American College of Cardiology

Blomström-Lundqvist ET AL., MANAGEMENT OF PATIENTS WITH Supraventricular Arrhythmias
J Am Coll Cardiol 2003;42:1493–531

ACC/AHA/ESC Guidelines for the Management of Patients With Supraventricular Arrhythmias

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias)

VI. SPECIAL CIRCUMSTANCES

A. Pregnancy Premature atrial beats are observed in approximately 50% of patients during pregnancy, but they are generally benign and well tolerated (460). Although sustained arrhythmias are relatively rare (2 to 3 per 1000), in those who have supraventricular arrhythmias, symptomatic exacerbation of paroxysmal SVT occurs during pregnancy in approximately 20% (461). Moreover, because the number of patients who have congenital heart diseases and are reaching reproductive age is increasing, more patients with SVT are to be anticipated. The major concern during treatment of SVT during pregnancy is the potential for adverse effects on the fetus, as all commonly used antiarrhythmic drugs cross the placental barrier to some extent. Although the first 8 weeks after conception is the period associated with the greatest teratogenic risk, other adverse effects may occur with drug exposure later in pregnancy. The major concern with taking antiarrhythmic drugs during the second and third trimesters is the adverse effect on fetal growth and development as well as the risk of proarrhythmia. Several of the physiological changes that occur during pregnancy, such as increased cardiac output and blood volume, decreased serum protein concentration, alterations in gastric secretion and motility, and hormonal stimulation of liver enzymes, can affect absorption, bioavailability, and elimination of many drugs. More careful monitoring of the patient and dose adjustments are, therefore, necessary because the above-mentioned changes vary in magnitude during different stages of pregnancy (462).

As with many other drugs used in pregnancy, use of certain antiarrhythmic agents has crept into common practice because of an absence of reported ill effects, rather than as a result of controlled studies. All antiarrhythmic drugs should be regarded as potentially toxic to the fetus and should be avoided if possible, especially during the first trimester. The U.S. Food and Drug Administration (FDA) drug classification is outlined in Table 4. All currently available antiarrhythmic drugs that are used for SVT are categorized as class C drugs, except for sotalol (a class B agent) and for atenolol and amiodarone (class D agents).

In patients with mild symptoms and structurally normal hearts, no treatment other than reassurance should be provided. Antiarrhythmic drug therapy should be used only if symptoms are intolerable or if the tachycardia causes hemo- dynamic compromise.

Catheter ablation should be recommended in women with symptomatic tachyarrhythmias before they contemplate pregnancy. Because of the potential problem of recurring tachyarrhythmias during pregnancy, the policy of withdrawing antiarrhythmic drugs and resuming them later can be recommended only as an alternative in selected cases. A large- scale clinical experience with catheter ablation procedures performed during pregnancy will never be reported, although fetal radiation dose and risk from the procedures have been calculated (463). Catheter ablation is the procedure of choice for drug refractory, poorly tolerated SVT. If needed, it should be performed in the second trimester.

1. Acute Conversion of Atrioventricular Node–Dependent Tachycardias

Intravenous adenosine is the drug of choice if vagal maneu- vers fail to terminate an episode of PSVT. This drug has been used safely in pregnant women, although most of the reports of adenosine administration were in the second and third trimesters (462,464).

If adenosine fails, then IV propranolol or metoprolol are recommended. Intravenous administration of verapamil may be associated with a greater risk of maternal hypotension and subsequent fetal hypoperfusion. Available data suggest that DC cardioversion is safe in all phases of pregnancy and can be used when necessary (465).

2. Prophylactic Antiarrhythmic Drug Therapy

If prophylactic drug therapy is needed, then digoxin or a beta-blocking agent (ie, propranolol or metoprolol) is the first-line agent. The experience with digoxin is extensive, and it is considered one of the safest antiarrhythmic drugs to take during pregnancy (462); however, its efficacy for arrhythmia treatment or prophylaxis has never been demonstrated. Propranolol and metoprolol are generally considered to be safe but are best avoided in the first trimester. Rare cases of adverse effects on the fetus, including bradycardia, hypoglycemia, premature labor, and metabolic abnormalities, have been reported but may be secondary to fetal distress in high-risk pregnancies. Prospective, randomized studies have failed to demonstrate a higher incidence of these complications with beta-blocking agents as compared to placebo (466,467). The potential for intrauterine growth retardation has been reported with propranolol and has raised concerns, especially when it is taken in the first trimester (462). Later studies reported growth retardation in babies receiving atenolol in the first trimester and a higher prevalence of preterm delivery (468,469). Atenolol is, therefore, classified as a category D agent by the FDA. In view of these results, beta blockers should be avoided during the first trimester, if possible. Beta blockers with selective B1 properties are theoretically preferable because they may interfere less with peripheral vasodilatation and uterine relaxation. If the above-mentioned drugs fail, then sotalol may be considered. Although sotalol has been used successfully during pregnancy for other indications, the experience is limited; so, caution is still advised (470). The reported experience with flecainide is also limited, but it appears to be relatively safe during pregnancy (471). The experience with propafenone is even more limited, although no adverse effects to the fetus have been reported when it is taken during the third trimester (472). Quinidine is considered to be relatively well tolerated, although isolated cases of adverse effects, such as fetal thrombocytopenia and eighth-nerve toxicity, have been reported (462). Procainamide is considered to be well tolerated and appears to be relatively safe for short-term therapy (473). The use of amiodarone, a category D agent, in pregnancy should be restricted to arrhythmias that are resistant to other drugs or are life threatening (474). It should be emphasized that these recommendations rely mainly on observational data; the cited references are, therefore, not all inclusive.

B. Supraventricular Tachycardias in Adult Patients With Congenital Heart Disease

1. Introduction

An increasing number of patients with congenital heart dis- ease are surviving to adulthood. Supraventricular arrhythmias are an important cause of morbidity and, in some of these patients, mortality. In patients who have not had operative repair of their malformation, AF and atrial flutter are the most common arrhythmias. Increased atrial filling pressures may contribute to the cause of AF or atrial flutter. Surgical repairs that place incisions in the atria predispose to incision-related atrial flutter late after surgery. There is currently interest in devising surgical procedures to avoid later development of atrial flutter. In addition, some patients may be candidates for percutaneous device closure of ASDs. Many patients warrant referral to an experienced specialist. The new development of atrial arrhythmias can be an indication of deteriorating hemodynamic function, which in some cases warrants specific investigation and occasionally operative treatment. An SVT itself dramatically impairs hemodynamic performance in some patients. Coexistent sinus node dysfunction is common after surgical repair of many of these conditions and can be further aggravated by antiarrhythmic therapy, requiring pacemaker implantation to allow management of the supraventricular arrhythmia. Cardiac malformations often increase the difficulty of pacemaker implantation and catheter ablation procedures. The presence of intracardiac shunts creates a risk of systemic embolism from clots that may form on pacing leads even though they are in the right-sided (ie, systemic venous) cardiac chambers.

2. Specific Disorders

a. Atrial Septal Defect

Atrial fibrillation or atrial flutter occurs in approximately 20% of adults who have an unrepaired ASD (475,476). Atrial fibrillation, rather than atrial flutter, predominates in the majority; incidence increases with patient age. Surgical or percutaneous closure of ASDs associated with pulmonary blood flow/systemic blood flow (Qp/Qs) greater than 1.5 and or symptoms before the age of 40 years may reduce atrial arrhythmias but has little effect after the age of 40 years (475-477).

Gatzoulis and coworkers retrospectively reviewed 218 adults who had surgical closure of an isolated ASD (475). Sustained atrial flutter or AF was present in 19% of patients prior to surgery, 5% had atrial flutter, 2.8% had AF and flutter, and 11% had AF. During a mean follow-up of 3.8 years, 60% of patients with preoperative AF or atrial flutter continued to have arrhythmias, and new AF or atrial flutter developed in 2.3% of patients. All of the patients with persistent arrhythmias and those who developed new atrial arrhythmias were older than 40 years of age at the time of repair. None of the 106 patients younger than 40 years of age at the time of surgery had late atrial arrhythmias during this follow-up period (P = 0.008).

Attie and coworkers randomized 521 adults older than 40 years of age who had isolated secundum or sinus venosus ASDs with a Qp/Qs greater than 1.7 and pulmonary artery systolic pressure less than 70 mm Hg to surgical closure versus medical therapy (476). Prior to randomization, 21% of patients had a history of AF or atrial flutter managed with rate control and anticoagulation, and 5% had a history of other types of SVT. During a median follow-up of 7.3 years, new atrial flutter or AF developed in 7.4% of patients in the surgical group and 8.7% of patients in the medical group. Cerebral embolic events occurred in 2.1% of patients. The risk was not different between the surgical and medically treated patients.

Management of atrial flutter is the same as described in Section V–F. In patients who have not had surgical repair, atrial flutter is likely to be dependent on conduction through the CTI and susceptible to catheter ablation. If closure of the ASD is not warranted by hemodynamic criteria, then catheter ablation of the atrial flutter is preferable to surgical closure of the septal defect, which is unlikely to abolish the atrial flutter. If closure of the septal defect is warranted in a patient with atrial flutter, then electrophysiological study with catheter ablation prior to surgery may still be considered or ablation of the atrial flutter isthmus may be performed during surgery in a center with experience in arrhythmia surgery. In patients with prior surgical repair, both CTI-dependent and non–CTI-dependent (so-called “incisional” or scar) atrial flutter occur and can coexist in a single patient (294,443,444,447,448,450,452-456,478). Management is as discussed above. If catheter ablation is warranted, then the possibility that the flutter will have a non-CTI-dependent mechanism should be considered. Ablation may be best performed in an experienced center with advanced, three- dimensional mapping equipment for defining non–CTI- dependent arrhythmias.

b. Transposition of the Great Vessels

Patients surviving to adulthood have generally had restora- tion of circulation by either an arterial switch procedure or rerouting of venous return. Atrial arrhythmias are uncommon late after arterial switch procedures (373). The Mustard and Senning repairs reroute systemic venous blood to the morphologic LV that is connected to the pulmonary artery, and they reroute the pulmonary venous blood to the morphologic right ventricle that is connected to the aorta. The atrial surgery is extensive, and sinus node dysfunction is common (369,479,480). Of 478 patients who survived the periopera- tive period after Mustard repair in a study reported by Gelatt and coworkers, atrial flutter subsequently occurred in 14%, and ectopic AT occurred in 1% (3 patients) (369). The actuarial rate of atrial flutter at 20 years after repair was 24%. An even greater incidence of atrial arrhythmias was observed in earlier series (481).

Loss of coordinated atrial activity and acceleration of rate can produce severe symptoms and hemodynamic compro- mise. Development of atrial arrhythmias is also associated with impaired ventricular function (372,482). For these reasons, development of atrial arrhythmias has been associated with an increased risk of death and sudden death in some, but not all, studies (369,480).

Acute management of rapid SVT is as discussed above (see Sections IV and V). These arrhythmias tend to be recurrent, and attempts to maintain sinus rhythm are usually warranted due to the hemodynamic compromise produced by the arrhythmia. Associated ventricular dysfunction and risk of sudden death and sinus node dysfunction can complicate selection of antiarrhythmic drug therapy. Referral to a specialist with experience in the care of these patients is usually warranted. Catheter ablation of the lesion related to the atrial flutter can be effective but is more difficult than for patients without structural heart disease and should be attempted only at experienced centers (478). In particular, access to the pulmonary venous atrium is usually required for ablation, which may be approached either in a retrograde or a transseptal fashion.

c. Tetralogy of Fallot

Atrial incisions are commonly made at the time of repair, predisposing to the late development of incision-related atrial flutter (371,374,483,484). During 35 years of follow-up after repair, 10% of patients developed atrial flutter, 11% developed sustained VT, and 8% died suddenly (484).

The sinus rhythm ECG shows RBBB in the vast majority of patients, such that SVTs are conducted with RBBB aber-
rancy. Ventricular tachycardia arises due to re-entry in the region of the right ventricular outflow tract or infundibular septum. Although most of these VTs have a QRS configuration resembling LBBB, the VT QRS resembles RBBB in approximately one-quarter of patients (485). An RBBB configuration of the tachycardia is not, therefore, a reliable guide for distinguishing a VT from an SVT. Atrial flutter precipitates hemodynamic compromise in some patients. Acute management is dictated by hemodynamic stability (see Section IV–B). Establishment of the correct diagnosis is crit- ical to guide further management. Electrophysiological test- ing may be required, and referral to a specialist is advised. Atrial flutter can be CTI dependent or incision related (444,478). Development of atrial flutter can be an indication of worsening ventricular function and tricuspid regurgitation (351,371,484,486). Hemodynamic reassessment of the repair and consideration for revision are sometimes warranted. Chronic management is as discussed above.

d. Ebstein’s Anomaly of the Tricuspid Valve

In Ebstein’s anomaly, the attachment of the septal and inferior leaflets of the tricuspid valve is displaced downward into the right ventricle. Patent foramen ovale or ostium secundum ASD are present in more than half of patients. Accessory AV and atriofascicular pathways occur in up to 25% of patients and are more often right sided and multiple than in patients without the disorder (487-490). In addition to AVRT, AF, atrial flutter, and ectopic AT can occur. Finally, Ebstein's anomaly is also often present in patients with congenitally corrected transposition of the great vessels (ie, ventricular inversion), in which the left-sided (ie, systemic) AV valve is morphologically a tricuspid valve.

Right bundle-branch block is usually present and, in the presence of a right-sided accessory pathway, ventricular pre- excitation can mask the ECG evidence of RBBB. Thus, patients may present with orthodromic AVRT with RBBB aberrancy and, after termination of the arrhythmia, there may be evidence of a right-sided accessory pathway causing pre- excitation during sinus rhythm. Left bundle-branch block- configuration tachycardias can be due to antidromic AVRT or conduction over a bystander accessory pathway during, for example, AT, AVRT, or atrial flutter.

The malformation can be mild, producing no symptoms. Alternatively, tricuspid regurgitation and a large ASD can cause cyanosis and hemodynamic compromise that may be exacerbated by arrhythmias. Depending on the severity of the malformation and the arrhythmia, SVTs can produce cyanosis and severe symptoms or death. Sudden death can also occur as a consequence of rapid repetitive conduction to the ventricles during AF or atrial flutter when an accessory pathway is present (490).

When hemodynamic consequences of the malformation warrant operative correction and supraventricular arrhythmias are present, arrhythmia management should be coordinated with the surgical team (491,492). Preoperative electrophysiological evaluation is often warranted. Failure to address potential accessory pathways can lead to recurrent arrhythmias and instability in the perioperative period. Catheter ablation prior to surgery is, therefore, recommended. Surgical division of accessory pathways may be considered as an option for selected patients in centers with experience. In general, management of accessory pathways in Ebstein's anomaly is as discussed in Section V–D. However, the associated malformation and common coexistence of multiple accessory pathways increase the difficulty of mapping and ablation. Of 65 patients reported in the Pediatric Radio- frequency Ablation Registry, acute success rates ranged from 75 to 89%, depending on pathway location (septal vs. free wall); late recurrences occurred in up to 32% of patients (493).

e. Fontan Repairs

The Fontan procedure and its modifications are used to direct systemic venous blood into the pulmonary artery for patients with single-ventricle physiology, including tricuspid atresia or single LV with pulmonary stenosis. The venous return, from the superior and inferior vena cava or right atrium, is directed to the pulmonary circulation without the benefit of assistance from right ventricular contraction. Incision-related atrial flutter or AF occurred in up to 57% of patients, depending on the particular type of repair (494,495). Atrial arrhythmias can cause rapid hemodynamic deterioration and are associated with more heart failure. Acute management is as discussed for atrial flutter above. Referral to a specialist is advised. Catheter ablation can be effective but is often difficult due to multiple circuits and should be attempted only at experienced centers. In addition to the low success rate of catheter ablation in the Fontan atriopulmonary connection, there is a high rate of recurrence after initially successful ablation procedures, limiting the usefulness of this approach (478).

C. Drug-Drug and Drug-Metabolic Interactions

The general tenets of the use of antiarrhythmic agents in supraventricular arrhythmias have been extensively outlined in the previously published ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation (1). In Tables 2 through 4 of these guidelines (1), the Vaughan- Williams Classification scheme of antiarrhythmic drugs, typical doses of drugs used to maintain sinus rhythm, and types of proarrhythmic side effects are summarized.

The vulnerable parameter (496) or target of therapy depends on the type of arrhythmia and the goals of treatment (ie, conversion of the arrhythmia, maintenance of sinus rhythm, suppression of triggers, or ventricular rate control). A major concern accompanying the use of antiarrhythmic drugs, particularly when treating an arrhythmia that is not life threatening, such as SVT, is the occurrence of ventricu- lar proarrhythmia (eg, torsade de pointes). A number of clinical factors increase the risk of proarrhythmia, including age, gender, fluid and electrolyte abnormalities, the presence of underlying heart disease, abnormalities of drug clearance, polypharmacy and drug-drug interactions. Drug-induced slowing of the rate of atrial flutter with the production of one-to-one conduction to the ventricle represents a potentially life-threatening form of proarrhythmia unique to the treatment of SVT. This phenomenon has been observed with (497). Concomitant administration of AV-nodal–blocking agents, such as a beta blocker, will reduce the likelihood of this form of proarrhythmia. Most antiarrhythmic drugs with class I and class III action, except for propafenone, can be started in an outpatient, provided the patient has no structural heart disease or other concomitant diseases and is taking no other drugs that may affect the metabolism of the partic- ular drug.

The removal of antiarrhythmic drugs from the systemic circulation typically depends on hepatic metabolism, renal excretion, or both. Patients with kidney or liver disease are at increased risk of drug toxicity, including proarrhythmia. Amiodarone is hepatically metabolized and, therefore, should be avoided in patients with significant hepatic dysfunction. In situations in which the SVT is readily treated by nonpharmacologic interventions, this is generally the preferred approach in patients with serious liver or kidney disease.

Kidney disease increases not only the incidence of cardiac arrhythmias but also the risk associated with their treatment. Patients with renal failure are at increased risk for cardiac morbidity and mortality; estimates suggest that half of the deaths in patients with renal failure result from concomitant cardiac disease (498).

Antiarrhythmic drug use is complicated in patients with renal disease for a number of reasons. In the case of drugs cleared by the kidneys, the incidence of toxicity may be unacceptably high, as in the case of sotalol or dofetilide. Furthermore, patients with kidney disease commonly have a myocardial substrate that renders them susceptible to proarrhythmic side effects of antiarrhythmic drugs (498-512). An example is hypertension and LV hypertrophy that accompany renal failure and are associated with abnormal ventricular (513) and atrial (514) repolarization. Patients with renal failure and ventricular hypertrophy also exhibit conduction abnormalities that seem to correlate with the degree of fibrosis (515-517). Finally, fluid and electrolyte shifts characteristic of dialysis are likely to act as triggers in susceptible hearts (500-508,510,511,518,519).

Perhaps the most consistent attribute of antiarrhythmic drugs is their narrow therapeutic window. For this reason and because most patients taking an antiarrhythmic drug are also receiving other drug therapy, drug interactions are prominent and clinically significant. Modification of the action of one drug by another may occur as a result of pharmacokinetic and/or pharmacodynamic interactions. Pharmacokinetic interactions occur when one drug influences the absorption, distribution, or metabolism and elimination of another drug (eg, the increase in serum dofetilide concentration produced by verapamil). Pharmacodynamic interactions result when a drug blunts or exaggerates the effect of another drug without altering its serum concentration, as might occur when a sodium-channel–blocking drug (eg, mexiletine) is added to drugs that have class III action (520). Numerous examples of both types of interactions involving antiarrhythmic agents have been described.

One of the most prominent pharmacokinetic interactions is the interference of one drug’s metabolism with another. Such interactions are most likely to be clinically significant when a drug is eliminated predominantly via a single pathway. The cytochrome P450 system plays a prominent role in antiarrhythmic drug metabolism (Table 5) (521). The table accurately suggests that the most important cytochrome P450 isoenzyme is 3A4 (CYP3A4), at least in terms of the number of drugs that are metabolized by this enzyme system (522). CYP3A4 has no known clinically important polymorphisms and is widely distributed in the liver, intestine and other parts of the gut and kidney (523). This isoenzyme is responsible for presystemic metabolism and, therefore, the first-pass effect exhibited by a number of oral agents metabolized by this pathway. Several notorious examples of adverse interactions resulting in torsades de pointes of compounds metabolized by CYP3A4 have been described, including the combination of terfenadine or cisapride with ketoconazole.

The CYP2D6 isoform is important in the metabolism of beta blockers and antiarrhythmic agents with class Ic action (522). The enzyme is expressed primarily in the liver and exhibits clinically important polymorphisms (524). Approximately 7% of Caucasians and African-Americans, but not Asians, are “poor” metabolizers (525). The important clinical consequence in treatment of cardiovascular disease is the exaggerated effect of beta blockers in patients who exhibit poor metabolism. Similarly, patients treated with CYP2D6 inhibitors, such as quinidine, especially if they are poor metabolizers, may have profound bradycardia from a low dose of beta blockers. Side effects related to the beta-blocking action of propafenone are more common in poor metabolizers (524).

P-glycoprotein is the most widely studied drug-transport molecule. It is structurally related to the family of proteins known as the ABC- or ATP-binding cassette family and actively transports substrates, including drugs, across cell membranes (526). It is expressed in the gut lumen, hepatocytes lining bile canniculi, and endothelial cells in the blood- brain barrier. Inhibition of P-glycoprotein is not clinically important for the elimination of most drugs because many have other pathways for elimination. An exception is digox- in, which does not undergo extensive P450 isoenzyme metabolism. Instead, its bioavailability is limited by P-glycoprotein–mediated re-excretion into the gut lumen (and possibly other transporters in the kidney and liver) (527). Many structurally unrelated drugs may increase digitalis concentrations by inhibition of P-glycoprotein.

D. Quality-of-Life and Cost Considerations

Improvement of quality of life is usually the major therapeutic goal of treatment for SVT. Although it was reported early that catheter ablation improves quality of life (528,529) and is cost effective compared with other strategies (530), these studies were observational rather than randomized (528,530) or were limited to more symptomatic patients on stable antiarrhythmic medical therapy (529). A later study compared the effect on quality of life between catheter ablation and pharmacologic therapy as an initial strategy for patients with SVTs (531). Both treatments improved quality of life and decreased frequency of disease-specific symptoms, but ablation improved quality of life in more general health categories and resulted in complete amelioration of symptoms in more patients (74 vs. 33%) than did medication. Potential long-term costs were similar for medication and ablation (531). Among patients who had monthly episodes of SVT, RF ablation was, however, the more effective and less expen- sive therapy compared with long-term drug therapy (532). Another prospective study compared the long-term effects on health outcome of catheter ablation and medical therapy as an initial treatment for patients with newly documented PSVT, excluding those with drug-refractory symptoms referred specifically for ablation (533). At 5-year follow-up, patients who received ablation had improved quality-of-life scores and a reduction in disease-specific symptoms when compared with patients who continued to take medical therapy. More patients reported complete elimination of symptoms with ablation therapy (70%) than did those taking medical therapy (43%). Over 5 years, the average cumulative cost for patients in the medical therapy group was statistically significantly lower than in patients initially treated with ablation therapy: $6249 plus or minus $1421 per patient versus $7507 plus or minus $1098 per patient (533). It was concluded that patient preference remains the critical determinant in choosing a particular treatment in cases of mildly to moderately symptomatic PSVT (533).

Baseline quality-of-life scores appear to be lower for patients with atrial flutter and AF than for those with other arrhythmias who are undergoing RF ablation (528). Several studies have described improvement in symptoms and quality of life after catheter ablation of atrial flutter (427,534- 537). Ablation of atrial flutter resulted in an improvement in quality of life as well as reductions in symptom-frequency scores and symptom-severity scores compared with preablation values (536). There was a reduction in the number of patients visiting accident and emergency departments, requiring cardioversion, or being admitted to a hospital for a rhythm problem. Patients with atrial flutter and concomitant AF before ablation and those with atrial flutter alone both derived significant benefit from atrial flutter ablation (536). Others reported that patients who had atrial flutter associated with AF before ablation had less improvement than those without AF (535). Moreover, in a prospective, randomized comparison of antiarrhythmic therapy versus first-line RF ablation in patients with atrial flutter, the sense of well-being and function in daily life improved after ablation but did not change significantly in patients treated with drugs (427). Ablation was associated with a better success rate and effect on quality of life, a lower occurrence of AF, and a lower need for rehospitalization at follow-up (427).