Prevention of Sudden Cardiac Death in Patients with Cardiomyopathy (Classification, Evaluation and Management of Cardiomyopathies) Part 1

Introduction

Sudden cardiac death (SCD) is a major public health issue with an estimated annual incidence of 300,000 – 400,000 cases per year. The ACC/AHA/ESC 2006 guidelines define SCD as "death from an unexpected circulatory arrest, usually due to a cardiac arrhythmia occurring within an hour of the onset of symptoms"(Zipes et al. 2006). Most of the patients experiencing sudden cardiac arrest have an ejection fraction (LVEF) more than 50%, with the majority of these patients having a history of coronary artery disease (CAD). However, the risk of death in patients with LVEF of less than 35% is higher than patients with better preserved LVEF (Gorgels et al. 2003). Beta blocker therapy, Angiotensin enzymes inhibitors (ACE-I), angtiotensin receptor blockers as well as aldosteron antagonists have been shown to decrease the risk of sudden cardiac death especially in post myocardial infarction patients (Seidl et al. 1998; Domanski et al. 1999; Pitt et al. 2003; McMurray et al. 2005). In contrast antiarrhythmic drug therapy doesn’t prevent sudden cardiac death in patients with cardiomyopathy. The focus of this topic is to review the major implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy trials and their effects on sudden cardiac death prevention in patients with cardiomyopathy who are receiving optimal medical therapy.

Trials examining the benefits of ICD therapy in sudden cardiac death prevention

Secondary prevention trials of defibrillator therapy

The earlier trials examined the highest risk population of patients who had cardiac arrest due to ventricular fibrillation or sustained ventricular tachycardia (VT) and syncope. These trials helped establish the benefit of ICD therapy in prevention of sudden cardiac death as well as identify patients who are at high risk of dying suddenly and might benefit from ICD therapy as a primary prevention approach.


The first trial is the Antiarrhythmic versus Implantable Defibrillators Trial (AVID). Patients were included if they were resuscitated from VT, had sustained VT with syncope or had sustained VT with LVEF < 40% and symptoms suggestive of hemodynamic compromise (angina or congestive heart failure or near syncope) (AVID 1997). Patients were excluded if the ventricular arrhythmia was due to a reversible cause, but those patients were followed in a registry. AVID enrolled 1016 patients and the primary end point was all cause mortality. Over 80% of the patients randomized to antiarrhythmic therapy (total of 509 patients) were on Amiodarone at end of follow up. AVID was terminated early when patients with ICD therapy (n=506) had a 38% reduction in all cause mortality compared to patients with antiarrhythmic drug therapy (HR 0.62, 95% CI of 0.47 to 0.81). Analysis of the AVID trial showed that patients with LVEF < 35% who received an ICD had significant reduction of sudden cardiac death while patients with LVEF > 35% who received an ICD did not see significant benefit compared to the antiarrhythmic drug therapy group (Domanski et al. 1999).

The patients with a reversible cause of ventricular arrhythmia who were not randomized were followed in a registry. These patients were in general younger, had a better mean LVEF and were more likely to have history of coronary artery disease and had underwent revascularization. Most of the reversible causes were due to ischemia or myocardial infarction (65%) or due to electrolytes imbalance (10%). Patients who were categorized as having VT/VF due to reversible causes had similar if not higher risk of sudden cardiac death compared to patients with no identifiable reversible cause(Wyse et al. 2001). Careful follow up and aggressive assessment for this patient group is advised.

The second study is the Canadian Implantable Defibrillator Study (CIDS), which enrolled 659 patients who had VT, sustained VT with syncope or sustained VT with LVEF < 35%. Patients were excluded if they had recent myocardial infarction (MI) with in the past 72 hours or if they had electrolytes imbalance. Primary end point was all cause mortality. The patients were followed for an average of 36 months. There was a 20% relative risk reduction of death with ICD therapy compared to amiodarone (p=0.14)(Connolly et al. 2000). Analysis of CIDS showed that patients with low LVEF benefited from ICD therapy more than patient with better-preserved LVEF(O’Brien et al. 2001).

The third study is the Cardiac Arrest Study Hamburg (CASH), which was a small trial randomizing 288 patients to ICD therapy with drug therapy. Inclusion criteria included patients successfully resuscitated from cardiac arrest due to documented sustained ventricular arrhythmia. Exclusion criteria included patients who had a cardiac arrest within 72 hours after MI or cardiac surgery or if they had a reversible cause due to electrolyte abnormality or proarrhythmic drug. There was a trend towards lower death with ICD therapy compared to drug therapy (23% relative risk reduction, p=0.16). Average follow up was 57 months. The lack of benefit in the CASH trial might be due to the fact that it had a small study population and better mean LVEF (45% ±18%) compared to the AVID trial(Kuck et al. 2000). Also, 44% of patient in CASH study had epicardial lead implantation as compared to only 4% in the AVID trial.

A pooled analysis of these trials demonstrated that all cause mortality was reduced by 27% (HR of ICD compared to Amiodarone of 0.73, 95% CI 0.60-0.87, p<0.001) (Connolly et al. 2000). Arrhythmic death was also reduced in the ICD group compared to the Amiodarone group (HR 0.49, 95% CI of 0.36 to 0.67, p<0.001). The metaanalysis also showed that patients with LVEF <35% had a significant benefit from ICD therapy compared to Amiodarone (HR 0.66, 95% CI of 0.53 to 0.83) while patients with LVEF >35% had no significant benefit from ICD therapy compared to Amiodarone therapy (HR of 1.2, 95% CI of 0.81 to 1.76). Furthermore, patients receiving epicardial lead systems had no benefit from ICD therapy compared to Amiodarone (HR 1.52, 95% CI of 0.92 to 2.50), while patients with transvenous lead had the most benefit (HR 0.69, 95% CI of 0.56 to 0.85). The three randomized trials examining the benefit of implantable cardioverter defibrillator (ICD) therapy in patients who survived cardiac arrest are summarized in Table 1.

Trial

N

Inclusion Criteria

Primary Endpoint

Age

Mean LVEF

HR (95%

Confidence

Interval)

P

Value

Antiarrhythmic s versus Implantable Defibrillators (AVID) (1016 patients)

1016

Resuscitated VF, sustained VT and syncope or sustained VT with LVEF < 40% and severe symptoms

All cause mortality

65

35%

0.62 (0.47-0.81)

0.02

Canadian Implatable Defibrillator Study (CIDS) (659 patients)

659

Resuscitated VF, sustained VT and syncope or sustained VT with LVEF < 35% or unmonitored syncope with subsequent inducible VT or sustained VT

All cause mortality

64

34%

0.82 (0.60 to 1.10)

0.14

Cardiac Arrest Study Hamburg (CASH)

288

cardiac arrest due to documented sustained ventricular arrhythmia

All cause mortality

58

45%

0.16

Table 1. Secondary prevention trials of ICD therapy. VT is for ventricular tachycardia, VF is for Ventricular Fibrillation, LVEF is for left Ventricular ejection Fraction. HR is for hazard Ratio, CI is confidence interval.

These trials established the benefits of ICD therapy in patients who survived cardiac arrest in the absence of reversible causes. Patients with reversible causes of the cardiac arrest remain high risk and should be followed closely. Even though the metaanalysis of these trials showed no benefits of ICD therapy in patients with LVEF >35%, this is not reflected in the guidelines due to the fact that LVEF was not an entry criterion in these trials. Furthermore, the mean time of cardiac arrest and measurement of LVEF was 3 days in the AVID trial, and the LVEF shortly after cardiac arrest might be depressed from myocardial injury and might improve over time. Table 2 lists current guidelines for ICD therapy.

Class I: (General agreement of benefit with ICD therapy)

1. ICD therapy is indicated in patients who are survivors of cardiac arrest due to VF or hemodynamically unstable sustained VT after evaluation to define the cause of the event and to exclude any completely reversible causes.

2. ICD therapy is indicated in patients with structural heart disease and spontaneous sustained VT, whether hemodynamically stable or unstable.

3. ICD therapy is indicated in patients with syncope of undetermined origin with clinically relevant, hemodynamically significant sustained VT or VF induced at electrophysiological study.

4. ICD therapy is indicated in patients with LVEF less than or equal to 35% due to prior

5.

MI who are at least 40 days post-MI and are in NYHA functional Class II or III. ICD therapy is indicated in patients with nonischemic dilated cardiomyopathy who have an LVEF less than or equal to 35% and who are in NYHA functional Class II or III.

6.

ICD therapy is indicated in patients with LV dysfunction due to prior MI who are at least 40 days post-MI, have an LVEF less than or equal to 30%, and are in NYHA functional Class I.

7.

ICD therapy is indicated in patients with nonsustained VT due to prior MI, LVEF less than or equal to 40%, and inducible VF or sustained VT at electrophysiological study.

Class IIa (Weight of evidence is in favor of usefulness of ICD therapy)

1.

ICD implantation is reasonable for patients with unexplained syncope, significant LV dysfunction, and non-ischemic dilated cardiomyopathy.

2.

ICD implantation is reasonable for patients with sustained VT and normal or near-normal ventricular function.

3.

ICD implantation is reasonable for patients with hypertrophic cardiomyopathy (HCM) who have 1 or more major risk factors for SCD. [Major risk factors for SCD in patients with HCM are: prior cardiac arrest, spontaneous sustained VT, spontaneous non-sustained VT, Family history of SCD, LV thickness > 30 mm and abnormal blood pressure response to exercise]

4.

ICD implantation is reasonable for the prevention of SCD in patients with ARVD/C who have 1 or more risk factors for SCD. [Risk factors for SCD in patients with ARVD/C are: prior cardiac arrest, spontaneous sustained VT, spontaneous non-sustained VT, evidence of extensive RV disease, LV involvement, presentation with polymorphic VT and RV apical aneurysm and induction of VT during electrophysiologic testing]

5.

ICD implantation is reasonable to reduce SCD in patients with long-QT syndrome who are experiencing syncope and/or VT while receiving beta blockers.

6.

ICD implantation is reasonable for non hospitalized patients awaiting transplantation.

7.

ICD implantation is reasonable for patients with Brugada syndrome who have had syncope.

8.

ICD implantation is reasonable for patients with Brugada syndrome who have documented VT that has not resulted in cardiac arrest.

9.

ICD implantation is reasonable for patients with catecholaminergic polymorphic VT who have syncope and/or documented sustained VT while receiving beta blockers.

10.

ICD implantation is reasonable for patients with cardiac sarcoidosis, giant cell myocarditis, or Chagas disease.

Class IIb (Efficacy of the ICD therapy is less well established)

1.

ICD therapy may be considered in patients with non-ischemic heart disease who have an LVEF of less than or equal to 35% and who are in NYHA functional Class I.

2.

ICD therapy may be considered for patients with long-QT syndrome and risk factors for SCD.

3.

ICD therapy may be considered in patients with syncope and advanced structural heart disease in whom thorough invasive and noninvasive investigations have failed

to define a cause.

4.

ICD therapy may be considered in patients with a familial cardiomyopathy associated with sudden death.

5.

ICD therapy may be considered in patients with LV noncompaction.

Class III (General agreement that an ICD is not effective and may be harmful)

1.

ICD therapy is not indicated for 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.

ICD therapy is not indicated for patients with incessant VT or VF.

3.

ICD therapy is not indicated in patients with significant psychiatric illnesses that may be aggravated by device implantation or that may preclude systematic follow-up.

4.

ICD therapy is not indicated for NYHA Class IV patients with drug-refractory congestive heart failure who are not candidates for cardiac transplantation or CRT-D.

5.

ICD therapy is not indicated for syncope of undetermined cause in a patient without inducible ventricular tachyarrhythmias and without structural heart disease.

6.

ICD therapy is not indicated when VF or VT is amenable to surgical or catheter ablation (e.g., atrial arrhythmias associated with the Wolff-Parkinson-White syndrome, RV or LV outflow tract VT, idiopathic VT, or fascicular VT in the absence of structural heart disease).

7.

ICD therapy is not indicated for patients with ventricular tachyarrhythmias due to a completely reversible disorder in the absence of structural heart disease (e.g., electrolyte imbalance, drugs, or trauma).

Table 2. Recommendations for ICD therapy based on the ACC/AHA/HRS 2008 Guidelines for Device Based Therapy.

Primary prevention trials of defibrillator therapy

Primary prevention of SCD in patients with ischemic cardiomyopathy with and without prior myocardial infarction

The earlier primary prevention trials used electrophysiologic testing as well as a reduced LVEF as part of entry criterion. Electrophysiologic testing (EP study) was thought to be a reliable method of risk stratification of patients with coronary artery disease (CAD) who survived myocardial infarction.

The First of these trials is the First Multicenter Automatic Defibrillator Implantation Trial (MADIT- I) which compared ICD therapy to conventional care in 196 patients post MI, LVEF < 35%, non-sustained VT on ambulatory monitoring and inducible VT by programmed electrical stimulation and failure of intravenous procainamide to prevent inducibility (Moss et al. 1996). Patients were excluded if they had prior cardiac arrest or syncope due to ventricular tachycardia (VT) not related to myocardial infarction (MI). Patients were also excluded if they had suffered myocardial infarction within 3 weeks of randomization, had coronary artery bypass surgery within 2 months of randomization or if they had angioplasty within 3 months of randomization. MADIT I started enrolling patients in December 1990, with only transthoracic implantation of ICD was available at the time. Nonthoracotomy transvenous leads were implanted after being approved in August of 1993. Of the 196 patients enrolled, 95 patients were assigned to the ICD group and 101 patients were assigned to the conventional medical therapy group (which also included use of antiarrhythmic drugs). Primary endpoint was all cause mortality. After a mean follow up of 27 months, patients assigned to the ICD group had lower mortality than patients assigned to the conventional treatment group (Hazard Ratio (HR) of 0.46, 95% confidence interval (CI) 0.26 to 0.82, p=0.009). The interval from last MI was > 6 months in 75% of patients in each treatment group. The benefit of ICD was similar in patients with thoracotomy and non-thoracotomy ICD implantation (p=0.78). MADIT-I trail was the first trail to include patients who had purely low LVEF and inducible non-suppressible sustained ventricular arrhythmias during electrophysiologic testing. The First Multicenter Unsustained Tachycardia Trial (MUSTT-I) trial was designed to determine whether inducibilty of VT identified risk of sudden cardiac death in patients with LVEF < 40%, prior myocardial infarction and non-sustained VT documented more than 4 days after MI. Patients were enrolled if they had a positive electrophysiology study (defined as an inducible monomorphic VT or inducible polymorphic VT with one or two extrastimuli). Those with negative EP study were followed in a registry. A total of 704 patients with positive EP study were randomized to electrophysiologic guided antiarrhythmic therapy (which included a drug or implantation of an ICD) versus best medial therapy (mainly beta blockers and angiotensin enzyme inhibitors but no antiarrhythmic drug therapy) (Buxton et al. 1999). Patients who failed suppression of inducibility of the ventricular arrhythmia after at least one antiarrhythmic drug trial could receive an ICD. The ICD implantation was not randomized in MUSTT-I. The primary endpoint was cardiac arrest or death from arrhythmia. Secondary endpoints included death from all causes, death from cardiac causes and spontaneous sustained VT. Over a follow up period of 39 months, patients assigned to electrophysiologic testing (n=351) had lower risk of arrhythmic death or cardiac arrest compared to patients receiving best medical therapy (n=353) (Relative risk 0.73, 95% CI 0.53 to 0.99, p =0.04). This is mostly attributable to lower risk of arrhythmic death or cardiac arrest in patients receiving an ICD compared to patients not receiving an ICD (relative risk 0.24, 95% CI of 0.13 to 0.45, p< 0.001). Patients who received an ICD had a lower risk of all cause mortality compared to patients with electrophysiology guided therapy who received antiarrhythmic drugs only (Relative risk 0.42, 95% CI of 0.29 to 0.61) This remained significant even after adjusting for all other clinical variables (Figure 1).

MUSTT-I showed that patients who had an inducible VT that was suppressed with antiarrhythmic drugs did not have any mortality benefit.

Patients who were screened for MUSTT-I but had a negative EP study were followed in a registry. Data was available for 1397 patients after 39 months of follow up. Total mortality was compared in this registry with the 353 patients in MUSTT-I with positive EP study that were assigned to best medical therapy. Only 35% of patients in the registry were on beta blockers compared to 51% of patients with inducible arrhythmias assigned to no antiarrhythmic therapy. The rate of used of ACE-I was similar (72% and 77% respectively). At 39 months, mortality was higher in patients with positive EP study assigned to best medical therapy (48%) compared to the patients with negative EP study in the registry (44%), (unadjusted p=0.09, adjusted p<0.001 for other clinical factors including use of beta blockers). Even though this difference was statistically significant, the absolute difference of 4% over 5 years is not clinically meaningful. Given these results as well as the consistency of LVEF <35% to predict a mortality benefit from ICD therapy, Electrophysiologic testing is not routinely performed in patients with coronary artery disease and LVEF < 35% as a risk stratifying tool. (Buxton et al. 2000).

Kaplan- Meier Estimates of the Rates of Death from All Causes. EPG denotes electrophysiologically guided.

Fig. 1. Kaplan- Meier Estimates of the Rates of Death from All Causes. EPG denotes electrophysiologically guided.

The Coronary Artery Bypass Graft Patch and The Second Multicenter Automatic Defibrillator Implantation Trial (MADIT- II) trials examined the benefits of ICD therapy in patients with reduced LVEF months after myocardial infarction and did not include electrophysiologic testing or arrhythmia suppression as part of entry criterion. The Coronary Artery Bypass Graft-Patch Trial (CABG-Patch) randomized 1055 patients undergoing coronary artery bypass surgery, LVEF <36% and positive signal-averaged electrocardiograms to receive ICD therapy (n=446) or conventional medical therapy (n=454) (Bigger 1997). Only 50% of the patients had prior myocardial infarction but all the patients received epicardial ICD systems. ICD therapy showed no survival benefit over conventional medical therapy (HR 1.06, 95% CI of 0.81 to 1.42, p=0.64). The lack of benefit of ICD therapy in this trial could be due to the methods used for patient selection, but most likely is due to the effects of complete revascularization on the risk of sudden cardiac death. In a subanalysis of Studies of Left Ventricular Dysfunction (SOLVD) trial, CABG was found to be associated with a 36% relative risk reduction of all cause mortality and a 46% reduction of sudden cardiac death regardless of the severity of heart failure or the decrease in the LVEF. This might have contributed to the lack of benefit from ICD early after coronary artery bypass surgery (Veenhuyzen et al. 2001).

The Second Multicenter Automatic Defibrillator Implantation Trial (MADIT- II) randomized 1232 patients in a 3:2 fashion with LVEF < 30% and prior MI to receive an ICD (n=742) compared to medical therapy (n=490). Patients were excluded if they had a recent MI (<1 month), if they had revascularization in the past 3 months prior to randomization or if they were New York Heart Association (NYHA) class IV at enrollment. Mean follow up was for 30 months and primary end point was all cause mortality. ICD therapy was associated with a 31% reduction in relative risk of death at 20 months (HR 0.69, 95% confidence interval of 0.53 to 0.93, p = 0.02) (Moss et al. 2002). There was no difference in subgroup analysis based on age, gender, ejection fraction, QRS duration as well as NYHA class in terms of ICD benefit. All ICD implantations were transvenous lead systems. No deaths were related to the implantation procedure and the complication of lead implantation was 1.8% and infection rate was 0.7%. Analysis of the mortality events showed that ICD therapy mainly prevented sudden cardiac death (HR 0.33, 95% CI of 0.2 to 0.53, p<0.001) but did not affect non-sudden cardiac death (p=0.32).

Even though MADIT-II did not require electrophysiologic testing as an entry criterion, the investigators sought to evaluate the predictive value of EP study to predict mortality and ICD efficacy as a pre-specified secondary endpoint. Patients assigned to the ICD group were encouraged to undergo an EP study and they received the ICD regardless of the results of the electrophysiologic testing. Of the 720 patients who received an ICD, only 593 patients underwent EP testing. A positive EP study was defined as sustained monomorphic or polymorphic VT induced with 3 or fewer extrastimuli or VF induced with 2 or fewer extrastimuli. A positive EP study according to this standard protocol did not predict the pre-specified primary endpoint of spontaneous VT or VF requiring treatment by the ICD (p=0.28). Patients with inducible VT were more likely to have VT during follow up (0.023) compared to patients with no inducible VT (Daubert et al. 2006). This confirms the findings of MUSTT-I trial in regards to the utility of EP testing in risk stratifying patients with coronary artery disease and LVEF < 35%.

Another subanalysis of MADIT-II trial showed that patients with ICD therapy who underwent coronary revascularization within 6 months of randomization had no survival benefit from ICD therapy compared to patients in the conventional treatment group (HR = 1.19; p = 0.76), while patients with ICD therapy who were randomized > 6 months after coronary revascularization had significant survival benefit from ICD therapy (HR =0.64, p = 0.01) after adjusting for other important clinical variables (Goldenberg et al. 2006). Furthermore, mortality risk in patients in MADIT II was shown to be time dependent, with benefit extending even for patients who had remote MI (>15 years) (Wilber et al. 2004). Two studies were conducted examine the benefits of ICD therapy early after myocardial infarction (MI). The first is The Defibrillators in Acute Myocardial Infarction Trial (DINAMIT) which was designed to evaluate the potential for ICD benefit early (6 to 40 days) after a MI in patients with LVEF <35%, and abnormal autonomic tone [high resting heart rate over 80 beats per minutes (bpm) or low heart rate variability]. Patients were excluded if they had three-vessel coronary intervention, if they already had an ICD or if they were planned to undergo coronary artery bypass graft surgery (CABG). A total of 647 patients were randomized to optimal medical therapy (n=342) or ICD therapy (n=332) (Hohnloser et al. 2004). The primary end point was all cause mortality and the secondary end point was arrhythmic death. After a mean follow up of 30 months, there was no overall survival benefit attributable to early implantation of an ICD compared to medical therapy [HR 1.08; 95% confidence interval (CI), 0.76 to 1.55; P=0.66]. The ICD group had less arrhythmic death compared to the medical therapy group (HR in the ICD group, 0.42; 95% CI, 0.22 to 0.83; P=0.009). There was an increase in non-sudden cardiac death in the ICD group compared to the medical therapy group (HR = 1.75; 95% CI, 1.11 to 2.76; P=0.02).

The second trial is the Immediate Risk Stratification Improves Survival (IRIS) Trial, which was a randomized, open label multicenter trial that studied the benefit of ICD therapy early after MI compared to optimal medical therapy. Patients were included if they had a history of myocardial infarction (5 to 31 days after MI), LVEF < 40% with either a baseline heart rate of > 90 bpm, non-sustained VT at >150 bpm on holter or both. A total of 898 patients were enrolled in the trial. Mean follow up was for 37 months, and almost 75% of the patients underwent revascularization. Most of the patients were on beta blockers (97% in the ICD group and 95% in the control group) and angiotensin receptor blockers (90% in ICD group and 91.1% in the control group). There was no difference in overall mortality between ICD group and the medical treatment group (HR 1.04, 95% CI of 0.81 to 1.35, p=0.78) (Steinbeck et al. 2009). Patients assigned to ICD therapy had lower incidence of sudden cardiac death (HR 0.55, 95% CI of 0.31 to 1.00, p = 0049) but higher incidence of non-sudden cardiac death (HR 1.92, 95% CI of 1.29 to 2.84).

The reasons for the lack of benefit of ICD therapy early after MI might never be known. Revascularization has a protective effect and leads to reverse remodeling especially if done in a timely fashion early after MI. Patients who died early in DINAMIT had pump failure. Other possibilities include side effects for ICD implantation early after MI or the negative effects of shocks or antitachycardia pacing on myocardial contractility.

In summary, the above trials support the use of ICD therapy for primary prevention of SCD in chronic ischemic cardiomyopathy. For patients who suffered a recent MI (<40 days), both IRIS and DINAMIT showed a decrease in arrhythmic death but no difference in all cause mortality. Currently, the guidelines support ICD therapy in patients with CAD who are > 40 days post MI and have LVEF < 35%.

Next post:

Previous post: