Chapter 40: Arrhythmias PDF

Access Provided by: DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition Chapter 40: Arrhythmias Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman UPDATE SUMMARY Update Summary September, 2023 The following table was updated: Table 407 Dose adjustments for sotalol were corrected for patients with atrial fibrillation/flutter with chronic kidney disease. Recommendations also added for hepatic dysfunction. CHAPTER SUMMARY FROM THE PHARMACOTHERAPY HANDBOOK For the Chapter in the Schwinghammer Handbook, please go to Chapter 6, Arrhythmias. KEY CONCEPTS KEY CONCEPTS The use of antiarrhythmic drugs (AADs) in the United States has declined because clinical trials have shown increased mortality with their use due to proarrhythmic adverse medication reactions and limited efficacy. AADs have been increasingly replaced by nonpharmacologic approaches such as ablation and the implantable cardioverter defibrillator (ICD). However, AADs remain a key tool in the management of many rhythm disorders. AADs frequently cause adverse medication reactions and are complex in their pharmacokinetic characteristics. Close monitoring is required of all of these medications to assess for adverse reactions as well as potential medication interactions. The most commonly prescribed AAD is amiodarone, which is effective in terminating and preventing a wide variety of symptomatic supraventricular and ventricular arrhythmias. However, amiodarone is plagued by frequent adverse medication reactions and requires close monitoring. The most concerning toxicity is pulmonary fibrosis. The side effect profiles of the intravenous (IV) (acute, shortterm) and oral (chronic, longterm) forms of amiodarone differ substantially. In patients with atrial fibrillation (AF), therapy is traditionally aimed at controlling the ventricular rate, preventing thromboembolic (TE) complications, and restoring and maintaining sinus rhythm (SR). Traditionally, many have pointed to the AFFIRM trial that maintenance of SR was often not necessary. However, several recent studies challenge this idea, particularly for patients with heart failure with reduced ejection fraction (HFrEF). AADs are also useful in reducing early AF recurrence in the periprocedural period and may improve longterm postablation outcomes. Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Paroxysmal Jessica J. Tilton; supraventricular Stephen(PSVT) tachycardia T. Phillips; Jerrya L. is usually Bauman result Page of either reentry (involving either the atrioventricular [AV] node or 1 / 72 ©2024incorporating McGraw Hill.an Allaccessory Rights Reserved. Terms of Use Privacy Policy Notice Accessibility pathway) or ectopic atrial activity (atrial tachycardia). Common supraventricular tachycardias are often terminated acutely with AV nodalblocking medications, such as adenosine. For most patients, catheter ablation effectively cures this arrhythmia. Access Provided by: For the Chapter in the Schwinghammer Handbook, please go to Chapter 6, Arrhythmias. KEY CONCEPTS KEY CONCEPTS The use of antiarrhythmic drugs (AADs) in the United States has declined because clinical trials have shown increased mortality with their use due to proarrhythmic adverse medication reactions and limited efficacy. AADs have been increasingly replaced by nonpharmacologic approaches such as ablation and the implantable cardioverter defibrillator (ICD). However, AADs remain a key tool in the management of many rhythm disorders. AADs frequently cause adverse medication reactions and are complex in their pharmacokinetic characteristics. Close monitoring is required of all of these medications to assess for adverse reactions as well as potential medication interactions. The most commonly prescribed AAD is amiodarone, which is effective in terminating and preventing a wide variety of symptomatic supraventricular and ventricular arrhythmias. However, amiodarone is plagued by frequent adverse medication reactions and requires close monitoring. The most concerning toxicity is pulmonary fibrosis. The side effect profiles of the intravenous (IV) (acute, shortterm) and oral (chronic, longterm) forms of amiodarone differ substantially. In patients with atrial fibrillation (AF), therapy is traditionally aimed at controlling the ventricular rate, preventing thromboembolic (TE) complications, and restoring and maintaining sinus rhythm (SR). Traditionally, many have pointed to the AFFIRM trial that maintenance of SR was often not necessary. However, several recent studies challenge this idea, particularly for patients with heart failure with reduced ejection fraction (HFrEF). AADs are also useful in reducing early AF recurrence in the periprocedural period and may improve longterm postablation outcomes. Paroxysmal supraventricular tachycardia (PSVT) is usually a result of either reentry (involving either the atrioventricular [AV] node or incorporating an accessory pathway) or ectopic atrial activity (atrial tachycardia). Common supraventricular tachycardias are often terminated acutely with AV nodalblocking medications, such as adenosine. For most patients, catheter ablation effectively cures this arrhythmia. Patients with WolffParkinsonWhite (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 ibutilide). AV nodal blocking medications are contraindicated in patients with WPW syndrome and AF. The mainstay of longterm therapy for WPW remains catheter ablation. AADs (except for βblockers) should not be used routinely in patients with prior myocardial infarction (MI) or left ventricular (LV) dysfunction for the treatment of premature ventricular complexes (PVCs). More specifically, the routine suppression of asymptomatic PVCs with AADs is not recommended. Patients with hemodynamically significant ventricular tachycardia (VT) or ventricular fibrillation (VF) not associated with an acute MI who are successfully resuscitated (with electrical cardioversion, epinephrine, amiodarone, and/or lidocaine) are at high risk for sudden cardiac death (SCD). In most cases, implantation of an ICD is recommended for “secondary prevention.” AADs can be useful to prevent recurrent ICD shocks, particularly when catheter ablation is not an option or has been unsuccessful. Implantation of an ICD should be considered for the primary prevention of SCD in certain highrisk patient populations. Highrisk 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 (NYHA) class II or III HFrEF. Lifethreatening medicationinduced ventricular proarrhythmia generally takes two forms: sinusoidal or incessant monomorphic VT (caused by class Ic AADs) and torsades de pointes (TdP) (caused by class Ia or III AADs and many other noncardiac medications). BEYOND THE BOOK BEYOND THE BOOK Downloaded 20241127 11:51 P Your IP is Chapter 40:video Watch the Arrhythmias, entitled Jessica “NormalJ.Sinus Tilton; Stephen Rhythm T. EKG” on an Phillips; JerryAcademy in Khan L. Bauman Page 2 /of (duration: 8:52) by Bianca Yoo. This video provides a brief overview 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility the cardiac conduction system and how it translates to an electrocardiogram. The video is useful to enhance student understanding regarding the COLLECT and ASSESS steps in the patient care process. (caused by class Ic AADs) and torsades de pointes (TdP) (caused by class Ia or III AADs and many other noncardiac medications). Access Provided by: BEYOND THE BOOK BEYOND THE BOOK Watch the video entitled “Normal Sinus Rhythm on an EKG” in Khan Academy (duration: 8:52) by Bianca Yoo. This video provides a brief overview of the cardiac conduction system and how it translates to an electrocardiogram. The video is useful to enhance student understanding regarding the COLLECT and ASSESS steps in the patient care process. INTRODUCTION 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). 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). 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. Instead, significant problems with medication toxicity and proarrhythmia (provoking a new arrhythmia or exacerbating a preexisting arrhythmia) have resulted in a decline in AAD usage in the United States since 1989. The other phenomenon that has significantly contributed to the decline in AAD use is the development of extremely effective nonpharmacologic therapies. Technical advances have made it possible to permanently interrupt reentry circuits with radiofrequency ablation, which renders longterm 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 SCD have led most clinicians to choose “device” therapy as the firstline treatment for patients who are at high risk for lifethreatening ventricular arrhythmias. These nonpharmacologic therapies have become increasingly popular for the management of arrhythmias, avoiding the potential proarrhythmic effects and organ toxicities associated with AADs. PATHOPHYSIOLOGY Normal Conduction Electrical activity is initiated by the sinoatrial (SA) node and moves through cardiac tissue through a specialized conduction system that rapidly propagates the electrical wavefront through the ventricular muscle (Fig. 401, panel A). The SA node initiates cardiac rhythm under normal circumstances because this tissue possesses the highest degree of automaticity or rate of spontaneous impulse generation at a rate of 60 to 100 beats/min. 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 (Fig. 401, panel C). 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 generally 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. FIGURE 401 Cardiac action potentials and electrocardiogram tracing. LAF, left anterior fascicle; SA, sinoatrial; AV, atrioventricular. (A) Characterizes the action potentials from different areas of the heart and how those action potentials are illustrated on an ECG. (B) Describes the different intervals of an ECG. Normal interval ranges for PR, QRS, and QT are provided. (C) Describes the influence the autonomic system has on cardiac pacemaker potentials. Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 3 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility From the SA node, electrical activity moves in a wave front through a specialized atrial conducting system and eventually gains entrance to the ventricle FIGURE 401 Access Provided by: Cardiac action potentials and electrocardiogram tracing. LAF, left anterior fascicle; SA, sinoatrial; AV, atrioventricular. (A) Characterizes the action potentials from different areas of the heart and how those action potentials are illustrated on an ECG. (B) Describes the different intervals of an ECG. Normal interval ranges for PR, QRS, and QT are provided. (C) Describes the influence the autonomic system has on cardiac pacemaker potentials. From the SA node, electrical activity moves in a wave front through a specialized atrial conducting system and eventually gains entrance to the ventricle via the AV node and a large bundle of conducting tissue referred to as the bundle of His. The AVN and bundle of His are largely influenced by autonomic input and possess a relatively high degree of inherent automaticity at about 40 beats/min. 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 innervates the mechanical myocardium and serves to initiate excitation–contraction coupling and the contractile process in a precise and organized fashion. Following electrical stimulation, cells within the heart enter a brief period during which they cannot again be excited, 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, referred to as the resting membrane potential (RMP), results from differences in ion concentrations inside and 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 (mmol/L), the extracellular sodium concentration at 135 to 142 mEq/L (mmol/L), the intracellular potassium concentration at 135 to 140 mEq/L (mmol/L), and the extracellular potassium concentration at 3 to 5 mEq/L (mmol/L). Electrical stimulation (or depolarization) of the cell will result in changes in membrane potential over time or a characteristic action potential (AP) curve (Fig. 402). The AP 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 (ie, the IKto current). Calcium begins to move into the intracellular space during phase 0, causing a slower depolarization. Calcium influx continues throughout phase 2 of the AP (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. 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 initiation of rapid sodium influx occurs, is referred to as the threshold potential of the cell. FIGURE 402 Cardiac action potentials and responsible ion currents. While there are similarities between cardiac nodal and muscle action potentials there are many differences in how the phases are influenced by particular ion currents. Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 4 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility FIGURE 402 Access Provided by: Cardiac action potentials and responsible ion currents. While there are similarities between cardiac nodal and muscle action potentials there are many differences in how the phases are influenced by particular ion currents. Not all cells in the cardiac conduction system rely on sodium influx for initial depolarization. Some tissues depolarize (phase 0) in response to a slower inward ionic current caused by calcium influx (L channels). These “calciumdependent” tissues are found primarily in the SA and AV nodes (both L and T channels) and possess distinct conduction properties in comparison to “sodiumdependent” fibers (Fig. 402). Calciumdependent cells generally have a slower conduction velocity and a less negative RMP. The RMP in nodal tissue is referred to as the slow depolarization phase or the pacemaker potential. This phase is initiated by the activation of funny current made up of sodium and potassium ions. It is referred to as the “funny” current because unlike most voltagesensitive currents, it is activated by hyperpolarization. This phase is highly influenced by the autonomic system as seen in Fig. 401, panel C. Furthermore, in calciumdependent tissues, recovery of excitability outlasts full repolarization, whereas in sodiumdependent tissues, recovery is prompt after repolarization. These two types of electrical tissues also differ dramatically in how medications modify their conduction properties. Ion conductance across the lipid bilayer of the cell membrane occurs via the formation of membrane pores or “channels” (Fig. 403). Selective ion channels probably form in response to specific electrical potential differences between the inside and the outside of the cell (voltage dependence). Changes in 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. Each ion channel conceptually has two types of gates: an activation gate and an inactivation gate (see Fig. 403). 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, and inactivated. 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 403 States of sodium (Na+) channels cycling through the cardiac action potential. Transitions between resting, activated, and inactivated states are dependent on membrane potential and time. The activation gate is shown as m and the inactivation gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The dashed line indicates that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable for reactivation. (Reproduced, with permission, from Katzung BG, ed. Basic & Clinical Pharmacology. 15th ed. New York: McGraw Hill; 2021.) Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 5 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility States of sodium (Na+) channels cycling through the cardiac action potential. Transitions between resting, activated, and inactivated states are Access Provided by: dependent on membrane potential and time. The activation gate is shown as m and the inactivation gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The dashed line indicates that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable for reactivation. (Reproduced, with permission, from Katzung BG, ed. Basic & Clinical Pharmacology. 15th ed. New York: McGraw Hill; 2021.) The impulse that is generated by the SA node disseminates to adjacent cells through gap junctions. The gap junctions provide a pathway for ions to travel to neighboring cells for AP propagation. The compilation of all the cardiac APs is presented on an ECG (Fig. 401, panel A). During a normal cardiac conduction cycle the ECG will have a P wave (atrial depolarization), QRS (ventricular depolarization and atrial repolarization), and T wave (ventricular repolarization). It is also important to note the PR interval, or the time from atrial depolarization to ventricular depolarization, and the QT interval, the duration of the ventricular AP (Fig. 401, panel B). Augmentation of the ECG is a product of alterations in the cardiac APs. Abnormal Conduction The mechanisms of tachyarrhythmias have been classically divided into two general categories: those resulting from an abnormality in impulse generation (“automatic” tachycardia and triggered automaticity) and those resulting from an abnormality in impulse conduction (“reentrant” tachycardias).1 Automatic tachycardias depend on spontaneous impulse generation in latent pacemakers and may be a result of several different mechanisms. Medications, such as digoxin or catecholamines, and conditions, such as hypoxia, electrolyte abnormalities (eg, hypokalemia), and fiber stretch (cardiac dilation), may lead to an increased slope of phase 4 depolarization in cardiac tissues other than the SA node.1 These factors are associated with abnormal automaticity in experimental models and arrhythmogenesis 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 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 (delayed afterdepolarizations [DADs]) but prior to phase 4 of the AP (Fig. 404).1 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 (eg, potassium) responsible for cellular repolarization. EADs provoked by medications that block potassium conductance and delay repolarization are the underlying cause of TdP. DADs may be precipitated by digoxin or catecholamines and suppressed by nondihydropyridine (non DHP) calcium channel blockers (CCBs). DADs have been suggested as the mechanism for multifocal atrial tachycardia, digoxininduced tachycardias, and exerciseprovoked VT. Triggered automatic rhythms possess some of the characteristics of automatic tachycardias and some of the characteristics of reentrant tachycardias (description follows). FIGURE 404 Afterdepolarizations. (EAD early afterdepolarization; DAD delayed afterdepolarization.) Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 6 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility of reentrant tachycardias (description follows). Access Provided by: FIGURE 404 Afterdepolarizations. (EAD early afterdepolarization; DAD delayed afterdepolarization.) 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. 405, panel A).1 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 the 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. FIGURE 405 (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 medication 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 antegrade pathway 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 medication 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 functional reentry and proarrhythmia. (a) Functionally determined 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) An instance where a medication 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 medication treatment. (c) An instance where a medication slows conduction velocity without significantly prolonging the refractory period (ie, class Ic antiarrhythmic medications) 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 medication treatment. (Reprinted, with permission, from McCollam PL, Parker RB, Beckman KJ, et al. Proarrhythmia: A paradoxic response to antiarrhythmic agents. Pharmacotherapy 1989;9:146.) Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 7 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility conduction velocity without significantly prolonging the refractory period (ie, class Ic antiarrhythmic medications) and accelerates the tachycardia. The Access Provided by: 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 medication treatment. (Reprinted, with permission, from McCollam PL, Parker RB, Beckman KJ, et al. Proarrhythmia: A paradoxic response to antiarrhythmic agents. Pharmacotherapy 1989;9:146.) Another model of reentry, referred to as a functional reentrant loop, may also occur (Fig. 405, panel B).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. 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. 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 medications on terminating, modifying, and causing cardiac rhythm disturbances (eg, proarrhythmia). 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. Of course, because reentry does not usually occur in normal, healthy conduction tissue, various forms of heart disease or conduction abnormalities are typically present before reentry becomes manifest. An oftenused example is reentry occurring as a consequence of ischemic or hypoxic damage. With inadequate cellular oxygenation, highenergy phosphate concentrations diminish, the activity of the transmembrane ion pumps declines, and RMP rises. This rise in RMP causes inactivation in the voltagedependent sodium channel, and the tissue begins to assume Downloaded slow conduction 20241127 11:51 P characteristics. Your IP is If changes in the tissue’s conduction parameters occur in a discordant manner due to varying degrees of Chapter 40:ischemia or hypoxia, Arrhythmias, then Jessica a reentry J. Tilton; circuit T. Stephen may become Phillips; manifest. Jerry Furthermore, an ischemic, dying cell releases intracellular potassium, L. Bauman Page 8 / 72 ©2024also which McGraw causesHill. All in a rise Rights RMP.Reserved. Terms In other cases, of Use reentry may occur Privacy Policy of because Notice Accessibility 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 system appears to provide a suitable substrate for the formation of microreentrant loops and is often used as a model to facilitate the understanding Access Provided by: of reentry concepts. Of course, because reentry does not usually occur in normal, healthy conduction tissue, various forms of heart disease or conduction abnormalities are typically present before reentry becomes manifest. An oftenused example is reentry occurring as a consequence of ischemic or hypoxic damage. With inadequate cellular oxygenation, highenergy phosphate concentrations diminish, the activity of the transmembrane ion pumps declines, and RMP rises. This rise in RMP causes inactivation in the voltagedependent sodium channel, and the tissue begins to assume slow conduction characteristics. If changes in the tissue’s 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 releases intracellular potassium, which also causes a rise in RMP. In other cases, reentry may occur because 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 (ie, premature beat); (b) the initiating beat is usually different in morphology from subsequent beats of the tachycardia; (c) the initiation of the tachycardia can usually be incited 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 AF, atrial flutter (AFl), AV nodal reentrant tachycardia (AVNRT), AV reentrant tachycardia (AVRT), and recurrent VT (Table 401). TABLE 401 Characteristics and Presumed Mechanisms of Arrhythmias Tachycardia Mechanism Origin Sinus tachycardia Automatic (normal) Sinus node Atrial fibrillation Reentry, automatic, triggered Atria, thoracic veins, pulmonary veins, and superior vena cava activity Atrial flutter Reentry Right (most common) and left atria Atrial tachycardia Reentry, automatic, triggered Atria activity AV nodal reentry Reentry AV junction tachycardia AV reentry tachycardia Reentry Circuit includes accessory AV connection, atria, AV node, HisPurkinje system, ventricles Ventricular tachycardia Reentry, automatic, triggered Ventricles Torsades de Pointes Reentry, triggered activity Ventricles AV, atrioventricular. PHARMACOLOGIC THERAPY In a theoretical sense, medications have antiarrhythmic activity by directly altering electrical conduction in several ways. First, a medication may depress the automatic properties of abnormal pacemaker cells. 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, medications may alter the conduction characteristics of a reentrant loop (Fig. 405).1,2 A medication may facilitate conduction (shorten refractoriness) in the area of unidirectional block, allowing antegrade conduction to proceed. On the other hand, a medication 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, medications 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 Downloaded refractoriness20241127 is prolonged11:51 P Your without IP is slowing conduction velocity, the tachycardia may terminate or slow in rate because of a greater circuit significantly Chapter 40: Arrhythmias, Jessica J. Tilton; length (see Fig. 405, panel B). There are otherStephen T. Phillips; theoretical ways toJerry stopL. Bauman reentry: Page 9 / 72 (a) a medication may eliminate the critically timed premature impulse ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility that triggers reentry; (b) a medication may slow conduction velocity to such an extent that conduction is extinguished; or (c) a medication may reverse the underlying form of heart disease that was responsible for the conduction abnormalities that led to the arrhythmia (ie, “reverse remodeling”). reentrant loop (Fig. 405).1,2 A medication may facilitate conduction (shorten refractoriness) in the area of unidirectional block, allowing antegrade Access Provided by: conduction to proceed. On the other hand, a medication 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, medications 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 because of a greater circuit length (see Fig. 405, panel B). There are other theoretical ways to stop reentry: (a) a medication may eliminate the critically timed premature impulse that triggers reentry; (b) a medication may slow conduction velocity to such an extent that conduction is extinguished; or (c) a medication may reverse the underlying form of heart disease that was responsible for the conduction abnormalities that led to the arrhythmia (ie, “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 402).2 This classification has been criticized for the following reasons: (a) it is incomplete and does not allow for the classification of medications such as digoxin or adenosine; (b) it is not pure, and many agents have properties of more than one class of medications; (c) it does not incorporate medication characteristics such as mechanisms of tachycardia termination/prevention, clinical indications, or side effects; and (d) medications become “labeled” within a class, although they may be distinct in many regards. Despite these criticisms, the Vaughan Williams classification remains the most frequently used for categorizing the electrophysiologic actions of AADs. TABLE 402 Classification of Antiarrhythmic Medications Class Medication Conduction Velocitya Refractory Period Automaticity Ion Block Ia Quinidine ↓ ↑ ↓ Sodium (intermediate) Potassium Procainamide Disopyramide Ib Lidocaine 0/↓ ↓ ↓ Sodium (fast on–off) Mexiletine Ic Flecainide ↓↓ ↑ (atrial) ↓ Sodium (slow on–off) Propafenoneb IIc βblockers ↓ ↑ ↓ Calcium (indirect) III Amiodaroned 0 ↑↑ 0 Potassium Dofetilide Dronedaroned Sotalolb Ibutilide IVc Verapamil ↓ ↑ ↓ Calcium Diltiazem aVariables for normal tissue models in ventricular tissue. Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 10 / 72 bAlso has βblocking actions. ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility cVariables for sinoatrial (SA) and atrioventricular (AV) nodal tissue only. classification of medications such as digoxin or adenosine; (b) it is not pure, and many agents have properties of more than one class of medications; Access Provided by: (c) it does not incorporate medication characteristics such as mechanisms of tachycardia termination/prevention, clinical indications, or side effects; and (d) medications become “labeled” within a class, although they may be distinct in many regards. Despite these criticisms, the Vaughan Williams classification remains the most frequently used for categorizing the electrophysiologic actions of AADs. TABLE 402 Classification of Antiarrhythmic Medications Class Medication Conduction Velocitya Refractory Period Automaticity Ion Block Ia Quinidine ↓ ↑ ↓ Sodium (intermediate) Potassium Procainamide Disopyramide Ib Lidocaine 0/↓ ↓ ↓ Sodium (fast on–off) Mexiletine Ic Flecainide ↓↓ ↑ (atrial) ↓ Sodium (slow on–off) Propafenoneb IIc βblockers ↓ ↑ ↓ Calcium (indirect) III Amiodaroned 0 ↑↑ 0 Potassium Dofetilide Dronedaroned Sotalolb Ibutilide IVc Verapamil ↓ ↑ ↓ Calcium Diltiazem aVariables for normal tissue models in ventricular tissue. bAlso has βblocking actions. cVariables for sinoatrial (SA) and atrioventricular (AV) nodal tissue only. dAlso has sodium, calcium, and βblocking actions; see Table 403. TABLE 403 Time Course and Electrophysiologic Effects of Amiodarone IV Oral Class Mechanism EP ECG Minutes–Hours Hours–Days Days–Weeks Weeks–Months Downloaded 20241127 11:51 P Your IP is Class I Na+ block ↑HV ↑QRS 0 + + ++ Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 11 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Class II βblock ↑AH ↑PR ++ ++ ++ ++ bAlso has βblocking actions. Access Provided by: cVariables for sinoatrial (SA) and atrioventricular (AV) nodal tissue only. dAlso has sodium, calcium, and βblocking actions; see Table 403. TABLE 403 Time Course and Electrophysiologic Effects of Amiodarone IV Oral Class Mechanism EP ECG Minutes–Hours Hours–Days Days–Weeks Weeks–Months Class I Na+ block ↑HV ↑QRS 0 + + ++ Class II βblock ↑AH ↑PR ++ ++ ++ ++ ↓HR Class III K+ block ↑VERP ↑QT 0 + ++ ++++ ↑AERP Class IV Ca2+ blocka ↑AH ↑PR + + + + ↓HR AERP, atrial effective refractory period; AH, atria–His interval; ECG, electrocardiographic effects; EP, electrophysiologic actions; HR, heart rate; HV, His–ventricle interval; IV, intravenous; VERP, ventricular effective refractory period. aRatedependent (for amiodarone). 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 medication 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 (Fig. 403). Several principles are inherent in antiarrhythmic sodium channel receptor theories3,4: 1. Class I AADs have predominant affinity for a particular state of the channel (eg, during activation or inactivation). For example, lidocaine blocks sodium current primarily when the cell is in the inactivated state, whereas quinidine, flecainide, and propafenone are predominantly open (or activated) channel blockers. 2. Class I AADs have specific binding and unbinding characteristics to the receptor, which has led to the subclassification (Ia, Ib, Ic) of these AADs. 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 use dependence (ie, sodium channel blockade and slowed conduction are greatest at fast heart rates and least during bradycardia). For “slow on–off” medications, 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 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 Nacetylprocainamide (manifests predominantly at high concentrations), the primary metabolite of procainamide. Downloaded 20241127 Additionally, propafenone11:51 P βblocking has Your IP is actions. Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 12 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility The class Ia AADs, quinidine, procainamide, and disopyramide, slow conduction velocity, prolong refractoriness, and decrease the automatic properties of sodiumdependent (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 medications generally 4. Class I AADs are weak bases with a pKa > 7 and block the sodium channel in their ionized form. Consequently, pH will alter these actions: acidosis Access Provided by: 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 Nacetylprocainamide (manifests predominantly at high concentrations), the primary metabolite of procainamide. Additionally, propafenone has βblocking actions. The class Ia AADs, quinidine, procainamide, and disopyramide, slow conduction velocity, prolong refractoriness, and decrease the automatic properties of sodiumdependent (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 medications generally depress conduction and prolong refractoriness, theoretically transforming the area of unidirectional block into a bidirectional block. Clinically, class Ia medications are broadspectrum AADs that are indicated for both supraventricular and ventricular arrhythmias. However, their use tends to be infrequent in clinical practice because of their limited efficacy and significant toxicities. The class Ib AADs, lidocaine and mexiletine were historically categorized separately from quinidinelike medications. Early work demonstrated 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. Arrhythmias do not usually arise from normal tissue. However, lidocaine possesses class Ia quinidinelike properties in diseased tissues. Therefore, it is probable that lidocaine acts in a similar fashion to the class Ia AADs (ie, 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, like lidocaine, occupy the sodium channel receptor, affecting the agent’s electrophysiologic actions. In addition, the intracellular acidosis that ensues due to 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 medications are relatively weak sodium channel blockers (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. The βblockers are classified as class II AADs. For the most part, the clinically relevant acute antiarrhythmic mechanisms of the βblockers result from their antiadrenergic actions.4 Because the SA and AV nodes are heavily influenced by adrenergic innervation, βblockers would be most useful in tachycardias in which these nodal tissues are abnormally automatic or are a portion of a reentrant loop. These medications are also helpful in slowing ventricular response in atrial arrhythmias (eg, AF) by their effects on the AV node. Furthermore, some tachycardias are exerciserelated or precipitated by states of high sympathetic tone (perhaps through triggered activity), and βblockers may be useful in these instances. Betaadrenergic stimulation results in increased conduction velocity, shortened refractoriness, and increased automaticity of the nodal tissues; βblockers will antagonize these effects. In the nodal tissues, βblockers interfere with calcium entry into the cell by altering catecholaminedependent channel integrity and gating kinetics. In sodiumdependent atrial and ventricular tissues, βblockers shorten repolarization somewhat but otherwise have little direct effect. The antiarrhythmic properties of βblockers observed with longterm, chronic therapy in patients with heart disease are less well understood. Although it is clear βblockers decrease the likelihood of SCD (presumably arrhythmic death) after MI, the mechanism for this benefit remains unclear; this benefit may relate to the complex interplay of changes in sympathetic tone, damaged myocardium, and ventricular conduction. In patients with HF, medications such as βblockers, angiotensinconverting 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 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 medications 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 βblocking actions, blocks potassium channels, and has a small degree of calcium channel blocking activity (Table 403). 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 beta 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, 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 possesses nonselective βblocking actions. Unlike amiodarone and sotalol, dronedarone,20241127 Downloaded ibutilide, and dofetilide 11:51 P YourareIPonly is approved for the treatment of supraventricular arrhythmias. Both ibutilide (only available IV) and Chapter dofetilide (only available orally) can be usedStephen 40: Arrhythmias, Jessica J. Tilton; T. Phillips; for the acute Jerryof conversion L.AF Bauman Page or AFl to SR. Dofetilide can also be used to maintain SR in patients 13 /AF with 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility or AFl of longer than 1 week’s duration who have been converted to SR. Dronedarone is approved to reduce the risk of hospitalization in patients with a history of paroxysmal or persistent AF who are currently in SR. Although structurally related to amiodarone, dronedarone’s structure has been actions, blocks potassium channels, and has a small degree of calcium channel blocking activity (Table 403). At normal heart rates and with chronic Access Provided by: use, its predominant effect is to prolong repolarization. With IV administration, its onset is relatively quick (unlike the oral form) and beta 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, 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 possesses nonselective βblocking 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 AFl to SR. Dofetilide can also be used to maintain SR in patients with AF or AFl of longer than 1 week’s duration who have been converted to SR. Dronedarone is approved to reduce the risk of hospitalization in patients with a history of paroxysmal or persistent AF who are currently in SR. 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). However, amiodarone is more effective than dronedarone. There are several 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). Sotalol, ibutilide, and dofetilide selectively block IKr, whereas amiodarone and dronedarone block both IKr and IKs. Potassium channel blockers (particularly those with selective IKr blocking properties) display “reverse use dependence” (ie, their effects on repolarization are greatest at low heart rates). Sotalol and medications like it also appear to be much more effective in preventing VF (in dog models) than the traditional sodium channel blockers. The safety concern of all class III AADs is an extension of their underlying ionic mechanism; that is, by blocking potassium channels and delaying repolarization, these medications may also cause proarrhythmia in the form of TdP by provoking EADs. The nonDHP CCBs, verapamil and diltiazem, are categorized as class IV AADs. They block Ltype calcium channels in SA and AV nodal tissues, slowing conduction, prolonging refractoriness, and decreasing automaticity (eg, due to EADs or DADs). Thus, these agents are effective in automatic or reentrant tachycardias which arise from or use the SA or AV nodes. In supraventricular arrhythmias (eg, AF or AFl), these medications can slow ventricular response by slowing AV nodal conduction. Furthermore, because calcium entry seems to be integral to exerciserelated 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 (eg, nifedipine) do not have significant antiarrhythmic activity as they do not affect AV nodal conduction. All AADs currently available have an impressive side effect profile (Table 404). A considerable percentage of patients cannot tolerate longterm therapy with these medications and will have to discontinue therapy because of adverse drug reactions. Flecainide, propafenone, quinidine, procainamide, disopyramide, sotalol, nonDHP CCBs, and dronedarone may worsen HF symptoms in patients with underlying LV systolic dysfunction. Consequently, these medications should be avoided in patients with HFrEF. The class Ib AAD, mexiletine, causes neurologic and/or gastrointestinal toxicity in a high percentage of patients. One of the most frightening adverse effects related to AADs is the aggravation of underlying ventricular arrhythmias or the precipitation of new, lifethreatening ventricular arrhythmias.4 TABLE 404 Adverse Drug Reactions of Class I and III Antiarrhythmic Medications Disopyramide Anticholinergic symptoms (dry mouth, urinary retention, constipation, blurred vision), nausea, anorexia, HF, conduction disturbances, ventricular arrhythmias (eg, TdP) Procainamide Hypotension, worsening HF, conduction disturbances, ventricular arrhythmias (eg, TdP) Quinidine Cinchonism, diarrhea, abdominal cramps, nausea, vomiting, hypotension, worsening HF, conduction disturbances, ventricular arrhythmias (eg, TdP), fever Lidocaine Dizziness, sedation, slurred speech, blurred vision, paresthesia, muscle twitching, confusion, nausea, vomiting, seizures, psychosis, sinus arrest, conduction disturbances Mexiletine Dizziness, sedation, anxiety, confusion, paresthesia, tremor, ataxia, blurred vision, nausea, vomiting, anorexia, conduction disturbances, ventricular arrhythmias Flecainide Blurred vision, dizziness, dyspnea, headache, tremor, nausea, worsening HF, conduction disturbances, ventricular arrhythmias Downloaded 20241127 Propafenone 11:51fatigue, Dizziness, P Your IP isvision, bronchospasm, headache, taste disturbances, nausea, vomiting, bradycardia or AV block, worsening HF, blurred Chapter 40: Arrhythmias, ventricular arrhythmias Stephen T. Phillips; Jerry L. Bauman Jessica J. Tilton; Page 14 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Amiodarone Tremor, ataxia, paresthesia, insomnia, corneal microdeposits, optic neuropathy/neuritis, nausea, vomiting, anorexia, constipation, TdP (2× normal 1 point with AST/ALT/AP >3× normal) each S Stroke (ischemic or hemorrhagic) 1 Downloaded 20241127 11:51 P Your IP is B 40: Arrhythmias, Chapter Bleeding (history Jessicaof major hemorrhage J. Tilton; or T. Stephen anemia or severe Phillips; Jerrythrombocytopenia) L. Bauman 1 Page 25 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility L Labile INR on warfarin (TTR 160 mm Hg) 1 A Abnormal renal +/− hepatic function (dialysis, transplant, serum creatinine >2.26 mg/dL (200 µmol/L), cirrhosis, bilirubin >2× normal 1 point with AST/ALT/AP >3× normal) each S Stroke (ischemic or hemorrhagic) 1 B Bleeding (history of major hemorrhage or anemia or severe thrombocytopenia) 1 L Labile INR on warfarin (TTR 65 years old or extremely frail) 1 D Drugs or alcohol use (concomitant use of antiplatelet or NSAID and/or ≥8 alcoholic drinks/week) 1 point each HASBLED score assesses a patient’s 1year risk of major bleeding when taking anticoagulants for atrial fibrillation. A score of 3 or greater is considered high risk for bleeding. The maximum score is 9. (AST, aspartate aminotransferase; ALT, alanine aminotransferase; AP, alkaline phosphatase; INR, international normalized ratio; NSAID, nonsteroidal antiinflammatory drug; TTR, time in therapeutic range.) FIGURE 407 Algorithm for the prevention of thromboembolism in atrial fibrillation. a Score based on nonsex risk factors. b The target INR for patients with prosthetic heart valves should be based on the type of valve that is present. (AF, atrial fibrillation; INR, international normalized ratio; MI, myocardial infarction; PAD, peripheral arterial disease.) Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 26 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility a Score based on nonsex risk factors. Access Provided by: b The target INR for patients with prosthetic heart valves should be based on the type of valve that is present. (AF, atrial fibrillation; INR, international normalized ratio; MI, myocardial infarction; PAD, peripheral arterial disease.) The efficacy and safety of two dabigatran doses (110 mg and 150 mg twice daily) were compared with those of warfarin in patients with AF.18 For the primary endpoint of stroke or systemic embolism, both dabigatran groups were shown to be noninferior to warfarin. Furthermore, the dabigatran 150 mg group was shown to be superior to warfarin in reducing this endpoint. The rate of major bleeding was similar between the dabigatran 150mg and warfarin groups, while the rate of major bleeding was significantly lower in the dabigatran 110mg group than in the warfarin group. The rate of intracranial hemorrhage (ICH) was significantly lower in both dabigatran groups than in the warfarin group. Even though the 110 and 150mg dosing regimens of dabigatran were evaluated in this trial, only the 150mg dose was initially approved by the FDA for AF. A lower 75mg dose was also approved for patients with a CrCl of 15 to 30 mL/min (0.25 to 0.5 mL/s) 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.19 It is important to note that the trial excluded patients with a CrCl less than 30 mL/min (0.5 mL/s). A 110mg dose of dabigatran has been approved for prophylaxis of venous thromboembolism in patients following hip replacement surgery. Although this dose has not been FDAapproved for stroke prevention in AF, the CHEST guidelines suggest using this dose (or apixaban or edoxaban) in patients with a history of or who are at high risk of bleeding.16 Dabigatran is contraindicated in patients with mechanical heart valves because its use in this population has been associated with an increased risk of TE complications and bleeding.20 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 (ROCKET AF).21 In this study, patients were randomized to receive rivaroxaban 20 mg daily or adjusteddose warfarin. For the primary endpoint 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 ICHs occurred in the rivaroxaban group compared with the warfarin 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 Downloaded Thromboembolic20241127 Events in11:51 AtrialPFibrillation Your IP is(ARISTOTLE) trial.22 Overall, apixaban was shown to be noninferior and superior to warfarin with regard Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 27 / 72 to the primary ©2024 McGraw endpoint Hill. All of stroke Rights or systemicTerms Reserved. embolism. of UseThe rate of major Privacy Policybleeding Notice in this trial was significantly lower in the apixaban group than in Accessibility the warfarin group. Additionally, significantly fewer ICHs occurred in the apixaban group compared with the warfarin group. Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).21 In this study, patients Access Provided by: were randomized to receive rivaroxaban 20 mg daily or adjusteddose warfarin. For the primary endpoint 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 ICHs occurred in the rivaroxaban group compared with the warfarin 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 (ARISTOTLE) trial.22 Overall, apixaban was shown to be noninferior and superior to warfarin with regard to the primary endpoint 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 ICHs occurred in the apixaban group compared with the warfarin group. The efficacy and safety of edoxaban were compared with those of warfarin in patients with AF in the Effective Anticoagulation with Factor Xa Next Generation in Atrial FibrillationThrombolysis in Myocardial Infarction (ENGAGE AFTIMI) 48 trial.23 In this study, patients were randomized to receive edoxaban 60 mg daily, edoxaban 30 mg daily, or adjusteddose warfarin. Overall, both doses of edoxaban were shown to be noninferior to warfarin with regard to the primary endpoint of stroke or systemic embolism. However, the edoxaban 60mg dosing regimen was also shown to be superior to warfarin with regard to this endpoint. The rate of major bleeding and the risk of ICH were significantly lower in both edoxaban groups than in the warfarin group. However, the risk of major gastrointestinal bleeding was significantly higher in the edoxaban 60mg group, but significantly lower in the edoxaban 30mg group when compared to the warfarin group. Guidelines recommend therapy with a DOAC over warfarin.16,17 However, it is essential that anticoagulant therapy be individualized for each patient, with consideration given to medication cost, insurance coverage, INR monitoring options, patient preference, drug interaction potential, anticipated medication adherence, and necessary followup. Specifically with warfarin, the target INR range should be 2 to 3, and the time in therapeutic range (TTR) should ideally be greater than 70%.16 The TTR is an important metric when evaluating the efficacy of warfarin therapy as the risk of TE events, major bleeding, and death is lower in patients with a TTR of at least 65% compared to patients with a TTR of less than 65%.24 The CHEST guidelines have recommended the use of the SAMeTT2R2 score to assist in the identification of patients who are likely or not likely to achieve good anticoagulation control with warfarin (ie, TTR of at least 65%).16 With this scoring system, patients with AF are given two points each if they use tobacco or are of a nonwhite race. Patients are given one point each for being female, being younger than 60 years of age, having at least two of the specified medical conditions (hypertension, diabetes, CAD/MI, congestive HF, previous stroke, pulmonary disease, hepatic disease, or renal disease), or receiving treatment with a medication that interacts with warfarin. SAMeTT2R2 is an acronym for each of these risk factors. Once the points for this scoring system are added up, a score of 0 to 2 suggests that patients are likely to achieve a TTR of at least 65%. Patients with a score of more than 2 are less likely to achieve a TTR of at least 65% and should be educated on strategies that could improve their TTR, including more frequent INR monitoring and medication reviews, adherence counseling, and dietary guidance. Alternatively, these patients could be considered for DOAC therapy. Additionally, if a patient has previously taken warfarin, the time that his/her INR has been within the therapeutic range should also be considered before making the decision to switch the patient to a DOAC. If a patient is unable to maintain a therapeutic INR while on warfarin, therapy with a DOAC is recommended. Strict adherence with the DOACs is important because missing a single dose could result in an increased risk of TE events.25 If treatment with warfarin must be temporarily interrupted for the patient to undergo a medical procedure, coverage with a parenteral anticoagulant (eg, unfractionated heparin, low molecular weight heparin [LMWH]) should be considered in patients with a high risk of stroke and/or have a mechanical heart valve. Moreover, warfarin is the anticoagulant of choice for patients with moderate to severe mitral stenosis or a mechanical heart valve; the INR should be based on the type and location of the valve placed. Dabigatran, edoxaban, and rivaroxaban should be avoided in patients with a CrCl less than 15 mL/min (0.25 mL/s). In this particular population, anticoagulant options are warfarin and apixaban. Edoxaban should also be avoided in patients with a CrCl greater than 95 mL/min (1.58 mL/s) because of the potential for reduced efficacy. Although it was previously an acceptable practice to discontinue antithrombotic therapy 4 weeks after successful cardioversion (with the belief that a patient’s risk for thromboembolism had abated since he/she was in SR), data from the RACE and AFFIRM trials strongly suggest that patients with AF and other risk factors for stroke continue to be at risk for stroke even when maintained in SR.26,27 It is possible that these patients may be having undetected episodes of paroxysmal AF, placing them at risk for stroke. Consequently, the decision regarding chronic antithrombotic therapy should be based on a patient’s risk for stroke using the CHA2DS2VASc scoring system.14 Should a patient have an increased risk of stroke but have a contraindication to longterm anticoagulation, a LAA occluder may be an alternative.5,14,17 The Watchman, the only FDAapproved device, is deployed into the left atrial appendage and designed to conform to the anatomy of the LAA, permanently sealing it off and reducing the risk of emboli. Although postimplantation antithrombotic practice patterns vary, patients should initiate aspirin the day before the procedure and an oral anticoagulant upon implantation. If an adequate seal has been formed at 45 days postimplant, oral anticoagulation should be discontinued, aspirin should be continued, and a P2Y12 inhibitor should be started. At 6 months postimplant, the P2Y12 Downloaded 20241127 inhibitor is stopped while 11:51 aspirinPis Your IP is lifelong. continued Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 28 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility B—Better Symptom Management Should patients receive rate control (regulate only the ventricular rate and remain in AF) or rhythm control (restoring and maintaining normal sinus Access Provided by: Should a patient have an increased risk of stroke but have a contraindication to longterm anticoagulation, a LAA occluder may be an alternative.5,14,17 The Watchman, the only FDAapproved device, is deployed into the left atrial appendage and designed to conform to the anatomy of the LAA, permanently sealing it off and reducing the risk of emboli. Although postimplantation antithrombotic practice patterns vary, patients should initiate aspirin the day before the procedure and an oral anticoagulant upon implantation. If an adequate seal has been formed at 45 days postimplant, oral anticoagulation should be discontinued, aspirin should be continued, and a P2Y12 inhibitor should be started. At 6 months postimplant, the P2Y12 inhibitor is stopped while aspirin is continued lifelong. B—Better Symptom Management Should patients receive rate control (regulate only the ventricular rate and remain in AF) or rhythm control (restoring and maintaining normal sinus rhythm)? Six landmark clinical trials have compared the efficacy of rate control and rhythm control treatment strategies in patients with AF.2631 The Atrial Fibrillation FollowUp Investigation of Rhythm Management (AFFIRM) trial is the largest rate control versus rhythm control study conducted to date in patients with AF.27 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. Ratecontrol treatment involved AV nodal blocking medications (digoxin, βblockers, and/or nonDHP CCBs) first, and then nonpharmacologic treatment (AV nodal ablation with pacemaker implantation), if necessary. All patients in this group were anticoagulated. 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. 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 the rhythm control group, anticoagulation was encouraged but could be discontinued if SR had been maintained for at least 4 weeks. Overall mortality was not statistically different between the two strategies. However, patients in the rhythmcontrol group were significantly more likely to be hospitalized or experience an adverse drug reaction. The results of the other four trials were consistent with those of the AFFIRM trial.26,2830 In addition, a metaanalysis of these data demonstrated no significant difference in overall mortality between rate control and pharmacological rhythm control strategies, which persisted even when the results from the AFFIRM trial were excluded from this analysis.32 Collectively, these trials demonstrate that a rate control strategy is a viable alternative to a rhythm control strategy in patients with persistent AF. However, only a small proportion of patients enrolled in these trials had HFrEF. Thus, a trial was conducted to specifically evaluate the safety and efficacy of rate control and rhythm control strategies in patients with HFrEF.31 Consistent with other rate control versus rhythm control studies, no significant difference in the primary endpoint of death from cardiovascular (CV) causes was observed between treatment groups. Though not statistically significant, patients in the rhythm control group tended to have more hospitalizations, primarily due to repeated cardioversions and adjustment of AAD therapy. It is important to note that the results of this trial should not be applied to patients with HFpEF. Together, these trials suggest that a pharmacological rhythm control strategy does not confer any advantage over a rate control strategy in patients with AF, with or without HFrEF. 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 AF, the decision to utilize one strategy over another is primarily driven by the goal of improving a patient’s quality of life (Table 4010). TABLE 4010 Considerations for Selecting a RateControl Versus RhythmControl Strategy in Patients with Atrial Fibrillation RateControl RhythmControl No or minimal symptoms Paroxysmal or persistent AF Treatment of choice for permanent AF Symptomatic despite adequate rate control Hemodynamically unstable Exacerbating heart failure Tachycardiamediated cardiomyopathy Other factors Younger age First episode of AF Downloaded 20241127 11:51 P Your IP is Patient preference Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 29 / 72 ©2024 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility AF, atrial fibrillation. HFrEF. Access Provided by: 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 AF, the decision to utilize one strategy over another is primarily driven by the goal of improving a patient’s quality of life (Table 4010). TABLE 4010 Considerations for Selecting a RateControl Versus RhythmControl Strategy in Patients with Atrial Fibrillation RateControl RhythmControl No or minimal symptoms Paroxysmal or persistent AF Treatment of choice for permanent AF Symptomatic despite adequate rate control Hemodynamically unstable Exacerbating heart failure Tachycardiamediated cardiomyopathy Other factors Younger age First episode of AF Patient preference AF, atrial fibrillation. Rate Control Once the decision has been made to rate control a patient, the next important question is: What defines “adequate” ventricular rate control? A lenient rate control strategy targeting a resting heart rate less than 110 beats/min is recommended for asymptomatic patients with a preserved LV systolic function (LVEF greater than 40% [0.40]).14,33 In patients who are symptomatic or have LV systolic dysfunction (LVEF less than or equal to 40% [0.40]), a stricter rate control approach targeting a resting heart rate less than 80 beats/min should be considered. The selection of an AV nodalblocking medication to control ventricular rate is primarily based on the patient’s LV function.14 In patients with preserved LV function or in patients with stable HFpEF, a βblocker or nonDHP CCB (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 medications, the addition of digoxin may result in an additive lowering of the heart rate. However, digoxin tends to be ineffective for controlling ventricular rate under conditions of increased sympathetic tone (ie, surgery, thyrotoxicosis) because it slows AV nodal conduction primarily through vagotonic mechanisms. Verapamil and diltiazem should be avoided in patients with HFrEF (LVEF less than or equal to 40% [0.40]) because of their potent negative inotropic effects.14 Instead, βblockers and digoxin are preferred. Specifically, in patients with NYHA class II or III HF, βblockers should be considered over digoxin because of their survival benefits in patients with HFrEF. If patients are having an episode of decompensated HF (NYHA class IV), digoxin is preferred as firstline therapy to achieve ventricular rate control because of the potential for worsening HF symptoms with the initiation and subsequent titration of βblocker therapy. Several analyses have associated digoxin with a significant increase in the risk of mortality in patients with AF.34 The risk is highest when serum digoxin concentrations are 1.2 ng/mL (mcg/L; 1.5 nmol/L) or greater.35 If adequate ventricular rate control during rest and exercise cannot be achieved with βblockers, nonDHP CCBs, and/or digoxin in patients with normal or depressed LV function, amiodarone can be used as an alternative therapy to control the heart rate (Table 4011). 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 TE event, especially if the AF has persisted for at least 48 hours or is of unknown duration. TABLE 4011 EvidenceBased Pharmacologic Treatment Recommendations for Controlling Ventricular Rate, Restoring Sinus Rhythm, and Maintaining Sinus Rhythm in Patients with Atrial Fibrillation Downloaded 20241127 11:51 P Your IP is Chapter 40: Arrhythmias, Jessica J. Tilton; Stephen T. Phillips; Jerry L. Bauman Page 30 / 72 ©2024Treatment McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Recommendations ACC/AHA Guideline or depressed LV function, amiodarone can be used as an alternative therapy to control the heart rate (Table 4011). 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 Provided Access a TE by: event, especially if the AF has persisted for at least 48 hours or is of unknown duration. TABLE 4011 EvidenceBased Pharmacologic Treatment Recommendations for Controlling Ventricular Rate, Restoring Sinus Rhythm, and Maintaining Sinus Rhythm in Patients with Atrial Fibrillation Treatment Recommendations ACC/AHA Guideline Recommendation Ventricular rate control (acute setting) In the absence of an accessory pathway, an IV βblocker or IV nonDHP CCB is recommended for patients without HF. Class I In the absence of an accessory pathway, IV digoxin or IV amiodarone is recommended to control the ventricular rate in patients Class I with HF. In the absence of an accessory pathway, an IV βblocker is recommended to control the ventricular rate in patients with stable Class I HFrEF. In the absence of an accessory pathway, an IV nonDHP CCB is recommended to control

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