Prevention of Sudden Cardiac Death

Sudden Cardiac Death as the Initial Clinical Manifestation of Coronary Heart Disease

This is perhaps the most challenging group for both clinicians and researchers. It is estimated that this first event category contributes approximately one-third of all SCD events, accounting for over 100,000 cases every year in the United States. Unfortunately, strategies are lacking for risk stratification and identification of subjects at risk in the general population. Risk assessment relies primarily on identifying high-risk pockets within low-risk groups. The presence of CHD risk factors carries a risk of future SCD even in the absence of clinically recognized CHD, emphasizing the importance of risk factor control to prevent SCD in the general population.

Sudden Cardiac Death at the Time of Acute Myocardial Infarction or Acute Coronary Syndromes

This typically refers to the initial 24- to 48-hour period after the onset of an MI. Whereas it shares some features related to SCD from ischemia without infarction, elevated risk in this setting is characterized by a dynamic substrate, which is a manifestation of acute loss of blood supply; ischemia and cardiomyocyte death; abnormal local electrical activation patterns; reperfusion and dynamic heterogeneities in electrical properties in the infarct and peri-infarct zones; and systemic factors, such as inflammation, hemodynamic alterations, and neurohormonal alterations. The endpoint of these phenomena is predisposition to electrical reentry and vulnerability to ventricular arrhythmias.

The burden of arrhythmias in the acute phase of MI appears to have decreased with early interventions to restore blood flow that may reverse or at least stabilize the local arrhythmogenic process.

Ventricular arrhythmias occurring in the early phase after an acute MI have been considered transient without prognostic implications for long-term risk of recurrence. This is likely related to the multitude and dynamic nature of factors that contribute to arrhythmogenesis in the acute phase of MI. However, it has been suggested in some studies that a cardiac arrest in the early phase of acute MI might indicate some long-term risk ; however, it remains unknown whether this is related to individual predisposition, recurrent ischemia, subsequent remodeling, or further deterioration in LV function. Nevertheless, ventricular arrhythmias in the first 48 hours after MI do not serve as an indication for defibrillator implantation for secondary prevention purposes.

Sudden Cardiac Death from Acute Myocardial Ischemia Without Infarction

SCD from acute myocardial ischemia without infarction is typically from a supply-demand mismatch that results in transient ischemia and increased arrhythmic risk. Scenarios include either plaque rupture with acute thrombosis limiting blood flow, or vasospasm resulting in the same, as well as high-grade stable lesions in the setting of a sudden increase in demand. The abnormalities in myocardial perfusion and associated regional variations in ischemia and reperfusion result in regional heterogeneities in electrical properties and cell membrane electrophysiology with resultant vulnerability to triggered electrical activity, reentry, and SCD.

In transient ischemic states, both the ischemia and reperfusion phases are important in arrhythmogenesis, the former by creating electrical gradients across the myocardium and areas of inexcitability and the latter by affecting repolarization dispersion in affected areas. Triggered activity from this phenomenon typically generates polymorphic ventricular tachycardia (VT) that can degenerate into ventricular fibrillation (VF) and SCD.

Sudden Cardiac Death During Convalescence Post–Myocardial Infarction

This phase typically starts beyond the first 48 hours after MI and extends for weeks, months, or even years with continuing vascular and myocardial remodeling. Ventricular arrhythmias that occur during this phase, in contrast to arrhythmic events in the early post-MI phase, are strongly associated with risk of clinical recurrence of ventricular arrhythmias and with SCD. This risk appears to be further increased by the degree of LV dysfunction and remains elevated despite modern therapies.

Of note, not all SCD events in the early convalescence phase post-MI are arrhythmic in nature and many could be attributed to mechanical complications of the infarction, such as myocardial rupture. Nonetheless, arrhythmic SCD risk in the early convalescence phase post-MI remains high and predicts later events. However, defibrillator implants early after MI showed no significant benefit in terms of all-cause survival in two separate trials (Defibrillator in Acute Myocardial Infarction Trial [DINAMIT] and Immediate Risk Stratification Improves Survival Trial [IRIS]). Although both trials showed a benefit of implantable cardioverter defibrillator (ICD) implantation in reduction of arrhythmic deaths, this was counterbalanced by a higher rate of nonarrhythmic death.

In the late convalescence period after MI, typically referring to months or years after the index event, there continues to be a risk of SCD likely related to ischemic cardiomyopathy, continued remodeling, and heart failure. This risk is lower than the early convalescence period but is primarily a function of the degree of LV dysfunction.

Sudden Cardiac Death from Coronary Heart Disease–Related Structural Changes

Such changes include scar formation or ventricular dilatation from prior infarction or chronic ischemia. Whereas one-quarter of SCD cases occur in the first 3 months after an acute MI, half of all SCD cases occur beyond the year after the index event. The incidence of SCD after acute MI appears to be similar in ST elevation and non-ST elevation MIs. The risk is highest in the acute phase as previously noted but decreases gradually over time.

A prior history of an MI increases the risk of SCD 4-fold in women and 10-fold in men. The incidence rates of SCD after MI have declined over time with recent estimates of 1% per year in patients receiving optimal medical therapy and revascularization. Despite improvements in overall mortality rates in MI survivors and the decline in SCD rates, there are still subsets of MI survivors who are considered to be at a particularly high risk. The most powerful risk factors for SCD in chronic CHD are LV dysfunction and New York Heart Association (NYHA) functional class, which thus form the basis for why these were used as entry criteria for clinical trials of ICDs and therefore are the primary factors affecting decisions for defibrillator implants for the primary prevention of SCD. The impact of these factors reflects their nature as clinical markers of CHD burden and the extent of damaged myocardium. However, whereas they identify high-risk subgroups in CHD, the absolute number of SCD cases from these subgroups account for only a minority of all CHD-related SCDs. Furthermore, many patients who receive defibrillators for primary prevention purposes never require therapy from their devices. These caveats emphasize the need for better strategies for risk stratification.

Risk stratification remains a topic of intense research. Multiple noninvasive markers have been evaluated for the purpose of improving individual risk prediction, including clinical, imaging, electrophysiologic, genetic, and biologic markers. Although high-risk markers can be identified, clinical relevance is limited by an absence of evidence supporting use of these risk factors for selection of patients for risk-reducing therapies, such as ICD implantation. For example, in chronic ischemic heart disease and in post-MI patients, the presence of late potentials on signal-averaged electrocardiogram (ECG), reduced heart rate variability, and T-wave or repolarization alternans have been found to have significant associations with SCD, but available data have not supported incorporating these factors into the clinical criteria for ICD implantation ( Table 22.1 ).

Ischemic Cardiomyopathy, Heart Failure, and Sudden Cardiac Death

Ventricular arrhythmias are common in patients with heart failure and range from asymptomatic premature ventricular contractions to sustained VT, VF, or SCD. In patients with heart failure, progressive pump failure accounts for only one-third of all cardiovascular deaths, whereas SCD accounts for the other two-thirds and the latter is split equally between unexpected SCD or SCD during episodes of clinical worsening of heart failure. The most common mechanism of SCD in this population is VT degenerating into VF.

The severity of heart failure correlates with higher overall mortality and absolute rates of SCD, but the proportion of total deaths classified as SCD decreases with worsening NYHA class. For example, in the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), NYHA class II, III, and IV were associated with 1-year mortality rates of 6.3%, 10.5%, and 18.6%, respectively, but the proportions of total deaths classified as SCDs were 64%, 59%, and 33%, respectively. Also, not all sudden deaths in patients with heart failure are due to arrhythmia. In the Acute Infarction Ramipril Efficacy (AIRE) trial, only 39% of all SCD cases were thought to be due to arrhythmias. Other observations in the literature suggest that arrhythmic SCD cases account for most but not all unwitnessed deaths and deaths occurring within 1 hour of onset of symptoms.

Sudden Cardiac Arrest from Transient or Reversible Causes

Experts agree, based on available evidence, that the primary goal of management in patients who survived a sudden cardiac arrest from a transient or reversible cause is to address the underlying condition or disease process. There are, however, caveats to this approach, and decision-making in clinical practice may not be straightforward. For example, it has been traditionally thought that ventricular arrhythmias in the setting of acute ischemia have low risk for future SCD and as such may not benefit from ICD implants. The reality is that these patients may have experienced a prior MI or have a significant burden of coronary disease and despite revascularization may still have a myocardial scar or large myocardial territory at risk that would be a substrate for recurrent ventricular arrhythmia. Studies have indeed demonstrated increased subsequent risks in patients with ventricular arrhythmias in the setting of acute ischemia. Furthermore, in a subsequent analysis of the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial, the mortality rate of patients who were included in the AVID registry but not randomized due to a transient or correctable cause for VT/VF was no different, or was perhaps even worse, than that of the population considered to have high-risk VT/VF in the randomized trial.

As such, a careful approach to risk stratification and identification of both reversible and nonreversible causes on a case-by-case basis is valuable to optimize patient outcomes. In the specific setting of coronary disease, scar-dependent ventricular arrhythmias are mostly monomorphic tachycardia in nature, whereas arrhythmias related to acute ischemia are mostly polymorphic VT or VF. In general, patients with polymorphic VT or VF in the setting of acute ischemia should be treated with revascularization for the purpose of reducing the risk of SCD. Sustained monomorphic VTs in the setting of electrolyte abnormalities or antiarrhythmic drug use should be treated by identifying and correcting the underlying condition, but it is important not to assume that these were the only cause of sustained monomorphic VT.

Implantable Cardioverter Defibrillators for Secondary Prevention of Sudden Cardiac Death

The role of ICDs is well established for the purpose of secondary SCD prevention based on the results of randomized clinical trials ( Table 22.2 ), which have demonstrated that implantation of ICDs in patients who have survived a sudden cardiac arrest or experienced sustained VT results in reductions in SCD and total mortality compared to antiarrhythmic medications. An algorithm for ICD use for secondary prevention of SCD in patients with coronary artery disease (CAD) is presented in Fig. 22.2 . The use of ICDs for secondary prevention of SCD within 40 days after MI or 90 days after coronary revascularization is shown in Figs. 22.3 and 22.4 .

Cumulative Data of Landmark Trials and Generalizability of Outcomes

Whereas AVID showed a statistically significant benefit with ICD implant versus medical therapy, CIDS and CASH showed a nonsignificant trend toward benefit, which may have reflected a beta error and lack of statistical power to detect significance in the magnitude of benefit that was observed, different patient populations, or longer follow-up time in CIDS. It is also possible that patients who were considered by their managing physicians to be better candidates for ICD therapy than antiarrhythmics may have been referred for defibrillator implant rather than enrollment in the trial with randomization. This would introduce a bias that may have favored the outcomes in the medical intervention arm.

Conclusive evidence regarding the benefit of ICDs in these patients was observed in a meta-analysis of the three major trials and a fourth trial with a smaller population ( Fig. 22.5 ). When combined in a meta-analysis, data showed that patients with ICDs had a survival advantage over those treated with medical therapy with a 25% reduction in relative risk. This was primarily related to a positive effect on SCD rates, with a 50% relative risk reduction from this mode in death with ICDs. An important observation is that of an absolute risk reduction of 7% in all-cause mortality, which translates into a number needed to treat of 15 that supersedes most clinical trials in modern cardiovascular medicine.

The findings were reproduced in a second meta-analysis of AVID, CIDS, and CASH with a 28% relative risk reduction in all-cause mortality and a 50% reduction in sudden arrhythmic death and a superior benefit in patients with LVEF below 35% compared to those with LVEF above 35%. The generalizability of these benefits was explored by examining the effectiveness of defibrillators as applied in routine medical practice in a large cohort of patients from the National Veterans Administration database. For 3 years the study followed 6996 patients with new-onset ventricular arrhythmia and preexisting ischemic heart disease and congestive heart failure, of which 1442 received an ICD. The main finding was that ICD recipients had lower all-cause (odds ratio 0.52) and cardiovascular mortality (odds ratio 0.56) in multivariable analyses but no difference in noncardiovascular mortality. These benefits were observed despite a significantly lower frequency of use of angiotensin-converting enzyme inhibitors (ACE-I), β-blockers, and statins. An important observation was that the magnitude of benefit of ICD therapy was similar to or even greater than that observed in the clinical trials, with a finding that one death was prevented in this population for every four to five patients receiving an ICD over three years of follow-up.