US Pharm. 2006;6:HS-16-HS-24.

Cardiac arrhythmias or dysrhythmias are an important cause of morbidity and mortality for Americans. In 2002, almost 500,000 people died as a result of an arrhythmia, and in 2001, more than $2.5 billion was paid to Medicare beneficiaries for treatment of dysrhythmias.1 In the past 10 to 15 years, antiarrhythmic drug use has declined, due to clinical trials such as the Cardiac Arrhythmia Suppression Trials, which showed an increased mortality with certain antiarrhythmics in post–myocardial infarction patients with asymptomatic premature ventricular contractions. Undoubtedly, antiarrhythmics have limited benefits and high risks. Also, the use of technology, such as ablation and cardioverter defibrillators, has proven beneficial in managing arrhythmias in addition to or as an alternative to drug therapy. Since many patients still receive medications to treat dysrhythmias, pharmacists must understand the principles of arrhythmias and the pharmacology of antiarrhythmic medications to provide patients with up-to-date care and help maximize therapy and minimize side effects. Pharmacists also must assist in achieving the main goals of antiarrhythmic therapy--improving patient survival and reducing symptoms and complications of arrhythmias. This two-part article reviews commonly encountered dysrhythmias and treatment options.

Supraventricular Arrhythmias
Supraventricular arrhythmias are rhythm disturbances that occur in the atrial conducting tissue and include atrial fibrillation (AF) and paroxysmal supraventricular tachycardia (PSVT). These dysrhythmias occur more often than ventricular arrhythmias and are rarely life-threatening.

Atrial Fibrillation: AF is the most common sustained arrhythmia, affecting more than two million Americans every year.1 The incidence of AF increases with age (70% of patients are ages 65 to 85 years), and it affects men at higher rates than women.2 AF has many cardiac and noncardiac causes. Risk factors include hypertension, left ventricular hypertrophy, cardiomyopathy, diabetes, smoking, valvular disease, hyperthyroidism, and left atrial dilation (table 1). 2,3 In lone AF, there is no determinable cause for the rhythm disturbance.




AF is a supraventricular dysrhythmia that is defined as irregularly irregular, or having an irregular rhythm. AF can cause an unpredictable and rapid ventricular response rate, with an atrial rate between 400 and 600 beats per minute (bpm) and a ventricular rate between 120 and 180 bpm.

Two theories exist on the mechanism of AF. Most studies support the theory that AF results from multiple reentrant electrical wavelets that develop and move in a random manner around the atria. 3 The number of wavelets depends on factors such as the length of the refractory period, atrial mass, and the conduction velocity.4 An alternate theory suggests that AF may be caused by rapidly firing foci in the atrial myocardium. These ectopic foci are often located in left atrial tissue within and close to pulmonary veins, with the superior vena cava and the coronary sinus less frequently implicated.4

According to the American College of Cardiology/American Heart Association/European Society of Cardiology guidelines, AF can be recurrent, paroxysmal, persistent, or permanent. After a patient first presents with AF, subsequent episodes are classified based on the duration of the arrhythmia. When the patient has experienced two or more episodes of AF, the abnormal rhythm is considered recurrent. If the AF recurs but the patient experiences some periods of normal sinus rhythm, the rhythm is known as paroxysmal. Recurrent AF that is continuous or paroxysmal is persistent. Long-standing AF (usually greater than one year) is known as permanent. 5

Patients with AF can be managed with rhythm control or rate control. For those with persistent AF, electrical or chemical cardioversion may restore normal sinus rhythm. The electrical method involves direct current cardioversion (DCC), which delivers a shock that is synchronized with the electrical activity of the heart during the vulnerable phase of the cardiac cycle.5 DCC success rates for AF vary from 70% to 90% and depend on factors such as patient age, AF duration, degree of left atrial enlargement, and underlying heart disease. Additionally, the definition of success may vary based on the evaluation period.5 Chemical cardioversion involves the use of a Vaughn Williams classified Ia, Ic, or III drug to induce normal sinus rhythm (table 2). Drugs with proven efficacy include dofetilide, amiodarone, ibutilide, flecainide, propafenone, and quinidine. Pharmacologic conversion may be most effective when initiated within seven days after AF onset and is generally considered less efficacious than electrical cardioversion.5 When electrical or chemical cardioversion is successful, patients may receive maintenance drug therapy with a single drug (table 3) or a combination of antiarrhythmics (e.g., a beta-blocker, amiodarone, or sotalol with a type Ic medication). 5




When cardioversion is unsuccessful or a patient cannot tolerate DCC or pharmacologic therapy, ventricular rate control can be used to manage AF. This allows additional diastolic filling time and leads to an increased cardiac output and fewer symptoms such as shortness of breath, dizziness, and palpitations.6 In the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial, patients who received therapy to restore and maintain sinus rhythm had no advantage over those who received ventricular rate control and remained in AF. In addition, patients receiving the rate control strategy had a lower risk of adverse drug effects and hospitalizations than those receiving antiarrhythmic drugs.7 The goal of rate control therapy is to minimize the negative symptoms associated with AF by achieving a ventricular response of 60 to 80 bpm at rest and  90 to 110 bpm during mild to moderate exercise.5




Ventricular rate control is achieved using drugs that block the transmission of the cardiac impulse from the atria to the ventricles via the atrioventricular (AV) node. AV-nodal blocking agents include digoxin, beta-blockers, and the nondihydropyridine calcium channel blockers, diltiazem and verapamil. Digoxin decreases conduction through the AV node by increasing vagal tone through the parasympathetic nervous system. The cardiac glycoside also inhibits cardiac sodi­ um/potassium/adenosine triphosphatase, allowing more calcium into the myocardial cell.2 Use of digoxin for ventricular rate control has declined for several reasons. First, because of its vagomimetic activity, digoxin may not be effective for patients who are in a state of high adrenergic tone (e.g., during exercise, anxiety, or critical illness). In addition, digoxin's peak onset of action is at least six hours. The drug may paradoxically induce and prolong AF by delaying recovery from electrical remodeling of the atria. Finally, digoxin has a narrow therapeutic index and must be used cautiously in patients who are elderly or with renal dysfunction. Due to these limitations, digoxin is usually reserved for patients with AF who have left ventricular dysfunction or who are sedentary.6 Digoxin can also be used in combination with a beta-blocker or calcium channel blocker when additional rate control is needed.

The decision to use a beta-blocker or calcium channel antagonist (diltiazem or verapamil) for ventricular rate control depends on clinician preference and the presence of other disease states.4 Beta-blockers are especially useful for rate control in patients with coronary artery disease or congestive heart failure or who are in states of high adrenergic tone.2,4 Beta-blockers are often used prior to open heart surgery to decrease the incidence of postoperative AF. 2 Diltiazem or verapamil may be preferred in patients with chronic lung disease, diabetes, or peripheral vascular disease.2,4

AF is an independent risk factor for thromboembolism and stroke. In fact, AF is responsible for 15% to 20% of all strokes.1 Patients with AF who do not receive anticoagulants have an annual stroke risk of about 6%.2 Embolic stroke is a major cause of death and disability; yearly treatment costs in the United States have been estimated at $40 billion.6 Many large-scale trials have shown the benefit of anticoagulation in prevention of stroke. Pooled data from five trials showed that warfarin therapy reduced the risk of stroke by about 60% in patients with AF. Aspirin therapy was somewhat less effective, reducing the incidence of stroke by about 20%. However, the risk of bleeding is much higher with warfarin therapy, and warfarin requires international normalized ratio (INR) monitoring.3,6

According to the 2001 Chest guidelines, patients with recurrent or permanent AF who have at least one high-risk factor are considered to be at high risk for stroke. The high-risk factors include prior stroke, transient ischemic attack, or systemic embolus; history of hypertension; left ventricular dysfunction; age older than 75; rheumatic mitral valve disease; or prosthetic valve. High-risk patients should receive warfarin therapy with a target INR of 2.5 (range, 2 to 3). AF patients are placed into the moderate-risk group if they have only one moderate risk factor. The moderate-risk factors include age between 65 and 75, diabetes mellitus, and coronary heart disease. A patient with more than one moderate-risk factor is considered to be at high risk. Moderate-risk patients can be treated with either aspirin 325 mg/day or warfarin. The choice of therapy is based on the patient's risk of bleeding, ability to receive monitoring, and general preference. A low-risk patient with AF does not have any of the listed risk factors and should receive aspirin for anticoagulation. 8

All discussions of AF should include nonpharmacologic treatment. Patients who do not respond to antiarrhythmic drugs or pharmacologic rate control may be candidates for percutaneous interventions or surgical procedures for AF. Rate control is important, as persistent and paroxysmal AF with an uncontrolled rapid ventricular rate can lead to tachycardia-induced cardiomyopathy.9 Percutaneous AV nodal ablation can be performed by applying radiofrequency energy to the AV junction. This procedure is effective in controlling the ventricular rate but causes complete heart block, so patients must also receive a permanent pacemaker. In addition, these patients must receive long-term anticoagulation. 3,10 The most common surgery for AF is the maze operation. In this procedure, incisions, microwave, cryothermy, ultrasonography, or radiofrequency energy are used to form lines in the atrial tissue to prevent the formation of reentrant circuits and facilitate a pathway (maze) for the impulses to reach the AV node.3,4 The maze procedure is 98% effective but requires open heart surgery and can be associated with complications, including a need for a permanent pacemaker.4 Implantable devices, such as atrial pacers and atrial defibrillators, have also been used in AF treatment. Atrial pacing can prevent AF by decreasing the areas of refractoriness and suppressing triggers. This treatment has been particularly effective in treating sick sinus syndrome and might be efficacious in AF that is vagally mediated or due to bradycardia.3 Finally, the internal atrial defibrillator (IAD) has been used to terminate AF episodes. Leads for the IAD are transvenously placed into the right atrium and coronary sinus.3,4 Initially, these devices were manufactured only for AF, but newer models are atrial and ventricular defibrillators that terminate both AF and ventricular fibril­ lation (VF). Although the atrial part of the device usually is activated by the patient, it can be programmed to occur during sleep, preventing sudden painful shocks and allowing for preshock sedation or pain control.4,10

Paroxysmal Supraventricular Tachycardia
PSVT refers to a group of intermittent atrial arrhythmias caused by reentry or disturbances in conduction or automaticity.11 The most common type of PSVT is AV nodal reentry tachycardia (AVNRT), accounting for about 50% to 60% of cases. Although the exact reentry circuit has not been identified, the anterior and posterior AV nodal approaches and the perinodal tissue are involved.12 Most cases of AVNRT are classified as the slow-fast or common type and occur when two pathways with different conduction rates are present. The fast (retrograde) pathway, which is still refractory from the previous impulse, blocks the premature atrial impulse. The impulse is then redirected antegrade through the slow pathway. When the impulse reaches the end of the slow pathway, the fast pathway has recovered and conducts the impulse retrograde through the fast pathway and then again through the slow route. The process creates a self-sustaining closed circuit.13 Rarer variants of AVNRT include the fast-slow, slow-slow, and slow-sort-of-slow circuits.

Atrioventricular reentry (AVRT) is also a common type of PSVT and accounts for roughly one third of cases. Also known as a preexcitation syndrome, AVRTusually presents in patients who are younger than those affected by AVNRT. In orthodromic AVRT, the antegrade part of the circuit is normal, with impulse transmission though the AV node, bundle of His, and Purkinje fibers. However, the retrograde part of the circuit uses an accessory tract that is located along the mitral valve annulus.12

The most common type of orthodromic AVRT is Wolff-Parkinson-White syndrome (WPW), and the accessory tract is known as the Kent's bundle. During normal sinus rhythm in patients with WPW, the ventricles are depolarized simultaneously through the normal AV pathway and the Kent's bundle. As a result, the electrocardiogram (ECG) shows a shortened PR interval and a slurred upstroke to the QRS complex, known as a delta wave . Some patients with WPW may have a normal ECG during sinus rhythm, in which case the Kent's bundle is considered concealed.13 During the arrhythmia, the ECG usually shows a narrow-complex tachycardia at rates of 160 to 240 bpm and lacks the delta wave because the normal pathway is used for ventricular activation.13 WPW affects 0.1% to 0.3% of the general population and is twice as common in males as in females.12

Antidromic AVRT is more rare than the orthodromic type. In this variant, antegrade conduction is through the bypass tract and results in a wide-complex tachycardia that may be difficult to distinguish from ventricular tachycardia (VT).12,13 Intra-atrial reentry, atrial tachycardia, and sinus nodal reentry are relatively rare types of PSVT and are not discussed in this article.

Although PSVT is a benign, self-limiting arrhythmia for most patients, it can cause hemodynamic compromise, including angina and hypotension, as well as extreme anxiety.13 Treatment for PSVT is based on severity of symptoms. If the PSVT is sustained and the patient is experiencing angina, shortness of breath, hypotension, syncope, or heart failure, treatment is DCC.13,14 Electrical cardioversion is almost always effective in rapidly restoring normal sinus rhythm and reversing symptoms.14 Patients who are hemodynamically stable can receive nondrug or antiarrhythmic therapy for PSVT. Initially, patients should attempt vagal maneuvers that increase parasympathetic tone and slow conduction through the AV node (e.g., carotid sinus massage, Valsalva's maneuver, ice water facial immersion, gag reflex).13,14 Vagal techniques are successful in terminating 10% to 30% of PSVT.15

If nonpharmacologic therapy is ineffective, drug therapy is attempted. Adenosine is considered the drug of choice for acute episodes of PSVT, due to its rapid onset and ultrashort duration of action. Adenosine is a purine nucleoside that slows ventricular rate and AV nodal conduction.15 The drug is dosed as a 6-mg intravenous bolus for one to three seconds, followed by one or two 12-mg doses, if needed. The maximum dose is 30 mg. Adenosine's most common side effects are facial flushing, chest pain, dyspnea, and hypotension. These adverse effects are usually transient, due to the drug's short half-life.13 Adenosine may be advantageous in patients who are diagnosed with wide QRS complex PSVT (antidromic AVRT). If the dysrhythmia is actually VT, adenosine will not cause hemodynamic compromise, since it is short-acting and does not act as a negative inotrope. Heart transplant recipients should not use adenosine, as they may experience hypersensitivity.13

Verapamil or diltiazem can also be used to treat PSVT and are successful in approximately 85% of cases. Verapamil and possibly diltiazem are contraindicated in patients with a wide complex tachycardia because they are potent negative inotropes and may precipitate lethal hypotension or VF if the arrhythmia is ventricular in nature.13,15 If the PSVT is actually AF, verapamil or adenosine can cause a paradoxical increase in ventricular response with severe symptoms that may require cardioversion.14 Procainamide can be used as an alternative to adenosine for wide QRS-complex PSVT, especially in patients who have an irregular ventricular rate. Other agents that can be effective in treating PSVT include beta-blockers, digoxin, amiodarone, quinidine, and flecainide.

Radiofrequency ablation has become the treatment of choice for patients who do not respond to drug therapy or cannot tolerate adverse effects. Electrophysiologic testing is used to determine the location of the accessory tract, and radiofrequency energy is used to destroy the abnormal tissue. The success rate for radiofrequency ablation is about 95% in patients with AVNRT or AVRT and about 80% in patients with atrial tachycardia.13,15

Role of the Pharmacist
Pharmacists have a crucial role in managing patients with supraventricular arrhythmias. Some cases of AF may be prevented by appropriate pharmacologic and nondrug treatments for cardiac diseases, such as hypertension and congestive heart failure. Pharmacists can encourage their patients to avoid alcohol and recreational drugs that may contribute to the development of AF. In many institutions and clinics, pharmacists design and implement antiarrhythmic education programs for drugs such as dofetilide and amiodarone and provide anticoagulation monitoring. In addition, pharmacists may be responsible for monitoring drug levels of digoxin, procainamide, and quinidine and adjusting doses, if necessary. Supraventricular arrhythmias are common rhythm disturbances, and medication management for patients with these disorders provides a unique opportunity for pharmacists in all practice settings.

References
1. American Heart Association. Heart disease and stroke statistics. 2006 update. Circulation. 2006;113:e85-e151.
2. Panning C. Atrial fibrillation. U.S. Pharm. 2002;27:HS3-HS12.
3. Iqbal MB, Taneja AK, Lip GY, Flather M. Recent developments in atrial fibrillation. BMJ. 2005;330:238-243.
4. Sanoski C. Chronic Arrhythmia Management. Pharmacotherapy Self-Assessment Program. 5th ed. American College of Clinical Pharmacy; 2004:191-227.
5. Fuster V, Ryden LE, Asinger RW, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. J Am Coll Cardiol. 2001;38:1231-1266.
6. Tsikouris JP, Chow MSS, Meyerrose GE. Management of chronic atrial fibrillation: current therapeutic strategies. Formulary. 2001;36:580-593.
7. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-1833. 
8. Albers GW, Dalen JE, Laupacis A, et al. Antithrombotic therapy in atrial fibrillation. Chest. 2001;119:194S-206S.
9. Roffman DS. Medical management of atrial fibrillation. U.S. Pharm. 1999;24:89-102.
10. Falk RH. Medical progress: atrial fibrillation. N Engl J Med. 2001;344:1067-1078.
11. Bosen DM. Atrio-ventricular nodal reentry tachycardia. Dimens Crit Care Nurs. 2002;21:134-139.
12. Trohman RG. Supraventricular tachycardia: implications for the intensivist. Crit Care Med. 2000;28(10 suppl):N129-N135.
13. Hebbar AK, Hueston WJ. Management of common arrhythmias: part I. Supraventricular arrhythmias. Am Fam Physician. 2002;65:2479-2486.
14. Bauman JL, Schoen MD. Arrhythmias. In: DiPiro JT, Talbert LT, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York: McGraw-Hill; 2005:321-356.
15. Chow MSS, White M. Cardiac arrhythmias. In: Koda-Kimble MA, Young YY, eds. Applied Therapeutics: The Clinical Use of Drugs. 7th ed. Baltimore: Lippincott Williams & Wilkins; 2001:18-1–18-36.
16.  Brouse S. Critical Care Cardiology. Pharmacotherapy Preparatory Course. 2004: IV10-IV20.

To comment on this article, contact editor@uspharmacist.com.