Impact of Nontraditional Antiarrhythmic Drugs on Sudden Cardiac Death

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113

Impact of Nontraditional Antiarrhythmic Drugs on Sudden Cardiac Death

Leonard Ilkhanoff, Alan H. Kadish and Jeffrey J. Goldberger

Chapter Outline

Although mortality from coronary artery disease has declined in the United States, sudden cardiac death (SCD) remains a major clinical problem, with a reported range of 184,000 to 462,000 deaths occurring annually.¹ Strategies to decrease the incidence of sudden death include preventing underlying structural heart disease, screening for hereditary syndromes and cardiac conditions that predispose persons to sudden death, improving efforts in resuscitation medicine for patients who experience a cardiac arrest (secondary prevention), and identifying patients at high risk for sudden death to provide appropriate intervention.

Potential interventions to prevent sudden death include risk factor and lifestyle modifications, dietary changes, therapy with antiarrhythmic drugs, therapy with other cardiovascular drugs, or device therapy with implantable cardioverter-defibrillators (ICDs). Results of therapy with antiarrhythmic drugs that block sodium or potassium channels for the prevention of sudden death have been mostly disappointing. With the exception of amiodarone, these drugs have had either a neutral or a deleterious effect on mortality.²

Antiarrhythmic drugs have been classified using several different systems. The Vaughan-Williams classification is the oldest and most commonly used system for antiarrhythmic drugs. In this system, drugs that block sodium channels are considered class I drugs, those that block β-adrenergic receptors are considered class II drugs, those that block potassium channels are considered class III drugs, and those that block calcium channels are considered class IV drugs. Antiarrhythmic drugs that block specific ion channels—class I and class III antiarrhythmic drugs—were once thought to have the potential to reduce the incidence of SCD. However, human studies have been disappointing, because drugs that block sodium or potassium channels were either ineffective in preventing SCD or they paradoxically increased the risk of life-threatening arrhythmias. In contrast, other classes of drugs, such as β-blockers, which are considered class II antiarrhythmic drugs but do not specifically block ion channels and are not considered traditional antiarrhythmic drugs, and angiotensin-converting enzyme (ACE) inhibitors, which block the conversion of angiotensin I to angiotensin II, have been shown to reduce overall mortality and sudden death mortality in patients with underlying structural heart disease. Class IV agents—those that block calcium channels—do not reduce the incidence of SCD. This chapter focuses on the prevention of sudden death using pharmacologic agents whose primary mode of action is to not block specific ion channels. These drugs, termed nontraditional antiarrhythmic drugs, and their mechanisms and roles in mortality and sudden death reduction, will highlight this chapter.

Assessing the Impact of Nontraditional Antiarrhythmic Drugs on Sudden Cardiac Death

One difficulty in interpreting the results of clinical studies on SCD is the diversity of potential underlying mechanisms of death, with arrhythmic SCD representing a large fraction of underlying etiologies. This is further complicated by variable definitions of SCD. In some studies, all deaths that occurred up to 24 hours after the onset of symptoms were considered SCDs. This definition is not specific for sudden arrhythmic death because many patients who die from myocardial infarction (MI) within the first 24 hours of symptom onset do so from a cause unrelated to a primary arrhythmia. Thus, in evaluating the effect of nontraditional antiarrhythmic drugs on the incidence of SCD, we will also consider the effects on total mortality, with the understanding that it is possible that some of the mortality reduction may be the result of a decreased incidence of SCD. Studies have suggested that the major mechanisms responsible for sudden arrhythmic death are ventricular tachycardia (VT) and ventricular fibrillation (VF). However, there has been a decreased incidence of VF as a cause of out-of-hospital cardiac arrest and a concomitant increase in non-VF causes.3,4 Therefore, evaluating how therapies alter the occurrence of VT and VF provides more specific insight into the pathophysiological action of these agents to reduce SCD.

Broadly, the risk of sudden death stems from several key pathophysiological components: (1) left ventricular dysfunction; (2) myocardial scar or substrate; (3) autonomic nervous system effects; and (4) triggers, such as premature ventricular complexes. In theory, therapies that directly ameliorate these components can indirectly reduce the incidence of SCD. For example, one of the strongest predictors of arrhythmic sudden death is left ventricular dysfunction. The risk of VT and VF varies inversely with left ventricular function. Therefore, therapies that may improve myocardial structure and function and decrease disease progression may also reduce the risk of VT and VF and the risk of SCD. In addition, left ventricular dilatation may contribute to arrhythmogenesis by altering cardiac electrophysiological properties through contraction-excitation feedback. Thus, pharmacologic agents that modulate cardiac hemodynamics may be antiarrhythmic by altering ventricular function and size, even if direct antiarrhythmic activities are not present.

Despite extensive research in the field of sudden death, a coherent pathophysiological framework to identify the series of events or conditions necessary and sufficient to trigger sudden death has not been fully delineated. Although the majority of patients who experience SCD have coronary artery disease, patients with nonischemic cardiomyopathy also have substantial risk for SCD. In addition, in the minority of patients with coronary artery disease who have SCD, acute MI is the immediate cause. Transient autonomic and metabolic factors may also contribute to SCD. Thus, a pathophysiological framework underlying even arrhythmic SCD needs to broadly include many contributing factors.

One potential model of the pathophysiology of sudden death is shown in Figure 113-1. In this construct, transient factors or triggers interact with spontaneous arrhythmias on an abnormal, underlying anatomic substrate that contributes to electrophysiological conditions leading to SCD. This model recognizes that the triggering beats may be caused by reentry, abnormal automaticity, or triggered activity, and that the electrophysiological substrate could consist of either functional or anatomic reentry. Thus, transient metabolic and autonomic factors that alter electrophysiological properties can modulate the anatomic substrate to heighten the occurrence of sudden death.

Figure 113-1 Pathophysiological framework for arrhythmic SCD.

To target the electrophysiological substrate that forms part of the model, it is necessary to identify a specific electrophysiological mechanism and to identify specific ion channels or other targets that are present in the region of the myocardium that predisposes to sudden death. At present, antiarrhythmic drugs target sodium or potassium channels present throughout the myocardium and therefore are not specific for the arrhythmic mechanism (focal or reentrant) or abnormal myocardial region. Drugs such as β-blockers also operate on global regions of the myocardium, but their lack of specificity does not appear to be harmful, but rather is protective. Given the overall safety profile of nontraditional drugs compared with traditional antiarrhythmic drugs, it should not be surprising that nontraditional drugs that act on more global mechanisms of arrhythmogenesis are more effective in preventing sudden death than are drugs that indiscriminately block ion channels throughout the myocardium. Potential target sites for therapies that might reduce sudden death discussed in this chapter are shown in Figure 113-1. Table 113-1 shows interventions that may reduce mortality in patients with heart disease and the drugs that may reduce the incidence of sudden death.

Table 113-1

Pharmacologic Agents Shown to Decrease Mortality in Patients With Chronic Heart Disease

ACE, Angiotensin-converting enzyme; ?, possible effect.

β-Adrenergic Blockers

β-adrenergic blockers (β-blockers) have emerged as important pharmacologic agents for both primary and secondary prevention of SCD (Table 113-2). The mechanism of this class of drugs involves competitive β-adrenergic receptor blockade of sympathetically mediated triggering mechanisms, slowing of the sinus rate, and, possibly, inhibition of excess calcium release by the ryanodine receptor.^5,6 Given the presence of β-receptors throughout the heart, cardiac disease contributes to pathophysiological changes in cardiac sympathetic nerves, cardiac responsiveness to sympathetic stimulation, and circulating catecholamines. After MI, for example, there are changes in heart rate variability and baroreflex sensitivity that reflect abnormalities of parasympathetic and sympathetic tone. These abnormalities can also heighten the risk for ventricular arrhythmias.

Table 113-2

Efficacy of Drugs in Reducing Mortality and Preventing Sudden Death

ACE, angiotensin-converting enzyme; AMI, acute myocardial infarction; ARB, angiotensin receptor blockers; CHF, congestive heart failure; CI, confidence interval; CRF, cardiac risk factor; CV, cardiovascular; DM, diabetes mellitus; EF, ejection fraction; HR, hazard ratio; HTN, hypertension; LVH, left ventricular hypertrophy; MI, myocardial infarction; NS, not significant; RR, relative risk; SCD, sudden cardiac death.

^*See text for study abbreviations.

^†Cardiac arrest.

^‡Resuscitated cardiac arrest.

^§Sudden cardiac death plus resuscitated cardiac arrest.

Efficacy of β-Blockers After Myocardial Infarction

β-Blockers first were recognized as prophylactic agents for preventing sudden death in patients after MI through trials designed to address total mortality reduction. Analysis by Freemantle and colleagues ⁷ of more than 50,000 patients evaluated in numerous randomized clinical trials demonstrated a substantial reduction in total mortality as a result of β-blocker treatment (relative risk [RR], 0.77; 95% confidence interval [CI], 0.69 to 0.85). The largest observational report, including more than 200,000 patients in the Medicare database, supports the role of β-blockers in reducing total mortality.⁸ Their effect on sudden death was noted in the landmark Beta-Blocker Heart Attack Trial (BHAT), which tested the effect of long-term propranolol therapy in patients after a MI.⁹ More than 3800 patients were randomized to either propranolol or placebo starting 5 to 21 days after MI and were followed for 2 years. Total mortality was 7.2% in the propranolol group and 9.8% in the placebo group (26% reduction). Sudden cardiac death occurred in 3.3% of the propranolol patients versus 4.6% of the placebo patients (28% reduction). A subset of these patients also had ambulatory electrocardiographic monitoring at baseline and after 6 weeks of therapy. An increase in ventricular arrhythmias over the 6-week period was blunted by propranolol. Moreover, metoprolol therapy has also been shown to reduce total number of deaths, especially SCDs, after MI. The mortality reduction was independent of gender, age, and smoking habits.⁸ The survival benefit of β-blocker therapy was shown to extend at least 6 years after MI in the Norwegian Multicenter Study Group.⁸

The benefits of β-blocker therapy have withstood the test of time. In the CAPRICORN study,¹⁰ 1959 patients who had an MI within 3 to 21 days and an ejection fraction (EF) less than or equal to 40% were randomly assigned to treatment with either carvedilol (n = 975) or placebo (n = 984). Although all-cause mortality was not the primary endpoint, after a mean follow-up of 1.3 years, 12% mortality was seen in patients treated with carvedilol and 15% mortality was seen in those treated with placebo (risk reduction, 23%; 95% CI, 2 to 40).¹⁰ Further analysis from this study showed a lower incidence of malignant ventricular arrhythmias in the carvedilol-treated group (0.9% vs. 3.9% in the placebo group; P < .0001).¹¹ In an analysis of the VALIANT registry, Piccini and colleagues¹² found that patients presenting with VT/VF in the setting of acute MI had higher mortality if they did not receive β-blocker therapy within 24 hours (RR, 0.28; 95% CI, 0.10 to 0.75; P = .013).

Because clinical trials have demonstrated significant benefits of β-blocker therapy on survival, the vast majority (>90%) of survivors of MI are discharged receiving β-blocker therapy.¹³ Yet the majority of these patients are treated with doses that are substantially lower than the doses used in clinical trials. The effect of dose on survival benefit has not been definitively demonstrated, although there are reports indicating that low-dose β-blocker therapy does improve survival.

Efficacy of β-Blockers in Patients With Congestive Heart Failure

β-Blockers also are important agents in the prevention of SCD in patients with congestive heart failure. In this population, carvedilol has been shown to reduce mortality by 65%.¹⁴ In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II),¹⁵ the estimated annual mortality was 8.8% in patients treated with bisoprolol and 13.2% in those receiving placebo (risk reduction, 34%; 95% CI, 19 to 46). Metoprolol has also been shown to improve survival in patients with congestive heart failure. In the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), 3991 patients with class II to IV (96% had class II and III) congestive heart failure (EF <40%) were randomly assigned to treatment with metoprolol (n = 1990) or placebo (n = 2001).¹⁶ This trial was also terminated early by the safety committee because of the benefit of β-blocker therapy. The mortality rate was 7.2% per patient-year of follow-up in the metoprolol group versus 11.0% in the placebo group (RR reduction, 34%; 95% CI, 19 to 47). In both trials, prevention of sudden death was an important component of mortality reduction.

Efficacy of β-Blockers in Secondary Prevention of Sudden Death

β-Blockers also demonstrate efficacy in patients known to have significant ventricular tachyarrhythmias. Clinical information from the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial registry provides support for the role of β-blocker therapy in patients with sustained ventricular tachyarrhythmias,⁸ where there was an approximately 50% reduction in adjusted relative risk of mortality because of β-blocker therapy. β-Blockers have been shown to reduce the incidence of ventricular tachyarrhythmias in patients with ICDs.⁸ The overwhelming majority of the study populations in all of these reports were patients with coronary artery disease. Limited data suggest that β-blocker therapy in patients with nonischemic dilated cardiomyopathy and ICDs is associated with a marked reduction in appropriate therapy for ventricular tachyarrhythmias.⁸ In a multivariate analysis,⁸ β-blocker therapy was associated with a 0.15 relative risk (95% CI, 0.05-0.45; P < .0007) of appropriate ICD therapy.

Although β-blockers appear to be highly effective in reducing the risk of SCD, it is noteworthy that there still are other therapies that can provide incremental benefit when added to β-blocker therapy. In both the European Myocardial Infarct Amiodarone Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT),⁸ there appeared to be an interaction between the use of β-blockers and amiodarone; specifically, amiodarone therapy had a greater effect on mortality reduction in patients receiving β-blockers. In CAMIAT, there was a 29% reduction in relative risk related to amiodarone therapy (versus placebo) in patients who were receiving concomitant therapy with β-blockers.⁸ Thus, although β-blocker therapy appears to be an important agent in the strategy of preventing SCD, monotherapy with β-blockers is likely not sufficient for the prevention of SCD in susceptible populations.⁸