**2. β-blockers and sudden cardiac death prevention**

#### **2.1. Potential mechanisms of β-blockers on sudden cardiac death prevention**

Multiple studies have suggested that the major mechanisms responsible for the cardiac arrhythmias associated with sudden cardiac death are ventricular tachycardia (VT) and

ventricular fibrillation (VF). For these arrhythmias to occur, an interaction between substrate (ventricular enlargement and/or hypertrophy, myocardial scar due to ischemic or nonischemic injury) and triggers (electrolyte abnormalities, changes in the sympathetic and parasympathetic activity, neuro-humeral factors, and premature ventricular contractions) is necessary to initiate reentry leading to ventricular tachycardia and ventricular fibrillation (Figure 1).

Many anatomic or functional substrates such as coronary artery disease, cardiomyopathy or primary electrophysiological disease can lead to sudden cardiac death. Progression of these disease states leads to sympathetic activation. At the cellular level, sympathetic and vagal denervation caused by myocardial ischemia leads to an increase in interstitial potassium and intracellular calcium concentrations [3]. This results in slowed conduction and induces spontaneous electrical activity. All these factors contribute to reentry; which is the most common mechanism of ventricular tachycardia in patients with ischemic heart disease [4].

As myocardial ischemia progresses the neurohumoral system exerts further stimulation of the sympathetic system and the renin-angiotensin-aldosterone system (RAAS). This neurohu‐ moral cascade leads to increasing levels of norepinephrine, angiotensin II, aldosterone, endothelin and vasopressin. Increased norepinephrine levels lead to increased preload and after-load, which in turn increases myocardial oxygen demand. Furthermore, the activation of these systems promotes fibrosis and necrosis [5-7], which over time will lead to cardiac remodeling, left ventricular dilatation, fibrosis and progression into heart failure [8].

Three types of β-receptors are known, designated β1, β2 and β3 receptors. β1 receptors are located mainly in the heart and in the kidneys and are down regulated in heart failure due to chronically elevated norepinephrine levels. β2 receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3 receptors are located in fat cells. β1and β2receptors activate cyclic adenosine mono-phosphate (cAMP), which acts as a second messenger and leads to increased contractility (inotropy), increased heart rate (which increases myocardial oxygen demand), increased conduction velocity (which may promote reentry) and have a positive lusitropic effect, which improves active relaxation [9]. β2receptors promote the release of renin, which in turn activates angiotensin II and aldosterone, both of which elevate the blood pressure, increase after-load, promote potassium wasting and activate fibroblasts leading to fibrosis.

**Figure 1.** Venn diagram showing interaction of various anatomic/functional and transient factors that modulate po‐ tential arrhythmogenic mechanisms capable of causing sudden cardiac death (From Douglas P. Zipes and Hein J. J.

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**2.2. Effect of β-blockers on sudden cardiac death prevention in post myocardial infarction**

β-blockers therapy has been studied in the post myocardial infarction (MI) patients since 1965 when propranolol was found to reduce mortality after acute MI[13]. Pivotal trials such as the *Norwegian Multicenter Study Group* (utilizing Timolol at a starting dose of 5 mgs/day with target of 20 mgs/day), *β-blocker Heart Attack Trial* (*BHAT*, utilizing propranolol at a dose of 180 to 240 mgs/day) in the 1980s showed reduction in total mortality and sudden cardiac death [14, 15]. As therapies post- MI evolved and ACE-I inhibitors were introduced several other trials, including the *Survival and Ventricular Enlargement (SAVE)* and *Acute Infarction Ramipril Efficacy (AIRE)* trials demonstrated that β-blockers provided additional reduction in cardiovascular

Wellens "Sudden Cardiac Death" Circulation. 1998; 98:2334-2351, With Permission)

mortality independent of the use of ACE-I inhibitors[16, 17].

**patients**

β-blockers exert their protective effect on the heart via different mechanisms. β-blockers reduce ischemia by decreasing the heart rate, which is the major determinant of myocardial oxygen demand[10]. At the cellular level, β-blockers decrease electrical excitability by limiting calcium entry via catecholamine-dependent channels [9]. All this helps decrease left ventricular mass and volume, decrease LV end diastolic pressure and improve LV function [11]. β-blockers are also considered a class II antiarrhythmic medications. They decrease spontaneous depolari‐ zation, prolong the sinus node cycle length, atrioventricular conduction times and atrioven‐ tricular refractory periods. They also increase the excitable gap, which prevents reentry and increases the success of anti-tachycardia pacing [12].

ventricular fibrillation (VF). For these arrhythmias to occur, an interaction between substrate (ventricular enlargement and/or hypertrophy, myocardial scar due to ischemic or nonischemic injury) and triggers (electrolyte abnormalities, changes in the sympathetic and parasympathetic activity, neuro-humeral factors, and premature ventricular contractions) is necessary to initiate reentry leading to ventricular tachycardia and ventricular fibrillation

Many anatomic or functional substrates such as coronary artery disease, cardiomyopathy or primary electrophysiological disease can lead to sudden cardiac death. Progression of these disease states leads to sympathetic activation. At the cellular level, sympathetic and vagal denervation caused by myocardial ischemia leads to an increase in interstitial potassium and intracellular calcium concentrations [3]. This results in slowed conduction and induces spontaneous electrical activity. All these factors contribute to reentry; which is the most common mechanism of ventricular tachycardia in patients with ischemic heart disease [4].

As myocardial ischemia progresses the neurohumoral system exerts further stimulation of the sympathetic system and the renin-angiotensin-aldosterone system (RAAS). This neurohu‐ moral cascade leads to increasing levels of norepinephrine, angiotensin II, aldosterone, endothelin and vasopressin. Increased norepinephrine levels lead to increased preload and after-load, which in turn increases myocardial oxygen demand. Furthermore, the activation of these systems promotes fibrosis and necrosis [5-7], which over time will lead to cardiac

Three types of β-receptors are known, designated β1, β2 and β3 receptors. β1 receptors are located mainly in the heart and in the kidneys and are down regulated in heart failure due to chronically elevated norepinephrine levels. β2 receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3 receptors are located in fat cells. β1and β2receptors activate cyclic adenosine mono-phosphate (cAMP), which acts as a second messenger and leads to increased contractility (inotropy), increased heart rate (which increases myocardial oxygen demand), increased conduction velocity (which may promote reentry) and have a positive lusitropic effect, which improves active relaxation [9]. β2receptors promote the release of renin, which in turn activates angiotensin II and aldosterone, both of which elevate the blood pressure, increase after-load, promote potassium

β-blockers exert their protective effect on the heart via different mechanisms. β-blockers reduce ischemia by decreasing the heart rate, which is the major determinant of myocardial oxygen demand[10]. At the cellular level, β-blockers decrease electrical excitability by limiting calcium entry via catecholamine-dependent channels [9]. All this helps decrease left ventricular mass and volume, decrease LV end diastolic pressure and improve LV function [11]. β-blockers are also considered a class II antiarrhythmic medications. They decrease spontaneous depolari‐ zation, prolong the sinus node cycle length, atrioventricular conduction times and atrioven‐ tricular refractory periods. They also increase the excitable gap, which prevents reentry and

remodeling, left ventricular dilatation, fibrosis and progression into heart failure [8].

wasting and activate fibroblasts leading to fibrosis.

increases the success of anti-tachycardia pacing [12].

(Figure 1).

214 Cardiomyopathies

**Figure 1.** Venn diagram showing interaction of various anatomic/functional and transient factors that modulate po‐ tential arrhythmogenic mechanisms capable of causing sudden cardiac death (From Douglas P. Zipes and Hein J. J. Wellens "Sudden Cardiac Death" Circulation. 1998; 98:2334-2351, With Permission)

#### **2.2. Effect of β-blockers on sudden cardiac death prevention in post myocardial infarction patients**

β-blockers therapy has been studied in the post myocardial infarction (MI) patients since 1965 when propranolol was found to reduce mortality after acute MI[13]. Pivotal trials such as the *Norwegian Multicenter Study Group* (utilizing Timolol at a starting dose of 5 mgs/day with target of 20 mgs/day), *β-blocker Heart Attack Trial* (*BHAT*, utilizing propranolol at a dose of 180 to 240 mgs/day) in the 1980s showed reduction in total mortality and sudden cardiac death [14, 15]. As therapies post- MI evolved and ACE-I inhibitors were introduced several other trials, including the *Survival and Ventricular Enlargement (SAVE)* and *Acute Infarction Ramipril Efficacy (AIRE)* trials demonstrated that β-blockers provided additional reduction in cardiovascular mortality independent of the use of ACE-I inhibitors[16, 17].

A meta-analysis evaluated several randomized clinical trials looking at the benefits of βblockers treatment post MI. This analysis revealed a significant reduction in mortality with βblocker therapy (HR= 0.77, 95% confidence interval: 0.69 to 0.85)[18]. Secondary to lack of physician prescription of β-blocker therapy despite evidence of its benefit the Cooperative Cardiovascular Project was undertaken. This was an observational report that evaluated the care of 200,000 Medicare patients with the diagnosis of MI. Only 34% of the patients were given β-blockers. The mortality reduction for patients who were prescribed beta- blockers at the time of discharge from the hospital was 40% [19].

*The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial* examined the effect of Carvedilol in 2289 patients with severe CHF, defined as dyspnea at rest and LVEF ≤ 25%. This trial validated the mortality benefit of Carvedilol in patients with se‐ vere heart failure with a 50% reduction in all-cause mortality (HR 0.50, 95% CI of 0.10-0.63) [24]. Unfortunately this trial did not have data available on the impact of Car‐

Role of Traditional Heart Failure Medications on Sudden Cardiac Death Prevention in Patients with Cardiomyopathy

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217

*The Cardiac Insufficiency Bisoprolol Study (CIBIS) II* was a multicenter, double-blind, random‐ ized, placebo-controlled trial that evaluated the efficacy of Bisoprolol in reducing the incidence of all-cause mortality in heart failure. Bisoprolol is a β1receptor blocker, and the target dose was 10 mgs daily. All patients enrolled received standard therapy with diuretics and ACE-I inhibitors. A total of2647 patients with New York Heart Association (NYHA) class III or IV with LVEF of ≤ 35% were randomized to either Bisoprolol (n=1327) or placebo (n=1320). This study was stopped prematurely because Bisoprolol showed a significant mortality benefit. Death from any cause in the Bisoprolol group was 11.8% versus 17.3% in the placebo group (HR, 0.66, 95% CI, 0.54-0.80). Sudden death was also reduced in the Bisoprolol group by 42%

*The Metoprolol CR/XL Randomized Intervention Trial in CHF (MERIT-HF)* was a double-blind randomized controlled study which included 3991 patients with CHF, NYHA class II-IV with an LVEF of ≤40%. These patients were stable on optimal medical therapy. This trial evaluated whether controlled release/extended release formulation of Metoprolol taken daily would reduce mortality in this patient population. The starting dose was 12.5 mgs once daily with target dose of 200 mgs orally once daily. Patients were randomized to Metoprolol CR/XL (n=1990) up-titrated to 200 mg daily over and eight week period of time or placebo (n=2001). The trial demonstrated a 34% relative risk reduction in all-cause mortality with controlled release/extended release formulation of Metoprolol. Similar, to CIBIS II, MERIT–HF showed

**2.4. Effect of β-blockers on sudden cardiac death prevention in patients who survived a**

In patients who have implantable cardioverter defibrillators (ICDs), β-blockers have been shown to decrease the frequency of ICD shocks [27]. In an analysis of the Antiarrhythmics Versus Implantable Defibrillators Registry (*AVID registry*), β-blockers therapy was associated with lower mortality in patients with sustained ventricular tachycardia [28]. β-Blockers increase the time to first ICD shock in patients implanted for secondary prevention of sudden

Furthermore, the higher the dose of β-blockers used, the less patients experience VT and the more likely the therapies are successful. In a study of 282 patients with left ventricular dysfunction (EF < 50%) with standard indications for ICD without cardiac resynchronization

vedilol on sudden death.

compared to the placebo group [25].

**cardiac arrest**

death[29].

a 41% relative risk reduction of sudden death [26].

therapy, the higher the dose of β-blockers

A sub-analysis of *BHAT* trial showed that propranolol decreased mortality and sudden cardiac death in the subset of patients with depressed LVEF [20]. But it was not until the *Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction trial (CAPRICORN)* was a focus also placed on AMI patient with left ventricular (LV) dysfunction. *CAPRI‐ CORN* was a multinational prospective, randomized trial recruiting patients with recent acute MI (3-21 days) and left ventricular (LV) dysfunction with ejection fraction (EF) ≤ 40%. A total of 984 patients were placed on placebo and 975 patients were allocated to Carvedilol therapy post MI with an average follow up of 1.3 years. The initial starting dose was 6.25 mgs orally twice daily with target dose of 25 mgs orally twice daily. Allcause mortality was lower in the carvedilol group than in the placebo group (Hazard Ra‐ tio of 0.77, 95% CI of 0.60—0.98, p=0.03) [21]. Several secondary prevention trials had demonstrated significant reductions in ventricular arrhythmias but it was not until *CAP‐ RICORN* that patients with substantial left ventricular dysfunction also demonstrated a significant reduction in malignant ventricular arrhythmias (HR of 0.37 (95% CI 0.24 to 0.58; p < 0.0001)[22]. It is important to emphasise that in this trial that 98% of the pa‐ tients were treated with an ACE-I inhibitor. The effect of ACE-I inhibitors on reduction of ventricular arrhythmias will be discussed in a later section.

#### **2.3. Effect of β-blockers on sudden cardiac death prevention in patients with congestive heart failure**

β-blockers were initially thought to be contra-indicated in patients with heart failure due to their negative inotropic effects in the short term. However, later studies showed they consis‐ tently improve morbidity and mortality in patients with heart failure; they also lead to a 40% reduction in hospitalization. Currently, there are 3 medications available in the United States that have shown mortality benefits in patients with heart failure. Carvedilol is a non-selective β1, β2and α1 blocker that was tested in two trials and was shown to improve mortality. The first is the *US Carvedilol trial* which enrolled 1094 patients with congestive heart failure (CHF) and left ventricular ejection fraction (LVEF) of ≤ 35%. Patients were assigned to four treatment protocols based on exercise capacity. Within each protocol patients were assigned to either placebo (n=398) or Carvedilol (n=696). Although this trial was not designed as mortality trial, itdemonstrated a 65% decrease in the risk of death with Carvedilol compared to placebo (p<0.001). Sudden death was reduced from 3.8% in the placebo group to 1.7% in the Carvedilol group [23].

*The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial* examined the effect of Carvedilol in 2289 patients with severe CHF, defined as dyspnea at rest and LVEF ≤ 25%. This trial validated the mortality benefit of Carvedilol in patients with se‐ vere heart failure with a 50% reduction in all-cause mortality (HR 0.50, 95% CI of 0.10-0.63) [24]. Unfortunately this trial did not have data available on the impact of Car‐ vedilol on sudden death.

A meta-analysis evaluated several randomized clinical trials looking at the benefits of βblockers treatment post MI. This analysis revealed a significant reduction in mortality with βblocker therapy (HR= 0.77, 95% confidence interval: 0.69 to 0.85)[18]. Secondary to lack of physician prescription of β-blocker therapy despite evidence of its benefit the Cooperative Cardiovascular Project was undertaken. This was an observational report that evaluated the care of 200,000 Medicare patients with the diagnosis of MI. Only 34% of the patients were given β-blockers. The mortality reduction for patients who were prescribed beta- blockers at the time

A sub-analysis of *BHAT* trial showed that propranolol decreased mortality and sudden cardiac death in the subset of patients with depressed LVEF [20]. But it was not until the *Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction trial (CAPRICORN)* was a focus also placed on AMI patient with left ventricular (LV) dysfunction. *CAPRI‐ CORN* was a multinational prospective, randomized trial recruiting patients with recent acute MI (3-21 days) and left ventricular (LV) dysfunction with ejection fraction (EF) ≤ 40%. A total of 984 patients were placed on placebo and 975 patients were allocated to Carvedilol therapy post MI with an average follow up of 1.3 years. The initial starting dose was 6.25 mgs orally twice daily with target dose of 25 mgs orally twice daily. Allcause mortality was lower in the carvedilol group than in the placebo group (Hazard Ra‐ tio of 0.77, 95% CI of 0.60—0.98, p=0.03) [21]. Several secondary prevention trials had demonstrated significant reductions in ventricular arrhythmias but it was not until *CAP‐ RICORN* that patients with substantial left ventricular dysfunction also demonstrated a significant reduction in malignant ventricular arrhythmias (HR of 0.37 (95% CI 0.24 to 0.58; p < 0.0001)[22]. It is important to emphasise that in this trial that 98% of the pa‐ tients were treated with an ACE-I inhibitor. The effect of ACE-I inhibitors on reduction

**2.3. Effect of β-blockers on sudden cardiac death prevention in patients with congestive**

β-blockers were initially thought to be contra-indicated in patients with heart failure due to their negative inotropic effects in the short term. However, later studies showed they consis‐ tently improve morbidity and mortality in patients with heart failure; they also lead to a 40% reduction in hospitalization. Currently, there are 3 medications available in the United States that have shown mortality benefits in patients with heart failure. Carvedilol is a non-selective β1, β2and α1 blocker that was tested in two trials and was shown to improve mortality. The first is the *US Carvedilol trial* which enrolled 1094 patients with congestive heart failure (CHF) and left ventricular ejection fraction (LVEF) of ≤ 35%. Patients were assigned to four treatment protocols based on exercise capacity. Within each protocol patients were assigned to either placebo (n=398) or Carvedilol (n=696). Although this trial was not designed as mortality trial, itdemonstrated a 65% decrease in the risk of death with Carvedilol compared to placebo (p<0.001). Sudden death was reduced from 3.8% in the placebo group to 1.7% in the Carvedilol

of discharge from the hospital was 40% [19].

of ventricular arrhythmias will be discussed in a later section.

**heart failure**

216 Cardiomyopathies

group [23].

*The Cardiac Insufficiency Bisoprolol Study (CIBIS) II* was a multicenter, double-blind, random‐ ized, placebo-controlled trial that evaluated the efficacy of Bisoprolol in reducing the incidence of all-cause mortality in heart failure. Bisoprolol is a β1receptor blocker, and the target dose was 10 mgs daily. All patients enrolled received standard therapy with diuretics and ACE-I inhibitors. A total of2647 patients with New York Heart Association (NYHA) class III or IV with LVEF of ≤ 35% were randomized to either Bisoprolol (n=1327) or placebo (n=1320). This study was stopped prematurely because Bisoprolol showed a significant mortality benefit. Death from any cause in the Bisoprolol group was 11.8% versus 17.3% in the placebo group (HR, 0.66, 95% CI, 0.54-0.80). Sudden death was also reduced in the Bisoprolol group by 42% compared to the placebo group [25].

*The Metoprolol CR/XL Randomized Intervention Trial in CHF (MERIT-HF)* was a double-blind randomized controlled study which included 3991 patients with CHF, NYHA class II-IV with an LVEF of ≤40%. These patients were stable on optimal medical therapy. This trial evaluated whether controlled release/extended release formulation of Metoprolol taken daily would reduce mortality in this patient population. The starting dose was 12.5 mgs once daily with target dose of 200 mgs orally once daily. Patients were randomized to Metoprolol CR/XL (n=1990) up-titrated to 200 mg daily over and eight week period of time or placebo (n=2001). The trial demonstrated a 34% relative risk reduction in all-cause mortality with controlled release/extended release formulation of Metoprolol. Similar, to CIBIS II, MERIT–HF showed a 41% relative risk reduction of sudden death [26].

#### **2.4. Effect of β-blockers on sudden cardiac death prevention in patients who survived a cardiac arrest**

In patients who have implantable cardioverter defibrillators (ICDs), β-blockers have been shown to decrease the frequency of ICD shocks [27]. In an analysis of the Antiarrhythmics Versus Implantable Defibrillators Registry (*AVID registry*), β-blockers therapy was associated with lower mortality in patients with sustained ventricular tachycardia [28]. β-Blockers increase the time to first ICD shock in patients implanted for secondary prevention of sudden death[29].

Furthermore, the higher the dose of β-blockers used, the less patients experience VT and the more likely the therapies are successful. In a study of 282 patients with left ventricular dysfunction (EF < 50%) with standard indications for ICD without cardiac resynchronization therapy, the higher the dose of β-blockers
