7/6/23, 3:34 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF : Joseph E Marine, MD, FACC, FHRS, Andrea M Russo, MD, FACC, FHRS : Samuel L vy, MD, Bradley P Knight, MD, FACC : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Nov 12, 2021. INTRODUCTION Life-threatening ventricular arrhythmias, including sustained ventricular tachycardia (VT) and ventricular fibrillation (VF), are common in patients with systolic heart failure (HF) and dilated cardiomyopathy and may lead to sudden cardiac death (SCD). Primary prevention of SCD refers to medical or interventional therapy undertaken to prevent SCD in patients who have not experienced symptomatic life-threatening sustained VT/VF or sudden cardiac arrest (SCA) but who are felt to be at an increased risk for such an event. The primary prevention of SCD in patients with HF and cardiomyopathy with reduced ejection fraction, either due to coronary heart disease or a dilated nonischemic etiology, will be reviewed here with emphasis on the role of implantable cardioverter-defibrillators (ICDs). The different types of ventricular arrhythmias, the effects of HF therapy on ventricular arrhythmias, the role of electrophysiologic testing, and the secondary prevention of SCD are discussed separately. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy" and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) The approaches to the treatment of ventricular arrhythmias related to specific heart muscle diseases or primary electrical system diseases such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, isolated left ventricular noncompaction, Chagas disease, Brugada syndrome, long QT syndrome, and other channelopathies are discussed elsewhere. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 1/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate (See "Hypertrophic cardiomyopathy: Management of ventricular arrhythmias and sudden cardiac death risk", section on 'Recommendations for ICD therapy'.) (See "Arrhythmogenic right ventricular cardiomyopathy: Treatment and prognosis".) (See "Isolated left ventricular noncompaction in adults: Clinical manifestations and diagnosis".) (See "Chronic Chagas cardiomyopathy: Management and prognosis".) (See "Brugada syndrome or pattern: Management and approach to screening of relatives".) (See "Congenital long QT syndrome: Treatment".) CAUSES OF DEATH IN HEART FAILURE Causes of death in patients with heart failure include: Progressive pump failure. Unexpected SCD (usually from a ventricular tachyarrhythmia, but asystole and pulseless electrical activity [PEA] are also seen less frequently). SCD in the setting of worsening heart failure. The mode of death in patients with HF is more likely to be "sudden" in patients with class II or III HF, while the mode of death is more likely to be related to "pump" failure in patients with class IV HF ( figure 1) [1]. Therefore, primary prevention implantable cardioverter-defibrillator (ICD) trials (in the absence of cardiac resynchronization therapy [CRT]) have excluded patients with NYHA class IV HF. In fact, the 2017 American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS) Guidelines state that "ICD therapy is not indicated for NYHA Class IV patients with medication-refractory HF who are not also candidates for cardiac transplantation, an LVAD (left ventricular assist device), or CRT-D," listing this as a class III indication [2]. (See 'Class IV heart failure' below and "Heart transplantation in adults: Indications and contraindications" and "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) RISK STRATIFICATION STRATEGIES While implantable cardioverter-defibrillators (ICDs) are highly efficacious in the treatment of ventricular tachyarrhythmias and prevention of SCD, they are costly, require ongoing follow-up, and have numerous risks at the time of implantation (eg, bleeding, pneumothorax, perforation, etc) as well as over the lifetime of the device (eg, infection, device and lead malfunction, etc). In https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 2/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate addition, only a subset of patients with cardiomyopathy develop sustained ventricular tachyarrhythmias or SCD. As such, the risk stratification of patients prior to ICD therapy is important for providing therapy to patients at highest risk of SCD and minimizing the number of ICD implantations in patients who are unlikely to benefit. Numerous patient-related clinical markers as well as data derived from testing have been associated with increased risk of sudden death, and a variety of attempts have been made to develop risk stratification schema to more specifically identify an individual patient's risk of SCD. To date, however, the optimal approach to SCD risk stratification for placement of a primary prevention ICD continues to rely primarily upon the following: Etiology of left ventricular dysfunction Left ventricular ejection fraction Heart failure symptom classification Life expectancy greater than one year Inducible sustained ventricular tachycardia Nonsustained ventricular tachycardia on electrocardiogram (ECG) monitoring LVEF and risk Patients with significant reductions in left ventricular ejection fraction (LVEF) appear to be at greatest risk, and derive the greatest benefit, from primary prevention ICD implantation. (See 'Trials of primary prevention ICDs in ischemic cardiomyopathy' below and 'Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy' below.) Though most studies of prophylactic ICD implantation have included patients with an LVEF 35 percent, the large majority of patients included in most trials have had ejection fractions under 30 percent, resulting in some uncertainty regarding the potential benefit of prophylactic ICD insertion for patients with LVEF between 30 and 35 percent. This issue was addressed in a retrospective cohort study using registry data from the NCDR ICD registry of patients who underwent ICD implantation in 2006 or 2007 (median follow-up 4.4 years) and Get With The Guidelines-Heart Failure (GWTG-HF) patients without an ICD (enrolled between 2005 and 2009 with median follow-up of 2.9 years), in which the benefits of ICD implantation were separately evaluated among patients with LVEF <30 percent and those with LVEF 30 to 35 percent [3]. All- cause mortality was significantly lower in patients with an ICD and any level of LVEF, compared with those without an ICD: LVEF 30 to 35 percent hazard ratio (HR) 0.83, 95% CI 0.69-0.99 LVEF <30 percent HR 0.72, 95% CI 0.65-0.81 While this study is nonrandomized, the data suggest that patients with LVEF between 30 and 35 percent do appear to benefit from prophylactic ICD insertion. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 3/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate SCD risk prediction post-MI A number of clinical features have been evaluated as a means for identifying patients at the greatest risk of SCD following an acute myocardial infarction (MI). These include: Left ventricular (LV) dysfunction or reduced LVEF HF symptoms and the degree of heart failure LV aneurysm Q-waves on the surface ECG Intraventricular conduction delay Spontaneous ventricular premature beats (VPBs) and nonsustained ventricular tachycardia (NSVT) Late potentials on a signal-averaged ECG (SAECG) VT induced by electrophysiologic study (EPS) Reduced heart rate variability (HRV) Microvolt T-wave (repolarization) alternans (TWA) A detailed discussion of the utility of these clinical predictors is presented separately. (See "Incidence of and risk stratification for sudden cardiac death after myocardial infarction".) Clinical risk markers A variety of novel risk stratification schemes derived from retrospective studies have shown the ability to predict SCD risk, but none have been prospectively validated in independent populations or have become part of the routine practice for primary prevention ICD placement [4-13]. Therefore, traditional risk stratification based on etiology of cardiomyopathy, LVEF, HF class, and select other risk markers (eg, inducible sustained ventricular arrhythmias) continues to form the basis for recommendations regarding ICD use. Initial studies evaluating the role of ICD therapy in reducing mortality focused on patients with reduced LV systolic function and class II-III heart failure. As the mode of death in patients with class II-III heart failure was more likely sudden (in 59 to 64 percent of cases [1]), and enrollment criteria for ICD trials often included patients with class II-III HF symptoms. In contrast, patients with class IV heart failure were more likely to die from heart failure (56 percent) than from sudden death (33 percent). Studies examining the relationship between one-year mortality and LV function after MI in the pre- and post-thrombolytic era demonstrated a much higher cardiac mortality rate in patients with LVEF <40 percent [14,15]. The presence of NSVT or frequent ventricular ectopy was also associated with increased mortality post-MI, so NSVT was also used as a risk factor for inclusion in some of the randomized ICD trials. Earlier studies also demonstrated that inducible sustained monomorphic VT was associated with an increased risk of sudden death or sustained ventricular arrhythmias [16]. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 4/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate Myocardial fibrosis on CMR The presence of myocardial fibrosis, identified by late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging appears to be a robust predictor of ventricular arrhythmias or SCD across a wide spectrum of patients with non- ischemic cardiomyopathy, including those with a mean LVEF >35 percent. A 2017 systematic review and meta-analysis, which included 2948 patients from 29 observational studies, assessed the relationship between LGE and ventricular arrhythmias in patients with non-ischemic dilated cardiomyopathy [17]. Over a mean follow-up of three years, the primary endpoint (sustained ventricular arrhythmia, appropriate ICD intervention, or SCD) occurred in 350 patients, including 21 percent of patients with LGE (compared with 4.7 percent of patients without LGE; pooled odds ratio [OR] 4.3, 95% CI 3.3- 5.8). LGE was able to risk stratify patients at all levels of LVEF (both above and below 35 percent) and was most powerful among patients with ICDs previously placed for primary prevention (OR 7.8, 95% CI 1.7-35.8). In a 2019 Australian prospective, nonrandomized study of 452 patients with non-ischemic cardiomyopathy (LVEF 35 percent) who had all undergone CMR imaging and who met ESC/AHA criteria for primary prevention ICD placement, half received a primary prevention ICD according to the judgment of the treating physician and prevailing local practice [18]. Patients with myocardial fibrosis (manifest by LGE on CMR imaging) who received an ICD had lower mortality than those who did not get an ICD (HR 0.45, 95% CI 0.26-0.77). However, there was no difference in survival with or without an ICD for the 175 patients without myocardial fibrosis. The MARVEN (Clinical, Electrocardiographic, and Cardiac Magnetic Resonance Imaging Risk Factors Associated with Ventricular Tachyarrhythmias in Nonischemic Cardiomyopathy) Study is an NHLBI-sponsored prospective, observational study aimed at developing optimal risk stratification strategies to predict ventricular tachyarrhythmias in patients with nonischemic cardiomyopathy undergoing CRT-D implantation to determine whether LGE-CMR will further improve risk stratification in patients with nonischemic cardiomyopathy, LVEF 35 percent, and QRS 120 milliseconds [19]. While not currently utilized in SCD risk stratification guidelines, if these data are confirmed in additional prospective studies, then LGE on CMR may become a criterion used in future risk stratification schemes. USE OF AN ICD Malignant ventricular arrhythmias potentially leading to SCD are more frequently seen in patients with certain cardiomyopathies (compared with the general population), particularly in https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 5/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate association with heart failure (HF) symptoms. As in secondary prevention, randomized clinical trials have established a clear role for primary prevention implantable cardioverter-defibrillators (ICDs) in selected patients ( table 1). In contrast, antiarrhythmic drugs other than beta blockers do not appear to improve outcomes. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) The role of an ICD in the primary prevention of SCD among patients with HF and cardiomyopathy depends upon several factors: The severity of left ventricular (LV) systolic dysfunction. The severity of clinical HF ( table 2). The etiology of LV dysfunction (ie, ischemic or nonischemic cardiomyopathy). Competing co-morbidities that affect longevity and risk of ICD complications (eg, chronic kidney disease, chronic obstructive pulmonary disease, etc). The risk of SCD increases with the severity of both LV systolic dysfunction and clinical HF [20]. However, the risk of death due to other causes (eg, progressive HF) also increases with worsening HF and LV systolic dysfunction, reinforcing the importance of appropriate patient selection prior to primary prevention ICD placement. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Epidemiology'.) Cardiac resynchronization therapy (CRT) may be appropriate treatment for selected HF patients with ischemic or non-ischemic cardiomyopathy and reduced left ventricular ejection fraction (LVEF) ( 35 percent) with a wide QRS complex (especially if left bundle branch block QRS morphology), if left ventricular function does not improve with guideline-directed medical therapy. Ventricular dyssynchrony refers to the loss of coordinated contraction across the left ventricle. Dyssynchrony can further impair the pump function of a failing ventricle and exacerbate HF symptoms. CRT can improve pump performance, reverse the deleterious process of ventricular remodeling, and improve survival in appropriately selected patients. CRT can be achieved with a device designed for pacing only (CRT-P) or can be incorporated into a combination device with an ICD (CRT-D) ( figure 2) [21]. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system".) Ischemic cardiomyopathy Our approach for patients with ischemic cardiomyopathy We recommend ICD therapy for primary prevention of SCD in the following groups of patients with ischemic cardiomyopathy: https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 6/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate For patients with cardiomyopathy due to ischemic heart disease, left ventricular ejection fraction (LVEF) 35 percent, and associated HF with New York Heart Association (NYHA) functional class II or III status [2]. For patients with cardiomyopathy due to ischemic heart disease, LVEF 30 percent, and NYHA functional class I status [2]. In both instances, patients should be at least 40 days post-myocardial infarction (MI) and more than three months following revascularization and taking guideline-directed medical therapy. These restrictions recognize that revascularization and medical therapy may result in significant improvement in LVEF and/or HF class. For patients with nonsustained ventricular tachycardia (NSVT) associated with prior MI, LVEF 40 percent, and inducible sustained VT or ventricular fibrillation at electrophysiology study [2,22,23]. Patients should be past the acute phase of MI, on guideline-directed medical therapy, and have reasonable expectation for survival for at least one year. Patients who have had an MI resulting in reduced LVEF are at increased risk of SCD, most often due to a ventricular tachyarrhythmia. Prophylactic ICD implantation for the primary prevention of SCD reduces mortality in selected patients with ischemic cardiomyopathy. Coronary revascularization itself may also reduce the future risk of malignant arrhythmias and SCD, as shown in the early versus late ICD implantation strategies and differing results in various randomized trials. The best approach to selecting patients with ischemic cardiomyopathy for ICD therapy for primary prevention has been explored in several major randomized trials, with the indications for ICD implantation derived largely from the inclusion criteria of these trials. One caveat, however, is that these trials took place prior to the contemporary guideline-based approaches to optimal medical therapy for patients with heart failure and cardiomyopathy. Trials of primary prevention ICDs in ischemic cardiomyopathy MADIT-I trial The Multicenter Automatic Defibrillator Implantation Trial (MADIT, now called MADIT-I) was the first trial to demonstrate that the ICD has a role in primary prevention of SCD in certain high-risk, asymptomatic patients [22]. Patients had a prior MI with reduced LVEF ( 35 percent), NSVT on ECG monitoring, and inducible sustained monomorphic VT during electrophysiology study (EPS) that was also inducible after administration of intravenous procainamide. Among 196 patients who were randomly assigned to pharmacologic therapy (including an antiarrhythmic drug at the discretion of the clinician, with amiodarone administered to most patients) or an ICD and followed for an average of 27 months, patients assigned to ICD therapy had significant reductions in overall mortality, cardiac mortality, and arrhythmic deaths compared with patients assigned to medical therapy ( figure 3). While the https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 7/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate MADIT-I trial remains an important landmark study in the utilization of ICDs for primary prevention, it has largely been supplanted by subsequent studies with larger numbers of patients, better methodologies, and simpler risk stratification schemes for study entry. MUSTT trial The Multicenter Unsustained Tachycardia Trial (MUSTT trial), which was not primarily designed as a randomized ICD clinical trial but rather to study the management of high-risk patients using the results of electrophysiology study (EPS), enrolled patients with prior MI, reduced LVEF ( 40 percent), asymptomatic NSVT on ECG monitoring, inducible sustained VT during EPS, and no history of VT or syncope [23]. A total of 704 patients were randomly assigned to either standard medical therapy (353 patients) or EPS-guided antiarrhythmic therapy, which included either an antiarrhythmic agent (154 patients received a class IA drug with or without mexiletine, propafenone, sotalol, or amiodarone) or an ICD (161 patients) if at least one antiarrhythmic agent was ineffective. After a median follow-up of 39 months, the five-year (25 versus 32 percent, relative risk [RR] 0.73, 95% CI 0.53-0.99) rates for the primary endpoint (arrhythmic death or resuscitated SCD) were significantly lower for EPS-guided therapy compared with standard medical therapy. The reduction in the primary endpoint in the EPS- guided group was largely attributable to ICD therapy; at five years, the primary endpoint occurred in 9 percent of those receiving an ICD, compared with 37 percent of those receiving an antiarrhythmic drug (RR 0.24, 95% CI 0.13-0.45) ( figure 4). Whether inducible arrhythmia might be prognostically important in patients with an LVEF of 30 to 40 percent was addressed in another analysis from MUSTT [24]. The rate of arrhythmic death at five years was significantly increased for patients with inducible VT and LVEF between 30 and 40 percent, suggesting that for patients with LVEF 30 percent only, electrophysiology testing may have useful predictive value. CABG Patch trial The Coronary Artery Bypass Graft (CABG) Patch trial evaluated the efficacy of an epicardial ICD implanted at the time of coronary artery bypass graft surgery among 900 patients with severe coronary artery disease (CAD), reduced LVEF <36 percent, abnormal signal averaged ECG, and no prior sustained VT or syncope [25]. Epicardial ICD systems were predominantly used. Compared with standard medical therapy over an average of 32 months, there was no significant difference in overall or cardiovascular mortality among patients with an ICD (hazard ratio [HR] 1.07 for overall mortality compared with standard medical therapy, 95% CI 0.81-1.42) ( figure 5). This negative trial is a primary reason why current guidelines recommend against primary prevention ICD implantation for patients who have recently undergone coronary revascularization, as revascularization itself may reduce the future risk of malignant arrhythmias and SCD. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 8/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate MADT-II trial The Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) enrolled 1232 patients with a prior MI more than 30 days prior to enrollment (and more than three months if bypass surgery was performed) and reduced LVEF ( 30 percent); NSVT and inducible VT during EPS were not required [26]. The study, which randomly assigned patients to a prophylactic ICD or conventional medical therapy, was stopped early due to benefit of ICD therapy after an average follow-up of 20 months. Patients in the ICD group had reduced all- cause mortality (14.2 versus 19.8 percent for conventional therapy; HR 0.65, 95% CI 0.51-0.93) ( figure 6). SCD-HeFT trial The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), which evaluated ICD and amiodarone therapies in patients with both ischemic (52 percent) or nonischemic (48 percent) cardiomyopathy, enrolled patients with NYHA class II or III heart failure (CHF) for at least three months prior to randomization, reduced LVEF ( 35 percent), and treated with angiotensin converting enzyme (ACE) inhibitor and beta-blocker, if tolerated [27]: NYHA class II or III HF. Reduced. Congestive heart failure (CHF) present for at least three months prior to randomization and treated with ACE inhibitor and beta blocker, if tolerated. Among 2521 patients who were randomly assigned to ICD implantation, amiodarone, or placebo, and followed for a median of 46 months, total mortality at five years was significantly reduced with ICD therapy (29 versus 36 percent with placebo; HR 0.77, 95% CI 0.62-0.96). The benefit of an ICD was comparable among patients with either an ischemic or nonischemic cardiomyopathy. A long-term analysis of SCD-HeFT participants, published in July 2020, showed continued survival benefit in the ICD arm over placebo arm at a median follow-up of 11 years (HR 0.87, 95% CI 0.76-0.98) [28]. Long-term benefit was most evident for patients with ischemic cardiomyopathy and those with NYHA functional class II symptoms at enrollment. These results suggest that an ICD is beneficial in patients with chronic HF and a diminished LVEF ( 35 percent), despite appropriate medical therapy for at least three months. In contrast, amiodarone provided no benefit over placebo. DINAMIT trial The Defibrillator in Acute Myocardial Infarction Trial (DINAMIT), which evaluated the role of prophylactic ICD implantation compared with standard medical therapy, enrolled 674 patients with MI in the preceding 6 to 40 days (mean of 18 days), reduced LVEF ( 35 percent), and reduced heart rate variability or elevated resting heart rate ( 80 beats/minute) [29]. Patients with sustained VT >48 hours post-MI, NYHA class IV HF, or CABG or three-vessel https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef/ 9/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate percutaneous coronary intervention post-MI were excluded. After a mean follow-up of 30 months, there was no significant difference in annual all-cause mortality between the patients with and without an ICD (7.5 versus 6.9 percent annual mortality; HR 1.08, 95% CI 0.76-1.55). This negative trial provides an important rationale for the current guideline recommendation that ICD implantation should be deferred until at least 40 days after an MI. IRIS trial The Immediate Risk Stratification Improves Survival (IRIS) trial also evaluated the efficacy of ICD therapy versus standard therapy early post-MI and enrolled patients with an MI in the preceding 5 to 31 days and at least one of the following: reduced LVEF ( 40 percent) with a resting heart rate 90 beats/minute or NSVT at a rate of 150 beats/minute or both [30]. Among 898 randomized patients who were followed for an average of 37 months, there was no difference in all-cause mortality between patients randomly assigned to ICD therapy and those assigned to medical therapy (HR 1.04 for ICD therapy, 95% CI 0.81-1.35). Nonischemic dilated cardiomyopathy Our approach for patients with nonischemic dilated cardiomyopathy We recommend ICD therapy for primary prevention of SCD in the following groups of patients with nonischemic dilated cardiomyopathy: For patients meeting SCD-HeFT criteria, including an LVEF 35 percent and NYHA class II to III ( table 2) HF, we suggest ICD implantation rather than guideline-directed optimal medical therapy alone [2]. For most patients with LVEF 35 percent, class III or IV HF, and a QRS duration 120 milliseconds (especially if left bundle branch block [LBBB] QRS morphology), we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD). Additionally, many patients with specific non-ischemic cardiomyopathies (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, cardiac amyloidosis, etc) may be candidates for primary prevention ICD based on disease-specific risk markers. The approaches to selection of appropriate patients in a variety of conditions are discussed in the individual UpToDate topics. Ventricular arrhythmias are common in patients with HF and a nonischemic cardiomyopathy. While some small early trials suggested no benefit of ICD therapy in patients with nonischemic cardiomyopathy, subsequent larger trials and a 2004 meta-analysis have demonstrated greater overall survival following prophylactic ICD implantation in selected patients. While ICDs effectively reduce mortality from SCD, the benefit on total mortality appears diminished in the https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 10/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate setting of optimal guideline-directed medical therapy and CRT. (See "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy".) Trials of primary prevention ICDs in nonischemic dilated cardiomyopathy DEFINITE trial The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial evaluated the efficacy of an ICD versus standard medical therapy, in 458 patients with nonischemic dilated cardiomyopathy, reduced LVEF ( 35 percent), and premature ventricular beats or NSVT [31]. After mean follow-up of 29 months, there was a trend toward reduction in the primary endpoint of all-cause mortality in patients treated with an ICD (7.9 versus 14.1 percent with medical therapy alone; HR 0.65, 95% CI 0.40-1.06). Fewer sudden deaths occurred in the ICD arm, although the numbers were very small (3 deaths versus 14 deaths in the medical therapy arm; HR 0.20, 95% CI 0.06-0.71). The all-cause mortality rate in the "medical therapy only" arm of DEFINITE (14.1 percent at two years) was lower than had been anticipated when the study was designed, potentially contributing to the trial being underpowered for its primary endpoint. SCD-HeFT trial The Sudden Cardiac Death in Heart Failure trial (SCD-HeFT), which evaluated ICD and amiodarone therapies in patients with both ischemic (52 percent) or nonischemic (48 percent) cardiomyopathy, identified a significant reduction in overall mortality with ICD therapy (29 versus 36 percent with placebo; HR 0.77, 95% CI 0.62-0.96) [27]. The benefit of an ICD was comparable among patients with either an ischemic or nonischemic cardiomyopathy. (See 'Trials of primary prevention ICDs in ischemic cardiomyopathy' above.) COMPANION trial of ICD combined with CRT For most patients with LVEF 35 percent, class III or IV HF, and a QRS duration 120 milliseconds, we recommend implantation of a combined CRT-D device (biventricular pacing combined with an ICD) [32,33]. The benefit appears to be greatest in patients with a left bundle branch block and QRS duration 150 milliseconds [34-36]. Patients with right bundle branch block and a QRS duration <150 ms are much less likely to benefit from CRT. The Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial evaluated optimal medical therapy versus CRT with or without an ICD among 682 patients with nonischemic dilated cardiomyopathy, reduced LVEF ( 35 percent), and NYHA class III or IV HF symptoms requiring hospitalization within the prior year [33]. After median follow-up of 16 months, there was a significant reduction in the incidence of the combined endpoint of all-cause mortality and all-cause hospitalization in the two arms receiving CRT compared with the medical therapy only arm (56 versus 68 percent). The CRT-D arm, but not the CRT-P arm, experienced a significant improvement in the secondary endpoint of all-cause mortality alone. https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 11/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate DANISH trial The Danish Study to Assess the Efficacy of ICDs in Patients with Non- Ischemic Systolic Heart Failure on Mortality (DANISH) randomly assigned 1116 patients with symptomatic systolic HF (LVEF 35 percent) not caused by ischemic heart disease to an ICD with guideline-directed optimal medical therapy or medical therapy alone [37]. Over a median follow- up of 5.6 years, no significant difference was noted in the primary outcome of total mortality (120 deaths [21.6 percent] in the ICD group compared with 131 deaths [23.4 percent] in the group without an ICD; HR 0.87, 95% CI 0.68-1.12). A significant reduction was noted in the prespecified secondary outcome of SCD in the group receiving ICDs (24 deaths [4.3 percent] compared with 46 sudden deaths [8.2 percent] in the no ICD group; HR 0.50, 95% CI 0.31-0.82), as well as nonsignificant trends toward reduction in total cardiovascular mortality and increased device infections in the ICD group. Compared with prior primary prevention ICD trials, the overall mortality rate of patients in the DANISH trial was low, likely due to improved medical therapy for HF (notably a much higher utilization of ACE-I/ARB and beta blockers than in the older trials) and the use of CRT, which was not available during the older primary prevention trials. Because of this, the DANISH trial may have been underpowered to show a mortality benefit of ICD therapy. Finally, as there are competing causes of death with increasing age, one might not expect the same benefit of ICD therapy in older patients, who may have greater comorbidities which could contribute to nonarrhythmic causes of death. Our experts feel that it would be premature to use data from the DANISH study as the sole basis to withhold potentially life-saving ICD therapy from all patients with nonischemic cardiomyopathy. Instead, the results actually support the use of ICDs in younger patients who have a cardiomyopathy not caused by ischemic heart disease. For those patients who are likely to have a strong response to CRT or who are not considered good candidates for ICD therapy, a CRT-P device may be more suitable and compatible with therapeutic goals. Meta-analyses of ICD trials in nonischemic cardiomyopathy Several updated meta- analyses have been published that include patients with nonischemic cardiomyopathy receiving an ICD for primary prevention from the same original five ICD trials (CAT, AMIOVIRT, DEFINITE, SCD-HeFT, and COMPANION) as well as patients from the DANISH trial [38-46]. When considering all six trials collectively, each of the meta-analyses demonstrated a significant benefit of the ICD on all-cause mortality in patients with nonischemic cardiomyopathy (19 to 24 percent hazard reduction compared with medical therapy alone). When only patients who also received CRT in the COMPANION and DANISH trials were analyzed, there was a nonsignificant trend toward reduction in all-cause mortality among patients with an ICD (approximately 25 to 30 percent hazard reduction with nonsignificant confidence intervals) [38,40,43]. Despite the lack of a significant incremental benefit of the ICD in the two trials that included CRT, it is currently https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 12/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate premature to withhold ICD therapy in all patients with nonischemic cardiomyopathy who require concomitant CRT. Adequately powered randomized studies are needed before recommending a change in current practice guidelines. GUIDELINE-DIRECTED MEDICAL THERAPY For patients who meet criteria for insertion of an implantable cardioverter-defibrillator (ICD) for the primary prevention of SCD, in the absence of a contraindication, we recommend optimizing guideline-directed medical therapy prior to ICD implantation. Heart failure therapy Several of the components of appropriate medical therapy after a myocardial infarction (MI) reduce SCD as well as overall mortality. While these data are derived from trials in patients with ischemic heart disease, we can infer that many of the same benefits should apply to SCD risk reduction in patients with nonischemic cardiomyopathy. (See "Overview of the acute management of ST-elevation myocardial infarction" and "Overview of the acute management of non-ST-elevation acute coronary syndromes" and "Overview of the management of heart failure with reduced ejection fraction in adults".) Beta blockers In addition to reducing overall mortality in patients with an acute MI, beta blockers also reduced the risk of SCD [47,48]. The SCD benefit is better established in patients with chronic HF. (See "Acute myocardial infarction: Role of beta blocker therapy" and "Ventricular arrhythmias: Overview in patients with heart failure and cardiomyopathy", section on 'Heart failure therapy'.) Post-MI patients with an ICD also appear to derive a benefit from beta blockers. In a cohort of 691 patients with ischemic cardiomyopathy who received an ICD in the MADIT-II trial, the 433 patients treated with a beta blocker had significantly lower mortality (hazard ratio [HR] 0.43) compared with those not taking beta blockers; additionally, patients in the highest quartile of beta blocker dose had a significant reduction in the risk of ventricular tachyarrhythmias requiring ICD discharge (HR 0.48) [49]. ACE inhibitors A meta-analysis of 15,104 patients in 15 trials of acute MI found that angiotensin-converting enzyme (ACE) inhibitor therapy reduced the risk of SCD (odds ratio 0.80, 95% CI 0.70-0.92, absolute benefit approximately 1.4 percent) as well as overall and cardiovascular mortality [50]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials".) Angiotensin II receptor blockers Angiotensin II receptor blockers (ARBs) are often used for patients who cannot tolerate ACE inhibitors. At appropriate doses, it is likely that ARBs https://www.uptodate.com/contents/primary-prevention-of-sudden-cardiac-death-in-patients-with-cardiomyopathy-and-heart-failure-with-reduced-lvef 13/43 7/6/23, 3:35 PM Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF - UpToDate reduce the risk of SCD to the same degree as ACE inhibitors [51]. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Recommendations for use".) Angiotensin receptor-neprilysin inhibitor The combination of an ARB and neprilysin inhibitor, known as angiotensin receptor-neprilysin inhibitor or ARNI, is another therapy for use in patients with HF and reduced LVEF (HFrEF). A randomized double-blind trial (PARADIGM-HF) in patients with HFrEF found that sacubitril-valsartan reduced cardiovascular mortality and hospitalization for HF as well as all-cause mortality compared with a standard dose of the ACE inhibitor enalapril [52]. The ARNI combination is administered in conjunction with other HF therapies, in place of an ACE inhibitor or ARB.