General Principles Of Antiarrhythmic Therapy

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Steps in the Selection of Antiarrhythmic Therapy

Thorough evaluation of the individual patient and the clinical context is the essential first step in the selection of the optimal treatment strategy. This includes a determination of the underlying cardiac disorder and its severity, comorbid conditions, response to previous therapy, and other factors that affect prognosis and the response to various treatment alternatives. The second step includes risk assessment for each mode of death: arrhythmic, nonarrhythmic cardiovascular, and noncardiac. The third step is to determine possible treatment strategies. The fourth step is a risk-to-benefit analysis of each of the possible treatment alternatives. This is based on an estimate of impact of therapy on the risk of death and on quality of life. It must be acknowledged that it is rarely possible to comprehensively address any one of the "essential steps," much less all four. Nevertheless, a methodological approach is needed to select the therapy that will achieve the ultimate goal: prolongation of life and enhancement of quality of life. In the midst of the drama of a cardiac arrest and the urgency associated with VT, it is sometimes forgotten that the arrhythmia itself may be a secondary issue and may or may not be the only important target of therapy. The risk of another episode of VTA may be lower than other modes of death. The priorities of care should always be set after the physician defines 1) the ultimate goal (i.e., prolongation of life vs improving quality of life, 2) the specific therapeutic target (e.g., reduction of palpitations, elimination of syncope, reduction of shocks from an implantable cardioverter defibrillator (ICD), prevention of sudden death), 3) the target arrhythmia (e.g., sustained monomorphic VT (SMVT), recurrent ventricular fibrillation (VF), 4) the method to be used to evaluate the drug (e.g., symptoms (PVC) frequency on Holter monitoring, frequency of ICD interventions), and 5) the criteria to be used to define drug success (e.g., 80% reduction in PVC frequency, inability to induce SMVT with programmed electrical stimulation, ICD shock frequency < 1 per yr). Even after considerable experience, many of the elements defined before therapy is initiated will change during the course of treatment. However, this initial step provides a framework for subsequent changes, and a basis for educating and informing the patient, health care workers, and payers about the process that is necessary for optimal outcome.

Pharmacological Principles

In an effort to advance antiarrhythmic drug therapy past the traditional empiric approach, the "Sicilian Gambit" was proposed in 1980 (7). This paradigm professed to allow antiarrhythmic drug choice based on arrhythmia mechanisms, vulnerable sites, and pharmacokinetic and pharmacodynamic considerations. Unfortunately, despite substantial progress in the understanding of arrhythmias, it is rarely possible to accurately determine an effective therapy on the basis of known actions on known mechanisms of specific arrhythmias. Moreover, the expanding array of approaches is indicative of the limited effectiveness, safety, and tolerance of current choices. Therefore, anti-arrhythmic therapy selection remains largely empiric. The therapeutic range of most antiarrhythmic drugs is severely limited by low efficacy at small doses and the potential for toxicity at high doses. The most important adverse reactions are proarrhythmic effects. It is often difficult to distinguish between failure of therapy resulting from inadequate drug effect and drug-induced proarrhythmias. Too often, several trials must be conducted, which results in a time-consuming and costly process that tests the will and confidence of patients and referring physicians. Antiarrhythmic drugs are highly sensitive to factors that alter concentrations, are highly interactive, and have substantial interindividual variation. Because treatment options are often very limited, it is as important to avoid rejection of a potentially effective drug as it is to reject a toxic drug. Incorrect administration is often responsible for inadequate or excessive effects. For these reasons, an understanding of pharmacological principles and the specific pharmacological properties of each drug is critical to safe, predictable use of anti-arrhythmic medications (8).


Interactions of antiarrhythmic drugs are an important source of treatment failures and dangerous reactions. Three general categories can be observed: Pharmacokinetic interactions may occur with other drugs, foods, and other substances. These interactions can increase or decrease the concentration of the drug at the effector site by altering bioavailability, volume of distribution, protein binding, formation of metabolic products, or clearance. Pharmacodynamic interactions refer either to inhibition or augmentation of the physiological response to the drug as a consequence of the pharmacological properties of another drug or endogenous substance, or as a consequence of a change in physiological phenomena such as heart rate. Drug-device interactions are a type of pharmacodynamic effect in which a function of a device (ICD or pacemaker) is altered (9,9a). Drugs may alter the characteristics of spontaneous defibrillation energy requirements, capture threshold, or intracardiac signal amplitude or duration. Devices are usually set with wide margins of safety. Therefore, small changes caused by anti-arrhythmic drugs are usually of no clinical consequence. However, if the thresholds for an individual patient are near the maximum capacity of the device, there is a risk of failure to properly detect and terminate the arrhythmia. The effects may be of greater significance in the future, when devices will be programmed with narrower tolerances to reduce energy consumption. Of greater clinical significance are the effects of anti-arrhythmic drugs on the spontaneous VTA. Drugs can slow the rate of VTA, increase the beat-to-beat variability, and render the presumed reentrant circuit refractory to penetration by paced impulses. These changes can alter the detection and termination of VTA.

Hemodynamic Effects

All antiarrhythmic drugs can reduce cardiac output as a consequence of alterations of contractility, vascular resistance, or the neurohormonal milieu. The mechanisms are complex and interdependent. Contractility may be diminished as a consequence of reduced intracellular calcium ion activity caused by sodium- or calcium-channel blockade. Action-potential prolongation can increase intracellular calcium and partially restore contractility. However, contractility is rate-dependent. In normal hearts, contractility rises at rates as high as 180/min. In heart failure, however, contractility is reduced, and the heart rate at which it peaks may also be reduced to less than 100 beats per minute (BPM). Contractility would be expected to decline during faster rates. Sodium-channel blockade is also increased at faster rates while the influence of action-potential prolongation diminishes. It is probably for a combination of these reasons that hemody-namic collapse may occur with drugs that are widely believed to be hemodynamically neutral, such as lidocaine. If VTA recur despite the presence of an antiarrhythmic drug, the hemodynamic consequences may be more severe. In some cases, hemodynamic properties can be used to select therapy. For example, vasodilation maybe the mechanism by which quinidine is better tolerated than disopyramide (which causes vasoconstriction) in patients with heart failure.

Proarrhythmic Effects

Exacerbation or facilitation of existing arrhythmias or provocation of new arrhythmias are frequent and life-threatening complications of antiarrhythmic drugs (10). Most antiarrhythmic drugs depress normal automatically and may cause bradyarrhythmias. This complication is relatively rare in patients with normal sinus-node function. Indeed, drugs with atropine-like effects (muscarinic-receptor blockade) such as disopyramide and quinidine may cause an increase in heart rate. The calcium-channel blockers diltiazem and verapamil cause variable responses in heart rate. Although calcium-channel blockade reduces automaticity, increased sympathetic tone caused by vasodila-tion may result in an increase in heart rate. Beta-blockers usually decrease heart rate, but this is rarely clinically significant in patients with normal sinus-node function. Although drug-induced bradyarrhythmias are relatively rare, even in patients with sinusnode dysfunction, such patients are at riskfor severebradyarrhythmias. Evidence suggests that drug-induced bradycardia is a rare cause of death. In contrast, bradyarrhythmia-

Atrial Fibrillation Intracardiac Signal

Fig. 1. Episodes of nonsustained torsades de pointes in a patient with acquired LQTS caused by quinidine. Note the excessive QT prolongation following the longer R-R intervals, with the first beat of VT falling on the T wave. Quinidine was discontinued, and the patient was treated acutely with iv magnesium and temporary transvenous pacing. Once the quinidine washed out, the patient's QT interval returned to normal and no further torsades de pointes occurred.

Fig. 1. Episodes of nonsustained torsades de pointes in a patient with acquired LQTS caused by quinidine. Note the excessive QT prolongation following the longer R-R intervals, with the first beat of VT falling on the T wave. Quinidine was discontinued, and the patient was treated acutely with iv magnesium and temporary transvenous pacing. Once the quinidine washed out, the patient's QT interval returned to normal and no further torsades de pointes occurred.

induced VTA may not be a rare mechanism of drug-associated sudden death, and is usually related to treatment with class IA and III drugs. This drug-associated arrhythmia is polymorphic, often resembling torsades de pointes (see Fig. 1). This arrhythmia may account for some reports of drug-induced long QT syndrome (LQTS) associated with drugs that would not be expected to cause this complication, such as mexiletine and flecainide. Bradycardia-induced VTA also occur in patients who develop severe brady-arrhythmias in the absence of antiarrhythmic drugs. It is possible that this complication results from a genetic predisposition for LQTS. If so, advance prediction may be possible in the future. Although there has been concern that sodium-channel blockers will cause complete heart block in patients with conduction-system disease, this complication has rarely been observed. Unfortunately, the extent to which bradyarrhythmias are responsible for out-of-hospital drug-associated sudden death is unknown. Nevertheless, based on current knowledge, the presence of sinus-node dysfunction or severe atrioven-tricular (AV) conduction-system disease should not be considered contraindications to antiarrhythmic drug therapy. Such patients should be observed closely during initiation of antiarrhythmic drugs. Periodic monitoring during long-term treatment would seem prudent—e.g., 24-hour Holter monitoring at least every 6 mo. Unfortunately, no information exists to guide selection of the ideal method of repeat monitoring, the frequency, or the yield. Patients with ICDs should have their devices programmed for backup pacing at an appropriate lower rate limit to protect against significant bradycardia.

VTA associated with drug-induced LQTS, i.e., torsades de pointes (see Fig. 1), is relatively frequent with drugs that prolong action-potential duration (class IA and III

drugs) and may occur with an expanding group of noncardiac drugs and conditions (11,12). Precautions should be taken to minimize the incidence. The risk of this complication is related to the specific drug, the severity of myocardial dysfunction, the presenting arrhythmia, the sex of the patient, the genetic background ("reduced repolarization reserve"), heart rate, concomitant medications, and electrolyte disturbances (hypokalemia and hypomagnesemia). The long-term risk is related to the chance that risk factors will coincide in the future. For instance, alterations in diuretic dose and adequacy of supplementation with potassium and magnesium increase the likelihood of electrolyte disturbances. Drugs that delay repolarization should be used cautiously or not at all in patients with multiple risk factors for this form of the acquired LQTS. The type and intensity of monitoring should be proportional to the risk of torsades de pointes. The 12-lead ECG should be used to monitor QT duration. Rhythm monitoring is needed to assess danger signs including self-terminating runs of polymorphic VT (PVT), postpause U-wave accentuation, QT prolongation, T-wave alternans (TWA), and bradycar-dia. Patients at high risk should be continuously monitored in-hospital, and monitor staff should be trained to recognize the characteristic electrocardiogram (ECG) warning signs. The initiation of antiarrhythmic drugs to out-patients is debated, but this may be acceptable in patients at low risk of drug-induced LQTS. Nevertheless, it would seem prudent to obtain 12-lead ECGs and use other rhythm-monitoring methods at critical times—e.g., upon initiation of medications, achievement of steady-state concentrations, and during dose changes. Risk-factor minimization is essential during long-term therapy. Care must be taken to avoid electrolyte disturbances and exposure to drugs that augment the effects on repolarization by increasing concentration (usually by inhibition of metabolism) or by additive pharmacodynamic activity.

Excessive sodium-channel blockade is believed to be the mechanism of the most important arrhythmias caused by class IC drugs, flecainide, propafenone, and moricizine (13), but all of the sodium-channel blockers are capable of this reaction. Although presentation may consist of asymptomatic nonsustained ventricular arrhythmias, this complication requires immediate attention in order to prevent the highly malignant intractable VTA that characterizes this disorder. The appearance of these VTA may vary in a single episode from incessant SMVT to repeated runs of polymorphic VT (PVT) that degenerates into VF only to recur shortly after countershock. For this reason, the presence of an ICD may not provide adequate protection for this form of pro-arrhythmia. It is critical to distinguish this form of drug-induced proarrhythmia from torsades de pointes. Pacing therapy is indicated in the latter, but contraindicated in the former. Instead, efforts are directed toward maneuvers that reduce sodium-channel binding (e.g., heart-rate reduction, competition with fast-on, fast-off sodium-channel-binding drugs) and that restore the inward sodium current (infusion of hypertonic sodium solutions). Risk factors include the presence of structural heart disease, especially coronary artery disease (CAD), and a history of VTA. The presence of these risk factors are considered strong contraindications to therapy with class IC agents. Precipitating factors include tachycardia, myocardial ischemia, high concentrations of the drug, and addition of another sodium-channel blocker. Tachycardia and ischemia are especially provocative, because both cause increased binding of the drug to sodium channels, and they can establish a positive feedback process whereby tachycardia increases ischemia, and ischemia increases tachycardia (by augmenting sympathetic activity). Increasing sodium-channel blockade makes the arrhythmias more difficult to terminate and reduces contractility and systemic pressure, which further reduces myocardial perfusion. Careful avoidance of the precipitating factors is required in all patients receiving class IC agents. Steps must be taken to avoid tachycardia that may occur in several circumstances. A stress test may be useful for estimating the likelihood for high heart rates during daily activities. Implanted devices should be tested and adjusted to avoid excessive pacing rates during antitachycardia pacing, tracking of atrial arrhythmias, high sensormediated rates, and pacemaker-mediated-tachycardia. Concomitant administration of beta-blockers is highly recommended, and may be considered mandatory. Exercise-testing or 24-h monitoring should be considered to verify adequate beta-blockade.

Another form of proarrhythmia that may occur with any sodium-channel blocker— but is most often observed in patients receiving flecainide and propafenone—is a sudden increase in the ventricular-rate response to atrial tachyarrhythmias, especially atrial fibrillation (AF) or atrial flutter. The proposed mechanism is that the antiarrhythmic drug converts AF or rapid atrial flutter to a slow atrial flutter, which results in one-to-one activation of the ventricles. Often a wide QRS tachycardia is observed, which is difficult to distinguish from a SMVT.

There is uncertainty about the spectrum, frequency, and impact of proarrhythmic effects in patients with ICDs (9). Patients with ICDs may be protected from drug-related bradycardia-induced VTA because of backup pacing or by detection and termination of the sustained VTA. However, some drug-induced arrhythmias may be refractory to antitachycardia pacing and defibrillation, or be exacerbated by the programmed algorithms. AF or atrial flutter may result in heart rates that meet detection criteria and cause inappropriate and ineffective ICD pacing or defibrillation that could precipitate proarrhythmic effects. As noted earlier, antiarrhythmic drugs may alter myocardial properties and native VTA characteristics resulting in failure to detect and terminate spontaneous arrhythmias. Devices are not routinely programmed specifically for drug-induced arrhythmias. These concerns emphasize the need for careful monitoring of patients with ICDs who require antiarrhythmic drug therapy. Strong consideration should be given to reassessment of pacing, sensing, and defibrillation energy parameters. Retesting of detection and termination algorithms in the presence of antiarrhythmic drugs should be considered, but is often not possible in patients who do not have inducible arrhythmias. The distinction between arrhythmia recurrence resulting from ineffectiveness of the drug and proarrhythmia is critical, but may be difficult. Changes in the pattern of arrhythmias detected and treated based on symptoms, stored data, and electrograms, supplemented by Holter or event-monitor recordings, should be helpful.

There are major gaps in our understanding of proarrhythmic effects, particularly with regard to risks during long-term treatment. The strongest evidence for this are the inconsistencies between our current understanding, which is based on observations obtained at the time of initiation of drugs and on in-hospital observations, and the pattern of excess mortality associated with antiarrhythmic drugs in the CAST (6) and Survival with Oral d-Sotalol (SWORD) trial in patients with left ventricular dysfunction after myocardial infarction (MI) (14). There may be forms and mechanisms of fatal proarrhythmic effects that have not been discovered.

Implantable Cardioverter Defibrillators

For many clinicians, no other therapy provides as much assurance for an individual patient as an implantable cardioverter defibrillator (ICD). The results of recent clinical trials substantiate superiority over standard antiarrhythmic therapy in selected patients. There is a temptation to use the ICD in any patient with a significant risk of arrhythmic death. However, the Coronary Artery Bypass Graft—Implantable Defibrillator (CABG Patch) trial demonstrated that certain groups of patients do not benefit from ICD implantation (15). Subgroup analysis of the Antiarrhythmics Versus Implantable Defibrillator (AVID) trial indicated no benefit of ICD over amiodarone therapy in patients with ejection fractions greater than 0.35 (16); a similar conclusion has emerged from the CIDS study (17). Clinical trials that have demonstrated its successful application excluded categories of patients who were unlikely to benefit from protection against arrhythmic death. Appropriate application and informed consent required a thorough appreciation of the disadvantages and risks of current-generation ICDs. A partial list includes: 1) life-long complications of device-lead systems that require periodic replacement; 2) continued need for antiarrhythmic drugs for adequate arrhythmia control with exposure to risks of long-term drug use; 3) painful shocks caused by recurrent ventricular tachyarrhythmia (VT), atrial arrhythmias, or spurious signals and artifacts; 4) risk of interference from other devices and electromagnetic fields; 5) exclusion from tests and treatments that cannot be performed in patients with implanted devices; 6) psychological effects from anxiety related to unpredictable shocks, embarrassment, loss of control, dependency, humiliation, and other feelings that can lead to depression and psychosis; 7) driving, travel, and restrictions on other activities; 8) occupational effects such as job restrictions, time lost from work, reduced occupational status, and advancement; and 9) social exclusion.

Necessity should take precedence over cost. However, in many countries the patient bears the cost of the ICD. Also significant is the fact that health costs are controlled in most countries so that a high expense in one area forces a reduction in other areas. Rough calculations indicate the enormity of the problem: The United States has the highest ICD implantation rate in the world: about 40,000 devices in 1999. This rate would have to increase sevenfold if ICDs were provided to all patients who are expected to die suddenly in the coming year—i.e., 300,000 persons in the United States alone. Many clinicians consider a patient to be a candidate for an ICD if the risk of sudden death is between 1% and 10% per yr. This would increase the rate of implantation by 10-100 times over that limited to 100% risk. In addition, most patients in whom ICDs are implanted receive no benefit but are at risk for all of the complications—e.g., 90 out of every 100 patients in the 10% risk category. These facts are presented here to emphasize the importance of careful patient selection. Fortunately, it is likely that many of the problems with current-generation ICDs, including the cost, will be substantially reduced with a few years by the remarkable pace of technical advances.

Pharmacological agents play a major role in patients with ICDs. Amiodarone and sotalol are frequently used in ICD patients (18). Indications for antiarrhythmic therapy in patients with ICDs include: 1) to reduce the frequency of VTA events requiring ICD therapy, especially painful and battery-depleting shocks; 2) to slow the rate of VTA in order to increase the efficacy of antitachycardia pacing and reduce the need for shock; 3) to reduce the recurrence of supraventricular tachyarrhythmias that may cause inappropriate ICD therapies; 4) to reduce the ventricular-rate response to atrial tachyarrhythmias that may cause inappropriate ICD therapies; 5) to reduce the maximum sinus rate to avoid inappropriate ICD therapy; 6) to reduce the frequency and duration of nonsustained VT (NSVT) events to avoid unnecessary ICD therapy; and 7) to decrease defibrillation thresholds. The potential for proarrhythmic effects and drug-device interactions discussed here should be used to guide drug selection, administration of selected drugs, ICD programming, and the frequency and extent of periodic follow-up and monitoring.

Catheter Ablation and Operative Intervention

Operative and catheter-based ablation, excision, and interruption of tachycardia foci and circuits provide an opportunity for permanent cure. Catheter ablation appears to be highly effective for idiopathic SMVT and is considered first-choice therapy by many clinicians. In patients with ischemic heart disease, however, catheter ablation is often used adjunctively to control incessant VTA or to reduce the recurrence rate in patients with ICDs. Often, pharmacologic therapy does not result in adequate control, but is maintained at the time of ablation and often continued after the procedure (19). Antiarrhythmic drugs are often helpful in reducing the rate of VTA and improving hemodynamic stability. This allows electrical activation-sequence mapping and better control of ablation. There are reports of improved responsiveness of antiarrhythmic drugs after catheter-based and operative interventions, but the extent to which the beneficial effects of antiarrhythmic drugs are improved or adverse effects increased has not been established.

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