice daily, lisinopril 40 mg

every day, furosemide 40 mg twice daily, metoprolol 50 mg

twice daily and allopurinol 300 mg/day. J.K. does not smoke

or drink alcohol. Physical examination reveals a blood pressure (BP) of 136/84 mm Hg, pulse of 70 beats/minute in

normal sinus rhythm, respiratory rate of 12 breaths/minute,

and temperature of 98.2◦F. His body mass index (BMI) is

32 kg/m2. What factors in J.K.’s past medical history predispose him to development of AF? What is his 10-year risk of

developing AF?

AF is commonly associated with, or a manifestation of, other

diseases or disorders (Table 20-4).1 When treatable underlying

causes are present, they should be corrected because this may

resolve the AF. A risk prediction tool has been developed for

AF.2 With this tool, points are assigned for age, male sex, BMI,

systolic blood pressure, PR-interval duration, and presence of

either hypertension, heart failure, or valvular disease. The total

number of points correlates with risk of developing AF within

10 years. This point system highlights common factors associated

FIGURE 20-5 Atrial flutter. Note the sawtooth appearance of the rhythm strip. (Reproduced with permission from

Stein E. Rapid Analysis of Arrhythmias: A Self-Study Program. 2nd ed. Philadelphia, PA: Lea & Febiger; 1992.)

496 Section 2 Cardiac and Vascular Disorders

TABLE 20-4

Causes of Atrial Fibrillation and Flutter

Alcohol Nonrheumatic heart disease

Atrial septal defect Pericarditis

Cardiac surgery Pneumonia

Cardiomyopathy Pulmonary embolism

Cerebrovascular accident Sick sinus syndrome

Chronic obstructive

pulmonary disease

Stimulants

Thyrotoxicosis

Trauma

Tumors

Wolff-Parkinson-White syndrome

Fever

Hypothermia

Ischemic heart disease

Mitral valve disease

with the development of AF, particularly older age, hypertension,

heart failure, and valvular disease. It has been demonstrated that

AF may be more likely to develop in obesity as well.3 In a small

percentage of patients who do not have underlying heart disease,

AF is called “lone” AF and usually has a more benign course.

The point system described above demonstrates the factors

that contribute to risk of developing AF. Although the application

of the scoring system is beyond the scope of this chapter, J.K. has

risk factors for the development of AF within the next 10 years,

including the presence of treated hypertension, heart failure, his

age, and his sex. Given the information available, his 10-year

risk of developing AF would be greater than 30%.2 Details about

application of the scoring system above can be found in the

published manuscript.2

Consequences of Atrial Fibrillation

CASE 20-1, QUESTION 2: Two years later, J.K. presents

with complaints of dyspnea on exertion (DOE) and palpitations for the last 2 weeks. He experienced palpitations

of shorter duration three times in the last year, but these

were not associated with DOE. On physical examination, he

is found to have rales at both bases. Cardiac examination

reveals an irregularly irregular rhythm without murmurs, gallops, or rubs. His jugular veins are distended 4 cm, but

no organomegaly is found. His extremities have 1+ pitting

edema. The ECG shows AF (see Fig. 20-4), and the chest

radiograph is compatible with mild HF. A cardiac echocardiogram reveals the atrial size to be less than 5 cm (normal)

and a left ventricular ejection fraction of 30%. What clinical

findings demonstrated by J.K. are typically associated with

AF? What are the likely consequences of his AF?

The most common complaint in patients with AF, as with

J.K., is chest palpitations (the sensation of the heart beating

rapidly or unusually in the chest). This is a result of the rapid

ventricular contraction rate, which typically ranges from 100

to 160 beats/minute. The R-R interval (time from the R wave

in one QRS complex to the R wave in the next complex) is

irregularly irregular (random irregularity). During AF, the atrial

kick, or the atria’s contribution to stroke volume (via the FrankStarling mechanism), is lost. Because the atrial kick may account

for 20% to 30% of the total stroke volume, this, coupled with

rapid ventricular rates and irregular R-R interval spacing during AF, can cause symptoms of inadequate blood flow such as

light-headedness, dizziness, or reduced exercise tolerance. However, some patients are asymptomatic except for the palpitations.

Depending on the underlying ventricular function, signs of HF,

such as DOE and peripheral edema, may develop, as experienced

by J.K. Conversely, underlying HF may precipitate AF.

Patients with AF are at risk for thrombotic stroke (see Stroke

Prevention section below).4,5 With the chaotic movement of the

atria, normal blood flow is disrupted, and atrial mural thrombi

(usually in a pouch called the left atrial appendage) may form. The

risk of stroke increases after restoration of normal sinus rhythm,

which allows more efficient cardiac contractility and expulsion

of the thrombus. Patients with nonvalvular AF have a fivefold

increase in the risk of stroke; this risk increases as patients have

an increased number of associated risk factors. Other concurrent

diseases that may increase the risk of stroke are HF, cardiomyopathy, thyrotoxicosis, congenital heart disease, and valvular heart

disease.

TREATMENT OF ATRIAL FIBRILLATION

GOALS OF THERAPY

CASE 20-1, QUESTION 3: What are the therapeutic goals

and general approaches used to treat AF in patients like

J.K.?

The two primary goals of treatment are to control the ventricular response rate and to reduce the risk of stroke. In some

cases, a third therapeutic goal may be conversion to normal sinus

rhythm.

VENTRICULAR RATE CONTROL

CASE 20-1, QUESTION 4: J.K. is given a 1-mg loading dose

of digoxin, followed by a 0.25-mg every day maintenance

dose. What is the purpose of administering digoxin? What

are the relative advantages and disadvantages of digoxin

compared with other agents to control ventricular rate?

Digoxin

The first treatment goal is to slow the ventricular response rate,

which allows better ventricular filling with blood. Table 20-5

displays the agents commonly used to control the ventricular response and provides the loading and maintenance doses.

Because of its direct AV node-blocking effects and vagomimetic

properties, digoxin prolongs the effective refractory period of the

AV node and reduces the number of impulses conducted through

the AV node (negative dromotropy).6,7

Owing to several limitations associated with digoxin use, its

role is limited as a rate-controlling agent in AF. Digoxin’s use

is limited by its slow onset of action. After an intravenous (IV)

dose, it will take more than 2 hours for the onset of effect and 6

to 8 hours for the maximal effect, which is markedly slower than

other negative dromotropic agents.8 Digoxin is also less effective

than β-blockers and nondihydropyridine calcium-channel blockers during states of heightened sympathetic tone (e.g., exercise

or emotional stress), a common precipitant of PAF.6,7,9,10 The

2006 American College of Cardiology/American Heart Association/European Society of Cardiology Guidelines for the management of patients with AF recommend that digoxin use be

reserved for control of ventricular response rate in AF in patients

with impaired left ventricular function or HF or for use as an

add-on therapy when treatment with a β-blocker or calciumchannel blocker provides inadequate rate control.11,12 Patients

who require rate control of AF and have a lower blood pressure

may also benefit from rate control with digoxin. It should also

be noted that digoxin serum concentrations may be increased

when combined with P-glycoprotein inhibitors such as verapamil, propafenone, quinidine, flecainide, and amiodarone.13–16

Normally, P-glycoprotein in the brush border membrane of

497Cardiac Arrhythmias Chapter 20

TABLE 20-5

Agents Used for Controlling Ventricular Rate in Supraventricular Tachycardiasa

Drug Loading Dose Usual Maintenance Dose Comments

Digoxin (Lanoxin) 10–15 mcg/kg LBW up to 1–1.5

mg IV or PO for 24 hours (e.g.,

0.5 mg initially, then 0.25 mg

every 6 hours)

PO: 0.125–0.5 mg/d; adjust for renal

failure (see Chapter 19)

Maximal response may take several

hours; use with caution in patients

with renal impairment

Esmolol (Brevibloc) 0.5 mg/kg IV for 1 minute 50–300 mcg/kg/min continuous

infusion with bolus between

increases

Hypotension common; effects additive

with digoxin and calcium-channel

blockers

Propranolol (Inderal) 0.5–1.0 mg IV repeated every

2 minutes (up to 0.1–0.15

mg/kg)

IV infusion: 0.04 mg/kg/min

PO: 10–120 mg TID

Use with caution in patients with HF or

asthma; additive effects seen with

digoxin and calcium-channel blockers

Metoprolol (Lopressor) 5 mg IV at 1 mg/min PO: 25–100 mg BID Use with caution in patients with HF or

asthma; additive effects seen with

digoxin and calcium-channel blockers

Verapamil (Isoptin,

Calan)

5–10 mg (0.075–0.15 mg/kg) IV for

2 minutes; if response

inadequate after 15–30 minutes,

repeat 10 mg (up to 0.15 mg/kg)

IV infusion: 5–10 mg/h

PO: 40–120 mg TID or 120–480 mg

in sustained-release form daily

Hypotension with IV route; AV blocking

effects are additive with digoxin and

β-blockers; may increase digoxin

levels

Diltiazem (Cardizem) 0.25 mg/kg IV for 2 minutes; if

response inadequate after

15 minutes, repeat 0.35 mg/kg

for 2 minutes

IV infusion: 5–15 mg/h

PO: 60–90 mg TID or QID or

180–360 mg in extended-release

form daily

Response to IV therapy occurs in

4–5 minutes; hypotension; effects

additive with digoxin and β-blockers

aAV nodal ablation is a nonpharmacologic alternative to control the ventricular response, but the effect is permanent and requires chronic ventricular pacing afterward.

AV, atrioventricular; BID; twice a day; HF, heart failure; LBW, lean body weight; PO, orally; IV, intravenously; QID, four times a day; TID, three times a day.

intestinal enterocytes pumps digoxin into the lumen of the gut

and reduces its bioavailability; P-glycoprotein also resides in renal

tubules and pumps digoxin out of the body (see Chapter 19, Heart

Failure, for further discussion of digoxin and digoxin drug interactions).

CASE 20-1, QUESTION 5: J.K. has diabetes, which increases

the risk for diabetic nephropathy. Would the dosing be

changed if J.K. had renal dysfunction?

J.K.’s renal function is normal. If he had significant renal dysfunction, both the loading and the maintenance doses of digoxin

would need to be altered. Whereas a loading dose is used to

achieve a therapeutic level and, therefore, needs to overcome the

volume of distribution rather than clearance, digoxin volume of

distribution is reduced in patients with renal dysfunction. The

digoxin maintenance dose is highly dependent on renal clearance, because digoxin is eliminated 50% to 75% unchanged in

the urine. (See Chapter 19, Heart Failure, for further discussion of

digoxin dosing in patients with normal and impaired renal function.) Although the usual digoxin target range is generally 0.5 to

1.0 ng/mL in the management of patients with heart failure,17

higher target levels may be necessary when using digoxin as a

rate control agent for J.K.

CASE 20-1, QUESTION 6: What other drugs can be used for

ventricular rate control, and what are their relative advantages and disadvantages compared with digoxin?

β-Adrenergic Blocking Agents

β-Adrenergic blocking agents are another class of negative

dromotropic agents used in AF. Propranolol, metoprolol, and

esmolol are available for IV administration. Each agent rapidly

controls the ventricular rate both at rest and during exercise.

β-Blockers are the first choice in high catecholamine states such

as thyrotoxicosis and postcardiac surgery. However, given their

negative inotropic effects, β-blockers should not be used to

acutely control the ventricular response in patients with systolic HF. Even though β-blockers are used to treat systolic HF

(e.g., bisoprolol, carvedilol, and metoprolol), they need to be

started at low doses and titrated prudently for several weeks to

therapeutic doses.18–20 (See Chapter 19, Heart Failure.) When

trying to achieve rapid rate control, more aggressive dosing may

be needed. β-Blockers should also be avoided in patients with

asthma because of their β2-blocking properties, and blood glucose levels should be monitored more closely in patients with diabetes mellitus because the signs and symptoms of hypoglycemia

(except sweating) can be masked.

Calcium-Channel Blockers

Nondihydropyridine calcium-channel blockers are also effective

in slowing ventricular rate at rest and during exercise. Both verapamil and diltiazem can be administered IV for a rapid (4 to

5 minutes) reduction in heart rate.21,22 They work through their

effect on slow calcium channels within the AV node. Although

the duration of action produced by bolus dosing is short, both

agents can be administered either as a continuous drip or orally.

Given the ability of calcium-channel blockers to cause arteriolar dilation, a transient decrease in blood pressure can be

expected. IV calcium pretreatment can be used to attenuate

the blood pressure decrease among patients with hypotension,

near hypotensive blood pressure, or left ventricular dysfunction.

Calcium pretreatment does not appear to diminish the negative dromotropic effects of nondihydropyridine calcium-channel

blockers.23–26 Verapamil and diltiazem should be used with caution in HF, and verapamil can increase the concentrations of other

cardiovascular drugs such as digoxin, dofetilide, simvastatin, and

lovastatin.27 Verapamil and diltiazem are good alternatives to

β-blockers in asthmatics.11

For chronic therapy, oral negative dromotropic agents (usually a β-blocker or nondihydropyridine calcium-channel blocker)

498 Section 2 Cardiac and Vascular Disorders

are recommended. If higher-dose monotherapy with one of these

drugs is needed to control symptoms but is associated with intolerable side effects, adding lower-dose digoxin to a β-blocker or

calcium-channel blocker is recommended.10–12,28–30

J.K. has signs of HF, so digoxin is a reasonable choice, although

short-term IV diltiazem is often used in this type of patient as well.

IV verapamil andβ-blockers may worsen the signs and symptoms

of HF, and the β-blockers may mask signs of hypoglycemia in J.K.

The goal of rate control should be a resting heart rate between

60 and 80 beats/minute and an exercising heart rate between

90 and 115 beats/minute.11 A recent study has explored the use

of a more lenient target resting heart rate (<110 beats/minute)

and reported similar patient outcomes as compared with a more

strict target heart rate (resting heart rate <80 beats/minute).31

This study may suggest that it could be acceptable for a patient’s

heart rate to be greater than 80 beats/minute, if there is difficulty

in achieving this level of heart rate control.32

Rate Control Versus Rhythm Control

CASE 20-1, QUESTION 7: After loading of digoxin, J.K.’s

heart rate is still 120 beats/minute and he continues to experience palpitations. His blood pressure is 100/60 mm Hg,

and his symptoms of heart failure are improving, but he still

complains of mild shortness of breath. The decision is made

to cardiovert J.K. back to normal sinus rhythm. Is J.K. a good

candidate for a rhythm control strategy and if so, why? What

is the likelihood that J.K. will be successfully converted to

normal sinus rhythm?

The use of a rhythm control strategy has become much less

common during the last several years. This change is because

of the completion of at least six studies comparing the effect of

a rate or rhythm control strategy on patient outcomes.33–38 To

qualify for these trials, patients had to be asymptomatic except for

palpitations on a rate control strategy. The AFFIRM study (Atrial

Fibrillation Follow-up Investigation of Rhythm Management), a

randomized, multicenter study, was one of the largest to compare rate control with rhythm control for management of AF.

AFFIRM enrolled 4,060 patients with AF and a risk of stroke.33

The primary end point was all-cause mortality. Antiarrhythmic

drugs were chosen at the discretion of the treating physician,

but greater than 60% of the patients received amiodarone or

sotalol as the initial antiarrhythmic agent. Rate control agents

included digoxin, β-blockers, and nondihydropyridine calciumchannel blockers. After a mean follow-up of 3.5 years, there was

a trend toward lower overall mortality (p = 0.08) with significant reductions in hospitalizations (10% lower, p = 0.001) and

TdP (300% lower, p = 0.007) in the rate control group. Therefore, using rhythm control in patients with AF rather than rate

control does not improve outcomes and increases the risk of

hospitalizations and TdP.

The default long-term treatment strategy for most patients

should be a rate control strategy, in which heart rate is controlled

and anticoagulation is provided, if indicated. However, rhythm

control is necessary when patients experience symptoms despite

adequate rate control, when heart rate cannot be adequately

controlled with currently available treatments, or if patients cannot tolerate the adverse effects of rate-controlling medications.

J.K.’s heart rate is not adequately controlled with digoxin. An

oral β-blocker or nondihydropyridine calcium-channel blocker

could also be used to control his heart rate; however, his blood

pressure is likely too low to allow the use of these agents. Therefore, pursuit of a rhythm control strategy is warranted. It should

be noted that a rhythm control strategy is still often chosen by

clinicians (approximately 50% of the time in one study), despite

the existence of national guidelines supporting the use of a rate

control strategy for most.39

Likelihood of successful conversion to and maintenance of

normal sinus rhythm is determined by the duration of the

arrhythmia, underlying disease processes, and left atrial size.40

Duration of AF for more than 1 year significantly reduces the

chances of maintaining a normal sinus rhythm.41 When the atrial

size exceeds 5 cm, there is less than a 10% chance of maintaining

normal sinus rhythm at 6 months. J.K.’s chance of being maintained in normal sinus rhythm is good because the duration of his

AF is short and the echocardiogram revealed only slight enlargement of his left atrium.

CONVERSION TO NORMAL SINUS RHYTHM

CASE 20-1, QUESTION 8: Warfarin treatment is begun and

J.K.’s prothrombin time is to be maintained at an international normalized ratio (INR) of 2 to 3. J.K. is scheduled

for a transesophageal echocardiogram (TEE) to determine

whether cardioversion can be performed during this admission. How does a TEE help to determine whether cardioversion can be performed, and why is warfarin therapy being

used?

When the onset of AF is less than 48 hours, the likelihood of

atrial clot formation is low. However, when the duration of AF is

greater than 48 hours, or if duration is unknown, then warfarin

should be given for 3 weeks before cardioversion at doses providing an INR between 2 and 3.11,12,42 Studies in patients with

AF showed that those who were anticoagulated before cardioversion had a lower incidence (0.8%) of emboli than those who were

not anticoagulated (5.3%).43 Alternatively, a TEE can be used to

determine whether atrial clots have formed.11,12,44 Atrial clots

form most often in small side pouches on the atria called atrial

appendages.45 Because the frequency of right atrial appendage

thrombosis is half that of left atrial appendage thrombosis in AF

patients, the risk of stroke is enhanced much more than the risk

of pulmonary embolism.45

If no clot is observed on TEE, then there is low risk for stroke

with cardioversion of AF.44 However, if an atrial clot is evident

on TEE, J.K. would need to be adequately anticoagulated for

3 weeks before cardioversion to prevent embolization of the clot

and stroke. If cardioversion is successful, patients should remain

on warfarin for at least 4 weeks after cardioversion because normal atrial contraction may not return for up to 3 weeks, and

patients may be at risk of late embolization.46 The decision to provide long-term oral anticoagulation is dependent on the patient’s

underlying stroke and bleeding risk. This will be discussed further

below.

Chemical Conversion—Ibutilide, Propafenone, Flecainide

CASE 20-1, QUESTION 9: J.K. was found to be free of

atrial clots. Chemical cardioversion with ibutilide is planned

for tomorrow. If J.K. fails to convert with ibutilide, he will

be electrically cardioverted later in the day. How does ibutilide therapy compare with the other therapeutic choices

for chemical cardioversion?

The most effective method of cardioversion is by direct current cardioversion (see Electrical Cardioversion section below).

However, the use of direct current cardioversion may be undesirable if the patient is a poor candidate for conscious sedation

or if the patient is not willing to undergo direct current cardioversion. In these situations, pharmacologic cardioversion may

be attempted. Many class I and III antiarrhythmic agents have

499Cardiac Arrhythmias Chapter 20

been evaluated for efficacy in placebo-controlled trials for conversion of AF or atrial flutter to normal sinus rhythm. The available agents with the most positive data for chemical conversion

include IV ibutilide, oral propafenone, oral flecainide, oral and

IV amiodarone, and oral dofetilide. This section will focus on

ibutilide, propafenone, and flecainide.

IV ibutilide, a class III antiarrhythmic agent with potassiumchannel blocking and slow sodium-channel enhancing effects,

was the first agent that the US Food and Drug Administration

(FDA) approved for the termination of recent-onset AF and atrial

flutter.47 Ibutilide is administered as a 1-mg infusion for 10 minutes, followed by another 1-mg infusion for 10 minutes if conversion has not occurred by 10 minutes after the infusion. The

conversion rate for recent-onset AF is 35% to 50%; the conversion rate is 65% to 80% in atrial flutter. In a recent retrospective

study of hospital inpatients with either AF or atrial flutter, 50% of

patients converted initially (41% conversion AF, 65% atrial flutter), but only 33% of patients left the hospital in sinus rhythm.

If the duration of AF or atrial flutter before cardioversion was

fewer than 15 days, significantly more patients remained in sinus

rhythm at discharge compared with patients who had AF or atrial

flutter for more than 15 days before cardioversion.48 As is the case

with most class III antiarrhythmic agents, the main adverse effect

is TdP, which occurred in approximately 4% of patients. Aside

from the risk of TdP, therapy is well tolerated.49–52

There is preliminary evidence that magnesium may enhance

the efficacy of ibutilide. In a multicenter cohort study called the

Treatment with Ibutilide and Magnesium Evaluation (TIME),

adjunctive magnesium (2.2 ± 1 g) plus ibutilide was compared

with ibutilide alone. In this study of 323 patients, the successful

chemical conversion rate went from 60.3% with ibutilide alone

to 71.6% (p = 0.04) in the adjunctive magnesium group. The risk

of TdP was also reduced 33% with adjunctive magnesium therapy, but the study was not powered to determine this end point

(p = 0.388). Whether adjunctive magnesium would be of benefit

with other class Ia or III antiarrhythmic agents is not known.53

Propafenone is a class IC agent with β-blocking properties.

When given in doses of 450 to 750 mg orally (600 mg was

the most common dose), the initial conversion rate in patients

with AF ranged from 41% to 57%. In contrast to ibutilide, no

patients experienced ventricular arrhythmias (including TdP),

but a risk of hypotension, bradycardia, and QRS prolongation

was noted.54–56

Oral flecainide is another class IC antiarrhythmic agent. In

one study, 300 mg oral flecainide converted 68% of patients to

sinus rhythm within 3 hours and 91% of patients by 8 hours.

The efficacy in atrial flutter has yet to be established. Sinus node

dysfunction, prolongation of intraventricular conduction, dizziness, weakness, and gastrointestinal (GI) disturbances have been

reported.57,58

Electrical Conversion

CASE 20-1, QUESTION 10: J.K. received two doses of IV

ibutilide. After the second dose, he converted to normal

sinus rhythm for only 5 minutes, then returned to AF. J.K.

is scheduled for electrical cardioversion in 6 hours. What is

electrical cardioversion? How efficacious and safe is it?

Direct current (DC) cardioversion quickly and effectively

restores 85% to 90% of patients with AF to normal sinus

rhythm.46 If DC conversion alone is ineffective, it can be repeated

in combination with antiarrhythmic drugs.11,12,59 In one study,

the success rate of electrical cardioversion was significantly higher

in AF patients (duration of AF averaged 119 days) with ibutilide

pretreatment (1 mg) compared with those without pretreatment

(100% vs. 72%, p = 0.001).59 This is because ibutilide pretreatment lowered the energy requirement for atrial defibrillation

by 27% (p = 0.001). TdP occurred in 3% of patients receiving

ibutilide, all of whom had an ejection fraction less than 20%.

Flecainide, propafenone, amiodarone, and sotalol could also be

considered for enhancing DC cardioversion.11,12

DC cardioversion is clearly indicated for patients who are

hemodynamically unstable. A reason one may wish to avoid DC

conversion is because anesthesia (short-acting benzodiazepine,

barbiturate, or propofol) is required for the procedure. Chemical

conversion with ibutilide, with all failures subsequently receiving electrical cardioversion, may be more cost-effective (saving

$138/patient) than first-line DC conversion.48

Maintenance of Sinus Rhythm

CASE 20-1, QUESTION 11: J.K. is discharged after successful DC conversion. However, when he returns for a followup visit 2 weeks later, he is found to be in AF again. He

again reports frequent palpitations. His physician would like

to initiate an antiarrhythmic drug to maintain normal sinus

rhythm. Which agent(s) would be the best option for this

patient?

To choose the best antiarrhythmic agent for J.K., the efficacy

and adverse effect profiles for each agent should be reviewed.

Class Ia, Ic, and III antiarrhythmic drugs (see Table 20-2 for electrophysiologic and ECG effects and Table 20-3 for pharmacokinetics and side effects) prevent the recurrence of AF. Flecainide,

sotalol, dofetilide, and dronedarone are approved by the FDA for

maintenance of sinus rhythm. Although not FDA-approved for

AF, propafenone and amiodarone are commonly used as well.

For a multimedia slide set presenting an

overview of the guidelines on AF arrhythmia

management, go to http://thepoint.lww.

com/AT10e.

Flecainide and Propafenone

The class Ic agents flecainide and propafenone are effective in

suppressing AF.60–64 The efficacy rate may be as high as 61%

to 92% for flecainide.65,66 Flecainide and possibly other class Ic

agents may cause arrhythmias, especially in patients with structural heart disease, and they should be avoided in such patients.

Propafenone, a class Ic agent with β-blocking properties, is as

efficacious as flecainide and is relatively safe in patients without

ischemic heart disease and an ejection fraction greater than 35%;

it may be preferred in patients who require additional AV blockade to control ventricular response. In a direct comparison with

flecainide (200–300 mg/day), propafenone (450–900 mg/day) was

equally safe and effective. Over the course of 12 months, a similar percentage of patients (approximately 12% in each group) did

not have adequate control of their arrhythmia. Adverse events

were comparable and occurred in 10.3% of patients on flecainide

and 7.7% of patients on propafenone. Of all the adverse events

noted, only one patient who was receiving propafenone developed a ventricular arrhythmia. Another 1-year comparative study

of propafenone versus flecainide demonstrated similar efficacy,

but this study showed a trend toward better tolerability in the

flecainide group.67,68

Class III Agents

Class III agents (sotalol, dofetilide, amiodarone, dronedarone)

prolong refractoriness in the atria, ventricles, AV node, and

500 Section 2 Cardiac and Vascular Disorders

accessory pathway tissue and can prevent recurrence of AF. All of

these agents act by blocking potassium channels; however, sotalol

also has additional β-blocking properties. 69,70 Both amiodarone

and dronedarone block sodium channels and calcium channels,

and have antiadrenergic effects in addition to potassium-channel

blocking properties.71

Sotalol, Amiodarone, Dofetilide, and Dronedarone

The efficacy of sotalol in delaying the recurrence of AF was evaluated in a double-blind, placebo-controlled, multicenter, randomized trial that enrolled 253 patients with AF or atrial flutter.72

The median times to recurrence were 27, 106, 229, and 175 days

with placebo, sotalol 160 mg/day (divided in two doses), sotalol

240 mg/day (divided in two doses), and sotalol 320 mg/day

(divided in two doses), respectively. Sotalol is contraindicated

in patients with a creatinine clearance (CrCl) of less than

40 mL/minute because of the fact that the drug is largely renally

cleared and can cause TdP in high concentrations. In a comparative study versus propafenone, sotalol was similarly effective in

producing at least a 75% reduction in AF recurrence (79% of

patients on propafenone vs. 76% on sotalol) and was similarly

tolerated (4.8% of patients on propafenone had intolerable side

effects vs. 10.5% on sotalol). Bradycardia, dizziness, and GI disturbances were the most common intolerable side effects.73 Sotalol

should not be used in patients with systolic heart failure owing

to the negative inotropic effects of the drug. It may be useful as

a first-line agent in patients with AF and concomitant underlying coronary artery disease or in patients with no cardiovascular

disease.11,12

Amiodarone is more effective at maintaining sinus rhythm

than sotalol74 and propafenone.75 The Canadian Trial of Atrial

Fibrillation (CTAF) compared the ability of low-dose amiodarone

(200 mg/day) versus propafenone (450 to 600 mg/day) and sotalol

(160 to 320 mg/day) to prevent recurrence of AF in 403 patients

with a recent episode of AF (within the preceding 6 months).74

After a mean follow-up of 16 months, 35% of the amiodaronetreated patients had a recurrence of AF versus 63% in the combined group with sotalol and propafenone (p = 0.001). In view

of its unusual pharmacokinetics and potential serious adverse

effects (see Table 20-3 and Case 20-7, Question 2), amiodarone is

only recommended as a first-line choice for patients with HF, for

which it has specific safety data, or for patients with significant

left ventricular hypertrophy.11 Amiodarone could also be used

when other agents such as sotalol, propafenone, or dofetilide

have failed.11,12

Dofetilide has been shown to be an effective pharmacologic agent for conversion to, and maintenance of, normal sinus

rhythm. Two clinical trials, EMERALD (European and Australian Multicenter Evaluative Research on Atrial Fibrillation

Dofetilide)76 and SAFIRE-D (Symptomatic Atrial Fibrillation

Investigation and Randomized Evaluation of Dofetilide)77 have

shown conversion rates of 30% in patients with AF or atrial flutter receiving higher doses of dofetilide. Patients failing chemical

conversion received electrical conversion. If this conversion succeeded, they were continued on dofetilide for 1 year. At 1 year,

60% of those converted were still in sinus rhythm with the 500-

mcg dose. Also, dofetilide appears to exert neutral effects on

mortality rates in HF and post-MI patients.78,79

Dofetilide dose is based on the patient’s CrCl; the doses

are 500, 250, and 125 mcg twice daily with CrCl greater than

60 mL/minute, 40 to 60 mL/minute, and 20 to 39 mL/minute,

respectively. Drug interactions pose a significant problem

with dofetilide. Cimetidine, ketoconazole, prochlorperazine,

megestrol, and trimethoprim (including in combination with

sulfamethoxazole) inhibit active tubular secretion of dofetilide

and can elevate dofetilide plasma concentrations.70,80 Because the

incidence of TdP is directly related to dofetilide plasma concentrations, concomitant use with these agents is contraindicated.80

Concomitant administration of dofetilide with verapamil or

hydrochlorothiazide increases the incidence of TdP by an unclear

mechanism and is contraindicated as well.70 Concurrent use of

agents that can prolong the QTc interval is not recommended

with dofetilide.80 Dofetilide also undergoes metabolism by the

cytochrome P-450 CYP3A4 isoenzyme to a minor extent. Therefore, inhibitors of this isoenzyme (e.g., azole antifungal agents,

protease inhibitors, serotonin reuptake inhibitors, amiodarone,

diltiazem, nefazodone, zafirlukast) should be coadministered

with caution with dofetilide. Other agents that can potentially

increase dofetilide levels (through inhibition of tubular secretion)

include metformin, triamterene, and amiloride. Hence, these

agents should be cautiously coadministered with dofetilide.80

Dofetilide is considered a first-line agent for patients with

heart failure or coronary artery disease, as the impact on mortality in this patient population is neutral.78,79 Dofetilide can be

considered as a second-line agent for patients without cardiovascular disease or left ventricular hypertrophy.11,12

Dronedarone is the newest antiarrhythmic drug approved in

the United States. Dronedarone is structurally and pharmacologically similar to amiodarone; however, it lacks iodine, which gives

dronedarone a much smaller volume of distribution than amiodarone. The lack of iodine also may make dronedarone less likely

to cause thyroid-related or other adverse effects.71 Dronedarone

has been shown to have modest efficacy in maintaining sinus

rhythm when compared with placebo. Rate of recurrence of

AF at 1 year is approximately 40%, and the number of days to

recurrence is nearly doubled with dronedarone.81 The major

clinical trial evaluating dronedarone was the ATHENA study.

The primary end point of ATHENA was a composite of death

or cardiovascular hospitalization, and patients received either

dronedarone 400 mg twice daily or placebo for at least 1 year.82

The primary composite end point was significantly reduced from

39.4% with placebo to 31.9% with dronedarone. This reduction

in the composite was completely attributable to the reduction

in cardiovascular hospitalizations, most of which were related

to AF recurrence. Gastrointestinal events were the most common type of adverse effect with dronedarone in this study. It

should be noted that patients with recent decompensated HF or

New York Heart Association (NYHA) class IV heart failure were

excluded from this trial. The exclusion of patients with severe

or unstable heart failure was related to negative findings that

led to the early discontinuation of the ANDROMEDA study.83

ANDROMEDA was designed as a safety study, to evaluate the

impact of dronedarone on mortality in patients with HF. Patients

admitted with NYHA class III or IV systolic HF were included in

this study. The study was stopped early because of an approximate

doubling in the risk of death with dronedarone as compared with

placebo. Therefore, dronedarone is contraindicated in a patient

with severe or recently decompensated HF. Dronedarone has

also been compared directly with amiodarone.84 In this study,

dronedarone was less effective than amiodarone, but was less

likely than amiodarone to cause thyroid, neurological, skin,

or ocular adverse effects. Gastrointestinal adverse effects were

more common with dronedarone.84 Dronedarone is appropriate as a first- or second-line agent for patients with AF and

concomitant coronary artery disease, and possibly left ventricular hypertrophy or in patients with no cardiovascular disease.

Dronedarone should not be used in a patient with severe HF

symptoms or a recent hospitalization for HF, but may be used

with mild, well-controlled HF.12,32,83 It should also be noted

that, at the time of this writing, the FDA has issued a warning

regarding rare, but potentially serious