Strategies for the Prevention of Sudden Cardiac Death
Emad F. Aziz
Fahad Javed
Eyal Herzog
Sudden cardiac death (SCD) also known as sudden cardiac arrest, is a major health problem worldwide.1 Estimates for the United States range from <200,000 to >450,000 SCDs annually, with the most widely used estimates in the range of 300,000 to 350,000 SCDs annually.2,3 It is usually defined as an unexpected death from a cardiac cause occurring within a short duration of time in a person with or without preexisting heart disease owing to the abrupt loss of heart function (cardiac arrest). A dynamic triggering factor usually interacts with an underlying heart disease either genetically determined or acquired, and the final outcome is the development of lethal tachyarrhythmias or less frequently, bradycardia.4
There is no comprehensible consensus on the definition of SCD, which is witnessed in only two-thirds of cases. As the duration of symptoms preceding the terminal event usually defines the sudden nature of death, the World Health Organization defines SCD as unexpected death within 1 hour of symptom onset if witnessed or within 24 hours of the person having been observed alive and symptom-free if unwitnessed.5 Exclusion of noncardiac causes such as pulmonary embolus or drug overdose is also critical because sudden cardiac arrhythmias may be the final decisive pathology in these disease conditions.
According to the Framingham Heart Study, during a 20-year follow-up 13% of deaths were due to SCD.6 In >80% of cases, sudden death is caused by coronary disease.7 The mechanism of SCD is ventricular fibrillation (VF) in 65% to 85% cases, ventricular tachycardia (VT) in 7% to 10% cases, and electromechanical dissociation in 20% to 30% cases. Pathoanatomical findings can be observed on myocardium as fibrosis, edema, necrosis, cell infiltration, but rarely myocardium can be unchanged.
RISK FACTORS
Approximately 80% of individuals who suffer from SCD have coronary artery disease (CAD); the epidemiology of SCD to a great extent parallels that of CAD. Based on recent published data, the following variables have been associated with patients at higher risk of SCD: (1) syncope at the time of the first documented episode of arrhythmia, (2) NYHA class III or IV, (3) VT/VF occurring early after MI (3 days to 2 months), and (4) history of previous MI.8 Other factors such as age, hypertension, left ventricular (LV) hypertrophy, intraventricular conduction block, elevated serum cholesterol, glucose intolerance, decreased vital capacity, smoking, relative weight, and heart rate also are as contributory in identifying individuals at risk for SCD.9,10 and 11 Family history of MI has been reported to be associated with the risk of primary cardiac arrest.12 Another entity of patients at highest risk for early SCD are those with hereditary ion channel or myocardial defects such as a long or short QT syndrome (LQTS or SQTS), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular dysplasia (ARVD).
PATHOPHYSIOLOGY OF ARRHYTHMIAS
The most common electric sequence of events in SCD is degeneration of VT into VF during which disorganized contractions of the ventricles fail to eject blood effectively, often followed by asystole or pulseless electrical activity. Polymorphic VT or torsade de pointes may be the initial arrhythmia in patients with genetic or acquired forms of structural heart disease.13 Bradyarrhythmias or electromechanical dissociation may be the primary electrical event in advanced heart failure or in the elderly patients.14,15 Among patients with implantable cardioverter defibrillators (ICDs), arrhythmic death accounts for 20% to 35% of deaths, and electromechanical dissociation after shock is a frequent cause of death. Asystole may be the first rhythm observed in the field, but this may be a marker of the duration of arrest because coarse VF ultimately degenerates into asystole.
MANAGEMENT
RISK STRATIFICATION
Current parameters for risk stratification of patients with (CAD for SCD include medical history (presence of nonsustained VT or syncope), Ejection fraction (EF), electrocardiogram (QRS duration, QT interval, and QT dispersion), signal-averaged electrocardiogram, heart rate variability, and baroreflex sensitivity. However, the sensitivity and specificity of these parameters has not been studied yet in detail in large patient populations. The single major parameter associated with higher incidence and studied in many clinical trials is left ventricular ejection fraction (LVEF). At present, only LV dysfunction with reduced EF reliably defines “high risk” for SCD in patients with ischemic and nonischemic cardiomyopathy. The heart failure functional class and history of prior MI or CAD are also important
prognostic risk factors along with sudden specific definitive indications.16
prognostic risk factors along with sudden specific definitive indications.16
PREVENTION
Prevention of SCD is rendered as detection of high-risk patients and application of medical treatment to postpone it. The high risk of development of SCD is attributed principally to fatal ventricular arrhythmias. Electrophysiologic anomalies in cells lead to development of ventricular ectopic activity or ventricular arrhythmias, which comes to the end with fibrillation and eventually death if not terminated in time. As survival rates for out-of-hospital cardiac arrests are extremely low, ranging from 2% to 25% in the United States,17 secondary prevention strategies address only a small portion of patient population at risk of SCD. The accumulated data has allowed guidelines to be formulated, which allows us to predict with more certainty about patients at risk for SCD and address the challenge to identify patients at risk before the first event as primary prevention. However, applying those guidelines in practice requires systems to structure the environment in which care is delivered so that “doing the right thing” becomes automatic.18 This requires tools that simplify and provide focus by embedding the recommendations for evidence-based care into the care itself.
PHARMACOLOGIC THERAPY
β-BLOCKERS
Of the different drugs that have been evaluated, only β-blockers have reduced SCD in the MI survivors.19 The β-blocker heart attack trial (BHAT) study showed that β-blockade with propranolol reduced all-cause mortality by 25% especially in patients with diminished LV function and/or ventricular arrhythmias.20 A randomized trial of approximately 46,000 patients showed that in the acute MI setting, early administration of high-dose β-blocker drugs orally has been shown to prevent VF.21 In the metoprolol CR/XL randomized intervention trial in congestive heart failure trial (MERIT-HF), 3,991 patients with NYHA class II-IV heart failure and EF = 40% were randomized to longacting metoprolol with a dose escalation protocol.22 At 1-year follow-up, overall mortality was lower in the treated group compared with placebo (7.2% vs. 11% per patient-years of followup). There was also a 41% relative risk reduction in SCD with long-acting metoprolol. These data provide unequivocal benefit of β-blockade in acute MI, post-MI, and congestive heart failure for prevention of mortality and SCD.
ANTIARRHYTHMIC DRUGS
The sine qua non for efficacy of common antiarrhythmic drugs in prevention against SCD based on well-designed, placebo-controlled clinical trials have shown no added benefit.19,20,21,22 and 23 Class I drugs (mexiletine, encainide, flecainide), calcium antagonists, and class III drugs (d-sotalol, dofetilide) all failed to reduce the incidence, rather even increased the incidence of SCD after an MI.24 Amiodarone also has been shown to have no definitive effect on mortality in patients after MI in preventing SCD, as manifested in the sudden cardiac death in heart failure trial (SCD-HeFT).25
STATINS
The role of statins has been well studied in the patients with CAD and has been shown to be extremely beneficial in reducing mortality but whether they play any significant role in preventing SCD remains controversial. A multicenter automatic defibrillator implantation trial (MADIT-II) substudy26 demonstrated that among patients treated with ICDs, those with background statin therapy had a lower rate of ventricular tachyarrhythmias. This finding was intriguing because it was unclear whether this observation was due to reduction in coronary events, decreased inflammation, unique antiarrhythmic properties, or unidentified confounders. Recently, the Cholesterol Lowering and Arrhythmia Recurrences After Internal Defibrillator Implantation study demonstrated that intensive lipid-lowering therapy using 80 mg of atorvastatin led to a 40% relative risk reduction (from 38% to 21%) in VT/VF recurrence in ICD patients during a 12-month follow-up. Yet there are no definite guidelines supporting addition of statins as adjuvant therapy for prevention of SCD beyond conventional indications.
THE ROLE OF IMPLANTABLE CARDIOVERTER DEFIBRILLATOR DEVICES IN PRIMARY AND SECONDARY PREVENTION AGAINST SUDDEN CARDIAC DEATH
Multiple prospective randomized multicenter clinical trials have documented improved survival with ICD therapy in highrisk patients with LV dysfunction owing to either prior MI or nonischemic cardiomyopathy. On a background of optimal medical therapy (with or without antiarrhythmic drug therapy), ICD therapy has been associated with a 23% to 55% mortality reduction, almost exclusively owing to a reduction in SCD.
IMPLANTABLE CARDIOVERTER DEFIBRILLATOR TRIALS
AVID TRIAL
Superiority of an ICD over antiarrhythmic drug therapy for secondary prevention against SCD (predominantly amiodarone) was primarily noticed in the antiarrhythmic versus implantable defibrillator (AVID) trial.27 The AVID trial enrolled 1,016 patients resuscitated from an episode of VT (if associated with hemodynamic collapse, cardiac symptoms, or occurring in the setting of an EF = 40%) or VF. Patients were randomized to receive either medical therapy alone or in conjunction with an antiarrhythmic drug, which was most commonly amiodarone. The trial was stopped prematurely when a survival benefit was noted in patients receiving ICDs compared with those treated with sotalol or amiodarone. The unadjusted survival rates for the ICD versus drug groups were 89% versus 82% at 1-year, 82% versus 75% at 2-years, and 75% versus 65% at 3-years. The major effect of the ICD was to prevent arrhythmic death (4.7% vs. 10.8% in patients treated with an antiarrhythmic drug). Results consistent with the AVID study were also reported from the Canadian Implantable Defibrillator Study (CIDS)28 and the Cardiac Arrest Study Hamburg (CASH).29
MADIT TRIAL
To test the efficacy of ICDs in prevention of SCD, the MADIT trial randomized 196 patients with ischemic cardiomyopathy,30 EF ≤35%, a documented episode of nonsustained VT (NSVT), and inducible VT on electrophysiology study to ICD (n = 95) versus conventional medical therapy(n = 101). After a mean follow-up of 27 months, the relative risk reduction for all-cause mortality in the patients receiving ICDs was 54% (P = .009) thus showing the benefit of prophylactic ICD placement in a highrisk population.
MADIT II TRIAL
However, to make an impact on the overall population at risk for SCD, high-risk patients need to be identified before an episode of VT or VF (primary prevention). The MADIT II study highlighted the possibility of preventing sudden death in patients with CAD. According to this trial, patients with a previous MI and low LVEF (=30%) on optimal medical therapy were randomized to receive either an ICD or no ICD.26 Patients implanted with an ICD had mortality rate of 14.2% versus 19.8% in the conventional therapy group (P = .016); a 31% relative risk reduction in mortality during a follow-up period of 20 months. The survival benefit was entirely owing to a reduction in the incidence of SCD and became apparent at 9 months after device implantation. This trial was novel because there was no requirement for invasive electrophysiological testing of prior ventricular arrhythmias. This trial expanded on the findings of MADIT I, which showed the superiority of ICD therapy in patients with CAD with EF ≤35%.
SCD-HEFT TRIAL
The significant role of ICD therapy in primary prevention against SCD in both ischemic and nonischemic cardiomyopathy patients was further clarified by the SCD-HeFT.31 This trial enrolled 2,521 patients with New York Heart Association (NHYA) class II or III CHF and an EF of ≤35%. Patients were randomized to receive optimal medical therapy alone (847 patients), optimal medical therapy along with amiodarone (845 patients), or optimal medical therapy along with a conservatively programmed, shock-only, single-lead ICD (829 patients). Placebo and amiodarone were administered in a double-blind fashion. The primary endpoint of the study was all-cause mortality with mean follow-up of 3.8 years. A 23% reduction in mortality (P = .007) was observed with the ICD; the benefit of ICD was similar in both ischemic (hazard ratio, 0.79; P = .05) and nonischemic cardiomyopathy (hazard ratio, 0.73; P = .06). In contrast, mortality was similar in patients on either medical therapy alone or when combined with amiodarone. The benefit of ICD therapy was comparable for ischemic and nonischemic cardiomyopathy.
DEFINITE TRIAL
The defibrillators in nonischemic cardiomyopathy treatment evaluation (DEFINITE) trial was the MADIT II counterpart. This trial included 458 patients with nonischemic dilated cardiomyopathy, EF ≤35%, NSVT or premature ventricular contractions, and NYHA class I, II, or III who were randomly divided to standard medical therapy or ICD.33 At a 2-year follow-up, there was a trend in mortality reduction with ICD (7.9% vs. 14.1%; hazard ratio = 0.65, P = .08). The largest benefit was seen in NYHA class III patients (hazard ratio = 0.37). In part based on the results of this trial, the Centers for Medicare & Medicaid Services expanded coverage for ICD implementation to patients with nonischemic cardiomyopathy for more than 9 months in duration who have NYHA class III or IV heart failure and EF ≤35%.
TIMING OF CARDIOVERTER DEFIBRILLATOR IMPLANTATION
CABG PATCH TRIAL
In the CABG Patch study, 900 patients with LVEF of <36% and abnormal signal-averaged ECG who were undergoing elective coronary bypass surgery were randomized to ICD or antiarrhythmic therapy.34 This trail showed no difference in survival between the two groups at an average of 32-month follow-up. Of note, 88 patients enrolled were not randomized because they were deemed too unstable at time of surgery for ICD placement. In addition, EFs of these patients were not assessed postoperatively. Nevertheless, results suggest that revascularization should be performed when feasible and SCD risk stratification should be performed after revascularization.
DEFIBRILLATOR IN ACUTE MYOCARDIAL INFARCTION TRIAL
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