Impact of Nontraditional Antiarrhythmic Drugs on Sudden Cardiac Death

Introduction

Although mortality from coronary artery disease (CAD) has declined in the United States, sudden cardiac death (SCD; see Chapter 79 ) remains a major clinical problem, with a reported range of 184,000 to 462,000 deaths occurring annually. ^, Strategies to decrease the incidence of SCD include preventing underlying structural heart disease, screening for hereditary syndromes that predispose to SCD, improving efforts in resuscitation medicine for patients who experience a cardiac arrest (secondary prevention), and identifying patients at high risk for SCD to provide appropriate intervention. ^,

Results of therapy with antiarrhythmic drugs that block sodium or potassium channels for the prevention of SCD have largely been disappointing and, in some cases, may increase the risk for life-threatening arrhythmias. In contrast, β-blockers, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), and angiotensin receptor neprilysin inhibitors (ARNIs), which are not considered traditional antiarrhythmic drugs, have been shown to reduce overall mortality and SCD mortality in patients with underlying structural heart disease. This chapter focuses on the prevention of SCD using pharmacologic agents whose primary mode of action is not to block specific Na ⁺ or K ⁺ ion channels but to modulate β-adrenergic, inflammatory, atherosclerotic, and other metabolic pathways ( Fig. 118.1 ). These drugs, termed nontraditional antiarrhythmic drugs , and their mechanisms and roles in mortality and SCD reduction are highlighted.

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. This is further complicated by variable definitions of SCD ^, and the fact that SCD is not synonymous with sudden arrhythmic death. The POST-SCD study noted that only approximately one-half of epidemiologically defined SCD was determined by rigorous criteria, including autopsy, to be attributable to sudden arrhythmic death. Even within the category of sudden arrhythmic death, the relative frequency of different mechanisms of death has been changing. Although ventricular tachycardia (VT) and ventricular fibrillation (VF) had previously been the predominant form of SCD, asystole and pulseless electrical activity are currently more common. Thus, in evaluating the effect of nontraditional antiarrhythmic drugs on the incidence of sudden death, we will also consider the effects on total and cardiac mortality.

In general, the risk for SCD stems from several key pathophysiologic components (see Fig. 118.1 ); these include (1) left ventricular (LV) dysfunction; (2) myocardial scar and fibrosis; (3) autonomic nervous system modulation; (4) triggers, such as premature ventricular complexes (PVCs); (5) ischemia; (6) metabolic abnormalities; (7) inflammation; and (8) an underlying susceptibility to arrhythmias that is likely genetically predetermined. ^, Therapies that directly ameliorate these components can indirectly reduce the incidence of SCD (see Fig. 118.1 ). For example, the risk for VT and VF varies inversely with the LV ejection fraction (EF); thus arrhythmic risk declines as a patient’s EF improves. Nevertheless, patients with heart failure and improved EF still have residual risk for SCD. Many standard heart failure drugs improve outcomes in heart failure, in part by modulating adrenergic stimulation. In patients with ischemic heart disease, therapies that reduce ischemia may reduce ventricular arrhythmias. Therapy that reduces scar and fibrosis should diminish the substrate and hence be antiarrhythmic. Suppression of triggers (PVCs) can be antiarrhythmic (i.e., ablation of Purkinje-triggered VF); however, use of sodium channel blockers in patients with structural heart disease to suppress PVCs can be proarrhythmic. Thus pharmacologic agents that modulate the key pathophysiologic components may result in antiarrhythmic efficacy and reduction in SCD.

To specifically target the electrophysiologic (EP) substrate, it is necessary to identify a specific EP mechanism and to identify specific ion channels or other targets that are present in the region of the myocardium that predisposes to SCD. Drugs such as β-blockers operate on all regions of the myocardium, but their lack of specificity does not appear to be harmful; rather, it is protective. Given their overall safety profile 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 SCD than are drugs that indiscriminately block myocardial ion channels. Table 118.1 shows treatments that might reduce mortality in patients with heart disease and the potential mechanisms by which they might reduce the incidence of SCD.

β-Adrenergic Blockers

β-Adrenergic blockers (β-blockers) have emerged as important pharmacologic agents for both primary and secondary prevention of SCD ( Table 118.2 ). 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. Cardiac disease contributes to pathophysiologic changes in cardiac sympathetic innervation and regional cardiac denervation, which may alter cardiac responsiveness to sympathetic stimulation and circulating catecholamines.

There was concern that β-blockers were leading to a higher incidence of nonshockable rhythms (asystole, pulseless electrical activity). Nevertheless, the Toronto Rescu Epistry database did not confirm these findings because 18.4% and 17.5% of patients taking or not taking β-blockers at the time of cardiac arrest had shockable rhythms ( P = not significant). Thus there is no clear evidence that β-blockers influence the presenting rhythm associated with out-of-hospital cardiac arrest.

β-Blockers After Myocardial Infarction

β-Blockers first were recognized as prophylactic agents for preventing SCD in patients after myocardial infarction (MI). Multiple reviews of β-blocker use found a substantial reduction in total mortality because of β-blocker treatment (relative risk [RR], 0.69; 95% confidence interval [CI], 0.62–0.77). Their effect on reducing SCD is well appreciated and accounts for more than half of the reduction in total mortality.

Because the initial β-blocker trials were performed several decades ago, there have been questions about the current efficacy of β-blockers in patients who receive modern reperfusion for acute MI and pharmacologic therapy. The benefits of β-blocker therapy were shown to persist in the modern era in the CAPRICORN (Carvedilol Post-Infarct Survival Control in LV Dysfunction) study. In patients post-MI with an EF up to 40%, carvedilol-treated patients had a 23% lower total mortality and a 77% reduction in malignant ventricular arrhythmias (0.9% carvedilol treated vs. 3.9% placebo; P < .0001) compared with placebo at 15 months of follow-up. There has been controversy regarding mortality benefit regarding the use of β-blockers after acute MI in the reperfusion era ; a recent Cochrane analysis, however, found a survival benefit beyond 3 months for the use of β-blockers post-MI.

β-Blockers may also mitigate proarrhythmic effects from antiarrhythmic drugs and extend antiarrhythmic effects from one drug in particular, amiodarone, ^, after MI. A retrospective analysis from the CAST (Cardiac Arrhythmia Suppression) Trial showed that concomitant use of β-blocker with flecainide or encainide substantially mitigated the adverse effect on mortality that is attributed to proarrhythmic effects from these drugs. Furthermore, analyses from the European Myocardial Infarct Amiodarone (EMIAT) and Canadian Amiodarone Myocardial Infarction (CAMIAT) Trials showed a favorable interaction between amiodarone and β-blocker usage.

The majority of post-MI patients are treated with β-blocker doses that are substantially lower than the doses used in clinical trials. An effect of dose on survival benefit has not been definitively demonstrated, but there are reports that suggest low-dose β-blocker therapy does improve survival. ^, Furthermore, a pharmacogenetic substudy of Metoprolol CR/XL in MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure) study showed that poor metabolizers have substantially higher plasma metoprolol concentrations during dose titration, an observation that provides validation to the strategies to uptitrate β-blockers to effect rather than to a specific dose.

β-Blockers in Congestive Heart Failure

β-Blockers also are important agents for the prevention of SCD in patients with congestive heart failure (CHF). ^, The original β-blocker trials in heart failure demonstrated that carvedilol reduced SCD by 55% (carvedilol, 3.8% vs. placebo, 1.7%). Bisoprolol reduced SCD by 44% (bisoprolol, 3.6% vs. placebo, 6.3%), and metoprolol CR/XL reduced SCD by 41% (metoprolol CR/XL, 4.0% vs. placebo, 6.6%). A meta-analysis of 30 randomized controlled β-blocker trials showed an overall reduction of SCD by 31%, and total mortality by 33%, confirming a critical therapeutic role for β-blockers in patients with heart failure from either ischemic or nonischemic cardiomyopathy.

Efficacy of β-Blockers in Secondary Prevention of Sudden Death

β-Blockers are also efficacious in patients known to have significant ventricular tachyarrhythmias. A study from the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial registry provides support for the role of β-blocker therapy in patients with sustained ventricular tachyarrhythmias ; there was an approximately 50% reduction in adjusted relative risk for mortality in patients treated with β-blocker therapy from those patients who were not treated with an antiarrhythmic drug.

In patients with nonischemic dilated cardiomyopathy and ICDs implanted for primary or secondary indications, a multivariate analysis showed that β-blocker therapy was associated with a 0.15 relative risk reduction (95% CI, 0.05–0.45; P < .0007) of appropriate ICD therapy.

Thus β-blockers are indicated in a wide variety of patient populations who also have indications for ICD therapy. The extent to which β-blocker therapy may reduce the recurrence rate of VT/VF in patients who already had a VT/VF event is unclear. β-Blockers are indicated as adjuvant therapy but not sole primary therapy for secondary prevention in many patients with a history of VT/VF.