Importance of QT interval determination and renal function assessment during antiarrhythmic drug therapy.

A major concern associated with the use of antiarrhythmic drugs (AAD) is the occurrence of ventricular proarrhythmia, especially torsade de pointes (TdP). The AADs associated with TdP most commonly include quinidine, procainamide, disopyramide, sotalol, and the newer class III agents, such as ibutilide and dofetilide. It is not simply the administration and nature of an AAD but also several additional factors such as heart rate, ventricular hypertrophy, congestive heart failure, gender, age, concomitant drugs, and impaired drug clearance that influence TdP development. Dosing of these agents should be adjusted to take such factors into account to minimize the incidence of proarrhythmia.

Issues in the use of generic antiarrhythmic drugs.

Formulation substitution using generic preparations for innovator products is becoming increasingly prevalent in the name of cost containment. So long as generic substitutes are truly clinically equivalent to the innovator compounds, patient harm should not ensue. However, for drugs with a narrow therapeutic index, serious concerns about generic equivalence are beginning to arise, particularly with neurologic, immunosuppressive, anticoagulant, and antiarrhythmic drugs. This article reviews the guidelines used to approve a generic compound and their limitations and provides case-based information as to the adverse clinical consequences-arrhythmia recurrence, proarrhythmia, and death-that have now been reported in association with generic substitution of antiarrhythmic compounds. Additionally, guidelines for allowance or avoidance of antiarrhythmic drug formulation substitution are suggested.

Drug choices in the treatment of atrial fibrillation.

When considering therapy for atrial fibrillation (AF), the dominant issues are rate control, anticoagulation, rhythm control, and treatment of any underlying disorder. Drug choices for rate control include beta-blockers, verapamil and diltiazem, and digitalis as first-line agents, with consideration of other sympatholytics, amiodarone, or nonpharmacologic approaches in resistant cases. Anticoagulation may be accomplished with aspirin or warfarin, with the latter preferred in all older or high-risk patients. Antiarrhythmic drug therapy may be used (1) to produce cardioversion (most effective with ibutilide or class IC agents in recent onset AF); (2) to facilitate electrical conversion (class III agents); (3) to prevent early reversion after cardioversion; (4) to maintain sinus rhythm during chronic therapy; and/or (5) to facilitate conversion of fibrillation to flutter, which may then be amenable to termination or prevention with antitachypacing or ablative techniques. Antiarrhythmic drug selection for AF is guided by efficacy considerations (most drugs are similar), by convenience, cost, and discontinuation considerations; and, most importantly, by safety considerations. When possible, agents with serious organ toxicity potential and proarrhythmic risk should be avoided as first-line choices. In structurally normal hearts, class IC antiarrhythmic drugs are least proarrhythmic and least organ toxic (when considered together). In normal hearts, sotalol, dofetilide, and potentially azimilide also appear to have attractive profiles. Amiodarone has low proarrhythmic risk but can produce bradyarrhythmias and toxicity. In hypertrophied hearts, the risk of torsade de pointes with class III/IA agents is enhanced, whereas in ischemia or conditions with impaired cell contact, whether functionally (as by ischemia) or anatomically (as by fibrosis, infiltration, etc), proarrhythmic risk with class I antiarrhythmic drugs (sustained ventricular fibrillation/flutter) is greatly increased. The class I drugs should be avoided in these circumstances. Additional issues to consider are where to initiate therapy (in- or outpatient), what follow-up protocols to use, and whether to limit therapy to proprietary drugs or to allow generic formulation substitution. Each of these considerations is detailed in this article.

Formulation substitution and other pharmacokinetic variability: underappreciated variables affecting antiarrhythmic efficacy and safety in clinical practice.

The process of treating a patient with an antiarrhythmic drug only begins when a physician chooses the drug to be employed. In the given patient, not only must the drug be chosen, but so must the dose, the formulation, and the method of follow-up. Choosing the proper dose requires an understanding of clinical trial efficacy and safety data for the agent chosen in a population of patients resembling the individual to be treated. It also requires a detailed understanding of pharmacologic principles of drug kinetics (e.g., absorption, distribution, metabolism, and excretion) that might affect the dose needed for the specific patient. The physician must be familiar with subsequent changes in clinical circumstances that might indicate a need for a change in dose or drug. Many circumstances determining drug pharmacokinetics are not under the immediate control of physicians, such as genetic patterns, organ function, and disease circumstances. One, however, is-or should always be-the selection of the drug formulation used. Although generic versions of innovator drugs exist for many agents and often are clinically acceptable, most physicians are unaware of the meager degree of testing that is necessary for the release of a generic drug, and the wide range of attained serum levels that are called bioequivalent by the US Food and Drug Administration (FDA) when one formulation is compared with another. In patients with cardiac arrhythmias, arrhythmia recurrence, proarrhythmia, and death have been reported in association with antiarrhythmic drug formulation substitution. Despite their reported bioequivalence, the generic agents involved were clearly not therapeutically equivalent. Accordingly, this article was written to educate physicians further about the above-noted important pharmacokinetic variables that can affect a patient's outcome when an antiarrhythmic drug is employed, and to provide information on the generic drug approval process and guidelines for the use of formulation substitution.

Generic antiarrhythmics are not therapeutically equivalent for the treatment of tachyarrhythmias.

The consequences of antiarrhythmic drug formulation substitution were assessed by survey of 130 experts on arrhythmias. Fifty-four arrhythmia recurrences, 7 proarrhythmic events, and 3 deaths resulting from generic substitution are reported, thus raising serious concerns about both antiarrhythmic drug substitution and the adequacy of the generic drug approval process.

Inpatient versus outpatient antiarrhythmic drug initiation: safety and cost-effectiveness issues.

Debate exists as to the proper site for initiating antiarrhythmic therapy for supraventricular tachyarrhythmias and other benign forms of ectopy: inpatient versus outpatient. Rapid detection of efficacy and adverse effects, with immediate correction of the latter, favors the inpatient site. Convenience and, under most circumstances, lower cost favor the outpatient site. Circumstances under which adverse event rates, including proarrhythmia, are expectedly low, would favor outpatient initiation. So would the use of an agent whose elimination half-life is so long as to render in-hospital monitoring to steady state highly impractical. Accordingly, outpatient initiation would be suitable for patients without structural heart disease receiving class IC drugs, patients with low risk for torsades de pointes receiving selected class III agents, in whom data in the literature are supportive (as has occurred with sotalol and azimilide), and patients who are to receive amiodarone. Transtelephonic electrocardiographic monitoring can be used to facilitate assessment in the outpatient setting. Inpatient initiation should be considered for patients with underlying sinus node or atrioventricular conduction disturbances, for patients with significant structural heart disease, for patients receiving a drug whose proarrhythmia may be idiosyncratic (e.g., quinidine), and for patients who are to begin an antiarrhythmic drug while in a supraventricular tachyarrhythmia in whom sinus rhythm has not previously been seen. The relative costs and benefits of the approach chosen will be a reflection of the probability that a drug with a chosen mechanism will cause an adverse outcome in a patient with a specific clinical substrate during the period chosen for monitoring.

The importance of considering trial design when interpreting clinical trial results.

BACKGROUND: In recent decades, clinical trials have played an increasingly important role in determining how we practice. Trial results proving that a clinical finding poses risk have led to interventions that try to reduce risk. Clinical trials proving that a particular therapy provides better outcome than another therapy have changed the therapies we now use. Unfortunately, the results of clinical trials are too often affected by biases or design issues that may overtly or covertly alter the results or the way they should really be used. In addition, these biases and design and analysis issues are rarely evident in the abstract sections or key figures and tables in the publications reporting the trials, which may be all the busy physician either reads or remembers. METHODS AND MATERIALS: This manuscript discusses the issues involved in optimally understanding clinical trial design and interpretation so that practitioners can better understand how to intelligently read and apply trial results to clinical practice. CONCLUSIONS: Clinical trial results can not be properly applied without consideration of trial design features and intertrial comparisons.

The actions of ibutilide and class Ic drugs on the slow sodium channel: new insights regarding individual pharmacologic effects elucidated through combination therapies.

BACKGROUND: Ibutilide (I) has been reported to block I(k) and to delay inactivation of the slow Na(+) current (S-Na). There is debate about the clinical importance of the latter. Class Ic drugs block the fast Na(+) channel, but their effect on S-Na is uncertain. If Ic treatment before infusion lessened the QT increase with I, this result would suggest both an Ic effect on S-Na and significant S-Na actions of I. METHODS: We infused I, 2 mg over 30 minutes, to 6 patients pretreated with propafenone (n = 5) or flecainide (n = 1) (group 1) and compared their increase with the QT increase seen with I alone in a combined group of 85 patients from our lab and the multicenter I database (group 2). RESULTS: The QTc increased in group 2, 65 ms, from 413 to 478 ms. This effect was attenuated by 47% in group 1 patients to 34 ms (P <.01). There appeared to be a dose-response relationship between Ic dose and its effects on QTc prolongation. The lowest dose of propafenone had minimal effect on the increase in QTc with I (72 ms), while higher doses of propafenone and high doses of flecainide attenuated the increase to 13 to 39 ms. Nonetheless, ibutilide efficacy was not changed, possibly suggesting differing importance of K(+) channel and slow sodium-channel effects in atrial versus ventricular tissues, and having implications for means to reduce some antiarrhythmic drug proarrhythmia without reducing efficacy. CONCLUSIONS: (1) Pretreatment with Ic agents can reduce the increase in QTc seen with I; (2) I's effect in humans appears to be at least partly mediated through the delay of S-Na inactivation; and (3) Ic agents probably inhibit S-Na.

Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.

OBJECTIVES: To evaluate whether use of beta-adrenergic blocking agents, alone or in combination with specific antiarrhythmic therapy, is associated with improved survival in persons with ventricular fibrillation (VF) or symptomatic ventricular tachycardia (VT). BACKGROUND: The ability of beta-blockers to alter the mortality of patients with VF or VT receiving contemporary medical management is not well defined. METHODS: Survival of 1,016 randomized and 2,101 eligible, nonrandomized patients with VF or symptomatic VT followed in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial through December 31, 1996 was assessed using Cox proportional hazards analysis. RESULTS: The 817 (28%) patients discharged from hospital receiving beta-blockers had less ventricular dysfunction, fewer symptoms of heart failure and a different pattern of medication use compared with patients not receiving beta-blockers. Before adjustment for important prognostic variables, beta-blockade was not significantly associated with survival in randomized or in eligible, nonrandomized patients treated with specific antiarrhythmic therapy. After adjustment, beta-blockade remained unrelated to survival in randomized or in eligible, nonrandomized patients treated with amiodarone alone (n = 1142; adjusted relative risk [RR] = 0.96; 95% confidence interval [CI] 0.64-1.45; p = 0.85) or a defibrillator alone (n = 1347; adjusted RR = 0.88; 95% CI 0.55 to 1.40; p = 0.58). In contrast, beta-blockade was independently associated with improved survival in eligible, nonrandomized patients who were not treated with specific antiarrhythmic therapy (n = 412; adjusted RR = 0.47; 95% CI 0.25 to 0.88; p = 0.018). CONCLUSIONS: Beta-blocker use was independently associated with improved survival in patients with VF or symptomatic VT who were not treated with specific antiarrhythmic therapy, but a protective effect was not prominent in patients already receiving amiodarone or a defibrillator.

Selecting an antiarrhythmic agent for atrial fibrillation should be a patient-specific, data-driven decision.

Selecting an antiarrhythmic agent for atrial fibrillation (AF) should be a patient-specific decision. When possible, it should be based on sound rationale and available clinical data. This article details many of the thought processes that must go into this decision process and offers some suggested algorithmic starting points based on these considerations. With a patient's first episode of AF, termination is appropriate, but antiarrhythmic therapy should usually be withheld in order to assess the recurrence pattern. However, if severe hemodynamic or ischemic intolerance would make recurrence a serious risk, or if an early symptomatic recurrence is highly likely, antiarrhythmic therapy would be appropriate. Acute AF may terminate spontaneously or may be terminated iatrogenically. The latter may be achieved by direct current or pharmacologic approaches. The risks, benefits, and optimum utility of these approaches are addressed in the article. Infrequent recurrences may be treated with cardioversion; frequent or severely symptomatic episodes are best treated with attempts at suppression with chronic antiarrhythmic drug administration. Since the therapeutic efficacy of maintaining sinus rhythm is similar for the currently available agents, the drug selection process should be based in large part on safety and convenience considerations. The factors underlying this selection process and one suggested algorithm for drug choice are provided in this article.

Importance of beta blockade in the therapy of serious ventricular arrhythmias.

Beta blockers have traditionally been considered relatively poor antiarrhythmic agents for patients with ventricular arrhythmias. This view is based on the observations that beta blockers are less effective in suppressing spontaneous ventricular ectopy or inducible ventricular arrhythmias than are the class I and class III agents. However, there are convincing data that beta blockers can have a clinically important antiarrhythmic effect and prevent arrhythmic and sudden death. Beta blockers have multiple potential effects that can contribute to a therapeutic antiarrhythmic action, including an antiadrenergic/vagomimetic effect, a decrease in ventricular fibrillation threshold, and prevention of a catecholamine reversal of concomitant class I/III antiarrhythmic drug effects. Postinfarction trials, recent congestive heart failure studies, and observations in patients who are at risk for sustained ventricular arrhythmias all suggest a potent antiarrhythmic effect of beta blockade.

Antiarrhythmic drugs and devices for the management of ventricular tachyarrhythmia in ischemic heart disease.

Ischemic heart disease is the most frequent cardiac abnormality in patients with sustained or nonsustained ventricular tachyarrhythmias. The goals of therapy in such patients are to decrease the severity and incidence of symptoms and prolong life. In this article, we review the current views on antiarrhythmic drug therapy and an implantable cardioverter-defibrillator (ICD) in patients with ischemic heart disease. The importance of beta blockade as part of the therapy is emphasized. In addition, the superiority of sotalol and amiodarone over class I drugs, the benefits of combined treatment with amiodarone and a beta blocker, and the impact and limitations of current trials comparing the effectiveness of drug therapy with that of an ICD are all considered. Also discussed is the combined use of an antiarrhythmic drug and an ICD. In this approach sotalol is generally the agent of choice, with amiodarone the second choice.

Rhythm management in atrial fibrillation--with a primary emphasis on pharmacologic therapy: Part 3.

Atrial fibrillation (AF) is the most common, sustained, symptomatic tachyarrhythmia that clinicians are called upon to manage. Management strategies include ventricular rate control coupled with anticoagulation, versus restoration and maintenance of sinus rhythm. Rate control may be achieved pharmacologically, with agents that impair AV nodal conduction directly and/or by increasing parasympathetic/sympathetic balance, or by modifying or ablating the AV nodal region anatomically. Rhythm control may be achieved by electrical or pharmacologic conversion followed by maintenance of sinus rhythm by pharmacologic (or occasionally ablative) therapies. This article will present current approaches to rate and rhythm control issues in atrial fibrillation. Parts 1 and 2, published previously, dealt with rate control and with the restoration of sinus rhythm. Part 3, the current article, details the selection process of choosing a therapy to maintain sinus rhythm, including the likelihood of success, the risks of therapy, and individualization of therapy as dependent upon the nature of the structural heart disease present. It also discusses nonpharmacologic approaches that have been recently developed or are undergoing development. One suggested drug selection algorithm is provided.

Rhythm management in atrial fibrillation--with a primary emphasis on pharmacological therapy: Part 2.

Atrial fibrillation (AF) is the most common, sustained, symptomatic tachyarrhythmia that clinicians are called upon to manage. Management strategies include ventricular rate control coupled with anticoagulation, versus restoration and maintenance of sinus rhythm. Rate control may be achieved pharmacologically, with agents that impair AV nodal conduction directly and/or by increasing parasympathetic/sympathetic balance, or by modifying or ablating the AV nodal region anatomically. Rhythm control may be achieved by electrical or pharmacological conversion followed by maintenance of sinus rhythm by pharmacological (or occasionally ablative) therapies. This article will present current approaches to rate and rhythm control issues in AF. Part 1, published previously, dealt with rate control. Part 2, the current article, details approaches to the restoration of sinus rhythm by electrical and pharmacological means. The former may use transthoracic or catheter-based energy delivery systems. The latter may use intravenous or oral drug approaches. Part 3, to be published in a subsequent edition of PACE will deal with the maintenance of sinus rhythm.

Rhythm management in atrial fibrillation--with a primary emphasis on pharmacological therapy: Part 1.

Atrial fibrillation (AF) is the most common, sustained, symptomatic tachyarrhythmia that clinicians are called upon to manage. Management strategies include ventricular rate control coupled with anticoagulation, versus restoration and maintenance of sinus rhythm. Rate control may be achieved pharmacologically, with agents that impair AV nodal conduction directly and/or by increasing parasympathetic/sympathetic balance, or by modifying or ablating the AV nodal region anatomically. Rhythm control may be achieved by electrical or pharmacological conversion followed by maintenance of sinus rhythm by pharmacological (or occasionally ablative) therapies. This article will present current approaches to rate and rhythm control issues in AF. Part 1, the current manuscript, details approaches to rate control and includes a drug selection algorithmic conclusion. It also introduces the subject of the pursuit of sinus rhythm. Parts 2 and 3, to be published in subsequent editions of PACE, will deal with therapeutic measures to restore and maintain sinus rhythm.

Impact of structural heart disease on the selection of class III antiarrhythmics for the prevention of atrial fibrillation and flutter.

Antiarrhythmic agents may be beneficial or harmful. Among the harmful effects, or risks, is proarrhythmia. One of several factors that underlie proarrhythmic risk is the presence and nature of any underlying structural heart disease at the time of antiarrhythmic drug administration. The structural disease-antiarrhythmic drug interaction has been best studied and clearly delineated for class I antiarrhythmics. This review provides information to suggest that structural disease can enhance proarrhythmic risk with class III drugs as well, although this is least evident with amiodarone. Particularly pertinent are disorders that prolong action potential duration (such as ventricular hypertrophy or chronic dilatation), inhomogeneous dispersion of refractoriness (including conditions with cellular uncoupling), and reduced ventricular fibrillation threshold. These issues must be considered when choosing an antiarrhythmic drug for atrial and for ventricular arrhythmias and when selecting the dosing and monitoring protocol to be used.

Prolonging survival by reducing arrhythmic death: pharmacologic therapy of ventricular tachycardia and fibrillation.

Antiarrhythmic drug therapy of sustained ventricular tachyarrhythmias is undertaken to reduce arrhythmic symptoms, recurrences, and mortality. Ideally, reduction of arrhythmic death will reduce total mortality as well, although this may not hold true in the presence of competing risk. Whether, in fact, antiarrhythmic therapy actually reduces arrhythmic death remains uncertain in the absence of any placebo-controlled trials. Nonetheless, the following conclusions can be drawn from the Electrophysiologic Study versus Electrocardiographic Monitoring (ESVEM) trial, the Cardiac Arrest Study Hamburg (CASH), and the Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation (CASCADE) study, as well as a beta blocker study by Steinbeck et al: (1) class I antiarrhythmics are less effective than amiodarone or sotalol for the prevention of recurrent sustained ventricular tachycardia/ventricular fibrillation; (2) sympathetic inhibition as a component of the antiarrhythmic regimen may strongly contribute to mortality reduction; and (3) the respective roles of antiarrhythmic drugs, implantable devices, and the concurrent use of both are in a state of flux, awaiting results of randomized controlled clinical trials.