**5. Management**

#### **5.1. Pharmacotherapy and sudden cardiac death prevention**

The role of pharmacotherapy in the prevention of SCD is two-fold. First, many neuro-humoral modifiers for the treatment of heart failure result in reverse remodeling of the left ventricle and may therefore reduce the overall mortality, and the risk of SCD. Examples include ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists and beta-blockers. Second, antiarrhythmic medications have been used in patients with cardiomyopathy to reduce the risk of SCD. Examples would be beta-blockers including sotalol, amiodarone and other antiarrhythmic medications.

*Amiodarone* has been evaluated in large randomized trials in post-MI patients. The Canadian amiodarone myocardial infarction arrhythmia trial (CAMIAT) conducted in 1202 post-MI patients with a mean LVEF of 30% and greater than 10 PVC's per hour demonstrated a small but significant reduction in arrhythmic death (4.5% versus 6.9%, P = 0.016) but no reduction in all-cause mortality in patients on amiodarone. [56] The European Myocardial Infarct Amiodarone Trial (EMIAT) of 1486 similar patients did not show any difference in arrhythmic or all-cause mortality between the two groups of patients. [59] A meta-analysis of 15 random‐ ized controlled trials in a total of 8522 patients that evaluated amiodarone for prevention of SCD showed a small but significant reduction in SCD (7.1% vs 9.7%; OR 0.71, p<0.001) but no important change in overall mortality. [132] In the general population of heart failure patients the SCD-HeFT trial did not show any reduction in all-cause mortality with amiodarone treatment in comparison with placebo. [48]

*Sotalol* a beta-blocker that is also a class III antiarrhythmic drug (i.e., prolongs QT interval) has been studied for prevention of SCD in patients with post-MI LV systolic dysfunction with mixed results. A study by Julian et al evaluated the role of racemic d,l-sotlol in 1456 patients 5-14 days after MI. Racemic sotalol exhibits both beta blocking properties (the l-isomer) and class III antiarrhythmic effects (the d-isomer), and this combination showed a nonsignificant reduction in mortality over one-year follow up. [133] By contrast, oral d-sotalol, in the SWORD, trial showed increased mortality in 3121 patients with recent (6-42 days) MI or with remote (>42 days) MI with symptomatic CHF with LVEF ≤40%. [134] This lack of benefit or actual harm seen in SWORD trial may be due to lack of beta-blocking property of d-sotalol, which probably led to some benefit seen in the study by Julian et al using racemic sotalol. [135] As a result of the SWORD trial, d-sotalol was abandoned. On the other hand a multicenter placebo controlled trial in patients with ICD showed a reduction in mortality and ICD shocks in patients receiving d,l-sotalol. Moreover, the mortality benefit in this study did not differ between patients with LVEF <30% and >30%. [136]

Assessment of SCD risk in *cardiac amyloidosis* is not well defined. Little data is available on risk stratification, and the usual approach in these patients is secondary prophylaxis or extrapolation of risk factors from other types of cardiomyopathies, e.g., LV systolic dysfunc‐ tion. The degree of myocardial involvement in sarcoidosis may be important in clinical decision-making. Patients with *hereditary dystrophies* behave largely like dilated cardiomyop‐ athy and risk stratification in these patients again conforms to the risk stratification of dilated

The role of pharmacotherapy in the prevention of SCD is two-fold. First, many neuro-humoral modifiers for the treatment of heart failure result in reverse remodeling of the left ventricle and may therefore reduce the overall mortality, and the risk of SCD. Examples include ACE inhibitors, angiotensin receptor blockers, aldosterone antagonists and beta-blockers. Second, antiarrhythmic medications have been used in patients with cardiomyopathy to reduce the risk of SCD. Examples would be beta-blockers including sotalol, amiodarone and other

*Amiodarone* has been evaluated in large randomized trials in post-MI patients. The Canadian amiodarone myocardial infarction arrhythmia trial (CAMIAT) conducted in 1202 post-MI patients with a mean LVEF of 30% and greater than 10 PVC's per hour demonstrated a small but significant reduction in arrhythmic death (4.5% versus 6.9%, P = 0.016) but no reduction in all-cause mortality in patients on amiodarone. [56] The European Myocardial Infarct Amiodarone Trial (EMIAT) of 1486 similar patients did not show any difference in arrhythmic or all-cause mortality between the two groups of patients. [59] A meta-analysis of 15 random‐ ized controlled trials in a total of 8522 patients that evaluated amiodarone for prevention of SCD showed a small but significant reduction in SCD (7.1% vs 9.7%; OR 0.71, p<0.001) but no important change in overall mortality. [132] In the general population of heart failure patients the SCD-HeFT trial did not show any reduction in all-cause mortality with amiodarone

*Sotalol* a beta-blocker that is also a class III antiarrhythmic drug (i.e., prolongs QT interval) has been studied for prevention of SCD in patients with post-MI LV systolic dysfunction with mixed results. A study by Julian et al evaluated the role of racemic d,l-sotlol in 1456 patients 5-14 days after MI. Racemic sotalol exhibits both beta blocking properties (the l-isomer) and class III antiarrhythmic effects (the d-isomer), and this combination showed a nonsignificant reduction in mortality over one-year follow up. [133] By contrast, oral d-sotalol, in the SWORD, trial showed increased mortality in 3121 patients with recent (6-42 days) MI or with remote (>42 days) MI with symptomatic CHF with LVEF ≤40%. [134] This lack of benefit or actual harm seen in SWORD trial may be due to lack of beta-blocking property of d-sotalol, which probably led to some benefit seen in the study by Julian et al using racemic sotalol. [135] As a result of the SWORD trial, d-sotalol was abandoned. On the other hand a multicenter placebo

cardiomyopathy.

184 Cardiomyopathies

**5. Management**

antiarrhythmic medications.

treatment in comparison with placebo. [48]

**5.1. Pharmacotherapy and sudden cardiac death prevention**

*Beta-blockers* has a proven role in reducing cardiovascular mortality and SCD in patients with heart failure either from non-ischemic cardiomyopathy or ischemic heart disease. [114], [137]- [139] Similarly, ACE inhibitors, ARBs and aldosterone antagonist are used in heart failure patients to reduce all-cause mortality, however, neither ACE inhibitors nor ARB actually reduce SCD in patients with LV systolic dysfunction. [140]-[142] ELITE did show an unex‐ pected reduction of SCD with losartan but this was a non-prespecified endpoint and was never confirmed prospectively. [143]

Class I antiarrhythmic drugs have not been found to reduce SCD in patients with history of MI and LV systolic dysfunction, and in fact most often result in an increase in mortality. The Cardiac Arrhythmia Suppression Trial (CAST) and CAST-II trials, for example, showed increased mortality with the use of class Ic antiarrhythmic drugs in post MI patients. [144] Similarly, propafenone showed increased mortality compared to ICD in Cardiac Arrest Study Hamburg (CASH). [145]

As the data of ICD trials showed reduction in all-cause mortality and SCD in patients with cardiomyopathy as compared to amiodarone, the role of antiarrhythmic drugs in prevention of SCD has become adjunctive, with the goal of reducing ICD shocks. Beta-blockers and other humoral modifiers are generally used in the management of heart failure and improve survival in heart failure patients.

The role of amiodarone for prevention of SCD in HCM is controversial. In a study by McKenna et al, [146] amiodarone found to be effective but it is noteworthy that this study was used historical controls receiving either mexiletine, disopyramide or quinidine. In other studies antiarrhythmic drugs for the prevention of SCD in HCM have not been found to be effective. [147] Similarly, beta-blockers, sotalol and amiodarone have been used to suppress ventricular arrhythmias in ARVC. Efficacy has been variable [148], [149] and, with the increasing practice of use of ICD in the prevention of SCD in these patients, antiarrhythmic drugs are again used to reduce the need for ICD intervention.

#### **5.2. Device therapy: Implantable cardioverter-defibrillator**

Implantable cardioverter-defibrillator therapy has emerged as the most important manage‐ ment strategy for prevention of SCD in patients with cardiomyopathy at high risk of sudden cardiac death. The high incidence and high individual risk of SCD in cardiomyopathy patients with impaired left ventricular function, especially in those who had survived a ventricular arrhythmia, and the relative ineffectiveness of antiarrhythmic drugs in these patients led to a series of trials aimed at assessing the role of ICD therapy. This strategy was first tested in trials of patients with highest degree of risk. These were sudden death and ventricular arrhythmia survivors, and the studies are collectively referred to as secondary prevention trials. These trials were followed by trials of increasingly lower risk patients, principally those with heart failure, in primary prevention trials. The major message of these trials is that cost effectiveness is highest in highest risk patients, but that in this group, numerically the number of lives saved by defibrillators is relatively small. Use of defibrillators in lower risk cohorts decreases cost effectiveness, but increases the chance of making a numerical impact of the incidence of SCD in the contemporary US population.

Later subgroup analysis of these studies showed that the benefit of ICD therapy was largely restricted to patients with lower LVEF. A subgroup analysis of 396 patients in the AVID trial with LVEF >35% failed to show any survival benefit. In addition a smaller group of 140 patients in this study with LVEF <20% did not show statistically significantly survival benefit. This was in contrast to the 473 patients with LVEF between 20% and 34% who had signifi‐ cantly improved survival. [152] Similarly, in CIDS trial the benefit of ICD therapy was restricted to the patients with higher risk features (age >70 years, LVEF <35% and NYHA

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Primary prevention ICD trials in patients with heart failure due to ischemic and nonischemic cardiomyopathies have provided insights into prevention of SCD in a larger group of patients who are at a high risk of SCD based on epidemiological studies, but are at lower risk than patients who have suffered a ventricular arrhythmia. These studies have played instrumental role in formulation of guidelines for primary prevention of SCDs in patients with cardiomyo‐ pathies. The trials include MADIT (I and II), CABG Patch, MUSTT, DINAMIT, DEFINITE and

*Multicenter Automatic Defibrillator Implantation Trial (MADIT-I)* was the first trial evaluating the efficacy of ICD on survival in patients with history ischemic heart disease. Patients with an LVEF≤35%, non-sustained VT who also sustained VT induced at a ventricular stimulation study and not suppressed by procainamide were randomized to receive best medical therapy or an ICD. 196 of these very high-risk patients were enrolled and mean LVEF was 26%. All cause mortality was reduced from 32% to 13% in the ICD group after 2 years, for a relative risk

The *Multicenter Unsustained Tachycardia Trial (MUSTT)* trial recruited a lower risk IHD cohort, with NSVT and a LVEF ≤40%. All patients underwent a ventricular stimulation study, and those with inducible sustained ventricular tachycardia were randomized to receive either no specific antiarrhythmic therapy or antiarrhythmic therapy (either an antiarrhythmic drug or an ICD) guided by further ventricular stimulation studies. Patients not inducible into sustained VT were followed in a registry. Among 704 enrolled patients, the median LVEF was 30%. In comparison to controls, patient treated with antiarrhythmic drugs had an increase in overall mortality (from 48% to 55%) whereas patients receiving ICDs all cause mortality improved from 48% in controls to 24% in patients receiving ICD with absolute and relative risk reduction of 24% and 50% in a 5 year analysis (figure 6). [51] Interestingly the cohort of patients not inducible into VT who received no specific antiarrhythmic therapy had a significantly lower mortality than patients who were inducible into sustained VT, but the absolute improvement in mortality predicted by a negative EP study was small (absolute risk reduction and relative risk reduction of 7%,and 25% at 2 years and 4% and 8.3% at 5 years). [154] This study was the first to point out the limited value of ventricular stimulation studies in assessing SCD risk. These studies have now largely been abandoned, and future ICD trials have concentrated on

class III or IV). [153]

SCD-HeFT.

reduction of 59% [50]

wider, lower risk, patient cohorts.

**5.4. Primary prevention ICD trials**

#### **5.3. Secondary prevention ICD trials**

Antiarrhythmics versus implantable defibrillators (AVID), Canadian implantable defibrillator study (CIDS) and Cardiac arrest study Hamburg (CASH) trials gave an insight into the benefits of use of ICDs in secondary prevention of SCD after an arrhythmic event. In these studies patients with history of aborted SCD or patients with ventricular arrhythmia in the setting of reduced LV systolic function were enrolled.

The *AVID trial*, which enrolled 1016 patients with history of VF, VT with syncope or VT with LVEF ≤40% and symptoms of hemodynamic compromise (near syncope, congestive heart failure and angina). This study showed reduction in all-cause mortality from 25% to 18% (absolute risk reduction of 7% and relative risk reduction of 27%). The patients had a mean LVEF of 32% in this study. In each arm, 45% of the patients had history of VF and the rest of the patients had history of VT as the inclusion criteria for the study. *CIDS* enrolled 659 patients with VF, out of hospital cardiac arrest due to VF or VT, VT with syncope, VT with symptoms of presyncope or angina and LVEF ≤35%, and unmonitored syncope with subsequent spon‐ taneous or induced VT. The mean LVEF in these patients was 34%. After follow-up of 3 years there was a nonsignificant reduction in all-cause mortality (10.2% per year to 8.3% per year, p=0.142), and of arrhythmic death (4.5% per year to 3.0% per year, p=0.094) in ICD patients. At 2 years there was a reduction in all-cause mortality from 21% to 15% (absolute and relative risk reduction of 30% and 6% respectively).

The *CASH study* was a much smaller study with enrollment of 191 patients with a history of VF or VT without an identified transient reversible cause. In contrast to AVID and CIDS the mean LVEF was 46% making them healthier group of patients. Over a mean follow-up of 57 months the reduction in mortality was from 44% in control to 36% in those receiving ICD (absolute and relative risk reduction of 23% and 8% respectively). Overall survival was higher in the ICD arm, though not statistically significant (hazard ratio 0.766, 97.5% CI upper bound 1.112; p=0.081). There was higher survival free of sudden death in the ICD arm (hazard ratio 0.423, 97.5% upper bound 0.721; p=0.005).

Thus the trials were consistent in their message although CASH and CIDS trials were relatively underpowered to assess the reduction in all-cause mortality. A meta-analysis showed a 28% relative reduction in all cause mortality and a 50% reduction in SCD in patients receiving ICDs. [150] Patients with LVEF < 35% derived the most benefit with hazard ratio for this group of 0.66 (95% CI 0.53-0.83). [150] and overall the number needed to treat to save a life per year of follow-up was 29. [151] When the individual trials are compared it is noteworthy that LVEF was much higher in CASH, and that CIDS included a group of patients with unexplained syncope and VT inducible at EP study. These factors are markers of a lower risk population and reduced that trials' ability to detect the benefit of ICDs in reducing all cause mortality.

Later subgroup analysis of these studies showed that the benefit of ICD therapy was largely restricted to patients with lower LVEF. A subgroup analysis of 396 patients in the AVID trial with LVEF >35% failed to show any survival benefit. In addition a smaller group of 140 patients in this study with LVEF <20% did not show statistically significantly survival benefit. This was in contrast to the 473 patients with LVEF between 20% and 34% who had signifi‐ cantly improved survival. [152] Similarly, in CIDS trial the benefit of ICD therapy was restricted to the patients with higher risk features (age >70 years, LVEF <35% and NYHA class III or IV). [153]

#### **5.4. Primary prevention ICD trials**

is highest in highest risk patients, but that in this group, numerically the number of lives saved by defibrillators is relatively small. Use of defibrillators in lower risk cohorts decreases cost effectiveness, but increases the chance of making a numerical impact of the incidence of SCD

Antiarrhythmics versus implantable defibrillators (AVID), Canadian implantable defibrillator study (CIDS) and Cardiac arrest study Hamburg (CASH) trials gave an insight into the benefits of use of ICDs in secondary prevention of SCD after an arrhythmic event. In these studies patients with history of aborted SCD or patients with ventricular arrhythmia in the setting of

The *AVID trial*, which enrolled 1016 patients with history of VF, VT with syncope or VT with LVEF ≤40% and symptoms of hemodynamic compromise (near syncope, congestive heart failure and angina). This study showed reduction in all-cause mortality from 25% to 18% (absolute risk reduction of 7% and relative risk reduction of 27%). The patients had a mean LVEF of 32% in this study. In each arm, 45% of the patients had history of VF and the rest of the patients had history of VT as the inclusion criteria for the study. *CIDS* enrolled 659 patients with VF, out of hospital cardiac arrest due to VF or VT, VT with syncope, VT with symptoms of presyncope or angina and LVEF ≤35%, and unmonitored syncope with subsequent spon‐ taneous or induced VT. The mean LVEF in these patients was 34%. After follow-up of 3 years there was a nonsignificant reduction in all-cause mortality (10.2% per year to 8.3% per year, p=0.142), and of arrhythmic death (4.5% per year to 3.0% per year, p=0.094) in ICD patients. At 2 years there was a reduction in all-cause mortality from 21% to 15% (absolute and relative

The *CASH study* was a much smaller study with enrollment of 191 patients with a history of VF or VT without an identified transient reversible cause. In contrast to AVID and CIDS the mean LVEF was 46% making them healthier group of patients. Over a mean follow-up of 57 months the reduction in mortality was from 44% in control to 36% in those receiving ICD (absolute and relative risk reduction of 23% and 8% respectively). Overall survival was higher in the ICD arm, though not statistically significant (hazard ratio 0.766, 97.5% CI upper bound 1.112; p=0.081). There was higher survival free of sudden death in the ICD arm (hazard ratio

Thus the trials were consistent in their message although CASH and CIDS trials were relatively underpowered to assess the reduction in all-cause mortality. A meta-analysis showed a 28% relative reduction in all cause mortality and a 50% reduction in SCD in patients receiving ICDs. [150] Patients with LVEF < 35% derived the most benefit with hazard ratio for this group of 0.66 (95% CI 0.53-0.83). [150] and overall the number needed to treat to save a life per year of follow-up was 29. [151] When the individual trials are compared it is noteworthy that LVEF was much higher in CASH, and that CIDS included a group of patients with unexplained syncope and VT inducible at EP study. These factors are markers of a lower risk population and reduced that trials' ability to detect the benefit of ICDs in reducing all cause mortality.

in the contemporary US population.

186 Cardiomyopathies

**5.3. Secondary prevention ICD trials**

reduced LV systolic function were enrolled.

risk reduction of 30% and 6% respectively).

0.423, 97.5% upper bound 0.721; p=0.005).

Primary prevention ICD trials in patients with heart failure due to ischemic and nonischemic cardiomyopathies have provided insights into prevention of SCD in a larger group of patients who are at a high risk of SCD based on epidemiological studies, but are at lower risk than patients who have suffered a ventricular arrhythmia. These studies have played instrumental role in formulation of guidelines for primary prevention of SCDs in patients with cardiomyo‐ pathies. The trials include MADIT (I and II), CABG Patch, MUSTT, DINAMIT, DEFINITE and SCD-HeFT.

*Multicenter Automatic Defibrillator Implantation Trial (MADIT-I)* was the first trial evaluating the efficacy of ICD on survival in patients with history ischemic heart disease. Patients with an LVEF≤35%, non-sustained VT who also sustained VT induced at a ventricular stimulation study and not suppressed by procainamide were randomized to receive best medical therapy or an ICD. 196 of these very high-risk patients were enrolled and mean LVEF was 26%. All cause mortality was reduced from 32% to 13% in the ICD group after 2 years, for a relative risk reduction of 59% [50]

The *Multicenter Unsustained Tachycardia Trial (MUSTT)* trial recruited a lower risk IHD cohort, with NSVT and a LVEF ≤40%. All patients underwent a ventricular stimulation study, and those with inducible sustained ventricular tachycardia were randomized to receive either no specific antiarrhythmic therapy or antiarrhythmic therapy (either an antiarrhythmic drug or an ICD) guided by further ventricular stimulation studies. Patients not inducible into sustained VT were followed in a registry. Among 704 enrolled patients, the median LVEF was 30%. In comparison to controls, patient treated with antiarrhythmic drugs had an increase in overall mortality (from 48% to 55%) whereas patients receiving ICDs all cause mortality improved from 48% in controls to 24% in patients receiving ICD with absolute and relative risk reduction of 24% and 50% in a 5 year analysis (figure 6). [51] Interestingly the cohort of patients not inducible into VT who received no specific antiarrhythmic therapy had a significantly lower mortality than patients who were inducible into sustained VT, but the absolute improvement in mortality predicted by a negative EP study was small (absolute risk reduction and relative risk reduction of 7%,and 25% at 2 years and 4% and 8.3% at 5 years). [154] This study was the first to point out the limited value of ventricular stimulation studies in assessing SCD risk. These studies have now largely been abandoned, and future ICD trials have concentrated on wider, lower risk, patient cohorts.

**Figure 6.** MUSTT: Kaplan–Meier Estimates of the Rates of Overall Mortality According to Whether the Patients Re‐ ceived Treatment with a Defibrillator. The P value refers to two comparisons: between the patients in the group as‐ signed to electrophysiologically guided (EPG) therapy who received treatment with a defibrillator and those who did not receive such treatment, and between the patients assigned to electrophysiologically guided therapy who received treatment with a defibrillator and those assigned to no antiarrhythmic therapy. (From reference 51)

ble mechanism because RV pacing in heart failure patients is known to exacerbate heart

**Figure 7.** MADIT II: Kaplan–Meier Estimates of the Probability of Survival in the Group Assigned to Receive an Implant‐ able Defibrillator and the Group Assigned to Receive Conventional Medical Therapy. The difference in survival be‐

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tween the two groups was significant (nominal P=0.007, by the log-rank test). (From reference 47)

*Defibrillators in non-ishchemic cardiomyopathy: The DEFINITE* trial investigated the benefit of prophylactic ICD therapy in 458 enrolled patients with non-ischemic cardiomyopathy with LVEF <36% and premature ventricular complexes or NSVT. The patients were mainly symptomatic for heart failure with NYHA functional class of I-III and mean LVEF of the study population was 21%. At two years, the mortality in ICD group was 8% compared to 14% in the standard therapy group (absolute and relative risk reduction of 6% and 44% respectively). However this reduction in overall mortality was not statistically significant with hazard ratio of 0.65 among patients receiving ICD (95% CI 0.40-1.06). This difference reached statistical significance in patients with NYHA class III in subgroup analysis and showed a relative risk of death of 0.37 (95%confidence interval 0.15-0.90). Moreover, the difference in survival was

significantly more in males receiving ICD (HR 0.49, 95%CI 0.27-0.90; p=0.018). [113].

*Sudden cardiac death in heart failure (SCD-HeFT)* trial was conducted in patients with heart failure due to ischemic or nonischemic cardiomyopathy with LVEF≤35% and with NYHA functional class II-III. More than 2500 optimally medically managed patients were equally divided into

failure mortality. [156]-[158]

The *MADIT II* trial assessed the effect of an ICD in 1232 patients with prior myocardial infarction (>one month) and LVEF ≤30%. In this study, mainly of long term infarct survivors, mean LVEF was 23% and in the ICD group all-cause mortality was reduced at 16% compared to 22% in the controls after 2-year follow up (absolute and relative risk reduction of 6% and 28% respectively, figure 7). [47] In this cohort of IHD patients without inducible VT the benefit of an ICD was smaller, but the potential population of identified patients who could benefit from ICD therapy is much wider.

*Defibrillator use early after acute myocardial infarction trial: The DINAMIT trial* evaluated the role of ICD in potentially improving the survival of patients during acute phase of MI (6 to 40 days after MI) with reduced LVEF ≤35% and impaired cardiac autonomic function, as‐ sessed as impaired baroreflex sensitivity. During a mean follow-up of 2<sup>1</sup> /2 years, there was no reduction in overall mortality in these patients. Although there was a reduction in death due to arrhythmia, the benefit was offset by death from non-arrhythmic causes. [155] These data are challenging because the implication is that ICD implantation enhanced the risk for non-arrhythmic death, principally death from heart failure. If the amount of right ventricu‐ lar pacing in the ICD group accounted for more than 5-10% of heart beats this is a plausi‐

**Figure 7.** MADIT II: Kaplan–Meier Estimates of the Probability of Survival in the Group Assigned to Receive an Implant‐ able Defibrillator and the Group Assigned to Receive Conventional Medical Therapy. The difference in survival be‐ tween the two groups was significant (nominal P=0.007, by the log-rank test). (From reference 47)

ble mechanism because RV pacing in heart failure patients is known to exacerbate heart failure mortality. [156]-[158]

The *MADIT II* trial assessed the effect of an ICD in 1232 patients with prior myocardial infarction (>one month) and LVEF ≤30%. In this study, mainly of long term infarct survivors, mean LVEF was 23% and in the ICD group all-cause mortality was reduced at 16% compared to 22% in the controls after 2-year follow up (absolute and relative risk reduction of 6% and 28% respectively, figure 7). [47] In this cohort of IHD patients without inducible VT the benefit of an ICD was smaller, but the potential population of identified patients who could benefit

treatment with a defibrillator and those assigned to no antiarrhythmic therapy. (From reference 51)

**Figure 6.** MUSTT: Kaplan–Meier Estimates of the Rates of Overall Mortality According to Whether the Patients Re‐ ceived Treatment with a Defibrillator. The P value refers to two comparisons: between the patients in the group as‐ signed to electrophysiologically guided (EPG) therapy who received treatment with a defibrillator and those who did not receive such treatment, and between the patients assigned to electrophysiologically guided therapy who received

*Defibrillator use early after acute myocardial infarction trial: The DINAMIT trial* evaluated the role of ICD in potentially improving the survival of patients during acute phase of MI (6 to 40 days after MI) with reduced LVEF ≤35% and impaired cardiac autonomic function, as‐

no reduction in overall mortality in these patients. Although there was a reduction in death due to arrhythmia, the benefit was offset by death from non-arrhythmic causes. [155] These data are challenging because the implication is that ICD implantation enhanced the risk for non-arrhythmic death, principally death from heart failure. If the amount of right ventricu‐ lar pacing in the ICD group accounted for more than 5-10% of heart beats this is a plausi‐

/2 years, there was

sessed as impaired baroreflex sensitivity. During a mean follow-up of 2<sup>1</sup>

from ICD therapy is much wider.

188 Cardiomyopathies

*Defibrillators in non-ishchemic cardiomyopathy: The DEFINITE* trial investigated the benefit of prophylactic ICD therapy in 458 enrolled patients with non-ischemic cardiomyopathy with LVEF <36% and premature ventricular complexes or NSVT. The patients were mainly symptomatic for heart failure with NYHA functional class of I-III and mean LVEF of the study population was 21%. At two years, the mortality in ICD group was 8% compared to 14% in the standard therapy group (absolute and relative risk reduction of 6% and 44% respectively). However this reduction in overall mortality was not statistically significant with hazard ratio of 0.65 among patients receiving ICD (95% CI 0.40-1.06). This difference reached statistical significance in patients with NYHA class III in subgroup analysis and showed a relative risk of death of 0.37 (95%confidence interval 0.15-0.90). Moreover, the difference in survival was significantly more in males receiving ICD (HR 0.49, 95%CI 0.27-0.90; p=0.018). [113].

*Sudden cardiac death in heart failure (SCD-HeFT)* trial was conducted in patients with heart failure due to ischemic or nonischemic cardiomyopathy with LVEF≤35% and with NYHA functional class II-III. More than 2500 optimally medically managed patients were equally divided into three groups: ICD, amiodarone and placebo. Mean LVEF was 25%; 52% of the patients had ischemic cardiomyopathy and the remainder were non ischemic. All cause mortality at 5 years in patients receiving ICD was 29% compared to 36% for the control with absolute and relative risk reduction of 7% and 23%. Amiodarone arm did not show any significant reduction in risk of death (HR: 1.06; 97.5% CI 0.86-1.30; p=0.53)(see figure 8). In subgroup analysis by type of cardiomyopathy, reduction in the mortality risk were similar in both ischemic (HR: 0.79, 97.5% CI 0.60-1.04) and nonischemic cardiomyopathy (HR: 0.73, 97.5% CI 0.50-1.07) patients with ICD therapy compared to placebo, although the risk reduction did not reach a statistical significance. NYHA class did affect the effect of amiodarone as well as ICD therapy compared to placebo. Amiodarone was shown to increase the risk of mortality in NYHA class III by 44% (HR: 1.44, 97.5 CI 1.05-1.97), which was not seen in patients with NYHA class II (HR: 0.85, 97.5% CI 0.65-1-11). Similarly, with ICD therapy, patients with NYHA class III did not get mortaliy benefit (HR: 1.16, 97.5% CI 0.84-1.61) as opposed to patients with NYHA class II (HR: 0.54; 97.5% CI 0.40-0.74) [48]

large ICD trials is considerably younger than the people frequently needing ICD implantation in the current clinical practice. This issue has been addressed by two meta-analysis suggesting benefit of ICD therapy in older patients. [160], [161] Another meta-analysis of primary prevention ICD trials showed smaller benefit of ICD in women with dilated cardiomyopathy compared to men. Although overall mortality in both the genders were similar (HR 0.96, 95% CI 0.67-1.39), women received approprite therapy less frequently compared to men (HR 0.63, 95%CI 0.49-0.82) and hence received less benefit from defibrillator therapy. [162] This as well as another meta-analysis of primary prevention ICD trials failed to show significant mortality

**Figure 9.** Major implantable cardioverter-defibrillator (ICD) trials. Hazard ratios (vertical line) and 95% confidence in‐ tervals (horizontal lines) for death from any cause in the ICD group compared with the non-ICD group. \*Includes only ICD and amiodarone patients from CASH. For expansion of trial names, see Appendix 3. CABG: coronary artery bypass graft surgery; EP: electrophysiological study; LVD: left ventricular dysfunction; LVEF: left ventricular ejection fraction; MI: myocardial infarction; N: number of patients; NICM: nonischemic cardiomyopathy; NSVT: nonsustained ventricular tachycardia; PVCs: premature ventricular complexes; SAECG: signal-averaged electrocardiogram. (Adapted with per‐

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These ICD trials have established the role of ICDs in the primary and secondary prevention of SCD in patients with non-ischemic and ischemic cardiomyopathy (figure 9). Left ventricular ejection fraction has been recognized as the strongest risk stratifier and has been extensively used in all the trials. Based on these studies guidelines have been formulated for the appro‐ priate indications of ICD therapy in these patients. The table 3 summarizes the guidelines for

benefit of ICD in women. [162]

mission from reference 165)

implantation of ICD for prevention of SCD in these patients.

**Figure 8.** SCD-HeFT: Kaplan–Meier Estimates of Death from Any Cause. (From reference 48)

A meta-analysis of the primary prevention trials in patients with low ejection fraction due to coronary artery disease or dilated cardiomyopathy including eight trials and total of 5343 patients showed reduction of arrhythmic mortality (relative risk: 0.40; 95% CI: 0.27-0.67) and all-cause mortality (relative risk: 0.73; 95% CI: 0.64-0.82). The benefit of ICD therapy was similar in ischemic (relative risk: 0.67; 95% CI: 0.51-0.88) and non-ischemic (RR: 0.74; 95% CI: 0.59-0.93) cardiomyopathies. [159] Another important issue is that the age of the people enrolled in the

three groups: ICD, amiodarone and placebo. Mean LVEF was 25%; 52% of the patients had ischemic cardiomyopathy and the remainder were non ischemic. All cause mortality at 5 years in patients receiving ICD was 29% compared to 36% for the control with absolute and relative risk reduction of 7% and 23%. Amiodarone arm did not show any significant reduction in risk of death (HR: 1.06; 97.5% CI 0.86-1.30; p=0.53)(see figure 8). In subgroup analysis by type of cardiomyopathy, reduction in the mortality risk were similar in both ischemic (HR: 0.79, 97.5% CI 0.60-1.04) and nonischemic cardiomyopathy (HR: 0.73, 97.5% CI 0.50-1.07) patients with ICD therapy compared to placebo, although the risk reduction did not reach a statistical significance. NYHA class did affect the effect of amiodarone as well as ICD therapy compared to placebo. Amiodarone was shown to increase the risk of mortality in NYHA class III by 44% (HR: 1.44, 97.5 CI 1.05-1.97), which was not seen in patients with NYHA class II (HR: 0.85, 97.5% CI 0.65-1-11). Similarly, with ICD therapy, patients with NYHA class III did not get mortaliy benefit (HR: 1.16, 97.5% CI 0.84-1.61) as opposed to patients with NYHA class II (HR:

**Figure 8.** SCD-HeFT: Kaplan–Meier Estimates of Death from Any Cause. (From reference 48)

A meta-analysis of the primary prevention trials in patients with low ejection fraction due to coronary artery disease or dilated cardiomyopathy including eight trials and total of 5343 patients showed reduction of arrhythmic mortality (relative risk: 0.40; 95% CI: 0.27-0.67) and all-cause mortality (relative risk: 0.73; 95% CI: 0.64-0.82). The benefit of ICD therapy was similar in ischemic (relative risk: 0.67; 95% CI: 0.51-0.88) and non-ischemic (RR: 0.74; 95% CI: 0.59-0.93) cardiomyopathies. [159] Another important issue is that the age of the people enrolled in the

0.54; 97.5% CI 0.40-0.74) [48]

190 Cardiomyopathies

**Figure 9.** Major implantable cardioverter-defibrillator (ICD) trials. Hazard ratios (vertical line) and 95% confidence in‐ tervals (horizontal lines) for death from any cause in the ICD group compared with the non-ICD group. \*Includes only ICD and amiodarone patients from CASH. For expansion of trial names, see Appendix 3. CABG: coronary artery bypass graft surgery; EP: electrophysiological study; LVD: left ventricular dysfunction; LVEF: left ventricular ejection fraction; MI: myocardial infarction; N: number of patients; NICM: nonischemic cardiomyopathy; NSVT: nonsustained ventricular tachycardia; PVCs: premature ventricular complexes; SAECG: signal-averaged electrocardiogram. (Adapted with per‐ mission from reference 165)

large ICD trials is considerably younger than the people frequently needing ICD implantation in the current clinical practice. This issue has been addressed by two meta-analysis suggesting benefit of ICD therapy in older patients. [160], [161] Another meta-analysis of primary prevention ICD trials showed smaller benefit of ICD in women with dilated cardiomyopathy compared to men. Although overall mortality in both the genders were similar (HR 0.96, 95% CI 0.67-1.39), women received approprite therapy less frequently compared to men (HR 0.63, 95%CI 0.49-0.82) and hence received less benefit from defibrillator therapy. [162] This as well as another meta-analysis of primary prevention ICD trials failed to show significant mortality benefit of ICD in women. [162]

These ICD trials have established the role of ICDs in the primary and secondary prevention of SCD in patients with non-ischemic and ischemic cardiomyopathy (figure 9). Left ventricular ejection fraction has been recognized as the strongest risk stratifier and has been extensively used in all the trials. Based on these studies guidelines have been formulated for the appro‐ priate indications of ICD therapy in these patients. The table 3 summarizes the guidelines for implantation of ICD for prevention of SCD in these patients.


**Indication for ICD**

systematic follow-up.

structural heart disease).

for various cardiomyopathies.

might be futile.

disease (e.g., electrolyte imbalance, drugs, or trauma).

heart disease.

Patients with significant psychiatric illnesses that may be aggravated by device implantation or that may preclude

**NYHA Class IV patients with drug-refractory congestive heart failure who are not candidates for cardiac transplantation or implantation of a CRT device that incorporates both pacing and defibrillation capabilities.**

Syncope of undetermined cause in a patient without inducible ventricular tachyarrhythmias and without structural

Ventricular fibrillation or VT is amenable to surgical or catheter ablation (e.g., atrial arrhythmias associated with Wolff-Parkinson-White syndrome, right ventricular or LV outflow tract VT, idiopathic VT, or fascicular VT in the absence of

Patients with ventricular tachyarrhythmias due to a completely reversible disorder in the absence of structural heart

**5.5. Risk stratification of heart failure patients for sudden death prevention**

**Table 3.** ACC/AHA/HRS guidelines for implantation of ICDs (2008): indications in bold fonts refer to the indications

As data has accumulated suggesting that a strategy of wide ranging ICD implantation in patients with impaired left ventricular systolic function will result in improvements in sudden cardiac death mortality, concerns have been raised about the relatively low incidence of life saving therapies in implanted patients. For example in MADIT II 14% of patients received a potentially life saving defibrillator shock, whilst in SCD-HeFT only 21% of patients received appropriate ICD therapy. In addition it has frequently been noted that an appropriate shock does not necessarily represent an aborted sudden death. These considerations have lead to attempts to derive scoring strategies from the data sets in the large prospective trials to try to identify patients at low risk of requiring device therapy – and those in whom device therapy

Data from the MADIT II study in chronic IHD suggested that in very high risk (VHR) patients defined as those with a BUN ≥ 50 mg/dl, mortality was high at 50% in two years and was not improved by ICD therapy. ICD implantation in this patient group appears to be unjustified. Among non-VHR patients, SCD risk was to be increased with NYHA functional class >II, a history of atrial fibrillation, QRS duration >120 ms, age >70 years and BUN >26 mg/dl and <50 mg/dl. Patients with none of these risk factors were at low risk of SCD, and had no benefit from ICD therapy. Patients with one to two risk factors derived benefit from an ICD whereas patients with three or more risk factors did not derive as much benefit and behaved like VHR patients. [163] Similarly, analysis of data from the MUSTT study suggested LVEF alone was of limited value to predict the risk of SCD in this patient group. [164] The concern about using a binary cut off of LVEF in deciding on the advisability or otherwise of ICD therapy to reduce the risk of SCD is that SCD risk is a continuous variable and predicted by more than LVEF alone. Multiple factors predict SCD to some extent and hence a risk score based on multiple risk factors may be a better predictor of SCD. However, it should be noted that the mutiple

**3**

**4**

**5**

**6**

**7**

**Level of evidence** 193

**C**

Sudden Cardiac Death

http://dx.doi.org/10.5772/55636

**C**

**C**

**C**

**B**


**Table 3.** ACC/AHA/HRS guidelines for implantation of ICDs (2008): indications in bold fonts refer to the indications for various cardiomyopathies.

#### **5.5. Risk stratification of heart failure patients for sudden death prevention**

**Indication for ICD**

**NYHA functional Class II or III.**

Patients who are survivors of cardiac arrest due to ventricular fibrillation or hemodynamically unstable sustained VT

**Patients with structural heart disease and spontaneous sustained VT, whether hemodynamically stable or**

Patients with syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or

**Patients with LVEF less than or equal to 35% due to prior myocardial infarction who are at least 40 days post–**

**Patients with nonischemic dilated cardiomyopathy who have an LVEF less than or equal to 35% and who are in**

**Patients with nonsustained VT due to prior myocardial infarction, LVEF less than or equal to 40%, and inducible**

**1 Patients with unexplained syncope, significant LV dysfunction, and nonischemic dilated cardiomyopathy. C 2 Patients with sustained VT and normal or near-normal ventricular function. C 3 Patients with hypertrophic cardiomyopathy who have 1 or more major† risk factor for SCD. C**

**Patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy who have 1 or more risk factor for**

 Patients with long-QT syndrome who are experiencing syncope and/or VT while receiving beta blockers. **B Nonhospitalized patients awaiting transplantation. C** Patients with Brugada syndrome who have had syncope. **C** Patients with Brugada syndrome who have documented VT that has not resulted in cardiac arrest. **C**

Patients with catecholaminergic polymorphic VT who have syncope and/or documented sustained VT while receiving

**10 Patients with cardiac sarcoidosis, giant cell myocarditis, or Chagas disease. C**

**Patients with nonischemic heart disease who have an LVEF of less than or equal to 35% and who are in NYHA**

**2** Patients with long-QT syndrome and risk factors for SCD. B

**4 Patients with a familial cardiomyopathy associated with sudden death. C 5 Patients with LV noncompaction. C**

**Patients who do not have a reasonable expectation of survival with an acceptable functional status for at least 1 year, even if they meet ICD implantation criteria specified in the Class I, IIa, and IIb recommendations above.**

**2 Patients with incessant VT or ventricular fibrillation. C**

Patients with syncope and advanced structural heart disease in whom thorough invasive and noninvasive

**Patients with LV dysfunction due to prior myocardial infarction who are at least 40 days post–myocardial**

**infarction, have an LVEF less than or equal to 30%, and are in NYHA functional Class I.**

after evaluation to define the cause of the event and to exclude any completely reversible causes.

ventricular fibrillation induced at electrophysiological study.

**myocardial infarction and are in NYHA functional Class II or III.**

**ventricular fibrillation or sustained VT at electrophysiological study.**

**Class I**

192 Cardiomyopathies

**unstable.**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**4**

**9**

**1**

3

**1**

**Class IIa**

**SCD.**

beta blockers.

**functional Class I.**

investigations have failed to define a cause.

**Class IIb**

**Class III**

**Level of evidence**

**A**

**B**

**B**

**A**

**B**

**A**

**B**

**C**

**C**

**C**

**C**

**C**

As data has accumulated suggesting that a strategy of wide ranging ICD implantation in patients with impaired left ventricular systolic function will result in improvements in sudden cardiac death mortality, concerns have been raised about the relatively low incidence of life saving therapies in implanted patients. For example in MADIT II 14% of patients received a potentially life saving defibrillator shock, whilst in SCD-HeFT only 21% of patients received appropriate ICD therapy. In addition it has frequently been noted that an appropriate shock does not necessarily represent an aborted sudden death. These considerations have lead to attempts to derive scoring strategies from the data sets in the large prospective trials to try to identify patients at low risk of requiring device therapy – and those in whom device therapy might be futile.

Data from the MADIT II study in chronic IHD suggested that in very high risk (VHR) patients defined as those with a BUN ≥ 50 mg/dl, mortality was high at 50% in two years and was not improved by ICD therapy. ICD implantation in this patient group appears to be unjustified. Among non-VHR patients, SCD risk was to be increased with NYHA functional class >II, a history of atrial fibrillation, QRS duration >120 ms, age >70 years and BUN >26 mg/dl and <50 mg/dl. Patients with none of these risk factors were at low risk of SCD, and had no benefit from ICD therapy. Patients with one to two risk factors derived benefit from an ICD whereas patients with three or more risk factors did not derive as much benefit and behaved like VHR patients. [163] Similarly, analysis of data from the MUSTT study suggested LVEF alone was of limited value to predict the risk of SCD in this patient group. [164] The concern about using a binary cut off of LVEF in deciding on the advisability or otherwise of ICD therapy to reduce the risk of SCD is that SCD risk is a continuous variable and predicted by more than LVEF alone. Multiple factors predict SCD to some extent and hence a risk score based on multiple risk factors may be a better predictor of SCD. However, it should be noted that the mutiple risk models have not been evaluated in a prospective study and are entirely data derived. [68] This being said, it seems inevitable that the guidelines for the implantation of ICDs will be refined in the future and that risk scores will be incorporated.

In patients with sarcoidosis, cardiac involvement with history of spontaneous VT and/or severe LV systolic dysfunction may warrant ICD therapy despite lack of prospective trials. [165] Implantation of ICD in patients with sarcoidosis in the absence of LV systolic dysfunction or history of ventricular arrhythmias remains controversial. The ACC/AHA/HRS guidelines for device therapy lists cardiac sarcoidosis as reasonable indication for ICD implantation. [166] The use of ICD to prevent SCD in patients with cardiac amyloidosis is not well accepted and may not affect the outcome, although it can be used to bridge the patients to cardiac trans‐ plantation. [38], [165] Some of the muscular dystrophies with associated cardiomyopathy are

Sudden Cardiac Death

195

http://dx.doi.org/10.5772/55636

treated in a similar way as dilated non-ischemic cardiomyopathy from other causes.

Some cardiomyopathies are prone to cause conduction abnormalities. For example patients with muscular dystrophy due to lamin A/C gene mutation are particularly prone to conduction defect and atrioventricular block. The threshold for pacemaker implantation in these patients is very low to prevent SCD. Similarly, infiltrative myocardial diseases such as sarcoidosis can lead to heart block and SCD as a result of this. Other examples include myotonic muscular dystrophy, where SCD can result both from ventricular arrhythmias and from complete heart

The prevention of sudden cardiac death in patients with cardiomyopathy has evolved dramatically in recent years. With the increasing use of ICDs in conjunction with pharmaco‐ therapy for heart failure, large number patients have benefited from prevention of SCD. However, risk assessment for SCD is still far from accurate and many patients receiving ICDs ultimately will not use them. Although, attempts have been made to refine the risk stratifica‐ tion, the current risk stratification is insufficient at least for many kinds of cardiomyopathies. Data from subgroup analysis do provide some parameters for refining risk stratification, but testing them in a prospective study will be an expensive and time-consuming undertaking. Risk stratification for less common forms of cardiomyopathy has not largely been possible. Some newer parameters like genetic evaluation may help in refining the risk assessment in the future as more data on genetic analysis in various forms of cardiomyopathy comes forth. Finally, newer pharmacotherapy may help in reducing the risk of SCD in these patients.

Department of Medicine, University of North Carolina, Chapel Hill NC, USA

**5.7. Device therapy: Permanent pacemaker**

block.

**6. Future directions**

**Author details**

Prabhat Kumar and J Paul Mounsey

#### **5.6. ICD in other forms of cardiomyopathies**

Implantation of ICD in cardiomyopathy other than ischemic and non-ischemic dilated cardiomyopathy is not supported by evidence from large ICD trials. The majority of patients enrolled in the large ICD trials were post-MI patients with LV dysfunction and patients with dilated non-ischemic cardiomyopathy. In other forms of cardiomyopathies, like hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, sarcoidosis and other infiltrative cardiomyopathies, secondary prevention of sudden cardiac death with ICD implantation in survivors of SCD and in patients with history of sustained ventricular tachycardia is generally accepted clinical practice. However, implantation of ICD for primary prevention of SCD has remained an unsolved issue in these patients. This has become more of an issue with development of more effective screening of family members, and preparticipation screening of athletes. Risk stratification in them has been attempted for each of these groups.

Primary prevention in patients with *hypertrophic cardiomyopathy* is guided by multiple risk factors for sudden cardiac death as discussed above. These risk factors have been defined as discussed earlier and include (1) a family history of premature HCM-related sudden death; (2) a history of unexplained syncope; (3) multiple and/or prolonged runs of nonsustained VT on serial 24-hour ambulatory ECG monitoring at heart rates ≥120 beats/min; (4) a hypotensive or attenuated blood pressure response to exercise; and (5) massive left ventricular (LV) hypertrophy (maximum wall thickness ≥30 mm). The ACC/AHA/ESC guidelines on sudden cardiac death and ventricular arrhythmia recommend implantation of ICD in patients with one or more of these risk factors, for the primary prevention of SCD. [165]

Primary prevention of SCD in *arrhythmogenic right ventricular cardiomyopathy* is also guided by a set of high risk factors. A multicenter study evaluated the use of ICD for primary prophylaxis of SCD in patients with ARVC with at least one risk factor for SCD. These included syncope, NSVT, a malignant family history, and inducibility of ventricular arrhythmias with program‐ med ventricular stimulation. Over a mean follow-up of 58 months 25 of 106 patients received appropriate ICD intervention. ACC/AHA/ESC guidelines considers secondary prevention of SCD with AICD to be reasonable (class IIa) in patients with ARVC considered high risk due to LV involvement, one or more affected family member with SCD, or undiagnosed syncope when VT or VF has not been excluded as the cause of syncope, while receiving chronic optimal medical therapy. [165] ACC/AHA/HRS guidelines for device therapy for arrhythmia lists ARVC as reasonable indication for primary implantation of ICD in the presence of one or more risk of SCD. [166]

In patients with left ventricular non-compaction, ICD implantation is generally performed for secondary prevention and for primary prevention in the presence of LV systolic dysfunction. Although patients with normal LV systolic function or mild LV systolic dysfunction may be prone to SCD, [125] lack of data makes the decision ICD implantation in these patients difficult. In patients with sarcoidosis, cardiac involvement with history of spontaneous VT and/or severe LV systolic dysfunction may warrant ICD therapy despite lack of prospective trials. [165] Implantation of ICD in patients with sarcoidosis in the absence of LV systolic dysfunction or history of ventricular arrhythmias remains controversial. The ACC/AHA/HRS guidelines for device therapy lists cardiac sarcoidosis as reasonable indication for ICD implantation. [166] The use of ICD to prevent SCD in patients with cardiac amyloidosis is not well accepted and may not affect the outcome, although it can be used to bridge the patients to cardiac trans‐ plantation. [38], [165] Some of the muscular dystrophies with associated cardiomyopathy are treated in a similar way as dilated non-ischemic cardiomyopathy from other causes.

#### **5.7. Device therapy: Permanent pacemaker**

Some cardiomyopathies are prone to cause conduction abnormalities. For example patients with muscular dystrophy due to lamin A/C gene mutation are particularly prone to conduction defect and atrioventricular block. The threshold for pacemaker implantation in these patients is very low to prevent SCD. Similarly, infiltrative myocardial diseases such as sarcoidosis can lead to heart block and SCD as a result of this. Other examples include myotonic muscular dystrophy, where SCD can result both from ventricular arrhythmias and from complete heart block.
