Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

8. The Arrhythmias

Cynthia A. Sanoski and Jerry L. Bauman


 Images The use of antiarrhythmic drugs (AADs) in the United States has declined because of major trials that show increased mortality with their use in several clinical situations, the realization of proarrhythmia as a significant side effect, and the advancing technology of nonpharmacologic therapies such as ablation and the implantable cardioverter-defibrillator (ICD).

 Images AADs frequently cause side effects and are complex in their pharmacokinetic characteristics. Close monitoring is required of all of these drugs to assess for adverse effects as well as potential drug interactions.

 Images The most commonly prescribed AAD is now amiodarone. This drug is effective in terminating and preventing a wide variety of symptomatic supraventricular and ventricular arrhythmias. However, because this AAD is plagued by frequent side effects, it requires close monitoring. The most concerning toxicity is pulmonary fibrosis; side effect profiles of the IV (acute, short-term) and oral (chronic, long-term) forms of amiodarone differ substantially.

 Images In patients with atrial fibrillation (AF), therapy is traditionally aimed at controlling ventricular rate (digoxin, nondihydropyridine calcium channel blockers, β-blockers), preventing thromboembolic complications (warfarin, aspirin), and restoring and maintaining sinus rhythm (AADs, direct current cardioversion). Studies show there is no need to aggressively pursue strategies to maintain sinus rhythm (i.e., long-term AAD therapy); rate control alone (leaving the patient in AF) is often sufficient in patients who can tolerate it. Nonetheless, chronic AAD therapy may still be needed in patients who continue to have symptoms despite adequate ventricular rate control.

 Images Paroxysmal supraventricular tachycardia is usually a result of reentry in or proximal to the atrioventricular (AV) node or AV reentry incorporating an extranodal pathway; common tachycardias can be terminated acutely with AV nodal blocking drugs such as adenosine, and recurrences can be prevented by ablation with radio-frequency current.

 Images Patients with Wolff-Parkinson-White (WPW) syndrome may have several different tachycardias that are acutely treated by different strategies: orthodromic reentry (adenosine), antidromic reentry (adenosine or procainamide), and AF (procainamide or amiodarone). AV nodal blocking drugs are contraindicated in patients with WPW syndrome and AF.

 Images Because of the results of the Cardiac Arrhythmia Suppression Trial and other trials, AADs (with the exception of β-blockers) should not be routinely used in patients with prior myocardial infarction (MI) or left ventricular (LV) dysfunction and minor ventricular rhythm disturbances (e.g., premature ventricular complexes).

 Images Patients with hemodynamically significant ventricular tachycardia (VT) or ventricular fibrillation not associated with an acute MI who are successfully resuscitated (electrical cardioversion, vasopressors, amiodarone) are at high risk for sudden cardiac death (SCD) and should receive an ICD (“secondary prevention”).

 Images Implantation of an ICD should be considered for the primary prevention of SCD in certain high-risk patient populations. High-risk patients include those with a history of MI and LV dysfunction (regardless of whether they have inducible sustained ventricular arrhythmias), as well as those with New York Heart Association class II or III heart failure as a result of either ischemic or nonischemic causes.

 Images Life-threatening ventricular proarrhythmia generally takes two forms: sinusoidal or incessant monomorphic VT (class Ic AADs) and torsade de pointes (class Ia or III AADs and many other noncardiac drugs).

The heart has two basic properties, namely, an electrical property and a mechanical property. The synchronous interaction between these two properties is complex, precise, and relatively enduring. The study of the electrical properties of the heart has grown at a steady rate, interrupted by periodic salvos of scientific breakthroughs. Einthoven’s pioneering work allowed graphic electrical tracings of cardiac rhythm and probably represents the first of these breakthroughs. This discovery of the surface electrocardiogram (ECG) has remained the cornerstone of diagnostic tools for cardiac rhythm disturbances. Since then, intracardiac recordings and programmed cardiac stimulation have advanced our understanding of arrhythmias, and microelectrode, voltage clamping, and patch clamping techniques have allowed considerable insight into the electrophysiologic actions and mechanisms of antiarrhythmic drugs (AADs). Certainly, the new era of molecular biology and mapping of the human genome promises even greater insights into mechanisms (and potential therapies) of arrhythmias. Noteworthy in this regard is the discovery of genetic abnormalities in the ion channels that control electrical repolarization (heritable long QT syndrome) or depolarization (Brugada syndrome).

The clinical use of drug therapy started with the use of digitalis and then quinidine. A surge of new agents followed somewhat later in the 1980s. A theme of drug discovery during this decade was initially to find orally absorbed lidocaine congeners (such as mexiletine and tocainide); later, the emphasis was on drugs with extremely potent effects on conduction (i.e., flecainide-like agents). The most recent focus of investigational AADs is the potassium channel blockers, with dronedarone being the most recently approved AAD in the United States in nearly a decade. Previously, there was some expectation that advances in AAD discovery would lead to a highly effective and nontoxic agent that would be effective for a majority of patients (i.e., the so-called magic bullet). Instead, significant problems with drug toxicity and proarrhythmia have resulted in a decline in the overall volume of AAD usage in the United States since 1989.

Images The other phenomenon that has significantly contributed to the decline in AAD utilization is the development of extremely effective nonpharmacologic therapies. Technical advances have made it possible to permanently interrupt reentry circuits with radiofrequency ablation, which renders long-term AAD use unnecessary in certain arrhythmias. Furthermore, the impressive survival data associated with the use of implantable cardioverter-defibrillators (ICDs) for the primary and secondary prevention of sudden cardiac death (SCD) have led most clinicians to choose “device” therapy as the first-line treatment for patients who are at high risk for life-threatening ventricular arrhythmias. Both of these nonpharmacologic therapies have become increasingly popular for the management of arrhythmias so that the potential proarrhythmic effects and organ toxicities associated with AADs can be avoided.

This chapter reviews the principles involved in both normal and abnormal cardiac conduction and addresses the pathophysiology and treatment of the more commonly encountered arrhythmias. Certainly, many volumes of complete text could be (and have been) devoted to basic and clinical electrophysiology. Consequently, this chapter briefly addresses those principles necessary for clinicians.


Normal Conduction

Electrical activity is initiated by the sinoatrial (SA) node and moves through cardiac tissue by a tree-like conduction network. The SA node initiates cardiac rhythm under normal circumstances because this tissue possesses the highest degree of automaticity or rate of spontaneous impulse generation. The degree of automaticity of the SA node is largely influenced by the autonomic nervous system in that both cholinergic and sympathetic innervations control the sinus rate. Most tissues within the conduction system also possess varying degrees of inherent automatic properties. However, the rates of spontaneous impulse generation of these tissues are less than that of the SA node. Thus, these latent automatic pacemakers are continuously overdriven by impulses arising from the SA node (primary pacemaker) and do not become clinically apparent.

From the SA node, electrical activity moves in a wave front through an atrial specialized conducting system and eventually gains entrance to the ventricle via the atrioventricular (AV) node and a large bundle of conducting tissue referred to as the bundle of His. Aside from this AV node–bundle of His pathway, a fibrous AV ring that will not permit electrical stimulation separates the atria and ventricles. The conducting tissues bridging the atria and ventricles are referred to as the junctional areas. Again, this area of tissue (junction) is largely influenced by autonomic input and possesses a relatively high degree of inherent automaticity (about 40 beats/min, less than that of the SA node). From the bundle of His, the cardiac conduction system bifurcates into several (usually three) bundle branches: one right bundle and two left bundles. These bundle branches further arborize into a conduction network referred to as the Purkinje system. The conduction system as a whole innervates the mechanical myocardium and serves to initiate excitation–contraction coupling and the contractile process. After a cell or group of cells within the heart is electrically stimulated, a brief period of time follows in which those cells cannot again be excited. This time period is referred to as the refractory period. As the electrical wave front moves down the conduction system, the impulse eventually encounters tissue refractory to stimulation (recently excited) and subsequently dies out. The SA node subsequently recovers, fires spontaneously, and begins the process again.

Prior to cellular excitation, an electrical gradient exists between the inside and the outside of the cell membrane. At this time, the cell is polarized. In atrial and ventricular conducting tissues, the intracellular space is approximately 80 to 90 mV negative with respect to the extracellular environment. The electrical gradient just prior to excitation is referred to as the resting membrane potential (RMP) and is the result of differences in ion concentrations between the inside and the outside of the cell. At RMP, the cell is polarized primarily by the action of active membrane ion pumps, the most notable of these being the sodium–potassium pump. For example, this specific pump (in addition to other systems) attempts to maintain the intracellular sodium concentration at 5 to 15 mEq/L and the extracellular sodium concentration at 135 to 142 mEq/L, and the intracellular potassium concentration at 135 to 140 mEq/L and the extracellular potassium concentration at 3 to 5 mEq/L. The RMP can be calculated by using the Nernst equation:


Electrical stimulation (or depolarization) of the cell will result in changes in membrane potential over time or a characteristic action potential curve (Fig. 8-1). The action potential curve results from the transmembrane movement of specific ions and is divided into different phases. Phase 0 or initial, rapid depolarization of atrial and ventricular tissues is caused by an abrupt increase in the permeability of the membrane to sodium influx. This rapid depolarization more than equilibrates (overshoots) the electrical potential, resulting in a brief initial repolarization or phase 1. Phase 1 (initial repolarization) is caused by a transient and active potassium efflux (i.e., the IKto current). Calcium begins to move into the intracellular space at about –60 mV (during phase 0), causing a slower depolarization. Calcium influx continues throughout phase 2 of the action potential (plateau phase) and is balanced to some degree by potassium efflux. Calcium entrance (only through L channels in myocardial tissue) distinguishes cardiac conducting cells from nerve tissue and provides the critical ionic link to excitation–contraction coupling and the mechanical properties of the heart as a pump. The membrane remains permeable to potassium efflux during phase 3, resulting in cellular repolarization. Phase 4 of the action potential is the gradual depolarization of the cell and is related to a constant sodium leak into the intracellular space balanced by a decreasing (over time) efflux of potassium. The slope of phase 4 depolarization determines, in large part, the automatic properties of the cell. As the cell is slowly depolarized during phase 4, an abrupt increase in sodium permeability occurs, allowing the rapid cellular depolarization of phase 0. The juncture of phase 4 and phase 0 where rapid sodium influx is initiated is referred to as the threshold potential of the cell. The level of threshold potential also regulates the degree of cellular automaticity.


FIGURE 8-1 Purkinje fiber action potential showing specific ion flux responsible for the change in membrane potential. Ions outside of the line (e.g., sodium) move from the extracellular space to the intracellular space and ions on the inside of the line (e.g., potassium) move from the inside of the cell to the outside.

Not all cells in the cardiac conduction system rely on sodium influx for initial depolarization. Some tissues depolarize in response to a slower inward ionic current caused by calcium influx. These “calcium-dependent” tissues are found primarily in the SA and AV nodes (both L and T channels) and possess distinct conduction properties in comparison to “sodium-dependent” fibers. Calcium-dependent cells generally have a less negative RMP (–40 to –60 mV) and a slower conduction velocity. Furthermore, in calcium-dependent tissues, recovery of excitability outlasts full repolarization, whereas in sodium-dependent tissues, recovery is prompt after repolarization. These two types of electrical fibers also differ dramatically in how drugs modify their conduction properties.

Ion conductance across the lipid bilayer of the cell membrane occurs via the formation of membrane pores or “channels” (Fig. 8-2). Selective ion channels probably form in response to specific electrical potential differences between the inside and the outside of the cell (voltage dependence). The membrane itself is composed of both organized and disorganized lipids and phospholipids in a dynamic sol-gel matrix. During ion flux and electrical excitation, changes in this sol-gel equilibrium occur and permit the formation of activated ion channels. Besides channel formation and membrane composition, intrachannel proteins or phospholipids, referred to as gates, also regulate the transmembrane movement of ions. These gates are thought to be positioned strategically within the channel to modulate ion flow (Fig. 8-2). Each ion channel conceptually has two types of gates: an activation gate and an inactivation gate. The activation gate opens during depolarization to allow the ion current to enter or exit from the cell, and the inactivation gate later closes to stop ion movement. When the cell is in a rested state, the activation gates are closed and the inactivation gates are open. The activation gates then open to allow ion movement through the channel, and the inactivation gates later close to stop ion conductance. Thus, the cell cycles between three states: resting, activated or open, and inactivated or closed. Activation of SA and AV nodal tissue is dependent on a slow depolarizing current through calcium channels and gates, whereas the activation of atrial and ventricular tissues is dependent on a rapid depolarizing current through sodium channels and gates.


FIGURE 8-2 Lipid bilayer, sodium channel, and possible sites of action of the class I AADs (A). Class I AADs may theoretically inhibit sodium influx at an extracellular, intramembrane, or intracellular receptor site. However, all approved agents appear to block sodium conductance at a single receptor site by gaining entrance to the interior of the channel from an intracellular route. Active ionized drugs block the channel predominantly during the activated or inactivated state and bind and unbind with specific time constants (described as fast on–off, slow on–off, and intermediate). (AADs, antiarrhythmic drugs.)

Abnormal Conduction

The mechanisms of tachyarrhythmias have been classically divided into two general categories: those resulting from an abnormality in impulse generation or “automatic” tachycardias and those resulting from an abnormality in impulse conduction or “reentrant” tachycardias.

Automatic tachycardias depend on spontaneous impulse generation in latent pacemakers and may be a result of several different mechanisms. Drugs, such as digoxin or catecholamines, and conditions, such as hypoxia, electrolyte abnormalities (e.g., hypokalemia), and fiber stretch (cardiac dilation), may lead to an increased slope of phase 4 depolarization in cardiac tissues other than the SA node. These factors that experimentally lead to abnormal automaticity are also known to be arrhythmogenic in clinical situations. The increased slope of phase 4 causes heightened automaticity of these tissues and competition with the SA node for dominance of cardiac rhythm. If the rate of spontaneous impulse generation of the abnormally automatic tissue exceeds that of the SA node, then an automatic tachycardia may result. Automatic tachycardias have the following characteristics: (a) the onset of the tachycardia is unrelated to an initiating event such as a premature beat; (b) the initiating beat is usually identical to subsequent beats of the tachycardia; (c) the tachycardia cannot be initiated by programmed cardiac stimulation; and (d) the onset of the tachycardia is usually preceded by a gradual acceleration in rate and termination is usually preceded by a gradual deceleration in rate. Clinical tachycardias resulting from the classic forms of enhanced automaticity already described are not as common as once thought. Examples are sinus tachycardia and junctional tachycardia.

Triggered automaticity is also a possible mechanism for abnormal impulse generation. Briefly, triggered automaticity refers to transient membrane depolarizations that occur during repolarization (early afterdepolarizations [EADs]) or after repolarization (late afterdepolarizations [LADs]) but prior to phase 4 of the action potential. Afterdepolarizations may be related to abnormal calcium and sodium influx during or just after full cellular repolarization. Experimentally, EADs may be precipitated by hypokalemia, class Ia AADs, or slow stimulation rates—any factor that blocks the ion channels (e.g., potassium) responsible for cellular repolarization. EADs provoked by drugs that block potassium conductance and delay repolarization are the underlying cause of torsade de pointes (TdP). LADs may be precipitated by digoxin or catecholamines and suppressed by calcium channel blockers (CCBs), and have been suggested as the mechanism for multifocal atrial tachycardia, digoxin-induced tachycardias, and exercise-provoked ventricular tachycardia (VT). Triggered automatic rhythms possess some of the characteristics of automatic tachycardias and some of the characteristics of reentrant tachycardias (description follows).

Reentry is a concept that involves indefinite propagation of the impulse and continued activation of previously refractory tissue. There are three conduction requirements for the formation of a viable reentrant focus: 1) two pathways for impulse conduction, 2) an area of unidirectional block (prolonged refractoriness) in one of these pathways, and 3) slow conduction in the other pathway (Fig. 8-3). Usually, a critically timed premature beat initiates reentry. This premature impulse enters both conduction pathways but encounters refractory tissue in one of the pathways at the area of unidirectional block. The impulse dies out because the tissue is still refractory from the previous (sinus) impulse. Although it fails to propagate in one pathway, the impulse may still proceed in a forward direction (antegrade) through the other pathway because of this pathway’s relatively shorter refractory period. The impulse may then proceed through a loop of tissue and “reenter” the area of unidirectional block in a backward direction (retrograde). Because the antegrade pathway has slow conduction characteristics, the area of unidirectional block has time to recover its excitability. The impulse can proceed in a retrograde fashion through this (previously refractory) tissue and continue around the loop of tissue in a circular fashion. Thus, the key to the formation of a reentrant focus is crucial conduction discrepancies in the electrophysiologic characteristics of the two pathways. The reentrant focus may excite surrounding tissue at a rate greater than that of the SA node, leading to formation of a clinical tachycardia. The above model is anatomically determined in that there is only one pathway for impulse conduction with a fixed circuit length. Another model of reentry, referred to as a functional reentrant loop or leading circle model, may also occur (Fig. 8-4).1 In a functional reentrant focus, the length of the circuit may vary depending on the conduction velocity and recovery characteristics of the impulse. The area in the middle of the loop is continually kept refractory by the inwardly moving impulse. The length of the circuit is not fixed but is the smallest circle possible, such that the leading edge of the wave front is continuously exciting tissue just as it recovers, that is, the head of the impulse nearly catches its tail. It differs from the anatomic model in that the leading edge of the impulse is not preceded by an excitable gap of tissue, and it does not have an obstacle in the middle or a fixed anatomic circuit. Clinically, many reentrant foci probably have both anatomic and functional characteristics. In the figure 8 model, a zone of unidirectional block is present, allowing for two impulse loops that join and reenter the area of block in a retrograde fashion to form a pretzel-shaped reentrant circuit. This model combines functional characteristics with an excitable gap. All of these theoretical models require a critical balance of refractoriness and conduction velocity within the circuit and as such have helped to explain the effects of drugs on terminating, modifying, and causing cardiac rhythm disturbances.


FIGURE 8-3 Conduction system of the heart. The magnified portion shows a bifurcation of a Purkinje fiber traditionally explained as the etiology of reentrant VT. A premature impulse travels to the fiber, damaged by heart disease or ischemia. It encounters a zone of prolonged refractoriness (area of unidirectional block; cross-hatched area) but fails to propagate because it remains refractory to stimulation from the previous impulse. However, the impulse may slowly travel (squiggly line) through the other portion of the Purkinje twig and will “reenter” the cross-hatched area if the refractory period is concluded and it is now excitable. Thus, the premature impulse never meets refractory tissue; circus movement ensues. If this site stimulates the surrounding ventricle repetitively, clinical reentrant VT results. (VT, ventricular tachycardia.)


FIGURE 8-4 A. Possible mechanism of proarrhythmia in the anatomic model of reentry. 1a. Nonviable reentrant loop due to bidirectional block (shaded area). 1b. Instance where a drug slows conduction velocity without significantly prolonging the refractory period. The impulse is now able to reenter the area of unidirectional block (shaded area) because slowed conduction through the contralateral limb allows recovery of the block. A new reentrant tachycardia may result. 2a. Nonviable reentrant loop due to a lack of a unidirectional block. 2b. Instance where a drug prolongs the refractory period without significantly slowing conduction velocity. The impulse moving antegrade meets refractory tissue (shaded area) allowing for unidirectional block. A new reentrant tachycardia may result. B. Mechanism of reentry and proarrhythmia. a. Functionally determined (leading circle) reentrant circuit. This model should be contrasted with anatomic reentry; here the circuit is not fixed (it does not necessarily move around an anatomic obstacle) and there is no excitable gap. All tissue inside is held continuously refractory. b. Instance where a drug prolongs the refractory period without significantly slowing conduction velocity. The tachycardia may terminate or slow in rate as shown as a consequence of a greater circuit length. The dashed lines represent the original reentrant circuit prior to drug treatment. c. Instance where a drug slows conduction velocity without significantly prolonging the refractory period (i.e., class Ic antiarrhythmic drugs) and accelerates the tachycardia. The tachycardia rate may increase (proarrhythmia) as shown as a consequence of a shorter circuit length. The dashed lines represent the original reentrant circuit prior to drug treatment. (Reproduced with permission from McCollam PL, Parker RB, Beckman KJ, et al. Proarrhythmia: A paradoxic response to antiarrhythmic agents. Pharmacotherapy 1989;9:146.)

What causes reentry to become clinically manifest? Reentrant foci may occur at any level of the conduction system: within the branches of the specialized atrial conduction system, within the Purkinje network, and even within portions of the SA and AV nodes. The anatomy of the Purkinje system appears to provide a suitable substrate for the formation of microreentrant loops and is often used as a model to facilitate the understanding of reentry concepts (Fig. 8-4). Of course, because reentry does not usually occur in normal, healthy conduction tissue, various forms of heart disease or conduction abnormalities must usually be present before reentry becomes manifest. In other words, the various forms of heart disease (e.g., coronary artery disease [CAD], left ventricular [LV] dysfunction) can result in changes in conduction in the pathways of a suitable reentrant substrate. An often-used example is reentry occurring as a consequence of ischemic or hypoxic damage: with inadequate cellular oxygen, cardiac tissue resorts to anaerobic glycolysis for adenosine triphosphate production. As high-energy phosphate concentration diminish, the activity of the transmembrane ion pumps declines and RMP rises. This rise in RMP causes inactivation in the voltage-dependent sodium channel, and the tissue begins to assume slow conduction characteristics. If changes in conduction parameters occur in a discordant manner due to varying degrees of ischemia or hypoxia, then a reentry circuit may become manifest. Furthermore, an ischemic, dying cell liberates intracellular potassium, which also causes a rise in RMP. In other cases, reentry may occur as a consequence of anatomic or functional variants in the normal conduction system. For instance, patients may possess two (instead of one) conduction pathways near or within the AV node, or have an anomalous extranodal AV pathway that possesses different electrophysiologic characteristics from the normal AV nodal pathway. Reentry in these cases may occur within the AV node or encompass both atrial and ventricular tissues. Reentrant tachycardias have the following characteristics: (a) the onset of the tachycardia is usually related to an initiating event (i.e., premature beat); (b) the initiating beat is usually different in morphology from subsequent beats of the tachycardia; (c) the initiation of the tachycardia is usually possible with programmed cardiac stimulation; and (d) the initiation and termination of the tachycardia is usually abrupt without an acceleration or deceleration phase. There are many examples of reentrant tachycardias, including atrial fibrillation (AF), atrial flutter, AV nodal or AV reentrant tachycardia, and recurrent VT.


In a theoretical sense, drugs may have antiarrhythmic activity by directly altering conduction in several ways. First, a drug may depress the automatic properties of abnormal pacemaker cells. A drug may do this by decreasing the slope of phase 4 depolarization and/or by elevating threshold potential. If the rate of spontaneous impulse generation of the abnormally automatic foci becomes less than that of the SA node, normal cardiac rhythm can be restored. Second, drugs may alter the conduction characteristics of the pathways of a reentrant loop.1,2 A drug may facilitate conduction (shorten refractoriness) in the area of unidirectional block, allowing antegrade conduction to proceed. On the other hand, a drug may further depress conduction (prolong refractoriness) either in the area of unidirectional block or in the pathway with slowed conduction and a relatively shorter refractory period. If refractoriness is prolonged in the area of unidirectional block, retrograde propagation of the impulse is not permitted, causing a “bidirectional” block. In the anatomic model, if refractoriness is prolonged in the pathway with slow conduction, antegrade conduction of the impulse is not permitted. In either case, drugs that reduce the discordance and cause uniformity in conduction properties of the two pathways may suppress the reentrant substrate. In the functionally determined model, if refractoriness is prolonged without significantly slowing conduction velocity, the tachycardia may terminate or slow in rate as a consequence of a greater circuit length (Fig. 8-4). There are other theoretical ways to stop reentry: a drug may eliminate the critically timed premature impulse that triggers reentry, a drug may slow conduction velocity to such an extent that conduction is extinguished, or a drug may reverse the underlying form of heart disease that was responsible for the conduction abnormalities that led to the arrhythmia (i.e., “reverse remodeling”).

AADs have specific electrophysiologic actions that alter cardiac conduction in patients with or without heart disease. These actions form the basis of grouping AADs into specific categories based on their electrophysiologic actions in vitro. Vaughan Williams proposed the most frequently used classification system (Table 8-1).2 This classification has been criticized for the following reasons: (a) it is incomplete and does not allow for the classification of drugs such as digoxin or adenosine; (b) it is not pure, and many agents have properties of more than one class of drugs; (c) it does not incorporate drug characteristics such as mechanisms of tachycardia termination/prevention, clinical indications, or side effects; and (d) drugs become “labeled” within a class, although they may be distinct in many regards.3These criticisms formed the basis for an attempt to reclassify AADs based on a variety of basic and clinical characteristics (called the Sicilian Gambit3). Nonetheless, the Vaughan Williams classification remains the most frequently used despite many proposed modifications and alternative systems.

TABLE 8-1 Classification of Antiarrhythmic Drugs


The class Ia AADs, quinidine, procainamide, and disopyramide, slow conduction velocity, prolong refractoriness, and decrease the automatic properties of sodium-dependent (normal and diseased) conduction tissue. Although class Ia AADs are primarily considered sodium channel blockers, their electrophysiologic actions can also be attributed to blockade of potassium channels. In reentrant tachycardias, these drugs generally depress conduction and prolong refractoriness, theoretically transforming the area of unidirectional block into a bidirectional block. Clinically, class Ia drugs are broad-spectrum AADs that are effective for both supraventricular and ventricular arrhythmias. Procainamide is only available in the IV formulation as all of its oral formulations have been discontinued.

The class Ib AADs, lidocaine, mexiletine, and phenytoin, were historically categorized separately from quinidine-like drugs. This was a result of early work demonstrating that lidocaine had distinctly different electrophysiologic actions. In normal tissue models, lidocaine generally facilitates actions on cardiac conduction by shortening refractoriness and having little effect on conduction velocity. Thus, it was postulated that these agents could improve antegrade conduction, eliminating the area of unidirectional block. Of course, arrhythmias do not usually arise from normal tissue, leading investigators to study the actions of lidocaine and phenytoin in ischemic and hypoxic tissue models. Interestingly, studies have shown these drugs to possess class Ia quinidine-like properties in diseased tissues. Therefore, it is probable that lidocaine acts in a similar fashion to the class Ia AADs (i.e., prolongs refractoriness in diseased ischemic tissues leading to bidirectional block in a reentrant circuit). Lidocaine and similar agents have accentuated effects in ischemic tissue caused by the local acidosis and potassium shifts that occur during cellular hypoxia. Changes in pH alter the time that local anesthetics occupy the sodium channel receptor, thereby affecting the agent’s electrophysiologic actions. In addition, the intracellular acidosis that ensues as a consequence of ischemia could cause lidocaine to become “trapped” within the cell, allowing increased access to the receptor. The class Ib AADs are considerably more effective in ventricular arrhythmias than supraventricular arrhythmias. As a group, these drugs are relatively weak sodium channel antagonists (at normal stimulation rates).

The class Ic AADs, propafenone and flecainide, are extremely potent sodium channel blockers, profoundly slowing conduction velocity while leaving refractoriness relatively unaltered. The class Ic AADs theoretically eliminate reentry by slowing conduction to a point where the impulse is extinguished and cannot propagate further. Although the class Ic AADs are effective for both ventricular and supraventricular arrhythmias, their use for ventricular arrhythmias has been limited by the risk of proarrhythmia.

Class I AADs are grouped together because of their common action in blocking sodium conductance. The receptor site for these AADs is probably inside the sodium channel so that, in effect, the drug plugs the pore. The AAD may gain access to the receptor either via the intracellular space through the membrane lipid bilayer or directly through the channel. Several principles are inherent in antiarrhythmic sodium channel receptor theories4:

   1. Class I AADs have predominant affinity for a particular state of the channel (e.g., during activation or inactivation). For example, lidocaine and flecainide block sodium current primarily when the cell is in the inactivated state, whereas quinidine is predominantly an open (or activated)-channel blocker.

   2. Class I AADs have specific binding and unbinding characteristics to the receptor. For example, lidocaine binds to and dissociates from the channel receptor quickly (“fast on–off”) but flecainide has very “slow on–off” properties. This explains why flecainide has such potent effects on slowing ventricular conduction, whereas lidocaine has little effect on normal tissue (at normal heart rates). In general, the class Ic AADs are “slow on–off,” the class Ib AADs are “fast on–off,” and the class Ia AADs are intermediate in their binding kinetics.

   3. Class I AADs possess rate dependence (i.e., sodium channel blockade and slowed conduction are greatest at fast heart rates and least during bradycardia). For “slow on–off” drugs, sodium channel blockade is evident at normal rates (60 to 100 beats/min), but for “fast on–off” agents, slowed conduction is only apparent at fast heart rates.

   4. Class I AADs (except phenytoin) are weak bases with a pKa >7 and block the sodium channel in their ionized form. Consequently, pH will alter these actions: acidosis accentuates and alkalosis diminishes sodium channel blockade.

   5. Class I AADs appear to share a single receptor site in the sodium channel. It should be noted, however, that a number of class I AADs have other electrophysiologic properties. For instance, quinidine has potent potassium channel blocking activity (manifests predominantly at low concentrations) as does N-acetylprocainamide (manifests predominantly at high concentrations), the primary metabolite of procainamide. Additionally propafenone has β-blocking actions.

These principles are important in understanding additive drug combinations (e.g., quinidine and mexiletine), antagonistic combinations (e.g., flecainide and lidocaine), and potential antidotes to excess sodium channel blockade (sodium bicarbonate). They also explain a number of clinical observations, such as why lidocaine-like drugs are relatively ineffective for supraventricular tachycardia. The class Ib AADs are “fast on–off,” inactivated sodium channel blockers; atrial cells, however, have a very brief inactivated phase relative to ventricular tissue.

The β-blockers are classified as class II AADs. For the most part, the clinically relevant acute antiarrhythmic mechanisms of the β-blockers result from their antiadrenergic actions. Because the SA and AV nodes are heavily influenced by adrenergic innervation, β-blockers would be most useful in tachycardias in which these nodal tissues are abnormally automatic or are a portion of a reentrant loop. These drugs are also helpful in slowing ventricular response in atrial arrhythmias (e.g., AF) by their effects on the AV node. Furthermore, some tachycardias are exercise-related or precipitated by states of high sympathetic tone (perhaps through triggered activity), and β-blockers may be useful in these instances. β-Adrenergic stimulation results in increased conduction velocity, shortened refractoriness, and increased automaticity of the nodal tissues; β-blockers will antagonize these effects. In the nodal tissues, β-blockers interfere with calcium entry into the cell by altering catecholamine-dependent channel integrity and gating kinetics. In sodium-dependent atrial and ventricular tissues, β-blockers shorten repolarization somewhat but otherwise have little direct effect. The antiarrhythmic properties of β-blockers observed with long-term, chronic therapy in patients with heart disease are less well understood. Although it is clear that β-blockers decrease the likelihood of SCD (presumably arrhythmic death) after myocardial infarction (MI), the mechanism for this benefit remains unclear but may relate to the complex interplay of changes in sympathetic tone, damaged myocardium, and ventricular conduction. In patients with heart failure (HF), drugs such as β-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers may prevent arrhythmias such as AF by attenuating the structural and/or electrical remodeling process in the myocardium.5,6

The class III AADs include those agents that specifically prolong refractoriness in atrial and ventricular tissues. This class includes amiodarone, dronedarone, sotalol, ibutilide, and dofetilide; these drugs share the common effect of delaying repolarization by blocking potassium channels. Amiodarone and sotalol are effective in most supraventricular and ventricular arrhythmias. Amiodarone displays electrophysiologic characteristics of all four Vaughan Williams classes; it is a sodium channel blocker with relatively “fast on–off” kinetics, has nonselective β-blocking actions, blocks potassium channels, and also has a small degree of calcium channel blocking activity (Table 8-2). At normal heart rates and with chronic use, its predominant effect is to prolong repolarization. With IV administration, its onset is relatively quick (unlike the oral form) and β-blockade predominates initially. Theoretically, amiodarone, like class I AADs, may interrupt the reentrant substrate by transforming an area of unidirectional block into an area of bidirectional block. However, electrophysiologic studies using programmed cardiac stimulation imply that amiodarone may leave the reentrant loop intact. The impressive effectiveness of amiodarone coupled with its low proarrhythmic potential has challenged the notion that selective ion channel blockade by AADs is preferable. Sotalol is a potent inhibitor of outward potassium movement during repolarization and also possesses nonselective β-blocking actions. Unlike amiodarone and sotalol, dronedarone, ibutilide, and dofetilide are only approved for the treatment of supraventricular arrhythmias. Both ibutilide (only available IV) and dofetilide (only available orally) can be used for the acute conversion of AF or atrial flutter to SR. Dofetilide can also be used to maintain SR in patients with AF or atrial flutter of longer than 1 week’s duration who have been converted to sinus rhythm (SR). Dronedarone is approved to reduce the risk of cardiovascular hospitalization in patients with a history of paroxysmal or persistent AF. Although structurally related to amiodarone, dronedarone’s structure has been modified through the addition of a methylsulfonyl group and the removal of iodine. Dronedarone is also similar to amiodarone in exhibiting electrophysiologic characteristics of all four Vaughan Williams classes (sodium channel blocker with relatively “fast on–off” kinetics, nonselective β-blocker, potassium channel blocker, and calcium channel antagonist).

TABLE 8-2 Time Course and Electrophysiologic Effects of Amiodarone


There are a number of different potassium channels that function during normal conduction; all approved class III AADs inhibit the delayed rectifier current (IK) responsible for phase 2 and phase 3 repolarization. Subcurrents make up IK: an ultrarapid component (IKur), a rapid component (IKr), and the slow component (IKs). N-Acetylprocainamide, sotalol, ibutilide, and dofetilide selectively block IKr, whereas amiodarone and dronedarone block both IKrand IKs. New drugs that selectively block IKur (found predominantly in the atrium but not ventricle) are being investigated for supraventricular arrhythmias. The clinical relevance of selectively blocking components of the delayed rectifier current remains to be determined. Potassium channel blockers (particularly those with selective IKr blocking properties) display “reverse use dependence” (i.e., their effects on repolarization are greatest at low heart rates). Sotalol and drugs like it also appear to be much more effective in preventing ventricular fibrillation (VF) (in dog models) than the traditional sodium channel blockers. They also decrease defibrillation threshold in contrast to class I AADs, which tend to increase this parameter. This feature could be important in patients with ICDs, as concurrent therapy with class I AADs may require more energy for successful cardioversion or may render the ICD ineffective in terminating the ventricular arrhythmia. The Achilles’ heel of all class III AADs is an extension of their underlying ionic mechanism (i.e., by blocking potassium channels and delaying repolarization, they may also cause proarrhythmia in the form of TdP by provoking EADs).

The nondihydropyridine (non-DHP) CCBs, verapamil and diltiazem, are categorized as class IV AADs. At least two types of calcium channels are operative in SA and AV nodal tissues: an L-type channel and a T-type channel. Both L-type channel blockers (verapamil and diltiazem) and selective T-type channel blockers (mibefradil was previously approved but withdrawn from the market) will slow conduction, prolong refractoriness, and decrease automaticity (e.g., due to EADs or LADs) of the calcium-dependent tissue in the SA and AV nodes. Therefore, these agents are effective in automatic or reentrant tachycardias, which arise from or use the SA or AV nodes. In supraventricular arrhythmias (e.g., AF), these drugs can slow ventricular response by slowing AV nodal conduction. Furthermore, because calcium entry seems to be integral to exercise-related tachycardias and/or tachycardias caused by some forms of triggered automaticity, these agents may be effective in the treatment of these types of arrhythmias. The DHP CCBs (e.g., nifedipine) do not have significant antiarrhythmic activity because a reflex increase in sympathetic tone caused by vasodilation counteracts their direct negative dromotropic action.

All AADs currently available have an impressive side effect profile (Table 8-3). A considerable percentage of patients cannot tolerate long-term therapy with these drugs and will have to discontinue therapy because of side effects. Images Flecainide, propafenone, and disopyramide may precipitate congestive HF in a significant number of patients with underlying LV systolic dysfunction; consequently, these drugs should be avoided in this patient population.7 The class Ib AAD, mexiletine, causes neurologic and/or gastrointestinal (GI) toxicity in a high percentage of patients. One of the most frightening side effects related to AADs is the aggravation of underlying ventricular arrhythmias or the precipitation of new (and life-threatening) ventricular arrhythmias.8

TABLE 8-3 Side Effects of Antiarrhythmic Drugs


Amiodarone has assumed a prominent place in the treatment of both chronic and acute supraventricular and ventricular arrhythmias and is now the most commonly prescribed AAD.9 Once considered a drug of last resort, it is now the first AAD considered in many arrhythmias. Yet amiodarone is a peculiar and complex drug, displaying unusual pharmacologic effects, pharmacokinetics, dosing regimens, and multiorgan side effects. Amiodarone has an extremely long elimination half-life (greater than 50 days) and large volume of distribution; consequently, its onset of action with the oral form is delayed (days to weeks) despite the use of a loading regimen, and its effects persist for a long period (months) after discontinuation. Amiodarone is a substrate of the cytochrome P450 (CYP) 3A4 isoenzyme, a moderate inhibitor of many CYP isoenzymes (e.g., CYP2C9, CYP2D6, CYP3A4), and a P-glycoprotein inhibitor, all of which can result in the potential for numerous drug interactions. Amiodarone interacts with digoxin and warfarin and can significantly increase plasma concentrations of both drugs. By inhibiting P-glycoprotein, amiodarone can increase digoxin concentrations by approximately twofold; therefore, the digoxin dose should be empirically reduced by 50% when amiodarone is initiated. When amiodarone and warfarin are initiated concurrently, warfarin should be started at a dose of 2.5 mg daily. When amiodarone is initiated in a patient already receiving warfarin, the warfarin dose should be reduced by approximately 30%.10 Acute administration of amiodarone is usually well tolerated by patients, but severe organ toxicities may result with chronic use. Severe bradycardia (sometimes requiring pacing to allow the patient to remain on amiodarone), hyperthyroidism, hypothyroidism, peripheral neuropathy, GI discomfort, photosensitivity, and a blue-gray skin discoloration on exposed areas are common. Fulminant hepatitis (uncommon) and pulmonary fibrosis (5% to 10% of patients) have caused death.11,12Although amiodarone can cause corneal microdeposits (usually do not affect vision) in virtually every patient, it has also been associated with the development of optic neuropathy/neuritis, which can lead to blindness. All of these side effects mandate close and continued monitoring (liver enzymes, thyroid function tests, eye examinations, chest radiographs, pulmonary function tests) and have led to a proliferation of “amiodarone clinics” designed just for patients receiving this drug on a chronic basis (Table 8-4). Images 13,14

TABLE 8-4 Amiodarone Monitoring


The modifications to dronedarone’s chemical structure may confer an improved safety profile when compared with amiodarone. With the addition of a methylsulfonyl group and the deletion of the iodine moiety, dronedarone is less lipophilic than amiodarone; consequently, dronedarone is supposed to be less likely to accumulate in tissues and cause various organ toxicities. Dronedarone also has a considerably shorter half-life (∼24 hours) when compared with amiodarone, which allows for steady state to be achieved in 5 to 7 days, without the need for using loading doses. Like amiodarone, dronedarone is a substrate of the CYP3A isoenzyme and a moderate inhibitor of the CYP2D6 and CYP3A isoenzymes. Its use with potent CYP3A4 inhibitors or inducers should be avoided. Dronedarone may increase plasma concentrations of (S)-warfarin; therefore, the international normalized ratio (INR) should be closely monitored with concurrent use of these drugs. Dronedarone also inhibits P-glycoprotein and can increase digoxin concentrations by about 2.5-fold. Consequently, when concomitantly using dronedarone and digoxin, the digoxin dose should be empirically reduced by 50%. Additionally, dronedarone can increase dabigatran and rivaroxaban concentrations in patients with renal impairment. To minimize the risk of bleeding when concomitantly using dronedarone and dabigatran in this patient population, the dose of dabigatran should be reduced to 75 mg twice daily in those with moderate renal impairment (creatinine clearance [CrCl] 30 to 50 mL/min). The concomitant use of dronedarone and dabigatran should be avoided in patients with severe renal impairment (CrCl 15 to 30 mL/min). Rivaroxaban should only be used if the benefit outweighs the risk in patients receiving dronedarone who have a CrCl of 15 to 50 mL/min.

Table 8-5 summarizes the pharmacokinetics of the AADs and Table 8-6 lists recommended dosages of the oral dosage forms. Table 8-7 lists the dosing recommendations for the IV forms of various AADs.

Table 8-5 Pharmacokinetics of Antiarrhythmic Drugs


Table 8-6 Typical Maintenance Doses of Oral Antiarrhythmic Drugs


Table 8-7 IV Antiarrhythmic Dosing



The common supraventricular tachycardias that often require drug treatment are: (a) AF or atrial flutter, (b) paroxysmal supraventricular tachycardia (PSVT), and (c) automatic atrial tachycardias. Other common supraventricular arrhythmias that usually do not require drug therapy include premature atrial complexes, wandering atrial pacemaker, sinus arrhythmia, and sinus tachycardia. As an example, premature atrial complexes rarely cause symptoms and never cause hemodynamic compromise; therefore, drug therapy is usually not indicated. Likewise, sinus tachycardia is usually the result of underlying metabolic or hemodynamic disorders (e.g., infection, dehydration, hypotension), and therapy should be directed at the underlying cause, not the tachycardia per se. Of course, there are exceptions to these suggestions. For example, sinus tachycardia may be deleterious in patients after cardiac surgery or MI. Therefore, AADs, such as β-blockers, may be indicated in these situations. Stated in another way, although many arrhythmias generally do not require therapy, clinical judgment and patient-specific variables play an important role in this decision. AF, atrial flutter, and PSVT tend to be the most common supraventricular arrhythmias seen in clinical practice; therefore, this discussion will focus only on these arrhythmias.

Atrial Fibrillation and Atrial Flutter

Mechanisms and Background

AF continues to be the most common sustained arrhythmia encountered in clinical practice, affecting between 2.7 and 6.1 million Americans.15 In the general population, the overall prevalence of AF is 0.4% to 1%, and this increases with age (e.g., approximately an 8% prevalence in patients >80 years old).16 The prevalence of AF also appears to increase as patients develop more severe HF, increasing from 4% in asymptomatic New York Heart Association (NYHA) class I patients to 50% in patients with NYHA class IV HF.17 With the aging population, improved survival in patients with HF, CAD, and hypertension, and the increased frequency of surgical procedures being performed, it is expected that the prevalence of AF will dramatically increase to an estimated 12 to 15 million by the year 2050.17 Based on data derived from the Framingham study cohort, the general lifetime risk for AF in men and women at least 40 years of age is estimated to be 1 in 4.18

AF and atrial flutter may present as a chronic, established tachycardia, an acute tachycardia, or a self-terminating, paroxysmal form. The following semantics and definitions are sometimes used specifically for AF16,19: acute AF (onset within 48 hours), paroxysmal AF (terminates spontaneously in <7 days), recurrent AF (two or more episodes), persistent AF (duration >7 days and does not terminate spontaneously), and permanent AF (does not terminate with attempts at pharmacologic or electrical cardioversion). AF is characterized by extremely rapid (atrial rate of 400 to 600 beats/min) and disorganized atrial activation. With this disorganized atrial activity, there is a loss of the contribution of synchronized atrial contraction (atrial kick) to forward cardiac output. Supraventricular impulses penetrate the AV conduction system in variable degrees resulting in an irregular activation of the ventricles and an irregularly irregular pulse. The AV junction will not conduct most of the supraventricular impulses, causing the ventricular response to be considerably slower (120 to 180 beats/min) than the atrial rate. It is sometimes stated that “AF begets AF,” that is, the arrhythmia tends to perpetuate itself. Long episodes are more difficult to terminate perhaps because of tachycardia-induced changes in atrial function (mechanical and/or electrical “remodeling”).

CLINICAL PRESENTATION Supraventricular Tachycardias

Atrial Fibrillation/Flutter


    • These arrhythmias are usually not directly life-threatening and do not generally cause hemodynamic collapse or syncope; 1:1 atrial flutter (ventricular response ∼300 beats/min) is an exception. Also, patients with underlying forms of heart disease who are heavily reliant on atrial contraction to maintain adequate cardiac output (e.g., mitral stenosis, obstructive cardiomyopathy) display more severe symptoms of AF or atrial flutter.


    • Most often, patients complain of rapid heart rate/palpitations and/or worsening symptoms of HF (shortness of breath, fatigue). Medical emergencies are severe HF (i.e., pulmonary edema, hypotension) or AF occurring in the setting of acute MI.

Diagnostic tests/signs (ECG; see text for details)

    • AF is an irregularly irregular supraventricular rhythm with no discernible, consistent atrial activity (P waves). Ventricular rate is usually 120 to 180 beats/min and the pulse is irregular. Atrial flutter is (usually) a regular supraventricular rhythm with characteristic flutter waves (or sawtooth pattern) reflecting more organized atrial activity. Commonly, the ventricular rate is in factors of 300 beats/min (e.g., 150, 100, or 75 beats/min).

Paroxysmal Supraventricular Tachycardia

Caused by Reentry


    • This arrhythmia can be transient, resulting in little, if any, symptoms.


    • Patients frequently complain of intermittent episodes of rapid heart rate/palpitations that abruptly start and stop, usually without provocation (but occasionally as a result of exercise). Severe symptoms include syncope. Often (in particular, those with AV nodal reentry), patients complain of a chest pressure or neck sensation. This is caused by simultaneous AV contraction with the right atrium contracting against a closed tricuspid valve. Life-threatening symptoms (syncope, hemodynamic collapse) are associated with an extremely rapid heart rate (e.g., >200 beats/min) and AF associated with an accessory AV pathway.

Diagnostic tests/signs (ECG; see text for details)

    • Most commonly, PSVT is a rapid, narrow QRS tachycardia (regular in rhythm) that starts and stops abruptly. Atrial activity, although present, is difficult to ascertain on surface ECG because P waves are “buried” in the QRS or T wave.

Atrial flutter occurs less frequently than AF but is similar in its precipitating factors, consequences, and drug therapy approach. This arrhythmia is characterized by rapid (atrial rate of 270 to 330 beats/min) but regular atrial activation. The slower and regular electrical activity results in a regular ventricular response that is in approximate factors of 300 beats/min (i.e., 1:1 AV conduction = ventricular rate of 300 beats/min; 2:1 AV conduction = ventricular rate of 150 beats/min; 3:1 AV conduction = ventricular rate of 100 beats/min). Atrial flutter may occur in two distinct forms (type I and type II). Type I flutter is the more common classic form with atrial rates of approximately 300 beats/min and the typical “sawtooth” pattern of atrial activation as shown by the surface ECG. Type II flutter tends to be faster, being somewhat of a hybrid between classic atrial flutter and AF. Although the ventricular response usually has a regular pattern with this arrhythmia, atrial flutter with varying degrees of AV block or that occur with episodes of AF (“fib-flutter”) can cause an irregular ventricular rate.

It is generally accepted that the predominant mechanism of AF and atrial flutter is reentry. AF appears to result from multiple atrial reentrant loops (or wavelets), whereas atrial flutter is caused by a single, dominant, reentrant substrate (counterclockwise circus movement in the right atrium around the tricuspid annulus). AF or atrial flutter usually occurs in association with various forms of structural heart disease (SHD) that cause atrial distension, including myocardial ischemia or infarction, hypertensive heart disease, valvular disorders such as mitral stenosis or mitral insufficiency, congenital abnormalities such as septal defects, dilated or hypertrophic cardiomyopathy, and obesity. Disorders that cause right atrial stretch and are associated with AF or atrial flutter include acute pulmonary embolus and chronic lung disease resulting in pulmonary hypertension and cor pulmonale. AF may also occur in association with states of high adrenergic tone such as thyrotoxicosis, surgery, alcohol withdrawal, sepsis, and excessive physical exertion. AF that develops in the absence of clinical, electrocardiographic, radiographic, and echocardiographic evidence of SHD is defined as lone AF. Other states in which patients are predisposed to episodes of AF are the presence of an anomalous AV pathway (i.e., Kent’s bundle) and sinus node dysfunction (i.e., sick sinus syndrome).

Patients with AF or atrial flutter may experience the entire range of symptoms associated with other supraventricular tachycardias, although syncope as a presenting symptom is uncommon. Because atrial kick is lost with the onset of AF, patients with LV systolic or diastolic dysfunction may develop worsening signs and symptoms of HF as they often depend on the contribution of their atrial kick to maintain an adequate cardiac output. Thromboembolic events, resulting from atrial stasis and poorly adherent mural thrombi, are an additional complication of AF. Of course, the most devastating complication in this regard is the occurrence of an embolic stroke. The average rate of ischemic stroke in patients with AF who are not receiving antithrombotic therapy is approximately 5% per year.20,21 Stroke can precede the onset of documented AF, probably as a result of undetected paroxysms prior to the onset of established AF. The risk of stroke significantly increases with age, with the annual attributable risk increasing from 1.5% in individuals 50 to 59 years of age to almost 24% in those 80 to 89 years of age.20 Patients with concomitant AF and rheumatic heart disease are at particularly high risk for stroke, with their risk being increased 17-fold compared with patients in SR.20 Other risk factors for stroke identified from recent trials are previous ischemic stroke, transient ischemic attack, or other systemic embolic event; age >75 years; moderate or severe LV systolic dysfunction and/or congestive HF; hypertension; and diabetes.20 The risk of stroke in patients with only atrial flutter has been traditionally believed to be low, prompting some to recommend only aspirin for prevention of thromboembolism in this particular patient population. However, because patients with atrial flutter may also intermittently have episodes of AF, this patient population may also be at risk for a thromboembolic event. Although the role of antithrombotic therapy in patients with atrial flutter has not been adequately studied in clinical trials, the most recent guidelines suggest that the same risk stratification scheme and antithrombotic recommendations used in patients with AF should also be applied to those with atrial flutter.20


The traditional approach to the treatment of AF can be organized into several sequential goals. First, evaluate the need for acute treatment (usually administering drugs that slow ventricular rate). Next, contemplate methods to restore SR, taking into consideration the risks (e.g., thromboembolism). Lastly, consider ways to prevent the long-term complications of AF such as arrhythmia recurrence and thromboembolism. Images One of the biggest controversies in the management of AF is whether restoring and maintaining SR is a desirable goal for all patients. A review of the management of AF and atrial flutter, including a discussion of this controversy, follows, organized according to the goals already outlined. Figure 8-5 shows an algorithm for the management of AF and atrial flutter. In addition, Table 8-8summarizes the recommendations for pharmacologically controlling ventricular rate and restoring and maintaining SR from the most recent AF guidelines developed by the American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC).16,22


FIGURE 8-5 Algorithm for the treatment of AF and atrial flutter. aIf AF <48 hours, anticoagulation prior to cardioversion is unnecessary; may consider TEE if patient has risk factors for stroke. bAblation may be considered for patients who fail or do not tolerate ≥1 AAD. cChronic antithrombotic therapy should be considered in all patients with AF and risk factors for stroke regardless of whether or not they remain in sinus rhythm. (AAD, antiarrhythmic drug; AF, atrial fibrillation; BB, β-blocker; CCB, calcium channel blocker [i.e., verapamil or diltiazem]; DCC, direct current cardioversion; LMWH, low-molecular-weight heparin; TEE, transesophageal echocardiogram.)

Table 8-8 Evidence-Based Pharmacologic Treatment Recommendations for Controlling Ventricular Rate, Restoring Sinus Rhythm, and Maintaining Sinus Rhythm in Patients with Atrial Fibrillation


Acute Treatment First, consider the patient with new-onset, symptomatic AF or atrial flutter. Although uncommon, patients may present with signs and/or symptoms of hemodynamic instability (e.g., severe hypotension, angina, or pulmonary edema), which qualifies as a medical emergency. In these situations, direct current cardioversion (DCC) is indicated as first-line therapy in an attempt to immediately restore SR (without regard to the risk of thromboembolism). Atrial flutter often requires relatively low energy levels of countershock (i.e., 50 J), whereas AF often requires higher energy levels (i.e., greater than 200 J).

If patients are hemodynamically stable, there is no emergent need to restore SR. Instead, the focus should be directed toward controlling the patient’s ventricular rate. Achieving adequate ventricular rate control should be a treatment goal for all patients with AF. To achieve this goal, drugs that slow conduction and increase refractoriness in the AV node (e.g., β-blockers, non-DHP CCBs, or digoxin) should be used as initial therapy. Although loading doses of digoxin have been historically recommended as first-line treatment to slow ventricular rate, use of this drug for this purpose, especially in patients with normal LV systolic function (left ventricular ejection fraction [LVEF] >40%), has declined.9 In this patient population, IV β-blocker (propranolol, metoprolol, esmolol), diltiazem, or verapamil is preferred. A few of the potential reasons for the declining use of digoxin in this patient population are its relatively slow onset and its inability to control the ventricular rate during exercise. Although an initial decrease in the ventricular rate can sometimes be observed within 1 hour of IV administration of digoxin, full control (heart rate <80 beats/min at rest and <100 beats/min during exercise) is usually not achieved for 24 to 48 hours. In addition, digoxin tends to be ineffective for controlling ventricular rate under conditions of increased sympathetic tone (i.e., surgery, thyrotoxicosis) because it slows AV nodal conduction primarily through vagotonic mechanisms. In contrast, IV β-blockers and non-DHP CCBs have a relatively quick onset and can effectively control the ventricular rate at rest and during exercise. β-Blockers are also effective for controlling ventricular rate under conditions of increased sympathetic tone.

Based on the most recent guidelines for the treatment of AF, the selection of a drug to control ventricular rate in the acute setting should be primarily based on the patient’s LV function.16 In patients with normal LV function (LVEF >40%), IV β-blocker, diltiazem, or verapamil is recommended as first-line therapy to control ventricular rate.16 All of these drugs have proven efficacy in controlling the ventricular rate in patients with AF. Propranolol and metoprolol can be administered as intermittent IV boluses, whereas esmolol (because of its very short half-life of 5 to 10 minutes) must be administered as a series of loading doses followed by a continuous infusion. Likewise, because control of ventricular rate can be transient with a single bolus, verapamil or diltiazem can be given as an initial IV bolus followed by a continuous infusion.23 These continuous infusions can be adjusted in monitored settings to the desired ventricular response (e.g., acutely <100 beats/min). In situations where AF or atrial flutter is precipitated by states of increased sympathetic tone (i.e., surgery, thyrotoxicosis), IV β-blockers can be highly effective and should be considered first.

In patients with LV dysfunction (LVEF ≤40%), both IV diltiazem and verapamil should be avoided because of their potent negative inotropic effects. IV β-blockers should be used with caution in this patient population and should be avoided if patients are in the midst of an episode of decompensated HF. In those patients who are having an exacerbation of HF symptoms, IV administration of either digoxin or amiodarone should be used as first-line therapy to achieve ventricular rate control.16 IV amiodarone can also be used in patients who are refractory to or have contraindications to β-blockers, non-DHP CCBs, and digoxin.16 However, clinicians should be aware that the use of amiodarone for controlling ventricular rate may also stimulate the conversion of AF to SR and place the patient at risk for a thromboembolic event, especially if the AF has persisted for at least 48 hours or is of unknown duration.

Patients may present with a slow ventricular response (in the absence of AV nodal blocking drugs) and thus do not require therapy with β-blockers, non-DHP CCBs, or digoxin. This type of presentation should alert the clinician to the possibility of preexisting SA or AV nodal conduction disease such as sick sinus syndrome. In these patients, DCC should not be attempted without a temporary pacemaker in place.

Restoration of Sinus Rhythm? After treatment with AV nodal blocking drugs and a subsequent decrease in the ventricular rate, the patient should be evaluated for the possibility of restoring SR if AF persists. Within the context of this evaluation, several factors should be considered. First, many patients spontaneously convert to SR without intervention, obviating the need for therapy to achieve this goal. For instance, AF occurs frequently as a complication of cardiac surgery and often spontaneously reverts to SR without therapy. Second, restoring SR is not a necessary or realistic goal in some patients. The results of six landmark clinical trials (Pharmacological Intervention in Atrial Fibrillation [PIAF], Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation [RACE], Atrial Fibrillation Follow-Up Investigation of Rhythm Management [AFFIRM], Strategies of Treatment of Atrial Fibrillation [STAF], How to Treat Chronic Atrial Fibrillation [HOT-CAFE], and Atrial Fibrillation and Congestive Heart Failure [AF-CHF]) have shed significant light on the comparative efficacy of rate-control (controlling ventricular rate; patient remains in AF) and rhythm-control (restoring and maintaining SR) treatment strategies in patients with AF.2429 The AFFIRM trial is the largest rate-control versus rhythm-control study to be conducted to date in patients with AF.26 In this trial, patients with AF and at least one risk factor for stroke were randomized to either a rate-control or a rhythm-control group. Rate-control treatment involved AV nodal blocking drugs (digoxin, β-blockers, and/or non-DHP CCBs) first, and then nonpharmacologic treatment (AV nodal ablation with pacemaker implantation), if necessary. All patients in this group were anticoagulated with warfarin to achieve an INR of 2 to 3. In the rhythm-control group, class I or III AADs were used to maintain SR. The choice of AAD therapy was left up to each patient’s physician; however, by the end of the trial, more than 60% of patients had received at least one trial of amiodarone and approximately 40% of patients had received at least one trial of sotalol. In this group, anticoagulation was encouraged but could be discontinued if SR had been maintained for at least 4 weeks. After a mean follow-up period of 3.5 years, overall mortality was not statistically different between the two strategies but tended (P = 0.08) to be higher in the rhythm-control group. The results of the PIAF, RACE, STAF, and HOT-CAFE trials were consistent with those of the AFFIRM trial.24,25,27,28 In addition, a meta-analysis of the data from all of these trials demonstrated no significant difference in overall mortality between rate-control and rhythm-control strategies, which persisted even when the results from the AFFIRM trial were excluded from this analysis.30

Even though the results of the PIAF, RACE, STAF, HOT-CAFE, and AFFIRM trials collectively demonstrate that a rate-control strategy is a viable alternative to a rhythm-control strategy in patients with persistent AF, a significant limitation of these results is that they cannot be applied to patients with HF because only a small proportion of patients enrolled in these trials had LV systolic dysfunction. The AF-CHF trial was conducted to specifically evaluate the safety and efficacy of rate-control and rhythm-control strategies in patients with systolic HF.29 In this trial, patients with an LVEF ≤35%, a history of HF (defined as NYHA class II to IV HF within the last 6 months, NYHA class I HF with a hospitalization for HF during the previous 6 months, or an LVEF ≤25%), and a history of AF were randomized to either a rate-control or a rhythm-control group. Rate-control treatment involved concomitant therapy with a β-blocker and digoxin first, and then nonpharmacologic treatment (AV nodal ablation with pacemaker implantation), if necessary. In the rhythm-control group, amiodarone was the preferred AAD, whereas sotalol and dofetilide were considered alternatives (most of the patients ultimately received amiodarone). If patients in this group did not convert to SR within 6 weeks, electrical cardioversion was performed. Anticoagulation was recommended for all patients in both treatment groups. After a mean follow-up period of 37 months, no significant difference was observed between the treatment groups with regard to the primary end point of death from cardiovascular causes. Patients in the rhythm-control group tended to have more hospitalizations, primarily due to repeated cardioversions and adjustment of AAD therapy, compared with patients in the rate-control group; however, this difference was not statistically significant (P = 0.06). It is important to note that the results of this trial should not be applied to patients with HF and preserved LV function (i.e., diastolic HF). Nevertheless, the results of this trial are generally consistent with those of the PIAF, RACE, AFFIRM, STAF, and HOT-CAFE trials and suggest that a rhythm-control strategy does not confer any advantage over a rate-control strategy in patients with AF and systolic HF.

Clearly, these important findings temper the old approach of aggressively attempting to maintain SR. Because a rhythm-control strategy does not offer any significant advantage over a rate-control strategy in the management of patients with persistent or recurrent AF (including those with concomitant HF), it is acceptable to allow patients to remain in AF, while being chronically treated not only with AV nodal blocking drugs to achieve adequate ventricular rate control but also with appropriate antithrombotic therapy to prevent thromboembolic complications. Images The important question with this rate-control approach is: What defines “adequate” ventricular rate control? While adequate ventricular rate control was previously considered to be achieving a heart rate <80 beats/min at rest and <100 beats/min during exercise, evidence from the RACE II trial has suggested that selecting a more lenient rate-control strategy (resting heart rate <110 beats/min) may be a reasonable approach for certain patients with AF.31 In this trial, a lenient rate-control strategy (resting heart rate <110 beats/min) was considered to be noninferior to a strict heart rate-control strategy (resting heart rate <80 beats/min and heart rate during moderate exercise <110 beats/min) with regard to the primary end point of cardiovascular death, hospitalization for HF, stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. According to the most recent treatment guidelines for AF, this lenient rate-control strategy is recommended for those patients with persistent AF who have no or acceptable symptoms and stable LV function (LVEF >40%).22 In patients with LV systolic dysfunction (LVEF ≤40%), a stricter rate-control approach (resting heart rate <80 beats/min) should be considered to minimize the potential harmful effects of a rapid heart rate response on ventricular function.

As in the acute setting, the selection of an AV nodal blocking drug to control ventricular rate in the chronic setting should be primarily based on the patient’s LV function.16 In patients with normal LV function (LVEF >40%), an oral β-blocker, diltiazem, or verapamil is preferred over digoxin because of their relatively quick onset and maintained efficacy during exercise. When adequate ventricular rate control cannot be achieved with one of these drugs, the addition of digoxin may result in an additive lowering of the heart rate. Verapamil and diltiazem should not be used in patients with LV dysfunction (LVEF ≤40%). Instead, β-blockers (i.e., metoprolol succinate, carvedilol, or bisoprolol) and digoxin are preferred in these patients, as these drugs are also concomitantly used to treat chronic HF. Specifically, in patients with NYHA class II or III HF, β-blockers should be considered over digoxin because of their survival benefits in patients with LV systolic dysfunction. If patients are having an episode of decompensated HF (NYHA class IV), digoxin is preferred as first-line therapy to achieve ventricular rate control because of the potential for worsening HF symptoms with the initiation and subsequent titration of β-blocker therapy. If adequate ventricular rate control during rest and exercise cannot be achieved with β-blockers, non-DHP CCBs, and/or digoxin in patients with normal or depressed LV function, oral amiodarone can be used as alternative therapy to control the heart rate.16

Because a rate-control strategy is now considered a reasonable initial approach for the chronic management of AF, the question that remains to be answered is, “In which patients should restoration of SR be considered?” Electrical or pharmacologic cardioversion should be considered for those patients with AF who remain symptomatic despite having adequate ventricular rate control or for those patients in whom adequate ventricular rate control cannot be achieved. In addition, a rhythm-control strategy may be considered in patients who are experiencing their first episode of AF if they are likely to convert to and remain in SR. Chronic AAD therapy is usually not needed in the latter population since the AF is often self-limiting.

In those patients in whom it is decided to restore SR, one must consider that this very act (regardless of whether an electrical or pharmacologic method is chosen) places the patient at risk for a thromboembolic event. The reason for this heightened risk is that the return of SR restores effective contraction in the atria, which may dislodge poorly adherent thrombi. Administering antithrombotic therapy prior to cardioversion not only prevents clot growth and the formation of new thrombi but also allows existing thrombi to become organized and well adherent to the atrial wall. It is a generally accepted principle that the risk of thrombus formation and a subsequent embolic event increases if the duration of the AF exceeds 48 hours. Therefore, it is vital for clinicians to estimate the duration of the patient’s AF, so that appropriate antithrombotic therapy can be administered prior to cardioversion if needed.

According to the most recent guidelines on antithrombotic and thrombolytic therapy developed by the American College of Chest Physicians (ACCP), patients with AF lasting at least 48 hours or an unknown duration should be given therapeutic anticoagulation with warfarin (INR target range 2 to 3), a low-molecular-weight heparin (subcutaneously at treatment doses), or dabigatran for 3 weeks before cardioversion.20 If the 3 weeks of therapeutic warfarin, low-molecular-weight heparin, or dabigatran therapy is not feasible, patients may alternatively undergo transesophageal echocardiography (TEE) to provide guidance regarding the need for antithrombotic therapy prior to cardioversion. If no thrombus is noted on TEE, these patients can be cardioverted without the mandatory 3 weeks of warfarin, low-molecular-weight heparin, or dabigatran pretreatment. In these patients, anticoagulation therapy with either IV unfractionated heparin or a low-molecular-weight heparin (subcutaneously at treatment doses) should be administered during the TEE and cardioversion procedure to prevent the formation of thrombi during the pericardioversion and postcardioversion periods. Cardioversion should then be performed within 24 hours of the TEE. Alternatively, warfarin therapy (INR target range of 2 to 3) may be used for at least 5 days prior to the TEE and cardioversion. If cardioversion is successful, therapeutic anticoagulation with either warfarin (INR target range of 2 to 3) or dabigatran should be continued for at least 4 weeks, regardless of the patient’s baseline risk of stroke. The reason for continuing anticoagulation for this additional 4-week time period is that after restoration of SR, full atrial contraction does not occur immediately. Rather, it returns gradually to a maximum contractile force over a 3- to 4-week period. Decisions regarding long-term antithrombotic therapy after this 4-week time period should be primarily based on the patient’s risk for stroke and not on whether he or she is in SR. If a thrombus is seen on TEE, cardioversion should not be performed and the patient should be anticoagulated indefinitely. If cardioversion is considered in these patients at a later time, a TEE should again be performed. Overall, the use of a TEE-guided approach to cardioversion in patients with AF has been compared with the conventional 3 weeks of anticoagulation before cardioversion in a large, multicenter, randomized trial.32 In this trial, the incidence of thromboembolic events was not different between the two strategies, but bleeding episodes were higher in the group that received 3 weeks of warfarin therapy before cardioversion. Patients in the TEE strategy group had a higher success rate of achieving SR, probably because it is more difficult to terminate AF the longer a patient remains in this arrhythmia.

In patients with AF that is less than 48 hours in duration, anticoagulation prior to cardioversion is unnecessary because there has not been sufficient time to form atrial thrombi.20 However, it is recommended that these patients should receive either IV unfractionated heparin or a low-molecular-weight heparin (subcutaneously at treatment doses) at presentation prior to and when proceeding to cardioversion. If these patients have risk factors for stroke, a TEE could alternatively be performed prior to cardioversion to exclude the presence of thrombus. If cardioversion is successful, therapeutic anticoagulation with either warfarin (INR target range 2 to 3) or dabigatran should be continued for at least 4 weeks, regardless of the patient’s baseline risk of stroke. Decisions regarding long-term antithrombotic therapy after this 4-week time period should be primarily based on the patient’s risk for stroke and not on whether he or she is in SR.

After prior anticoagulation or TEE, the process of restoring SR can be considered. There are two methods of restoring SR in patients with AF or atrial flutter: pharmacologic cardioversion and DCC. The decision to use either of these methods is generally a matter of clinical preference. The disadvantages of pharmacologic cardioversion are the risk of significant side effects (e.g., drug-induced TdP),33 the potential for drug–drug interactions (e.g., digoxin–amiodarone), and the lower efficacy of AADs when compared with DCC. The advantages of DCC are that it is quick and more often successful (80% to 90% success rate). The disadvantages of DCC are the need for prior sedation/anesthesia and a risk (albeit small) of serious complications such as sinus arrest or ventricular arrhythmias.

Nonetheless, despite the relatively high success rate associated with DCC, clinicians often elect to use AADs first, and then resort to DCC in the event that these drugs fail. Pharmacologic cardioversion appears to be most effective when initiated within 7 days after the onset of AF.16 According to the most recent treatment guidelines for AF, there is relatively strong evidence for efficacy of the class III pure IKblockers (ibutilide and dofetilide), the class Ic AADs (e.g., flecainide and propafenone), and amiodarone (oral or IV) within this time frame.16 Class Ia AADs have limited efficacy or have not been adequately studied in this setting. Sotalol is not effective for cardioversion of paroxysmal or persistent AF. Single, oral loading doses of propafenone (600 mg) and flecainide (300 mg) are effective compared with placebo for conversion of recent-onset AF and have been incorporated into the “pill-in-the-pocket” approach endorsed by the treatment guidelines.16,34 With this method, outpatient, patient-controlled self-administration of a single, oral loading dose of either flecainide or propafenone can be a relatively safe and effective approach for the termination of recent-onset AF in a selected patient population that does not have sinus or AV node dysfunction, bundle-branch block, QT interval prolongation, Brugada syndrome, or SHD.35 In addition, this treatment regimen should only be considered in patients who have previously been successfully cardioverted with these drugs on an inpatient basis. In patients with AF that is longer than 7 days in duration, only dofetilide, amiodarone, and ibutilide have proven efficacy for cardioversion.16 The class Ia and Ic AADs have limited efficacy or have been inadequately studied in this setting.

Overall, when considering pharmacologic cardioversion, the selection of an AAD should be based on whether the patient has SHD (e.g., LV dysfunction, CAD, valvular heart disease, LV hypertrophy).16 In the absence of any type of SHD, the use of a single, oral loading dose of flecainide or propafenone is a reasonable approach for cardioversion. Ibutilide can also be used as an alternative in this patient population; however, use of this agent is restricted to a monitored setting in the hospital because it requires QT interval monitoring. In patients with underlying SHD, flecainide, propafenone, and ibutilide should be avoided because of the increased risk of proarrhythmia; amiodarone or dofetilide should be used instead. Although amiodarone can be administered safely on an outpatient basis because of its low proarrhythmic potential, dofetilide therapy can only be initiated in the hospital (for QT interval monitoring). Additionally, it should be remembered that a patient’s ventricular rate should be adequately controlled with AV nodal blocking drugs prior to administering a class Ic (or Ia) AAD for cardioversion. The class Ia and Ic AADs may paradoxically increase ventricular response. Traditionally, this observation has been attributed to the vagolytic action of these drugs despite the fact that only disopyramide displays significant anticholinergic side effects. Therefore, a more likely alternative explanation exists: all of these drugs slow atrial conduction, decreasing the number of impulses reaching the AV node; as a result, the AV node paradoxically allows more impulses to gain entrance to the ventricular conduction system, thereby increasing ventricular rate.

Long-Term Complications There are two forms of therapy that the clinician must consider in each patient with AF: long-term antithrombotic therapy to prevent stroke and long-term AADs to prevent recurrences of AF. Consider the issue of antithrombotic therapy first. Historically, warfarin has been the standard of care for stroke prevention in patients considered to be moderate or high risk for stroke. However, while warfarin is undoubtedly effective in preventing strokes in patients with AF, its use can be associated with a number of potential limitations, including a narrow therapeutic window, requirement for INR monitoring, food and drug interactions, and pharmacogenetic influences. Therefore, researchers have long been searching for an antithrombotic therapy that could be used as an alternative or even as a replacement for warfarin in patients with AF. Over the past few years, several oral antithrombotic therapies have been approved by the Food and Drug Administration for stroke prevention in patients with AF. These oral anticoagulant drugs include the direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors, rivaroxaban and apixaban.

When initiating chronic antithrombotic therapy in patients with AF, assessing the patient’s risk for stroke becomes important for selecting the most appropriate regimen. Based on the most recent ACCP guidelines, the CHADS2 index continues to be recommended for stroke risk stratification in patients with AF.20 With this risk index, patients with AF are given two points if they have a history of a previous stroke or transient ischemic attack, and one point each for being ≥75 years old, having hypertension, having diabetes, or having congestive HF (CHADS2 is an acronym for each of these risk factors). The points are added up and the total score is then used to determine the most appropriate antithrombotic therapy for the patient (Fig. 8-6). Patients with a CHADS2 score of ≥2, 1, or 0 are considered to be at high risk, intermediate risk, and low risk for stroke, respectively. Based on the most recent ACCP guidelines, oral anticoagulant therapy is preferred over aspirin or aspirin plus clopidogrel therapy in patients who are at either high or intermediate risk for stroke. With regard to selection of an oral anticoagulant in both high-risk and intermediate-risk patients with AF, the updated ACCP guidelines suggest that dabigatran should be used rather than warfarin (INR target range 2 to 3). Either no antithrombotic therapy or aspirin is recommended for patients who are at low risk for stroke; however, no therapy is preferred in these patients. If the decision is made to initiate antithrombotic therapy in these low-risk patients, aspirin (75 to 325 mg/day) can be used.


FIGURE 8-6 Algorithm for the prevention of thromboembolism in paroxysmal, persistent, or permanent AF. aNo antithrombotic therapy preferred for low-risk patients. bThe target INR for patients with prosthetic heart valves should be based on the type of valve that is present. (AF, atrial fibrillation; HF, heart failure; INR, international normalized ratio; LV, left ventricular.)

The efficacy and safety of dabigatran were compared with those of warfarin in patients with AF in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.36 In this study, patients were randomized to receive dabigatran 110 mg twice daily, dabigatran 150 mg twice daily or adjusted-dose warfarin. The median follow-up period was 2 years. For the primary end point of stroke or systemic embolism, both dabigatran groups were shown to be noninferior to warfarin. However, superiority was also assessed and the dabigatran 150-mg group was shown to be superior to warfarin in reducing this end point. The rate of major bleeding was similar between the dabigatran 150-mg and warfarin groups, while the rate of major bleeding was significantly lower in the dabigatran 110-mg group than in the warfarin group. The rate of intracranial hemorrhage was significantly lower in both dabigatran groups than in the warfarin group. Even though the 110- and 150-mg dosing regimens of dabigatran were evaluated in this trial, only the 150-mg dose was approved by the Food and Drug Administration. A lower 75-mg dose was also approved for patients with a CrCl of 15 to 30 mL/min, even though this dose has not been evaluated in a randomized, prospective clinical trial in patients with AF; this dose has only pharmacokinetic data to support its use.37 It is important to note that the RE-LY trial excluded patients with a CrCl <30 mL/min. Therefore, the most recent ACCP guidelines made the evidence-based decision to recommend that dabigatran be contraindicated in patients with a CrCl <30 mL/min. Dabigatran is also contraindicated in patients with mechanical heart valves. The use of dabigatran is also not recommended in patients with bioprosthetic heart valves since the safety and efficacy of this antithrombotic have not been evaluated in this population. Patients with hemodynamically significant valvular disease or advanced liver disease are also not appropriate candidates for dabigatran therapy.38

The efficacy and safety of rivaroxaban were compared with those of warfarin in patients with AF in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation.39 In this study, patients were randomized to receive rivaroxaban 20 mg daily or adjusted-dose warfarin. The median follow-up period was 1.9 years. For the primary end point of stroke or systemic embolism, rivaroxaban was shown to be noninferior to warfarin. The rate of major and nonmajor clinically relevant bleeding was similar between the rivaroxaban and warfarin groups. Significantly fewer intracranial hemorrhages occurred in the rivaroxaban group compared with the warfarin group.

The efficacy and safety of the other factor Xa inhibitor, apixaban, were compared with those of aspirin in patients with AF in the Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who have Failed or are Unsuitable for Vitamin K Antagonist Treatment trial.40 This particular trial enrolled patients who failed or were considered unsuitable candidates for vitamin K antagonist therapy. This study was stopped prematurely when a significant benefit with regard to the primary efficacy outcome of stroke and systemic embolism was observed in the apixaban group. The efficacy and safety of apixaban were compared with those of warfarin in patients with AF in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial.41 Overall, apixaban was shown to be noninferior and superior to warfarin with regard to the primary end point of stroke or systemic embolism. The rate of major bleeding in this trial was significantly lower in the apixaban group than in the warfarin group. Additionally, significantly fewer intracranial hemorrhages occurred in the apixaban group compared with the warfarin group.

Recently, the AHA and American Stroke Association issued revised recommendations regarding the use of various antithrombotic agents for stroke prevention in patients with nonvalvular AF.42 These recommendations state that warfarin, dabigatran, rivaroxaban, and apixaban are all indicated for the prevention of initial and recurrent strokes in patients with nonvalvular AF. Therapy should be individualized for each patient with consideration given to stroke risk factors, drug cost, tolerability, patient preference, and drug interaction potential. Additionally, if a patient has previously taken warfarin, the time that his or her INR has been within the therapeutic range should be considered before making the decision to switch him or her to dabigatran, rivaroxaban, or apixaban. With regard to the newer antithrombotic agents, these recommendations state that dabigatran 150 mg twice daily should be considered an effective alternative to warfarin for initial or recurrent stroke prevention in patients with nonvalvular AF who have at least one additional risk factor for stroke and a CrCl >30 mL/min. Additionally, these recommendations state that rivaroxaban 20 mg daily should be considered as a reasonable alternative to warfarin in those patients who are at moderate-to-high risk of stroke (e.g., prior history of TIA, stroke, or systemic embolism, or at least 2 additional risk factors for stroke); a dosing regimen of 15 mg daily may be considered for those patients with a CrCl of 15 to 50 mL/min. These recommendations also state that apixaban 5 mg twice daily is an effective alternative to warfarin in patients with nonvalvular AF who have at least one risk factor for stroke; a dosing regimen of 2.5 mg twice daily may be considered for those patients with at least two of the following: age ≥80 years, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 μmol/L). Apixaban 5 mg twice daily is also considered an effective alternative to aspirin in those patients with nonvalvular AF who have at least one risk factor for stroke and are considered unsuitable candidates for warfarin; a similar dosage adjustment can be made based on the age, weight, and renal function criteria listed above.

Based on the most recent ACCP guidelines, dual antiplatelet therapy with aspirin plus clopidogrel is recommended over aspirin monotherapy for patients who are at high or intermediate risk for stroke and are not candidates for oral anticoagulant therapy for reasons other than bleeding (i.e., patient preference, unable to adhere to monitoring or dosing regimen requirements).20 These recommendations are based on the results of the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) W and ACTIVE A.43,44 Both of these trials evaluated the efficacy and safety of this combination therapy in patients with AF and at least one risk factor for stroke. In the ACTIVE W, patients were randomized to receive oral anticoagulation therapy (with the vitamin K antagonist used in the investigator’s country) titrated to achieve a target INR of 2 to 3 or clopidogrel 75 mg/day plus aspirin 75 to 100 mg/day.43 This trial was prematurely discontinued when the oral anticoagulation therapy was found to be superior to the combination antiplatelet regimen in reducing the occurrence of stroke, non–central nervous system systemic embolism, MI, or vascular death. While major bleeding events were similar between the two groups, significantly more minor bleeding episodes occurred in the clopidogrel plus aspirin group than in the oral anticoagulation group. Patients who had a contraindication to or were unwilling to take oral anticoagulant therapy were enrolled in the ACTIVE A.44 In this trial, patients were randomly assigned to receive clopidogrel 75 mg/day plus aspirin 75 to 100 mg/day or aspirin monotherapy (75 to 100 mg/day). After a median follow-up of 3.6 years, the incidence of stroke, non–central nervous system systemic embolism, MI, or vascular death was significantly reduced in the clopidogrel plus aspirin group when compared with the aspirin group. However, significantly more patients in the clopidogrel plus aspirin group experienced major bleeding than in the aspirin group.

Although it was previously an acceptable practice to continue antithrombotic therapy for only 4 weeks after successful cardioversion (with the belief that a patient’s risk for thromboembolism had abated since he or she was in SR), data from the RACE and AFFIRM trials, in particular, strongly suggest that patients with AF and other risk factors for stroke continue to be at risk for stroke even when maintained in SR.25,26 It is possible that these patients may be having undetected episodes of paroxysmal AF, placing them at risk for stroke. Consequently, the most recent ACCP guidelines recommend that chronic antithrombotic therapy be considered for all patients with AF and risk factors for stroke regardless of whether or not they remain in SR.20

The second form of chronic therapy to be considered is AADs to prevent recurrences of AF. Historically, many clinicians have aggressively attempted to maintain SR by prescribing oral AADs (usually quinidine) to prevent AF recurrences despite the fact that only small studies with conflicting results existed evaluating this approach. To evaluate the efficacy of quinidine in preventing AF, a well-known meta-analysis of the existing literature was completed.45 This meta-analysis demonstrated that indeed more patients remain in SR with quinidine therapy (compared with placebo); however, approximately 50% have recurrences of AF within a year despite quinidine. This reported effectiveness was at the cost of an associated increase in mortality (presumably due, in part, to proarrhythmia) in the quinidine-treated patients. These disturbing results (published soon after the Cardiac Arrhythmia Suppression Trial [CAST]46) became widely quoted and highly visible, making clinicians question the wisdom of long-term prevention of recurrences of AF with AADs. These results coupled with the findings of the PIAF, RACE, AFFIRM, STAF, HOT-CAFE, and AF-CHF trials question the need to use AADs to prevent AF recurrences.2429 In fact, based on the results of these landmark trials, the use of AADs to maintain SR may be more reasonable to consider in patients who remain symptomatic despite having adequate ventricular rate control or for those patients in whom adequate ventricular rate control cannot be achieved.

According to the most recent treatment guidelines for AF, the class Ic or III AADs are reasonable to consider to maintain patients in SR (Table 8-9).16 The role of the class Ia AADs for maintenance of SR has been deemphasized throughout these guidelines as they are considered less effective or incompletely studied compared with the class Ic and III AADs. Realistically, however, these drugs can still be considered as last-line therapy in select patients. Interestingly, a systematic review of AADs for the maintenance of SR after cardioversion in patients with AF demonstrated that AF recurrences were significantly reduced with the use of class Ia, Ic, and III AADs; however, mortality was significantly increased with the class Ia drugs, in particular.47

TABLE 8-9 Guidelines for Selecting Antiarrhythmic Drug Therapy for Maintenance of Sinus Rhythm in Patients with Recurrent Paroxysmal or Recurrent Persistent Atrial Fibrillation


The class Ic AADs, flecainide and propafenone, are effective for maintaining SR. However, because of the increased risk for proarrhythmia, these drugs should be avoided in patients with SHD.

Although all of the oral class III AADs have demonstrated efficacy in preventing AF recurrences, amiodarone is clearly the most effective agent and is now the most frequently used AAD despite its potential for causing significant organ toxicity.9 The superiority of amiodarone over other AADs for maintaining patients in SR has been demonstrated in a number of clinical trials. In the Canadian Trial of Atrial Fibrillation, amiodarone was significantly more effective than sotalol or propafenone in maintaining SR in patients with persistent or paroxysmal AF.48 Furthermore, in a substudy of the AFFIRM trial, amiodarone appeared to be the most effective AAD in maintaining SR of those used in the study.49 In the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial, amiodarone and sotalol were equally effective at converting AF to SR.50 However, amiodarone was significantly more effective than sotalol at maintaining SR in all patient subgroups, except for those with CAD where the efficacy of these two drugs was comparable.

Although sotalol is not effective for conversion of AF, it is an effective drug for maintaining SR. Sotalol appears to be at least as effective as quinidine or propafenone in preventing recurrences of AF.48,51However, treatment with either quinidine or sotalol is associated with a similar incidence of TdP. Because this form of proarrhythmia primarily occurs with higher doses of sotalol (quinidine usually causes TdP at low or therapeutic concentrations), it may be more easily predicted and therefore avoided. Nonetheless, sotalol may be similar to quinidine in increasing mortality in patients with AF; however, this finding requires further study.52

Dofetilide is effective in preventing recurrences of AF53 but has not been directly compared with either amiodarone or sotalol. In a large, multicenter trial,54 dofetilide was more effective than placebo in maintaining SR (approximately 35% to 50% at 1 year). The efficacy of dofetilide for the maintenance of SR has also specifically been demonstrated in patients with LV systolic dysfunction.53 Like sotalol and quinidine, dofetilide also has significant potential to cause TdP (in a dose-related fashion).

The safety and efficacy of dronedarone for the treatment of AF and atrial flutter have been evaluated in several clinical trials. In the European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm and the American–Australian–African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm, which were similar in design, dronedarone was more effective than placebo in maintaining SR in patients with paroxysmal or persistent AF or atrial flutter.55 In another trial, the use of dronedarone in patients with persistent or paroxysmal AF or atrial flutter was associated with significantly fewer hospitalizations due to cardiovascular events or death when compared with placebo.56 The safety and efficacy of dronedarone were also evaluated in a trial that included patients with NYHA class III or IV HF and an LVEF of 35% or less.57 This trial was prematurely terminated because all-cause mortality (primarily due to worsening HF) was significantly higher in the dronedarone group when compared with the placebo group. Consequently, based on these findings, dronedarone is contraindicated in and has received a black box warning for patients with advanced HF (NYHA class IV or NYHA class II or III with a recent hospitalization for decompensated HF). The efficacy and safety of dronedarone in patients with AF have been compared with those of amiodarone.58 In this trial, dronedarone was shown to be significantly less effective than amiodarone in reducing AF recurrences; however, tolerability was significantly better in the dronedarone group than in the amiodarone group as evidenced by higher rates of premature drug discontinuation and adverse events in the amiodarone group. Most recently, a trial that enrolled patients with permanent AF and risk factors for major vascular events was terminated prematurely after significantly more patients in the dronedarone group died (primarily from cardiovascular causes), were hospitalized for HF, and suffered a stroke when compared with the placebo group.59 Based on the results of this trial, dronedarone is contraindicated in and has received a boxed warning for patients with permanent AF.

Overall, the selection of an AAD to maintain SR should be primarily based on whether the patient has SHD.16,22 However, other factors, including renal and hepatic function, concomitant disease states and drugs, and the AAD’s side effect profile, also need to be considered. For those patients with no underlying SHD, dronedarone, flecainide, propafenone, or sotalol should be considered initially because these drugs have the most optimal long-term safety profile in this setting. However, amiodarone or dofetilide could be used as alternative therapy if the patient fails or does not tolerate one of these initial AADs. In the presence of SHD, flecainide and propafenone should be avoided because of the risk of proarrhythmia. If LV systolic dysfunction is present (LVEF ≤40%), amiodarone should be considered the AAD of choice. Dofetilide can be used as an alternative if patients develop intolerable side effects with amiodarone. At this time, only amiodarone and dofetilide have been shown to be mortality-neutral in patients with AF and HF. Both dronedarone and sotalol should be avoided in patients with LV systolic dysfunction because of the risk for increased mortality (dronedarone) or worsening HF (sotalol). In patients with CAD, dofetilide, dronedarone, or sotalol can be used initially. Again, dronedarone and sotalol should not be used in patients with LV systolic dysfunction. Amiodarone could be used as an alternative therapy if the patient fails or does not tolerate one of these initial AADs. The presence of LV hypertrophy may predispose the myocardium to proarrhythmic events. Because of its low proarrhythmic potential, amiodarone should be considered first-line AAD therapy in these patients.

Nonpharmacologic forms of therapy, designed to maintain SR, are becoming increasingly popular treatment options for patients with AF or atrial flutter. For patients who have “pure” (i.e., not associated with concurrent AF) type I atrial flutter, ablation of the reentrant substrate with radiofrequency current is highly effective (∼90%)60 and can be considered first-line treatment of atrial flutter to prevent recurrences.61 Catheter ablation for patients with AF is much more technically difficult for a variety of reasons, including the lack of a single, identifiable, and ablatable reentrant focus (as in atrial flutter). Nonetheless, progress has been made in this area. Patients with AF have been found to have arrhythmogenic foci that occur in atrial tissue near and within the pulmonary veins. During the ablation procedure, radiofrequency energy can be delivered to these areas in an attempt to abolish the foci. Historically, this procedure was often considered last-line therapy for patients who had failed all AADs, including amiodarone. However, in some of the recent trials, the use of catheter ablation in patients with AF has been associated with a significant reduction in recurrent episodes of AF and an improvement in quality of life when compared with AAD therapy.6264 There is even some evidence65,66 to suggest that this procedure may be superior to AADs as first-line therapy of symptomatic AF. According to the most recent guidelines, for those patients with symptomatic episodes of AF who fail or do not tolerate at least one class I or III AAD, catheter ablation is recommended for those with paroxysmal AF, reasonable for those with persistent AF, and may be considered for those with long-standing persistent AF.67 For those patients with symptomatic episodes of AF who have not yet received treatment with a class I or III AAD, catheter ablation is reasonable for those with paroxysmal AF and may be considered for persistent or long-standing persistent AF. This procedure is not without its risks, as major complications, such as pulmonary vein stenosis, thromboembolic events, cardiac tamponade, and new atrial flutter, have been reported in 4.5% of patients.68

Paroxysmal Supraventricular Tachycardia Caused by Reentry

PSVT arising by reentrant mechanisms includes those arrhythmias caused by AV nodal reentry, AV reentry incorporating an anomalous AV pathway, SA nodal reentry, and intraatrial reentry. AV nodal reentry and AV reentry are by far the most common of these tachycardias. Images


The underlying substrate of AV nodal reentry is the functional division of the AV node into two (or more) longitudinal conduction pathways or “dual” AV nodal pathways.69 It is now clear that there are not two distinct anatomic pathways inside the AV node itself; rather, it is likely that a fan-like network of perinodal fibers inserts into the AV node and represents the second pathway. The pathways possess key differences in conduction characteristics: one is a fast-conducting pathway with a relatively long refractory period (fast pathway) and the other is a slower-conducting pathway with a shorter refractory period (slow pathway). The presence of dual pathways does not necessarily imply that the patient will have clinical PSVT. In fact, it is estimated that between 10% and 50% of patients have discernible dual pathways, but the incidence of PSVT is considerably lower.69 Sustenance of the tachycardia depends on the critical electrophysiologic discrepancies and the ability of one pathway (usually the slow) to allow repetitive antegrade conduction, and the ability of the other pathway (usually the fast) to allow repetitive retrograde conduction. During SR, a patient with dual pathways conducts supraventricular impulses antegrade through both pathways. Electrical activity reaches the distal common pathway at the level of or above the His bundle and continues to depolarize the ventricles in an antegrade direction. Conduction proceeds via the two pathways but reaches the distal common pathway first through the fast AV nodal route (Fig. 8-7). For this reason, a short PR interval is sometimes observed during SR.


FIGURE 8-7 Reentry mechanism of dual AV nodal pathway PSVT. A. Sinus rhythm: the impulse travels from the atrium through the fast pathway (F) and then to the His-Purkinje system (His). The impulse also travels through the slow pathway (S) but is stopped when refractory tissue is encountered. B. Dual AV nodal reentry: a critically timed premature impulse (*) is stopped in the fast pathway (because of prolonged refractoriness) but is able to travel antegrade down the slow pathway and retrograde through the fast pathway. (AV, atrioventricular; PSVT, paroxysmal supraventricular tachycardia.)

PSVT caused by AV nodal reentry may occur by the following sequence of events. The occurrence of an appropriately timed premature impulse penetrates the AV node but is blocked in the fast pathway that is still refractory from the previous beat. However, the slow pathway, which has a shorter refractory period, permits antegrade conduction of the premature impulse. By the time the impulse has reached the distal common pathway, the fast pathway has recovered its excitability and now will permit retrograde conduction. The impulse reaches the common proximal pathway, preceded by an excitable gap of tissue, and reenters the slow pathway. A reentrant circuit that does not require atrial or ventricular tissue is completed within the AV node, and a tachycardia is thereby initiated (Fig. 8-7). The common form of this tachycardia uses the slow pathway for antegrade conduction and the fast pathway for retrograde conduction; an uncommon form exists in which the reentrant impulse travels in the opposite direction.

AV reentrant tachycardia depends on the presence of an anomalous, or accessory, extranodal pathway that bypasses the normal AV conduction pathway. Several different types of accessory pathways have been described, depending on the specific anatomic areas they connect (e.g., AV bundles or nodoventricular tracts); some are also referred to as eponyms, such as the Kent’s bundle. A Kent’s bundle is an extranodal AV connection that is associated with Wolff-Parkinson-White (WPW) syndrome. During SR (Fig. 8-8), patients with WPW syndrome depolarize the ventricles simultaneously through both AV pathways (AV nodal pathway and the Kent’s bundle), creating a fusion pattern on the early portion of the QRS complex (delta wave). The degree of ventricular “preexcitation” depends on the contribution of antegrade ventricular activation through the accessory pathway. Patients may have an accessory pathway that is not evident on ECG, which is referred to as a “concealed” Kent’s bundle. These concealed accessory pathways are often incapable of antegrade conduction and can only accept electrical stimulation in a retrograde fashion. The electrocardiographic expression of preexcitation (delta wave) depends on the location of the accessory pathway, the distance from the wave front of sinus activation, and the conduction characteristics of the various structures involved. It should be noted that (similar to patients with dual AV nodal pathways) not all patients with preexcitation with an accessory AV pathway are capable of having clinical PSVT.


FIGURE 8-8 Reentry mechanism for AV accessory pathway PSVT in Wolff-Parkinson-White syndrome. A. Sinus rhythm: the impulse travels from the atrium to the ventricle by two pathways—the AV node and an accessory bypass pathway. B. AV reentry: a critically timed premature impulse (*) is stopped in the Kent’s bundle (because of prolonged refractoriness) but travels antegrade through the AV node and retrograde through the Kent’s bundle. (AV, atrioventricular; His, His-Purkinje system; LB, left bundle branch; PSVT, paroxysmal supraventricular tachycardia; RB, right bundle branch; SA, sinoatrial.)

Patients with an accessory AV pathway may have three forms of supraventricular tachycardia: orthodromic reentry, antidromic reentry, and/or AF or atrial flutter. AV reentrant PSVT usually occurs by the following sequence of events. Analogous to AV nodal reentry, two pathways (the normal AV nodal pathway and the accessory AV pathway) exist that have different electrophysiologic characteristics. The AV nodal pathway usually has a relatively slower conduction velocity and shorter refractory period, and the accessory pathway has a faster conduction velocity and a longer refractory period. A critically timed premature impulse may be blocked in the accessory pathway because this area is still refractory from the previous sinus beat. However, the AV nodal pathway, with a relatively shorter refractory period, may accept antegrade conduction of the premature impulse. Meanwhile, the accessory pathway may recover its excitability and now allow retrograde conduction. A macroreentrant tachycardia is thereby initiated in which the antegrade pathway is the AV nodal pathway, the distal common pathway is the ventricle, the retrograde pathway is the accessory pathway, and the proximal common pathway is the atrium (Fig. 8-8). This sequence of events (down the AV node, up the Kent’s bundle), termed orthodromic PSVT, is the common variety of reentry in patients with an accessory AV pathway, resulting in a narrow QRS tachycardia. In the uncommon variety, conduction proceeds in the opposite direction (down the Kent’s bundle, up the AV node), resulting in a wide QRS tachycardia, which is termed antidromic PSVT. Patients with WPW syndrome can have a third type of tachycardia, namely, AF. The occurrence of AF in the setting of an accessory AV pathway (i.e., WPW syndrome) can be extremely serious. As AF is an extremely rapid atrial tachycardia, conduction can proceed down the accessory AV pathway, resulting in a very fast ventricular response or even VF. Unlike the AV nodal pathway, the refractory period of the accessory bundle shortens in response to rapid stimulation rates.

Sinus node reentry and intraatrial reentry occur less commonly and are not as well described as AV nodal reentry and AV reentry. Aside from a characteristic abrupt onset and termination, coupled with subtle changes in P-wave morphology, these tachycardias can be difficult to diagnose. Electrophysiologic studies may be necessary to determine the ultimate mechanism of the PSVT.


Both pharmacologic and nonpharmacologic methods have been used to treat patients with PSVT. Drugs used in the treatment of PSVT can be divided into three broad categories: (a) those that directly or indirectly increase vagal tone to the AV node (e.g., digoxin); (b) those that depress conduction through slow, calcium-dependent tissue (e.g., adenosine, β-blockers, and non-DHP CCBs); and (c) those that depress conduction through fast, sodium-dependent tissue (e.g., quinidine, procainamide, disopyramide, and flecainide). Drugs within these categories alter the electrophysiologic characteristics of the reentrant substrate so that PSVT cannot be sustained. In PSVT caused by AV nodal reentry, class I AADs, such as flecainide, act primarily on the retrograde fast pathway. Digoxin and β-blockers may work on either the retrograde fast or the antegrade slow pathway. Verapamil, diltiazem, and adenosine prolong conduction time and increase refractoriness, primarily in the slow antegrade pathway of the reentrant loop. In PSVT caused by AV reentry incorporating an extranodal pathway, class I AADs increase refractoriness in the fast accessory pathway or within the His-Purkinje system. β-Blockers, digoxin, adenosine, and verapamil all act by their effects on the AV nodal (antegrade, slow) portion of the reentrant circuit. Regardless of the mechanism, treatment measures are directed first at terminating an acute episode of PSVT and then at preventing symptomatic recurrences of the arrhythmia.

For those patients with PSVT who present with severe symptoms (i.e., syncope, near syncope, angina, or severe HF), synchronized DCC is the treatment of choice. Even at low energy levels (such as 25 J), DCC is almost always effective in quickly restoring SR and correcting symptomatic hypotension. Patients with only mild-to-moderate symptoms usually do not require DCC, and nonpharmacologic measures that increase vagal tone to the AV node can be used initially. Vagal techniques, such as unilateral carotid sinus massage, Valsalva maneuver, ice water facial immersion, or induced retching, are often successful in terminating PSVT, although carotid massage and Valsalva maneuver are the simplest, least obtrusive, and most frequently used of these techniques.

In the event that vagal maneuvers fail (approximately 80% of acute episodes) in those patients with tolerable symptoms, drug therapy is the next option. Figure 8-9 shows a therapeutic approach to the acute treatment of the different forms of reentrant PSVT. Images This approach is based on analysis of the electrocardiographic characteristics of the rhythm because PSVT is not always discernible from other arrhythmias, and some forms of PSVT require different treatment. In patients with a narrow QRS, regular arrhythmia (AV nodal reentry or orthodromic AV reentry), IV verapamil (5 to 10 mg), IV diltiazem (15 to 25 mg), and adenosine (6 to 12 mg) are all equally efficacious. Approximately 80% to 90% of PSVT episodes will revert to SR within 5 minutes of these drug therapies.70 The most recent guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care (ECC) from the AHA,71 and practice guidelines from the ACC/AHA/ESC,61 promote adenosine as the drug of first choice in patients with PSVT. Images These recommendations are particularly important when treating a patient who presents with a wide QRS, regular tachycardia that may be VT or PSVT (antidromic AV reentry or as a result of aberrancy). Because of its ultrashort duration of action (seconds), adenosine will not cause the severe and prolonged hemodynamic compromise seen in patients with VT who were mistakenly treated with verapamil and suffered from its negative inotropic effects and vasodilator properties.72 If, in fact, the arrhythmia is PSVT, adenosine will likely terminate it. An alternative treatment for this type of patient is IV procainamide, which works on the fast, sodium-dependent extranodal pathway and is also effective for VT. Likewise, IV procainamide, or perhaps IV amiodarone (particularly in patients with LV dysfunction) should be used for the patient who presents with a wide QRS, irregular arrhythmia that is hemodynamically stable.71 This rhythm could represent AF with rapid ventricular activation occurring primarily through an extranodal pathway. Administration of IV verapamil, diltiazem, digoxin, or adenosine to these patients may result in a paradoxical increase in ventricular response, causing severe symptoms requiring cardioversion. Consequently, these drugs are considered contraindicated in this specific setting.


FIGURE 8-9 Algorithm for the treatment of acute (top portion) PSVT and chronic prevention of recurrences (bottom portion). Note: For empiric bridge therapy prior to radiofrequency ablation procedures, CCBs (or other AV nodal blockers) should not be used if the patient has AV reentry with an accessory pathway. (AAD, antiarrhythmic drug; AF, atrial fibrillation; AP, accessory pathway; AV, atrioventricular; AVN, atrioventricular nodal; AVNRT, atrioventricular nodal reentrant tachycardia; AVRT, atrioventricular reentrant tachycardia; CCBs, calcium channel blockers; DCC, direct current cardioversion; ECG, electrocardiogram; EPS, electrophysiologic studies; PRN, as needed; PSVT, paroxysmal supraventricular tachycardia; VT, ventricular tachycardia.)

Once the acute episode of PSVT is terminated, a decision on long-term preventive therapy must follow. Most patients require long-term therapy; preventive treatment is indicated if (a) frequent episodes occur that necessitate therapeutic intervention (i.e., emergency department visits or interference with the patient’s lifestyle) or (b) infrequent but severely symptomatic symptoms occur. For those patients in whom a preventive treatment is deemed necessary, two methods of management have been used: preventive drug therapy and ablation.

AADs are no longer the treatment of choice to prevent recurrences of reentrant PSVT for the following reasons: (a) lifelong treatment is necessary in these generally young, but otherwise healthy, individuals; (b) there are few, if any, large controlled or comparative trials to assist the clinician in rationally choosing effective agents; and (c) most importantly, other nonpharmacologic treatments are clearly more effective. Nevertheless, drug therapy may occasionally be necessary in some patients, particularly those with mild symptoms and infrequent recurrences. A trial-and-error approach may be used, complemented by the use of ambulatory electrocardiographic recordings (Holter) or telephonic transmissions of cardiac rhythm (event monitors) to objectively document the efficacy or failure of the chosen drug regimen. Drugs known to be effective in preventing recurrences of PSVT are the AV nodal blocking drugs (digoxin, β-blockers, non-DHP CCBs, and combinations of these agents) and the class Ic AADs (flecainide, propafenone). Drugs such as quinidine, disopyramide, amiodarone, and dofetilide, although effective in some patients, should be discouraged because of the risk of toxicity with long-term treatment.

Transcutaneous catheter ablation using radiofrequency current on the PSVT substrate has dramatically altered the traditional treatment of these patients (Fig. 8-10).Images Radiofrequency energy delivered through a transvenous or arterial catheter causes small, discrete lesions through thermal energy. During invasive electrophysiologic studies, portions of the reentrant circuit can be located (or mapped) by the use of a number of catheters. Once this is completed, radiofrequency energy is applied, creating thermal injury in the tissue necessary for reentry. In this way, the substrate for reentry is destroyed, “curing” the patient of recurrent episodes of PSVT and obviating the need for chronic drug therapy. Complications, although unusual, include tamponade, pericarditis, valvular insufficiency, and AV block. Radiofrequency ablation is highly effective, preventing the recurrences of PSVT in 85% to 98% of patients.73,74 The procedure was originally used in patients with WPW syndrome.73 In these patients, the extranodal pathway is most often located at the left lateral free wall of the left ventricle (Fig. 8-10). After the pathway is located, the catheter is put as close to the site as possible, and radiofrequency current is applied to make small burns in the tissue. Ablation of the extranodal connection occurs promptly, and evidence of preexcitation (delta waves) disappears. Thereafter, a similar approach was developed for patients with AV nodal reentry, placing the catheter in the coronary sinus, proximal to the AV node.74 The preferred method in these individuals is to apply small amounts of radiofrequency current to the slow pathway of the reentrant circuit in order to modify its properties enough so that PSVT cannot recur.


FIGURE 8-10 Drawing showing catheter placement for radio-frequency ablation of a left lateral free wall accessory pathway. Here, a venous (atrial) transseptal puncture to gain access to the Kent’s bundle is shown; a retrograde arterial approach has also been used. (Data from Lerman BB, Basson CT. High risk patients with ventricular preexcitation: A pendulum in motion. N Engl J Med 2003;349:1787–1789. Copyright © 2003 Massachusetts Medical Society. All rights reserved.)

It has been suggested that all patients with symptomatic PSVT undergo radiofrequency catheter ablation.75 This is because the procedure is highly effective and curative, rarely results in complications, and obviates the need for chronic AAD therapy. In other words, radiofrequency catheter ablation should be considered in any patient who would previously be considered for chronic AAD treatment. Radiofrequency ablation is also a cost-effective approach (in the long term) because, if effective, the costs of drugs and repeated hospital visits are avoided. In one cost-effectiveness analysis, radiofrequency ablation improved quality of life and reduced lifetime medical expenditures by nearly $30,000 compared with chronic drug treatment.76


The common ventricular arrhythmias include (a) premature ventricular complexes (PVCs), (b) VT, and (c) VF. These arrhythmias may result in a wide variety of symptoms. PVCs often cause no symptoms or only mild palpitations. VT may be a life-threatening situation associated with hemodynamic collapse or may be totally asymptomatic. VF, by definition, is an acute medical emergency necessitating CPR.

Premature Ventricular Complexes and Prevention of Sudden Cardiac Death

PVCs are very common ventricular rhythm disturbances that occur in patients with or without SHD. Experimental models show that PVCs may be elicited by abnormal automaticity, triggered activity, or reentrant mechanisms. It is well known that PVCs are commonly observed in apparently healthy individuals; in these patients, the PVCs seem to have little, if any, prognostic significance. PVCs occur more frequently and in more complex forms in patients with SHD than in healthy individuals. The prognostic meaning of PVCs has been well studied in patients with MI (acute or remote) with several consistent themes. Patients with some forms of PVCs are at higher risk for SCD than if they did not have these minor rhythm disturbances. SCD can be defined as unexpected death occurring in a patient within 1 hour of experiencing symptoms. Studies of patients who experienced SCD (and happened to be wearing an electrocardiographic monitor at the time) often demonstrate the cause to be VF preceded by a short run of VT and frequent PVCs.77


Historically, investigators promoted the concept that patients in the acute phase of MI may have types of PVCs that are predictive of VF and SCD. These types of PVCs were referred to as “warning arrhythmias” and included frequent ventricular ectopy (more than 5 beats/min), multiform configuration (different morphology), couplets (two in a row), and R-on-T phenomenon (PVCs occurring during the repolarization phase of the preceding sinus beat in the vulnerable period of ventricular recovery). However, as a result of using continuous electrocardiographic monitoring techniques, it has become apparent that almost all patients have warning arrhythmias in the acute MI setting. In those patients who experience VF, warning arrhythmias are no more common than in those without VF. Consequently, warning arrhythmias observed during acute MI are neither sensitive nor specific for determining which patients will have VF. Thus, there is little need to direct drug therapy specifically at PVC suppression in these particular patients. Studies show that effective prevention of VF in the acute MI setting may be achieved without the abolition of PVCs.

CLINICAL PRESENTATION Ventricular Arrhythmias


    • PVCs are non–life-threatening and usually asymptomatic. Occasionally, patients will complain of palpitations or uncomfortable heartbeats. Since the PVC, by definition, occurs early and the ventricle contracts when it is incompletely filled, patients do not feel the PVC. Rather, the next beat (after the PVC and a compensatory pause) is usually responsible for the patient’s symptoms.


    • The symptoms of VT (monomorphic VT or TdP), if prolonged (i.e., sustained), can vary from nearly completely asymptomatic to pulseless, hemodynamic collapse. Fast heart rates and underlying poor LV function will result in more severe symptoms. Symptoms of nonsustained, self-terminating VT also correlate with duration of episodes (e.g., patients with 15-second episodes will be more symptomatic than those with three-beat episodes).


    • By definition, VF results in hemodynamic collapse, syncope, and cardiac arrest. Cardiac output and blood pressure are not recordable.

Conversely, data strongly imply that PVCs documented in the convalescence period of MI do carry important long-term prognostic significance.78 PVCs occurring after an MI seem to be a risk factor for patient death that is independent of the degree of LV dysfunction or the extent of coronary atherosclerosis. Ruberman et al.78 employed a simple classification of PVCs: simple or benign (infrequent and monomorphic) versus “complex” (≥5 PVCs/min, couplets, R-on-T beats, and multiform). These investigators found that the presence of complex (but not simple) ventricular ectopy in the setting of CAD was associated with a higher incidence of overall mortality and cardiac death.

Because PVCs without associated SHD, in apparently healthy individuals, carry little or no risk, drug therapy is unnecessary. However, because of the prognostic significance of complex PVCs in patients with SHD, the use of AAD therapy to suppress them has been controversial. Historically, many supported the aggressive use of AAD therapy to suppress PVCs, based on the underlying premise of eliminating a risk factor for SCD in patients with CAD (namely, the presence of complex PVCs). However, others favored a more conservative approach and disregarded the use of AAD therapy in the absence of significant symptoms. An important study, the CAST,46 abruptly put an end to this debate in noteworthy fashion; its results are reviewed in the following section because of its great historical significance and lingering impact.

The Cardiac Arrhythmia Suppression Trial

The CAST46,79 was initiated by the National Institutes of Health in 1987 to determine if suppression of ventricular ectopy with encainide, flecainide, or moricizine could decrease the incidence of death from arrhythmia in patients who had suffered an MI. Images Entrance criteria included documented MI between 6 days and 2 years prior to enrollment, and ≥6 PVCs/h (associated with no or minimal symptoms) without runs of VT >15 beats in length. Also, patients were required to have an LVEF ≤55% if recruited within 90 days of the MI or an LVEF ≤40% if recruited ≥90 days after the MI. Patients with an LVEF <30% were randomized only to encainide or moricizine. Patients were randomized to receive AAD therapy or placebo after demonstrating PVC suppression with one of the agents.

In April 1989, a routine, preliminary review of the study by the Safety and Monitoring Board revealed alarming results, and the study was interrupted. The results showed that when compared with placebo, treatment with encainide or flecainide was associated with a significantly higher rate of total mortality and death due to arrhythmia, presumably caused by proarrhythmia. Analysis of the moricizine arm indicated neither harm nor benefit from this therapy; therefore, only this portion of the study was allowed to continue as CAST II.79 However, in July 1991, CAST II was also prematurely discontinued because there was a trend toward an increase in mortality in moricizine-treated patients. This increase in mortality was primarily observed during the initiation of moricizine (dose titration phase) but not during the chronic treatment phase. The overall results of the two CASTs conclusively prove that the use of AAD therapy (beyond the general use of β-blockers) to suppress PVCs in patients after an MI does not improve survival and is most likely detrimental.

Even though the CAST was conducted more than 2 decades ago, it is considered one of the most important trials ever undertaken and has had a tremendous influence on the overall approach to the treatment of arrhythmias, as well as a far-reaching impact on AAD development. The results of the CAST have clearly had a negative influence on the long-term use of all AADs, causing a broad skepticism in the risk-versus-benefit analysis of this class of drugs. Consequently, pharmaceutical companies have shifted their drug discovery and investigative efforts away from potent sodium channel blockers. The findings of the CAST have also provided additional fuel for the pursuit of nonpharmacologic therapies for arrhythmias, such as ablation and implantable devices.

Despite the discouraging results of the CAST, post-MI patients with complex ventricular ectopy remain at risk for death. Other drugs, besides the class Ic AADs, have been studied in this patient population, including sotalol. Sotalol is marketed as a racemic mixture of a D and L isomers: both are class III potassium channel blockers but the L isomer has β-blocking actions. Chronic therapy with D-sotalol was studied in patients with a remote MI complicated by complex ectopy in the Survival with Oral D-Sotalol trial.80 In this trial, D-sotalol treatment was not designed to cause PVC suppression (unlike the CAST), yet (like the CAST) the trial was halted prematurely because of excessive mortality in the treatment arm. Again, the presumed reason for this observation was D-sotalol–related proarrhythmia. Currently, only two AADs have been shown not to increase mortality in post-MI patients with long-term use: amiodarone and dofetilide. A number of trials81,82 have shown amiodarone to decrease the incidence of sudden (or arrhythmic) death, but not total mortality, in post-MI patients with complex ventricular ectopy. A meta-analysis of all trials (6,553 combined patients) demonstrated a reduction in total mortality (by 13%) with long-term amiodarone therapy.83 It is unclear if these findings can be attributed to one of amiodarone’s electrophysiologic properties (e.g., β-blocking) or a combination of its complex pharmacologic effects on conduction. It is noteworthy to mention that in two major studies, patients treated with amiodarone and a β-blocker generally did better than when no β-blocker was used.81,82 Clearly, because of its impressive side effect profile and its inability to improve survival, amiodarone should not routinely be recommended in patients with heart disease such as remote MI and complex PVCs. Two randomized controlled trials84,85 have also shown that chronic therapy with dofetilide has no effect on overall mortality in post-MI patients with LV dysfunction.

How should the clinician approach the patient with documented asymptomatic PVCs? Clearly, attempts to suppress asymptomatic PVCs should not be made with any AAD. Indeed, those patients who are at risk for arrhythmic death (recent MI, LV dysfunction, complex PVCs) should also not be routinely given any class I or III AAD.86 If these patients have symptomatic PVCs, chronic drug therapy should be limited to the use of β-blockers. The use of β-blockers in post-MI patients is associated with a decrease in the incidence of total mortality and SCD, especially in the presence of LV dysfunction. β-Blockers can also be used in patients without underlying SHD to suppress symptomatic PVCs. Images

Ventricular Tachycardia

Mechanisms and Types of VT

VT is a wide QRS tachycardia that may acutely occur as a result of metabolic abnormalities, ischemia, or drug toxicity, or chronically recur as a paroxysmal form. On ECG, VT may appear as either repetitive monomorphic or polymorphic ventricular complexes. The definition of VT is three or more consecutive PVCs occurring at a rate >100 beats/min. An acute episode of VT may be precipitated by severe electrolyte abnormalities (hypokalemia or hypomagnesemia), hypoxia, or digoxin toxicity, or (most commonly) may occur during an acute MI or ischemia complicated by HF. In these cases, correction of the underlying precipitating factors will usually prevent further recurrences of VT. As an example, if VT occurs during the first 24 hours of an acute MI, it will probably not reappear on a chronic basis after the infarcted area has been reperfused or healed with scar formation. This form of acute VT may be caused by a transient reentrant mechanism within temporarily ischemic or dying ventricular tissue. In contrast, some patients have a chronic recurrent form of VT that is almost always associated with some type of underlying SHD. Common examples are paroxysmal VT associated with idiopathic dilated cardiomyopathy or remote MI with an LV aneurysm. In chronic, recurrent VT, microreentry within the distal Purkinje network is presumed to be responsible for the underlying substrate in a large majority of patients (Fig. 8-3). Theoretically, electrophysiologic discrepancies occur as a result of structural damage and heart disease within the ventricular conducting system. The reentrant circuit may possess both anatomically determined and functional properties coursing through normal tissue, damaged (but not dead) tissue, and islands of necrosed tissue. In a minority of patients, macroreentrant circuits may be responsible for recurrent VT, including reentry incorporating the bundle branches.

Patients with acute VT associated with a precipitating factor often suffer severe symptoms, requiring immediate treatment measures. Chronic recurrent VT may also cause severe hemodynamic compromise but may also be associated with only mild symptoms that are generally well tolerated. Sustained VT is that which requires therapeutic intervention to restore a stable rhythm or persists for a relatively long time (usually >30 seconds). Nonsustained VT is that which self-terminates after a brief duration (usually <30 seconds). If the patient has VT more frequently than SR (i.e., VT is the dominant rhythm), this is referred to as incessant VT. In monomorphic VT, the QRS complexes are similar in morphologic characteristics from beat to beat. In polymorphic VT, the QRS complexes vary in shape and/or size between beats. A characteristic type of polymorphic VT, in which the QRS complexes appear to undulate around a central axis and that is associated with evidence of delayed ventricular repolarization (long QT interval or prominent U waves), is referred to as TdP.

Most but not all forms of recurrent VT occur in patients with extensive SHD. VT occurring in a patient without SHD is sometimes referred to as idiopathic VT and may take several forms.8789 Fascicular VT arises from a fascicle of the left bundle branch (usually posterior) and is usually not associated with severe underlying SHD. In distinct contrast to the common form of recurrent VT associated with extensive SHD, non-DHP CCBs (but not adenosine) are effective in terminating an acute episode of fascicular VT. Ventricular outflow tract VT (usually originating from the right ventricular outflow tract) originates from near the pulmonic valve (or uncommonly the aortic valve or LV outflow tract) and also occurs in patients with normal LV function without discernible SHD.89 Unlike other forms of VT, right ventricular outflow tract VT often terminates with adenosine and may be prevented with β-blockers and/or non-DHP CCBs.

Some unusual forms of VT are congenital or heritable (Table 8-10). TdP can be associated with heritable defects in the flux of ions that govern ventricular repolarization. Although multiple syndromes and genetic mutations have been described, the more common examples are long QT syndrome 1 (depressed IKs), long QT syndrome 2 (depressed IKr), and long QT syndrome 3 (enhanced inward sodium ion flux during repolarization).90,91 Polymorphic VT (without a long QT interval) or VF may also occur as a result of a heritable defect in the sodium channel. This is the case in Brugada syndrome, which is described as a typical ECG pattern (ST-segment elevation in leads V1 to V3) in SR that is associated with SCD, and commonly occurs in males of Asian descent.92

TABLE 8-10 Heritable Polymorphic Ventricular Tachycardia



Consider the patient with the more common form of sustained monomorphic VT (i.e., those with SHD, usually ischemic in nature). Like other rapid tachycardias, the initial management of an acute episode of VT (with a pulse) requires a quick assessment of the patient’s status and symptoms. If severe symptoms are present (i.e., severe hypotension, angina, pulmonary edema), synchronized DCC should be delivered immediately to attempt to restore SR. An investigation should be made into possible precipitating factors, and these should be corrected if possible. The diagnosis of acute MI should always be entertained. If the episode of VT is thought to be an isolated electrical event associated with a transient initiating factor (such as acute myocardial ischemia or digoxin toxicity), there is no need for long-term AAD therapy once the precipitating factors are corrected (e.g., an MI has been reperfused and healed and the patient is stable). Nevertheless, the patient should be monitored closely for possible recurrences of VT.

Patients presenting with an acute episode of VT (with a pulse) associated with only mild symptoms can be initially treated with AADs. The reader is referred to the most recent AHA guidelines for CPR and ECC.71 IV procainamide, amiodarone, or sotalol can be considered in this situation. Lidocaine can be considered as an alternative. In one small study, procainamide was shown to be superior to lidocaine in terminating VT.93 Synchronized DCC should be delivered if the patient’s status deteriorates, VT degenerates to VF (would be unsynchronized in this situation), or drug therapy fails.

Once an acute episode of sustained VT has been successfully terminated by electrical or pharmacologic means and an acute MI has been ruled out, the possibility of a patient having recurrent episodes of VT should be considered. Evidence for the possibility of VT recurrence can often be gleaned from invasive electrophysiologic studies using programmed ventricular stimulation. Because these patients are at extremely high risk for death, trial-and-error attempts to find effective therapy are unwarranted. To gain some objective evidence of a response to a specific AAD regimen, serial testing of these drugs using the following two surrogate end points has been used: (a) inability to induce sustained VT with programmed extrastimuli by invasive electrophysiologic studies and (b) suppression of ventricular ectopic beats by serial 24-hour continuous electrocardiographic (Holter) monitoring. These two strategies have been compared94,95 but largely abandoned for several reasons. First, the yield for finding an effective AAD is low. For instance, sustained monomorphic VT can be rendered noninducible or nonsustained by programmed stimulation protocols in only 20% to 25% of patients. Therefore, the clinician frequently must search for other therapeutic options or settle for other treatment end points such as slower and more tolerable inducible VT. Second, amiodarone is clearly the most effective (approximately 50% effective after 2 years) AAD in patients with recurrent VT; however, electrophysiologic drug testing does not necessarily predict the clinical efficacy of amiodarone. Patients may have continued inducibility of VT on amiodarone despite long-term success. Indeed, empiric amiodarone has been compared with therapy (with other AADs) guided by electrophysiologic testing in patients at high risk for recurrent VT.96 In this trial, amiodarone therapy without invasive testing was superior in preventing SCD and recurrences of severe ventricular arrhythmias at all time points. Third, the recurrence rate of life-threatening VT is high (20% to 50% per year depending on the AAD chosen), regardless of the method of acute drug testing. Fourth, as referred to previously, there is a substantial side effect profile of the class I and III AADs. Lastly, and perhaps most importantly, is the impressive demonstrated effectiveness of nonpharmacologic approaches to the treatment of recurrent VT/VF.97 For instance, some forms of recurrent VT are amenable to catheter ablation therapy using radiofrequency current. This approach is highly effective (approximately 90%) in idiopathic VT (right ventricular outflow tract or fascicular VT), but less so in recurrent VT associated with a cardiomyopathic process or remote MI with LV aneurysm. In the latter patients, ablation is usually regarded as second-line therapy after other methods have failed. Additionally, numerous trials have established the ICD as a superior treatment over AAD therapy not only for the prevention of SCD in patients who have been resuscitated from an episode of cardiac arrest or had sustained VT (“secondary prevention”) but also for the prevention of an initial episode of SCD in certain high-risk patient populations (“primary prevention”).

The Implantable Cardioverter-Defibrillator The introduction of and advances in the ICD (Fig. 8-11) have obviated the need to rely solely on the use of AADs to prevent episodes of life-threatening ventricular arrhythmias.98 ImagesNumerous advancements in device technology have allowed the ICD to become smaller, less invasive to implant, and programmable with advanced functions. Early ICDs required a thoracotomy to place the generator in the abdomen, whereas with the newer, smaller models, the leads are implanted transvenously with the generator placed into the pectoral region in a manner similar to cardiac pacemakers. Modern ICDs now employ a “tiered-therapy approach,” meaning that overdrive pacing (i.e., antitachycardia pacing) can be attempted first to terminate the tachyarrhythmia (no painful shock delivered), followed by low-energy cardioversion, and, finally, by high-energy defibrillation shocks. In addition, backup antibradycardia pacing and extended battery lives have made these newer devices much more attractive. All models store recordings during delivery of pacing shocks, which is extremely important in discerning appropriate shocks (i.e., delivers shock for serious ventricular arrhythmia) from inappropriate shocks (i.e., delivers shock for AF with rapid ventricular rate) and in documenting true recurrences of the patient’s tachycardia.


FIGURE 8-11 Drawing showing implantable cardioverter-defibrillator. (Data from reference 98. Copyright © 2003 Massachusetts Medical Society. All rights reserved.)

Although the ICD is a highly effective method for preventing SCD due to recurrent VT or VF, several problems remain. First, the device itself, the implantation procedure, electrophysiologic studies, hospitalization, and physician fees are costly. Given that the indications for receiving an ICD have significantly expanded over the past several years, the total cost associated with the implantation of this device is likely to place a great burden on the healthcare system. Second, many patients (as high as 70% of patients) with ICDs end up receiving concomitant AAD therapy (usually amiodarone or sotalol).99,100 AADs can be initiated in these patients for a number of reasons, including (a) decreasing the frequency of VT/VF episodes to subsequently reduce the frequency of appropriate shocks; (b) reducing the rate of VT so that it can be terminated with antitachycardia pacing; and (c) decreasing episodes of concomitant supraventricular arrhythmias (e.g., AF, atrial flutter) that may trigger inappropriate shocks. As a result of these potential benefits, the concomitant use of AADs can minimize patient discomfort and prolong the battery life of the ICD. The decision to initiate concomitant AAD therapy should be individualized, with treatment usually being reserved for those with frequent shocks because of VT or AF. If AADs are added to ICD therapy, one should note that many of these drugs alter defibrillation thresholds; consequently, the device may need to be reprogrammed to account for this alteration.101

Secondary Prevention of Sudden Cardiac Death The results of three trials, the Antiarrhythmics Versus Implantable Defibrillators (AVID), Cardiac Arrest Study Hamburg (CASH), and Canadian Implantable Defibrillator Study (CIDS), definitively support the ICD as first-line therapy for the secondary prevention of SCD.102104 Of these, the AVID trial was the largest, randomizing more than 1,000 patients with resuscitated VF, sustained VT with syncope, or hemodynamically significant sustained VT (with LVEF ≤40%) to either an ICD or AADs (∼95% received amiodarone at discharge).102 The trial was stopped early because of a demonstrated superiority of the ICD; patients in the ICD group had a better overall survival when compared with those in the AAD group (75% vs. 64%, respectively, at 3 years). Although they were smaller trials, both CASH and CIDS demonstrated the efficacy of an ICD compared with amiodarone in patients with a history of sustained VT or VF, with the ICD reducing overall mortality by 20% to 25%.103,104 Overall, the results of these three trials provide strong support for the aggressive use of the ICD in patients who are at high risk for recurrent, life-threatening ventricular arrhythmias.

Primary Prevention of Sudden Cardiac Death One of the patient populations that appears to be at high risk for a first episode of SCD includes those with a prior MI, LV dysfunction, and nonsustained VT. The use of AADs to prevent SCD in this high-risk group has been significantly limited by the results of the CAST and other similar trials that have collectively demonstrated that these drugs may actually increase the risk of mortality in these patients. As a result of these trials, clinicians have sought a more clearly defined strategy for risk stratification in these patients before initiating drug therapy.

Traditionally, there are three strategies to approach the treatment of nonsustained VT: (a) conservative (i.e., no AAD treatment beyond β-blockers); (b) empiric amiodarone; and (c) aggressive (i.e., electrophysiologic studies with possible insertion of an ICD) (Fig. 8-12).Images A number of early studies105,106 suggested that tests such as electrophysiologic studies could be used to determine long-term risk in patients with nonsustained VT. For instance, Wilber et al.105 demonstrated that post-MI patients with nonsustained VT and inducible sustained VT after programmed stimulation were at increased risk for subsequent VT/VF or SCD compared with those in whom sustained VT could not be induced. These data provided the basis for the Multicenter Automatic Defibrillator Implantation Trial (MADIT) and the Multicenter Unsustained Tachycardia Trial (MUSTT).107,108 The MADIT was the first of these trials to be conducted to evaluate the efficacy of ICD therapy in this high-risk patient population. Specifically, this trial randomized patients with a previous MI, LVEF ≤36%, asymptomatic nonsustained VT, and inducible VT that was not suppressed with the use of IV procainamide to receive an ICD or conventional medical therapy (74% received amiodarone).107 This trial was terminated prematurely after a significant survival benefit was detected in the ICD group. The findings of the MADIT were subsequently supported by those of the MUSTT. In the MUSTT, patients with a history of MI, LVEF ≤40%, asymptomatic nonsustained VT, and inducible sustained VT were randomized to a conservative approach (no AAD therapy beyond β-blockers) or electrophysiologically guided therapy (AADs and/or ICD).108 The results showed that the conservative approach had a significantly higher event rate (cardiac arrest or death from arrhythmia). However, when the results of the electrophysiologically guided group were further stratified, those receiving only AADs (no ICD) were no different in terms of outcomes than those who received no treatment. In other words, only those treated with an ICD had a significantly lower event rate and greater survival. One problem with the MUSTT, however, is that, because the trial was initiated in 1989, nearly 50% of patients received class I AADs or drugs that are now known not to improve survival in patients with CAD, LV dysfunction, and ventricular arrhythmias; only 10% of patients received the most effective agent in this setting, amiodarone. Based on the results of the MADIT and MUSTT, it is reasonable for patients with CAD, LV dysfunction, and nonsustained VT to undergo electrophysiologic testing.109 If these patients do not have inducible sustained VT/VF, chronic AAD therapy is unnecessary; however, if these patients do have inducible sustained VT/VF, implantation of an ICD is warranted.


FIGURE 8-12 Algorithm for the primary prevention of SCD in patients with a history of MI or with a nonischemic dilated cardiomyopathy. aIn these patients, the β-blocker is being used to reduce post-MI mortality. bPatients should be >40 days post-MI prior to insertion of the ICD. cPatients with an ischemic cardiomyopathy should be >40 days post-MI prior to insertion of the ICD. (EPS, electrophysiologic study; HF, heart failure; ICD, implantable cardioverter-defibrillator; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSVT, nonsustained VT; SCD, sudden cardiac death; VF, ventricular fibrillation; VT, ventricular tachycardia.)

Although the MADIT and MUSTT provide clinicians with important information regarding risk stratification, both of these trials targeted patients who had a history of nonsustained VT. The results of two landmark trials, the MADIT II and Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), have provided clinicians with additional information regarding the treatment of other groups of high-risk patients who have no prior history of ventricular arrhythmia (Fig. 8-13).110,111 In the MADIT II, patients with a prior MI and LVEF ≤30% were randomized to receive either an ICD or a conventional therapy (routine post-MI and HF therapy).110 Neither a history of ventricular arrhythmia nor electrophysiologic testing was required for inclusion in this study. Patients in the ICD group experienced a significant reduction in mortality when compared with the conventional therapy group; the reduction in mortality in the ICD group was primarily due to a reduction in arrhythmic death. Whereas the MADIT, MUSTT, and MADIT II limited enrollment to patients with ischemic cardiomyopathy, the SCD-HeFT is the largest trial, to date, to evaluate the efficacy of an ICD in a nonischemic HF population. In this trial, patients with NYHA class II or III HF (of either ischemic or nonischemic etiology) and LVEF ≤35% were randomized to receive placebo, amiodarone, or an ICD.111 All patients were treated with appropriate HF therapies, as indicated. Implantation of an ICD resulted in a significantly lower mortality rate compared with treatment with either placebo or amiodarone (there was no difference between placebo and amiodarone). The survival benefits of the ICD were observed regardless of the etiology of the HF.


FIGURE 8-13 Torsade de pointes caused by quinidine. Note the presence of a couplet and two triplets following each extra systolic pause. The pause gets progressively longer until it is long enough to result in an episode of sustained torsade de pointes. Also, as the pause lengthens, discernible U waves (labeled ↑) (EADs?) begin to appear. The amplitude of the U wave is somewhat greater with the longest pause. (Reproduced with permission from Bauman JL. Drug safety: Cardiac arrhythmias. Antihistamine update symposium. Hosp Med 1995;31:24.)

Overall, as the ICD trials have evolved over the past decade, the indications for implanting these devices have significantly expanded (Table 8-11).112 Based on the results of the MUSTT, MADIT, MADIT II, and SCD-HeFT, many patients will be eligible for an ICD. Images In fact, just based on the results of the MADIT II and SCD-HeFT alone, it was estimated that an additional 500,000 Medicare beneficiaries would qualify for implantation of an ICD for primary prevention of SCD.

TABLE 8-11 Current Indications for ICD Implantation


Ventricular Proarrhythmia

All AADs have the potential to aggravate existing arrhythmias or to cause new arrhythmias. It is believed that AADs may cause proarrhythmia in nearly 30% of patients.8 Many definitions for proarrhythmia have been proposed; however, in the simplest terms, it indicates the development of a significant new arrhythmia (such as VT, VF, or TdP) or worsening of an existing arrhythmia (episodes are longer, faster, or more frequent). As with all arrhythmias, the consequences of proarrhythmia are varied. Some patients who develop proarrhythmia may be totally asymptomatic, others may notice a worsening of symptoms, and some may die suddenly. The development of proarrhythmia results from the same mechanisms that cause arrhythmias in general (e.g., quinidine-induced TdP due to EADs) or from an alteration in the underlying substrate due to the AAD (e.g., development of an accelerated tachycardia caused by flecainide, which decreases conduction velocity without significantly altering the refractory period).8 The diagnosis of proarrhythmia is sometimes difficult to make because of the variable nature of the underlying arrhythmias. However, in all cases, the AAD should be discontinued if proarrhythmia is detected or suspected.

Incessant Monomorphic VT

The prototypical form of proarrhythmia caused by the class Ic AADs is a rapid, sustained, monomorphic VT with a characteristic sinusoidal QRS pattern that is often resistant to resuscitation with cardioversion or overdrive pacing. Images It is sometimes referred to as sinusoidal or incessant VT and is the result of excessive sodium channel blockade and slowed conduction. Sinusoidal VT caused by the class Ic AADs was thought to occur within the first several days of drug initiation; however, the results of the CAST indicate that the risk for this type of proarrhythmia may exist as long as the AAD is continued. Factors that can predispose a patient to this form of proarrhythmia include: (a) the presence of underlying ventricular arrhythmias; (b) CAD; and (c) LV dysfunction. Provocation of proarrhythmia by the class Ic AADs is sometimes reported during exercise, which is most likely a result of augmented slowed conduction at rapid heart rates (i.e., rate-dependent sodium blockade). The incidence of proarrhythmia caused by class Ic AADs is greatest in patients with all three of the above risk factors (approximately 10% to 20%) and extremely uncommon in those without these risk factors, such as patients with supraventricular tachycardias and normal LV function. Other factors that have a less well-defined association with proarrhythmia are elevated AAD serum concentrations and rapid dosage escalation of the AAD. It has been proposed that the presence of underlying ventricular conduction delays may also pose a risk for proarrhythmia. As mentioned earlier, incessant monomorphic VT is often resistant to resuscitation; however, some have had success with lidocaine (“fast on–off” AAD, which successfully competes with a “slow on–off” agent such as flecainide for sodium channel receptor) or sodium bicarbonate (reverses the excessive sodium channel blockade).

Torsade de Pointes

As defined previously, TdP is a rapid form of polymorphic VT (Fig. 8-13) that is associated with evidence of delayed ventricular repolarization (long QT interval or prominent U waves) on ECG. It is important to note that most forms of polymorphic VT occurring in the setting of a normal QT interval are similar to monomorphic VT in terms of etiology and treatment strategies (thus, a long QT interval is crucial to the diagnosis of TdP). Much has been learned about the underlying etiology of TdP. Basic defects (genetic, drugs, or diseases) that delay repolarization by influencing ion movement (usually by blocking potassium efflux) provoke EADs preferentially in cells deep in the heart muscle (termed M cells), which, in turn, trigger reentry and TdP. Drugs that cause TdP usually delay ventricular repolarization in an inhomogeneous way (termed dispersion of refractoriness), which facilitates the formation of multiple reentrant loops in the ventricle.113 TdP may occur in association with hereditary syndromes or as an acquired form (i.e., a result of drugs or diseases). The underlying etiology in both cases is delayed ventricular repolarization due to blockade of potassium conductance. It is possible, however, that some individuals have a partially expressed form of these congenital syndromes but never suffer TdP unless some other external factor (e.g., drugs, diseases, electrolyte disturbances, abrupt heart rate changes) further delays ventricular repolarization. Specifically, acquired forms of TdP are associated with electrolyte disturbances (hypokalemia or hypomagnesemia), subarachnoid hemorrhage, myocarditis, liquid protein diets, arsenic poisoning, severe hypothyroidism, or, most commonly, drug therapy (notably phenothiazines, antibiotics, antihistamines, antidepressants, and AADs) (Table 8-12).Images

TABLE 8-12 Potential Causes of QT Interval Prolongation and Torsade de Pointes


The class Ia AADs (especially quinidine) and class III IKr blockers are most notorious for precipitating TdP; the class Ib and Ic AADs rarely, if ever, cause TdP as they do not appreciably delay repolarization. Most AADs with IKrblocking activity cause TdP in approximately 2% to 4% of patients, with the exceptions being amiodarone and dronedarone (<1%). Risk factors and associated features of drug-induced TdP have been identified and can be summarized as follows33,114: (a) high dosages or plasma concentrations of the offending drug (“dose-related”) (except for quinidine-induced TdP, which tends to occur more frequently at low-to-therapeutic plasma concentrations); (b) concurrent SHD (e.g., CAD, HF, and/or LV hypertrophy); (c) evidence of mild delayed repolarization (prolonged QT interval) at baseline; (d) evidence of a prolonged QT interval shortly after initiation of the offending drug; (e) concomitant electrolyte disturbances such as hypokalemia or hypomagnesemia; (f) female gender; and (g) a characteristic long–short initiating sequence (so-called “pause dependence”) of the episode of TdP (Fig. 8-13). However, none of these associations are absolute prerequisites to the development of drug-induced TdP. For instance, although TdP is usually documented early in the course of quinidine therapy, patients may develop this arrhythmia during chronic treatment.115 The reason for quinidine’s relatively unique propensity for causing TdP at relatively low dosages and plasma concentrations requires explanation. Quinidine’s ability to block IKr is clinically manifest at low plasma concentrations; at higher plasma concentrations, its sodium channel blocking properties predominate. Other drugs that block IKr usually do so in a concentration-dependent fashion. The observation that most patients who suffer drug-induced TdP have evidence of mildly delayed repolarization (long QT intervals) even before they are prescribed the offending drug has stimulated a search for a potential genetically linked risk. Indeed, it appears that at least some patients with acquired drug-induced TdP possess mutations of genes that encode for IKr or IKs.114

The common underlying electrophysiologic cause of TdP is a delay in ventricular repolarization (provoking EADs), which usually results from inhibition (drug-induced or genetic) of IK current and manifests as QT interval prolongation on the ECG. Therefore, the extent of QT interval prolongation has been used as a measurement of risk of TdP; however, considerable controversy exists regarding this practice. Amiodarone, for example, commonly causes significant QT prolongation but is a relatively infrequent cause of TdP. Nonetheless, the QT interval should be measured and monitored in all patients prescribed drugs that have a high potential for causing TdP (Table 8-12). Patients with a baseline QTc interval (QT interval corrected for heart rate, which can be calculated using Bazett’s formula: QTc = QT measured/Images should not be given drugs that have a high potential for causing TdP; an increase in the QTc interval to ≥560 milliseconds after the initiation of the drug is an indication to discontinue the agent or, at least, to reduce its dosage and carefully observe and monitor.

Drug-induced TdP has become an extremely visible hazard plaguing new drugs, sometimes resulting in public health disasters. For instance, several drugs (cisapride, astemizole, levomethadyl, grepafloxacin, sparfloxacin, terfenadine, and high-dose [32 mg] IV ondansetron) have been withdrawn from the market in the United States because of their significant potential for causing TdP. One of the most visible and striking examples of drug withdrawal due to TdP occurred with the popular nonsedating antihistamine, terfenadine. Terfenadine is a potent IKr blocker but is rapidly metabolized by CYP3A4 to an active moiety (fexofenadine) that is not associated with delayed repolarization. Consequently, in the presence of drugs that block the CYP3A4 isoenzyme (e.g., ketoconazole, erythromycin, diltiazem), accumulation of the parent compound, terfenadine, causes clinically significant blockade of IKrthat could result in TdP and even death.116 Because of experiences like this, all new drug entities under investigation are screened for their ability to block IK and cause significant QT prolongation.

Acute treatment of TdP is different than treatment for the more common acute monomorphic VT. For an acute episode of TdP, most patients will require and respond to DCC. However, TdP tends to be paroxysmal in nature and often will rapidly recur after DCC. Therefore, after the initial restoration of a stable rhythm, therapy designed to prevent recurrences of TdP should be instituted. AADs that further prolong repolarization such as IV procainamide are absolutely contraindicated. Lidocaine is usually ineffective. Although there are no true efficacy trials, IV magnesium sulfate, by suppressing EADs, is considered the drug of choice in preventing recurrences of TdP.117 If IV magnesium sulfate is ineffective, treatment strategies designed to increase heart rate, shorten ventricular repolarization, and prevent the pause dependency should be initiated. Either temporary transvenous pacing (105 to 120 beats/min) or pharmacologic pacing (isoproterenol or epinephrine infusion) can be initiated for this purpose. All drugs that prolong the QT interval should be discontinued, and exacerbating factors (e.g., hypokalemia or hypomagnesemia) should be corrected.

Ventricular Fibrillation

Background and Prevention

VF is electrical anarchy of the ventricle resulting in no cardiac output and cardiovascular collapse. Death will ensue rapidly if effective treatment measures are not taken. Patients who die abruptly (within 1 hour of initial symptoms) and unexpectedly (i.e., “sudden death”) usually have VF recorded at the time of death.118 SCD accounts for about 310,000 deaths per year in the United States.15 It occurs most commonly in patients with CAD and those with LV dysfunction; it occurs less commonly in those with WPW syndrome or mitral valve prolapse, and occasionally in those without associated heart disease (e.g., Brugada syndrome). Patients who have SCD (not associated with acute MI) but survive because of appropriate CPR and defibrillation (where warranted) often have inducible sustained VT and/or VF during electrophysiologic studies. These individuals are at high risk for the recurrence of VT and/or VF.

In contrast, patients who have VF associated with acute MI (i.e., within the first 24 hours after symptoms) usually have little risk of recurrence. Of all patients who die as a result of an acute MI, approximately 50% die suddenly prior to hospitalization. VF associated with acute MI can be subdivided into two types: primary VF and complicated or secondary VF. Primary VF occurs in an uncomplicated MI not associated with HF; secondary VF occurs in an MI complicated by HF. The time course, incidence, mechanisms, treatment, and complications of these two forms of VF are different. For example, approximately 2% to 6% of patients with acute MI suffer primary VF within 24 hours of chest pain, but the risk of VF declines rapidly over time and is nearly zero after the initial 24-hour period. Complicated or secondary VF does not follow such a predictable time course and may occur in the late infarction period. The premise of prophylactic AADs administered to all patients with uncomplicated MI is based on (a) the inability to predict which patients are at risk for primary VF and (b) the predictable time course of primary VF (in contrast to complicated VF). Of the prophylactic therapies used, lidocaine has been the most widely debated and studied. Lie et al.119 performed the classic study showing the effectiveness of lidocaine in preventing primary VF. Although lidocaine significantly reduced the incidence of VF compared with placebo, there was no significant difference in mortality due to VF between the groups. These results, along with the effectiveness of rapidly instituted defibrillation in modern coronary care units with sophisticated monitoring techniques, have caused most to reject the notion of prophylactic lidocaine administration for all patients with uncomplicated MI. In support of this, two meta-analyses120,121 concluded against the routine use of prophylactic lidocaine because of a possible increase in mortality in lidocaine-treated patients120 as well as the declining incidence of primary VF documented in recent years (probably a result of the more aggressive and rapid use of β-blockers, thrombolytics, and percutaneous intervention for the treatment of acute coronary syndromes).121

Acute Management

A patient with pulseless VT or VF should be managed according to the most recent AHA guidelines for CPR and ECC.71 A detailed discussion regarding the acute management of pulseless VT/VF can be found in Chapter 2.


The previous sections reviewed the pathophysiology and treatment of tachyarrhythmias, and this section serves to briefly consider the bradyarrhythmias. For the most part, the symptoms of bradyarrhythmias result from a decline in cardiac output. Because cardiac output decreases as heart rate decreases (to a point), patients with bradyarrhythmias may experience symptoms in association with hypotension, such as dizziness, syncope, fatigue, and confusion. If LV dysfunction exists, patients may experience worsening HF symptoms. Except in the case of recurrent syncope, symptoms associated with bradyarrhythmias are often subtle and nonspecific.

Sinus Bradycardia

Sinus bradyarrhythmias (heart rate <60 beats/min) are a common finding, especially in young, athletically active individuals, and usually are neither symptomatic nor in need of therapeutic intervention. On the other hand, some patients, particularly the elderly, have sinus node dysfunction. This may be the result of underlying SHD and the normal aging process that attenuate SA nodal function over time. Sick sinus syndrome refers to this process resulting in symptomatic sinus bradycardia and/or periods of sinus arrest.122 Sinus node dysfunction is usually reflective of diffuse conduction disease, and accompanying AV block is relatively common. Furthermore, symptomatic bradyarrhythmias may be accompanied by alternating periods of paroxysmal tachycardias such as AF. In this instance, AF sometimes presents with a rather slow ventricular response (in the absence of AV nodal blocking drugs) because of diffuse conduction disease. The occurrence of alternating bradyarrhythmias and tachyarrhythmias is referred to as the tachy-brady syndrome. The occurrence of paroxysmal AF in a patient with sinus node dysfunction may be a result of underlying SHD with atrial dysfunction or atrial escape in response to reduced sinus node automaticity. In fact, because the rate of impulse generation by the sinus node is generally depressed or may fail altogether, other automatic pacemakers within the conduction system may “rescue” the sinus node. These rescue rhythms often present as paroxysmal atrial rhythms (e.g., AF) or as a junctional escape rhythm.

The treatment of sinus node dysfunction involves the elimination of symptomatic bradycardia and potentially managing alternating tachycardias such as AF. In general, the long-term therapy of choice is a permanent ventricular pacemaker. Dual-chamber, rate-adaptive chronic pacing clearly improves symptoms and overall quality of life and decreases the incidence of paroxysmal AF and systemic embolism.122Drugs commonly employed to treat supraventricular tachycardias should be used with caution, if at all, in the absence of a functioning pacemaker. AADs prescribed to prevent AF recurrences may also suppress the escape or rescue rhythms that appear in severe sinus bradycardia or sinus arrest. Consequently, these drugs may transform an asymptomatic patient with bradycardia into a symptomatic one. The addition of class I AADs can also affect pacemaker threshold and result in loss of capture if the pacemaker is not appropriately interrogated and adjusted. Other drugs that depress SA or AV nodal function, such as β-blockers and non-DHP CCBs, may also significantly exacerbate bradycardia. Even drugs with indirect sympatholytic actions, such as methyldopa and clonidine, may worsen sinus node dysfunction. The use of digoxin in these patients is controversial; however, in most cases, it can be used safely.

Other Causes

Another reason for paroxysmal bradycardia and sinus arrest that is not directly due to sinus node dysfunction is carotid sinus hypersensitivity.123,124 Again, this syndrome occurs commonly in the elderly with underlying SHD, and may precipitate falls and hip fractures. Symptoms occur when the carotid sinus is stimulated, resulting in an accentuated baroreceptor reflex. Often, however, symptoms are not well correlated with the obvious physical manipulation of the carotid sinus (in the lateral neck region). Patients may experience intermittent episodes of dizziness or syncope because of sinus arrest caused by increased vagal tone and sympathetic withdrawal (the cardioinhibitory type), a drop in systemic blood pressure caused by sympathetic withdrawal (the vasodepressor type), or both (mixed cardioinhibitory and vasodepressor types). The diagnosis can be confirmed by performing carotid sinus massage with ECG and blood pressure monitoring in controlled conditions. Symptomatic carotid sinus hypersensitivity should also be treated with permanent pacemaker therapy.123 However, some patients, particularly those with a significant vasodepressor component, still experience syncope or dizziness. The choice of definitive drug therapy in this situation is marred by the lack of controlled trials, although α-adrenergic stimulants such as midodrine are often tried in addition to the pacemaker.124

Vasovagal syndrome, by causing bradycardia, sinus arrest, and/or hypotension, is the cause of syncope in many patients who present with recurrent fainting of unknown origin.125127 By history, many individuals can recount rare instances of fainting spells at times of duress or fear. These are most often caused by vasovagal syncope. However, some have extremely frequent, unexpected syncopal episodes that interfere with the patient’s quality of life and cause physical danger (sometimes referred to as neurocardiogenic syncope syndrome or malignant vasovagal syndrome). Vasovagal syncope is presumed to be a neurally mediated, paradoxical reaction involving stimulation of cardiac mechanoreceptors (i.e., Bezold-Jarisch reflex). Forceful contraction of the ventricle (e.g., as with adrenergic stimulation) coupled with low ventricular volumes (e.g., with upright posture or dehydration) provides a powerful stimulus for cardiac mechanoreceptors. Syncope results from the spontaneous development of transient hypotension (sympathetic withdrawal) and bradycardia (vagotonia). However, the true mechanism of vasovagal syncope remains to be definitively determined. For instance, patients with denervated hearts (e.g., heart transplant recipients) can still experience this form of syncope. This observation has led some to question the ultimate role of the Bezold-Jarisch reflex in these patients. Regardless, patients believed to have frequent episodes of vasovagal syncope have been evaluated and diagnosed using the upright body-tilt test,128 a potent stimulus for the development of vasovagal symptoms. Although commonly used, the sensitivity and reproducibility of this test have been questioned.129

Traditionally, β-blockers, such as metoprolol, were frequently chosen as the drugs of choice in preventing episodes of vasovagal syncope. Although these drugs may seem inappropriate to treat a syndrome resulting from vasodilation and bradycardia, the therapeutic approach is designed to block an inappropriate vasovagal reaction (i.e., they inhibit the sympathetic surge that causes forceful ventricular contraction and precedes the onset of hypotension and bradycardia). To most clinicians’ surprise, most controlled trials of the use of β-blockers in patients with severe vasovagal syncope have shown no effect compared with placebo in preventing syncopal episodes.130Some trials have suggested that β-blockers are more effective and should be used in older patients (>40 years of age) with vasovagal syncope rather than the relatively young.131 Other drugs that have been used successfully (with or without β-blockers) include mineralocorticoids as volume expanders (fludrocortisone), anticholinergic drugs (scopolamine patches, disopyramide), α-adrenergic agonists (midodrine), adenosine analogs (theophylline, dipyridamole), and selective serotonin receptor antagonists (sertraline, paroxetine).132 Permanent pacing has been used with some success but should be reserved for drug-refractory patients.126,127 Because of the questionable effectiveness of β-blockers and the paucity of controlled or comparative trials, there is not a true drug of choice for severe vasovagal syncope, and clinicians are left with choosing agents and judging clinical effectiveness in individual patients on a case-by-case basis.

Atrioventricular Block

Conduction delay or block may occur in any area of the AV conduction system: the AV node, the His bundle, or the bundle branches. AV block is usually categorized into three different types based on ECG findings (Table 8-13). First-degree AV block is 1:1 AV conduction with a prolonged PR interval. Second-degree AV block is divided into two forms: Mobitz I AV block (Wenckebach periodicity) is less than 1:1 AV conduction with progressively lengthening PR intervals until a ventricular complex is dropped; Mobitz II AV block is intermittently dropped ventricular beats in a random fashion without progressive PR lengthening. Third-degree AV block is complete heart block where AV conduction is totally absent (AV dissociation). First-degree AV block usually represents prolonged conduction in the AV node. Mobitz I, second-degree AV block is also usually caused by prolonged conduction in the AV node. Indeed, Wenckebach periodicity is a normal AV nodal response to rapid supraventricular stimulation or high vagal tone. In contrast, Mobitz II, second-degree AV block is usually caused by conduction disease below the AV node (i.e., His bundle). Third-degree AV block may be caused by disease at any level of the AV conduction system: complete AV nodal block, His bundle block, or trifascicular block. In this situation, the ventricle beats independently of the atria (AV dissociation), and the rate of ventricular activation and QRS configuration are determined by the site of the AV block. The usual degree of automaticity of ventricular pacemakers progressively declines as the site of impulse generation moves down the ventricular conduction system. Therefore, the ventricular escape rate in cases of trifascicular block will be significantly less than complete AV nodal block. Consequently, trifascicular block is a much more dangerous form of AV block. For instance, complete AV block at the level of the AV node usually results in the ventricular rhythm being controlled by the stable AV junctional pacemaker (rate ∼40 beats/min). In contrast, in complete AV block due to trifascicular or His bundle block, a much less reliable pacemaker with slower rates below the site of block controls ventricular rhythm.

TABLE 8-13 Forms of Atrioventricular Block


AV block may be found in patients without underlying SHD such as trained athletes or during sleep when vagal tone is high. Also, AV block may be transient where the underlying etiology is reversible such as in myocarditis, myocardial ischemia, after cardiovascular surgery, or during drug therapy. β-Blockers, digoxin, or non-DHP CCBs may cause AV block, primarily in the AV nodal area. Class I AADs may exacerbate conduction delays below the level of the AV node (sodium-dependent tissue). In other cases, AV block may be irreversible, such as that caused by acute MI, rare degenerative diseases, primary myocardial disease, or congenital heart disease.

If patients with Mobitz II AV block or third-degree AV block develop signs or symptoms of poor perfusion (e.g., altered mental status, chest pain, hypotension, shock), IV atropine (0.5 mg given every 3 to 5 minutes, up to 3 mg total dose) should be administered.71 If these patients do not respond to atropine, transcutaneous pacing can be initiated. Sympathomimetic infusions such as epinephrine (2 to 10 mcg/min) or dopamine (2 to 10 mcg/kg/min) can also be used in the event of atropine failure and are particularly effective in sinus bradycardia/arrest and AV nodal block. An isoproterenol infusion (2 to 10 mcg/min) may be considered if the patient does not respond to dopamine or epinephrine; however, this drug should be used with caution because of its vasodilating properties and ability to increase myocardial oxygen consumption (particularly during active MI). As would be expected, these drugs usually do not help when the site of AV block is below the AV node (e.g., Mobitz II or trifascicular AV block) because their primary mechanism is to accelerate conduction through the AV node. If patients with bradycardia or AV block present with signs and symptoms of adequate perfusion, no acute therapy other than close observation is recommended.

Patients with chronic symptomatic AV block should be treated with the insertion of a permanent pacemaker. Patients without symptoms can sometimes be followed closely without the need for a pacemaker. The reader is referred for more detail to the national consensus guidelines for pacemaker implantation.112,133 Patients with acute MI and evidence of new AV block or conduction disturbances will often require the insertion of a temporary transvenous pacemaker. AV block more commonly occurs as a complication of inferior wall MIs because of high vagal innervation at this site, and the coronary blood flow to the nodal areas usually supplies the inferior wall. However, the AV block may only be transient, obviating the need for permanent pacing.


Generally, patients who suffer from tachyarrhythmias can be monitored for one or several possible therapeutic outcomes. Obviously, the presence or recurrence of any arrhythmia can be documented by electrocardiographic means (e.g., surface ECG, Holter monitor, or event monitor). Furthermore, patients may experience a decrease in blood pressure that may result in symptoms ranging from light-headedness to abrupt syncope, depending on the rate of the arrhythmia and the status of the underlying heart disease. For some patients, the potential alteration in hemodynamics may result in death if the arrhythmia is not detected and treated immediately. Besides these clinical outcomes, many patients with tachyarrhythmias experience alterations in quality of life as a result of recurrent symptoms of the arrhythmia or from side effects of therapy. And, finally, there are the economic considerations of medical or surgical intervention, continued medical care, and chronic drug or nonpharmacologic treatment.134,135 Most of the studies are limited to the use of nonpharmacologic therapies such as the ICD or radiofrequency ablation.76,136Because that technology is rapidly evolving, what is not very cost-effective now may indeed be cost-effective in the next several years. For example, original cost-effectiveness analysis of the ICD showed it to be highly sensitive to the life of the generator, yet newer-generation devices have made significant advances not only in their size but also in their battery life. More recent data on the effect of the ICD on mortality coupled with the declining costs of an ICD imply that the device is indeed cost-effective in certain subsets of patients, which is similar to well-proven drug therapies used for other disorders.136 Other nonpharmacologic treatments, such as radiofrequency ablation for PSVT, not only improve quality of life but also save money on medical expenditures compared with chronic drug therapy.76

There are some therapeutic outcomes that are unique to certain arrhythmias. For instance, patients with AF or atrial flutter need to be monitored for thromboembolism and for complications of antithrombotic therapy (bleeding, drug interactions). However, the most important monitoring parameters for most patients fall into the following categories: (a) mortality (total and arrhythmic); (b) arrhythmia recurrence (duration, frequency, symptoms); (c) hemodynamic consequences (heart rate, blood pressure, symptoms); and (d) treatment complications (side effects or need for alternative or additional drugs, devices, surgery) (Table 8-14). When evaluating the arrhythmia literature, care should be taken to consider real outcomes. For example, total mortality is more meaningful than SCD rates; it is possible an intervention prevents arrhythmic death but patients die from other causes, leaving all-cause mortality unaltered. Likewise, surrogate markers of drug efficacy (e.g., noninducible tachycardia, suppression of minor arrhythmias) should be judged with a degree of skepticism. One should ask: Did the treatment make patients live longer (reduce mortality)? Did the treatment make them feel better (improve humanistic outcomes or quality of life)? Was the treatment economically worth it (cost-effective)?

TABLE 8-14 Arrhythmia Outcomes







    1. Alice MA, Bonke FIM, Schopman FJG. Circus movement in rabbit atrial muscle as a mechanism of tachycardia III. The “leading circle” concept: A new model of circus movement in cardiac tissue without the involvement of an anatomic obstacle. Circ Res 1977;41:9–18.

    2. Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol 1984;24:129–147.

    3. Working Group on Arrhythmias of the European Society of Cardiology. The Sicilian Gambit: A new approach to the classification of antiarrhythmic drugs based upon their actions on arrhythmogenic mechanisms. Circulation 1991;84:1831–1851.

    4. Hondeghem LM, Katzung BG. Antiarrhythmic agents: The modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Annu Rev Pharmacol Toxicol 1984;24:387–423.

    5. Nasr IR, Bouzamondo A, Hulot JS, et al. Prevention of atrial fibrillation onset by beta-blocker treatment in heart failure: A meta-analysis. Eur Heart J 2007;28:457–462.

    6. Makkar KM, Sanoski CA, Spinler SA. Role of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and aldosterone antagonists in the prevention of atrial and ventricular arrhythmias. Pharmacotherapy 2009;29:31–48.

    7. Podrid PJ, Schoeneburger A, Lown B. Congestive heart failure caused by oral disopyramide. N Engl J Med 1980;302:614–617.

    8. Podrid PJ. Proarrhythmia, a serious complication of antiarrhythmic drugs. Curr Cardiol Rep 1999;1:289–296.

    9. Fang MC, Stafford RS, Ruskin JN, et al. National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation. Arch Intern Med 2004;164:55–60.

   10. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: Dosing relationships with long-term therapy. Chest 2002;121:19–23.

   11. Camus P, Martin WJ, Rosenow EC. Amiodarone pulmonary toxicity. Clin Chest Med 2004;25:65–75.

   12. Babatin M, Lee SS, Pollak PT. Amiodarone hepatotoxicity. Curr Vasc Pharmacol 2008;6:228–236.

   13. Sanoski C, Schoen MD, Gonzalez RD, et al. Rationale, development and outcomes of a multidisciplinary clinic for patients receiving chronic oral amiodarone. Pharmacotherapy 1998;18:1465–1515.

   14. Goldschlager N, Epstein AE, Naccarelli GV, et al. A practical guide for clinicians who treat patients with amiodarone: 2007. Heart Rhythm 2007;4:1250–1259.

   15. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics 2013 update: A report from the American Heart Association. Circulation 2013;127:e6–e245.

   16. Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). J Am Coll Cardiol 2006;48: e149–e246.

   17. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation 2006;114:119–125.

   18. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for developing atrial fibrillation: The Framingham Heart Study. Circulation 2004;110:1042–1046.

   19. Levy S, Camm AJ, Saksena S, et al. International consensus on nomenclature and classification of atrial fibrillation. A collaborative project of the Working Group on Arrhythmias and the Working Group on Cardiac Pacing of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Europace 2003;5:119–122.

   20. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e531S–e575S.

   21. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449–1457.

   22. Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:104–123.

   23. Phillips BG, Gandhi AJ, Sanoski CA, et al. Comparison of intravenous diltiazem and verapamil for the acute treatment of atrial fibrillation and flutter. Pharmacotherapy 1997;17:1238–1245.

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

   25. Van Gelder IC, Hagens VE, Bosker HA, et al. The Rate Control Versus Electrical Cardioversion for Persistent Atrial Fibrillation Study Group. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834–1840.

   26. The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–1833.

   27. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: The Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol 2003;41:1690–1696.

   28. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: The results of the Polish How to Treat Chronic Atrial Fibrillation (HOT CAFE) Study. Chest 2004;126: 476–486.

   29. Roy D, Talajic M, Nattel S, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667–2677.

   30. de Denus S, Sanoski CA, Carlsson J, Opolski G, Spinler SA. Rate vs rhythm control in patients with atrial fibrillation: A meta-analysis. Arch Intern Med 2005;165:258–262.

   31. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med 2010;362:1363–1373.

   32. Klein AL, Grimm RA, Murray D, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 2001;344: 1411–1420.

   33. Bauman JL, Bauernfeind RA, Hoff JV, et al. Torsade de pointes due to quinidine: Observations in 31 patients. Am Heart J 1984;107:425–430.

   34. Slavik RS, Tisdale JE, Borzak S. Pharmacologic conversion of atrial fibrillation: A systematic review of available evidence. Prog Cardiovasc Dis 2001;44:121–152.

   35. Alboni P, Botto GL, Baldi N, et al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med 2004;351:2384–2391.

   36. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–1151.

   37. Liesenfeld KH, Lehr T, Dansirikul C, et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011;9:2168–2175.

   38. Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:1144–1150.

   39. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–891.

   40. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364: 806–817.

   41. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–992.

   42. Furie KL, Goldstein LB, Albers GW, et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation: A science advisory for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2012;43: 3442–3453.

   43. Connolly SJ, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): A randomised controlled trial. Lancet 2006;367:1903–1912.

   44. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 2009;360:2066–2078.

   45. Coplen SE, Antman EM, Berlin JA, et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: A meta-analysis of randomized control trials. Circulation 1990;82:1106–1116.

   46. Echt DS, Liebson PR, Mitchell B, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med 1991;324:781–788.

   47. Lafuente-LaFuente C, Mouly S, Longás-Tejero MA, et al. Antiarrhythmic drugs for maintaining sinus rhythm after cardioversion of atrial fibrillation. Arch Intern Med 2006;166:719–728.

   48. Roy D, Talajic M, Dorian P, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med 2000;324: 913–920.

   49. AFFIRM First Antiarrhythmic Drug Substudy Investigators. Maintenance of sinus rhythm in patients with atrial fibrillation: An AFFIRM substudy of the first antiarrhythmic drug. J Am Coll Cardiol 2003;42:20–29.

   50. Singh BN, Singh SN, Reda DJ, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352: 1861–1872.

   51. Juul-Moller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation 1990;82:1932–1939.

   52. Southworth MR, Zarembski D, Viana M, Bauman JL. Comparison of sotalol versus quinidine for maintenance of normal sinus rhythm in patients with chronic atrial fibrillation. Am J Cardiol 1999;83:1629–1632.

   53. Pedersen OD, Bagger H, Keller N, et al. Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function, a Danish Investigation of Arrhythmia and Mortality on Dofetilide (DIAMOND) Substudy. Circulation 2001;104:292–296.

   54. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter. The Symptomatic Atrial Fibrillation Investigative Research on Dofetilide (SAFIRE-D) Study. Circulation 2000;102: 2385–2390.

   55. Singh BN, Connolly SJ, Crijns HJGM, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med 2007;357:987–999.

   56. Hohnloser SH, Crijns HJGM, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668–678.

   57. Køber L, Torp-Pedersen C, McMurray JJV, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:2678–2687.

   58. Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short-term, randomized, double-blind, parallel-group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation: The DIONYSOS study. J Cardiovasc Electrophysiol 2010;21:597–605.

   59. Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:2268–2276.

   60. Spector P, Reynolds MR, Calkins H, et al. Meta-analysis of ablation of atrial flutter and supraventricular tachycardia. Am J Cardiol 2009;104:671–677.

   61. Blomstrom-Lundgrist C, Scheimanman MM, Aliot EM, et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias. A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003;42: 1493–1531.

   62. Pappone C, Augello G, Sala S, et al. A randomized trial of circumferential pulmonary vein ablation versus antiarrhythmic drug therapy in paroxysmal atrial fibrillation: The APAF Study. J Am Coll Cardiol 2006;48:2340–2347.

   63. Oral H, Pappone C, Chugh A, et al. Circumferential pulmonary-vein ablation for chronic atrial fibrillation. N Engl J Med 2006;354:934–941.

   64. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: A randomized controlled trial. JAMA 2010;303:333–340.

   65. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: A randomized trial. JAMA 2005;293:2634–2640.

   66. Jaïs P, Cauchemez B, Macle L, et al. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: The A4 study. Circulation 2008;118:2498–2505.

   67. Calkins H, Kuck KH, Cappato R, et al. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: Recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design. Heart Rhythm 2012;9:632–696.

   68. Cappato R, Calkins H, Chen SA, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010;3:32–38.

   69. Sung RJ, Lauer MR, Chun H. Atrioventricular node reentry: Current concepts and new perspectives. Pacing Clin Electrophysiol 1994;17:1413–1430.

   70. DiMarco JP, Miles W, Akhtar M, et al. Adenosine for paroxysmal supraventricular tachycardia: Dose ranging and comparison with verapamil. Assessment in placebo-controlled, multicenter trials. Ann Intern Med 1990;1113:104–110.

   71. 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Circulation 2010;122:5640–5933.

   72. Rankin AC, McGovern BA. Adenosine or verapamil for the acute treatment of supraventricular tachycardia? Ann Intern Med 1991;114:513–515.

   73. Jackman WM, Wang Z, Friday KJ, et al. Catheter ablation of accessory atrioventricular pathways (Wolff-Parkinson-White syndrome) by radiofrequency current. N Engl J Med 1991;324:1605–1611.

   74. Jackman WM, Beckman KJ, McClelland JH, et al. Treatment of supraventricular tachycardia due to atrioventricular nodal reentry by radiofrequency catheter ablation of slow pathway conduction. N Engl J Med 1992;327:313–318.

   75. Scheinman MM. Radiofrequency catheter ablation for patients with supraventricular tachycardia. Pacing Clin Electrophysiol 1993;16:671–679.

   76. Cheng CH, Sanders GD, Hlatky MA, et al. Cost effectiveness of radio-frequency ablation for supraventricular tachycardia. Ann Intern Med 2000;133:864–876.

   77. Bayes deLuna A, Coumel P, LeClercq IF. Ambulatory sudden cardiac death: Mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J 1989;117:151–159.

   78. Ruberman W, Weinblatt E, Goldberg JD, et al. Ventricular premature beats and mortality after myocardial infarction. N Engl J Med 1977;297:750–757.

   79. The Cardiac Arrhythmia Suppression Trial II Investigators. Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. N Engl J Med 1992;327: 227–233.

   80. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction and remote myocardial infarction. Lancet 1996;348:7–12.

   81. Julian DG, Camm AJ, Frangin G, et al. Randomized trial of effect of amiodarone on mortality in patients with left ventricular dysfunction after recent myocardial infarction: EMIAT. Lancet 1997;349:667–674.

   82. Cairns JA, Connolly SJ, Roberts R, et al. Randomized trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarizations: CAMIAT. Lancet 1997;349:675–682.

   83. Amiodarone Trials Meta-Analysis Investigators. Effect of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: Meta-analysis of individual data from 6,500 patients in randomized trials. Lancet 1997;350:1417–1424.

   84. Torp-Pederson C, Moller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Engl J Med 1999;341:857–865.

   85. Kober L, Block-Thomsen PE, Moller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left ventricular dysfunction: A randomized trial. Lancet 2000;356:2052–2058.

   86. Hilleman DE, Bauman JL. Role of antiarrhythmic therapy in patients at risk for sudden cardiac death: An evidence-based review. Pharmacotherapy 2001;21:556–575.

   87. Edhouse J, Morris F. Broad complex tachycardia—Part I. BMJ 2002;312:719–722.

   88. Edhouse J, Morris F. Broad complex tachycardia—Part II. BMJ 2002;324:776–779.

   89. Cole CR, Marrouche NF, Natale A. Evaluation and management of ventricular outflow tract tachycardias. Card Electrophysiol Rev 2002;6:442–447.

   90. Modell SM, Lehmann MH. The long QT syndrome family of cardiac ion channelopathies: A HuGE review. Genet Med 2006;8:143–155.

   91. Keating MT, Sanguinetti MC. Molecular and cellular mechanisms of cardiac arrhythmias. Cell 2001;104:569–580.

   92. Antzelevitch C, Brugada P, Brugada J, et al. Brugada syndrome: 1992–2002: A historical perspective. J Am Coll Cardiol 2003;41:1665–1671.

   93. Gorgels A, van den Dool A, Hofs A, et al. Comparison of procainamide and lidocaine in terminating sustained monomorphic ventricular tachycardia. Am J Cardiol 1996;78:43–46.

   94. Mason JW, Electrophysiologic Study Versus Electrocardiographic Monitoring Investigators. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic drug efficacy for ventricular tachyarrhythmias. N Engl J Med 1993;329: 445–451.

   95. Mason JW, Electrophysiologic Study Versus Electrocardiographic Monitoring Investigators. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. N Engl J Med 1993;329: 452–458.

   96. The Cascade Investigators. Randomized antiarrhythmic drug therapy in survivors of cardiac arrest (the CASCADE Study). Am J Cardiol 1993;72:280–287.

   97. Aliot EM, Stevenson WG, Almendral-Garrote JM, et al. EHRA/HRS expert consensus on catheter ablation of ventricular arrhythmias: Developed in a partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC), and the Heart Rhythm Society (HRS); in collaboration with the American College of Cardiology (ACC) and the American Heart Association (AHA). Europace 2009;11:771–817.

   98. DiMarco JP. Implantable cardioverter-defibrillators. N Engl J Med 2003;349:1836–1847.

   99. Pacifico A, Hohnloser SH, Williams JH, et al. Prevention of implantable-defibrillator shocks by treatment with sotalol. N Engl J Med 1999;340:1855–1862.

  100. Connolly SJ, Dorian P, Roberts RS, et al. Comparison of beta-blockers, amiodarone plus beta-blockers, or sotalol for prevention of shocks from implantable cardioverter defibrillators: The OPTIC Study: A randomized trial. JAMA 2006;295:165–171.

  101. Dopp AL, Miller JM, Tisdale JE. Effects of drugs on defibrillation capacity. Drugs 2008;68:607–630.

  102. The AVID Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337:1576–1583.

  103. Connolly SJ, Gene M, Roberts TS, et al. Cardiac Implantable Defibrillator Study (CIDS): A randomized trial of the implantable cardioverter-defibrillator against amiodarone. Circulation 2000;101:1297–1302.

  104. Kuck KH, Cappato R, Siebels J, et al. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: The Cardiac Arrest Study Hamburg (CASH). Circulation 2000;102:748–754.

  105. Wilber DJ, Olshansky B, Moran JF, et al. Electrophysiological testing and nonsustained VT. Use and limitations in patients with coronary artery disease and impaired ventricular function. Circulation 1990;82:350–358.

  106. Buxton AE, Leek KL, DiCarlo L, et al. Electrophysiologic testing to identify patients with coronary artery disease who are at risk for sudden death. Multicenter Unsustained Tachycardia Trial. N Engl J Med 2000;342:1937–1945.

  107. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med 1996;335:1933–1940.

  108. Buxton AE, Lee KL, Fisher JD, et al. A randomized study of the prevention of sudden death in patients with coronary artery disease. N Engl J Med 1999;341:1882–1890.

  109. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death—Executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death). Circulation 2006;114:1–45.

  110. Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002;346:877–883.

  111. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 2005;352:225–237.

  112. Epstein AE, DiMarco JP, Ellenbogen KA, et al. ACC/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the ACC/AHA/NASPE 2002 Guideline Update for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices). J Am Coll Cardiol 2008;51:e1–e62.

  113. Antzelevitch C. Heterogeneity of cellular repolarization in LQTS: The role of M cells. Eur Heart J 2001;3:K2–K16.

  114. Roden DM. Long QT syndrome: Reduced repolarization reserve and the genetic link. J Intern Med 2006;259:59–69.

  115. Oberg KC, O’Toole MF, Gallastegui JL, Bauman JL. “Late” proarrhythmia due to quinidine. Am J Cardiol 1994;74: 192–194.

  116. Bauman JL. The role of pharmacokinetics, drug interactions and pharmacogenetics in the acquired long QT syndrome. Eur Heart J 2001;3:K93–K100.

  117. Tzivoni D, Banai S, Schuger C, et al. Treatment of torsade de pointes with magnesium sulfate. Circulation 1987;77: 392–397.

  118. Koplan BA, Stevenson WG. Ventricular tachycardia and sudden cardiac death. Mayo Clin Proc 2009;84:289–297.

  119. Lie KI, Wellens HJJ, Van Capelle FJ. Lidocaine in the prevention of primary ventricular fibrillation. N Engl J Med 1974;291:1324–1326.

  120. MacMahon S, Collin R, Peto R, et al. Effects of prophylactic lidocaine in suspected acute myocardial infarction: An overview of results from the randomized controlled trials. JAMA 1988;260:1910–1916.

  121. Antman EM, Berlin JA. Declining incidence of ventricular fibrillation in myocardial infarction: Implications for the prophylactic use of lidocaine. Circulation 1992;86:764–773.

  122. Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J 2009;30:2631–2671.

  123. Sugrue DD, Gersh BJ, Holmes DR, et al. Symptomatic “isolated” carotid sinus hypersensitivity: Natural history and results of treatment with anticholinergic drugs or pacemaker. J Am Coll Cardiol 1986;7:158–162.

  124. Seifer C. Carotid sinus syndrome. Prog Cardiol Clin 2013;31: 111–121.

  125. Zagga M, Massumi A. Neurally mediated syncope. Tex Heart Inst J 2000;27:268–272.

  126. Grubb BP. Neurocardiogenic syncope and related disorders of orthostatic intolerance. Circulation 2005;111:2997–3006.

  127. Grubb BP. Neurocardiogenic syncope. N Engl J Med 2005;352:1004–1010.

  128. Milstein S, Reyes WJ, Benditt DG. Upright body tilt for evaluation of patients with recurrent, unexplained syncope. Pacing Clin Electrophysiol 1989;12:117–124.

  129. Almquist A, Goldenberg I, Milstein S. Provocation of bradycardia and hypotension by isoproterenol and upright posture in patients with unexplained syncope. N Engl J Med 1990;320:346–351.

  130. Brignole M. Randomized clinical trials of neurally mediated syncope. J Cardiovasc Electrophysiol 2003;14(Suppl): S64–S69.

  131. Sheldon R, Connolly S, Rose S, for the POST Investigators. Prevention of Syncope Trial (POST). A randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 2006;113:1164–1170.

  132. Armaganijan L, Morillo CA. Treatment of vasovagal syncope: An update. Curr Treat Options Cardiovasc Med 2010;12:472–488.

  133. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/AHA/HRS focused updated of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:1297–1313.

  134. Kupersmith J, Holmes-Novner M, Hogan A, et al. Cost-effectiveness analysis in heart disease, I: General principles. Prog Cardiovasc Dis 1994;37:161–184.

  135. Kupersmith J, Holmes-Novner M, Hogan A, et al. Cost-effectiveness analysis in heart disease, III: Ischemia, congestive heart failure, and arrhythmias. Prog Cardiovasc Dis 1995;37:307–346.

  136. Sanders GD, Hlatky MA, Owens DK. Cost-effectiveness of implantable cardioverter-defibrillators. N Engl J Med 2005;353:1471–1480.