Who Needs An ICD? Cesar Alberte, MD, Douglas P. Zipes, MD, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN Sudden cardiac arrest is one of the most common causes of death in developed countries. It has an incidence of 3 million cases/year worldwide and an overall survival rate 1%. In the US, 450,000 people die suddenly every year, and only 5% are successfully resuscitated. The most common underlying cause is ischemic heart disease, present in about 80% of the cases. The results of recent clinical trials have broadened the indications for implantable cardiodefibrillator (ICD) implantation beyond the cardiac arrest survivor. The purpose of this review is to analyze the different clinical presentations of patients for whom an ICD becomes the primary therapeutic modality and the clinical studies that support its efficacy (Figure 1). Indications for an ICD Secondary Prevention of Sudden Cardiac Death Historical controls from studies in the 1970s and early 1980s suggest that the recurrence rate in survivors of sudden cardiac death (SCD) approximates 15 25% per year. Current medical therapy in high-risk SCD survivors has reduced the rate of SCD to 1 2% per year. Because most of these patients have significant coronary artery disease, they die from heart failure. This shifts the cause of death from arrhythmic to non-arrhythmic, making total mortality a necessary end point of any clinical trial assessing the use of ICD as secondary prevention. Secondary prevention trials. Three landmark clinical trials (Table 1) support the use of ICD therapy in survivors of SCD with ischemic heart disease. The Cardiac Arrest Survival in Hamburg (CASH) randomized 349 cardiac arrest survivors regardless of the underlying disease or ventricular function to ICD, amiodarone, metoprolol or propafenone. After 2 years, there was a significant difference in SCD rate favorable to the ICD, but there was no difference in total mortality between ICD, amiodarone, or metoprolol. Because of increased mortality in the group taking propafenone, this agent was discontinued for the rest of the trial. After a 5-year, there was a 23% reduction in total mortality in patients receiving an ICD compared to those treated with amiodarone and metoprolol. However, when amiodarone and metoprolol were analyzed separately, the significant difference among the three groups was lost. The Antiarrhythmic Drug Vs. Implantable Defibrillator (AVID) trial enrolled 1016 patients with previous ventricular tachycardia (VT), ventricular fibrillation (VF) or arrhythmia-related syncope for randomization of ICD vs. sotalol or amiodarone (most of the drug patients received Arrhythmias Focused Review amiodarone). At 3 years, the ICD provided a 31% relative reduction and a 7% absolute reduction in total mortality. An analysis of mortality based on the left ventricular ejection fraction (LVEF) further clarified the impact of the study. In patients with a LVEF 35%, there was no difference in survival between either group; in patients with LVEF 20 34%, ICD had the greatest benefit; finally, in patients with LVEF 20%, there was a nonstatistically significant mortality reduction in the ICD group. The Canadian Implantable Defibrillator (CIDS) used similar enrollment criteria as AVID (but also included patients with unexplained syncope who had VT induction during electrophysiologic testing) to randomize 659 patients to amiodarone or ICD. After a 5-year, the total mortality was not significantly reduced with the ICD compared to amiodarone, and there was also a nonsignificant reduction in arrhythmic death. With the use of a multivariate risk model and applying age (older than 70 years), LVEF (equal or less than 35%) and NYHA class (III or IV) as independent predictors of risk, there was significant reduction of death from the ICD in patients with two or more risk factors. Individually, and when combined in a meta-analysis, these three trials support the following ICD indications for secondary prevention of SCD: 1. Spontaneous sustained VT or VF not due to a transient or reversible cause (Class I Indication). 2. Syncope of undetermined origin with clinically relevant, hemodynamically sustained VT or VF induced at electrophysiologic study when antiarrhythmic drug therapy is ineffective, not tolerated or not preferred (Class I Indication). Primary Prevention of SCD in Ischemic Heart Disease Because SCD frequently can be the initial clinical presentation of ischemic heart disease, a major effort has been undertaken to identify therapeutic strategies for primary prevention. The Multicenter Automatic Defibrillator Implantation trial (MADIT) was the first study to demonstrate the benefit of an ICD for primary prevention of SCD in a high-risk, asymptomatic population. A total of 196 patients with a prior myocardial infarction, LVEF less than 35%, nonsustained VT and inducible sustained monomorphic VT that was unresponsive to procainamide were randomized to ICD vs. antiarrhythmic therapy (primarily amiodarone). This very high-risk group experienced a 54% reduction in total mortality and a 75% reduction in arrhythmic mortality with ICD therapy. At about the same time, the CABG Patch trial enrolled 900 patients undergoing coronary bypass surgery with LVEF 35% and a positive signal-averaged ECG, to receive concomitant ICD vs medical therapy to 2002 by the American College of Cardiology 1062-1458/02/$22.00 Published by Elsevier Science Inc. PII S1062-1458(02)00867-X 77
Figure 1. Who Needs an ICD? reduce risk of arrhythmic death. No reduction in total mortality was found. Another landmark trial was the Multicenter Unsustained Tachycardia (MUSTT) trial that included 704 patients with coronary artery disease, asymptomatic nonsustained VT, an LVEF 40% and inducible VT in an electrophysiology study. Patients were randomized to no therapy or electrophysiologically guided antiarrhythmic therapy or an ICD if at least one antiarrhythmic agent was ineffective. At 5 years, the treated group had a reduction in total mortality and arrhythmic death of 55 60%, and this was virtually entirely attributed to ICD therapy, with no difference in outcome between patients receiving no therapy and those treated with an antiarrhythmic drug alone. The demonstration in the MADIT and MUSTT trials of a consistent superiority of ICD therapy over drug therapy has made unnecessary the requirement to show failure of a class I antiarrhythmic agent before implanting an ICD. Importantly, a registry of patients from MUSTT with noninducible VT showed a 44% death rate at 5 years. This observation can be related to the results of a recent trial that will broaden the indications for ICD: the MADIT-II trial. In this trial, patients with prior Table 1. ICD Trials for Primary and Secondary SCD Prevention Trial Number of Patients Enrolled Enrollment Criteria Event Rates in the ICD Arm Event Rates in the Non-ICD Arm Conclusion CASH 288 SCD survivors with documented ventricular arrhythmia AVID 1016 SCD survivors; sustained VT with syncope; hemodynamically significant sustained VT with EF 40% CIDS 659 SCD survivors; sustained VT with syncope; hemodynamically significant sustained VT with EF 35%; unmonitored syncope with previously known VT MADIT 196 Prior MI; EF 35%; asymptomatic NSVT; inducible VT on EPS CABG-Patch 1055 Elective CABG; EF 35%; abnormal signal-averaged ECG MUSTT 704 CAD, EF 40%; asymptomatic (161 received ICD) NSVT; inducible VT on EPS 36.4% mortality rate 44.4% mortality rate 23% nonsignificant reduction in all-cause mortality in the ICD group after 5-year 15.8% mortality rate 24% mortality rate 31% significant reduction in all-cause mortality in the ICD group after 3-year 6.7% cardiac death per year 8.6% cardiac death per year 20% nonsignificant reduction in all-cause mortality in the ICD group after 3-year 15 deaths 39 deaths 54% significant reduction in all-cause mortality in the ICD group after 27- month mean 101 deaths 95 deaths No improved survival with ICD 24% mortality rate 55% mortality rate 55% significant reduction in all-cause mortality in the ICD group after 5-year MADIT II 1232 Prior MI, EF 30% 14.2% mortality rate 19.8% mortality rate 31% significant reduction in all-cause mortality in the ICD group after 20- month mean 78
myocardial infarction and LVEF 30% were included. No ventricular arrhythmia was required. A total of 1232 patients were randomized to ICD vs. conventional postmyocardial infarction medical therapy. The ICD group had a 31% reduction in total mortality, supporting a potential indication of an ICD for postmyocardial infarction patients with significant reduction of LVEF. Additional future analysis of different clinical subgroups of patients participating in MADIT-II will probably clarify which patients derive the major benefits of an ICD. These trials support ICD indications as primary prevention of SCD in patients with ischemic heart disease who have: 1. Nonsustained VT with coronary disease, prior MI, LVEF 35% and inducible VF or sustained VT at EP study that is not suppressible by a Class I antiarrhythmic drug (Class I Indication). 2. Nonsustained VT with coronary artery disease (CAD), prior MI, LVEF 40% and inducible sustained VT or VF at EP study (Class IIb Indication). 3. Prior MI and LVEF 30%. This indication has not yet been approved but is likely to be in the near future. Primary Prevention of SCD in Nonischemic Dilated Cardiomyopathy The indication of an ICD as prophylactic therapy for SCD in patients with nonischemic dilated cardiomyopathy is still uncertain. Risk stratification of these patients is difficult because there are few clinical predictors specific for SCD. A study currently in progress, the SCD-HeFT trial, compares the mortality benefit of an ICD vs. amiodarone and placebo in this patient population. A smaller trial, the Cardiomyopathy Trial (CAT), was prematurely terminated due to the absence of mortality benefit from ICD vs. medical therapy. The only current indication for ICD implantation in this population is secondary prevention after an episode of resuscitated sudden death or the presence of VT-induced syncope (Class I Indication). Syncope The approach to patients presenting with syncope with a background of ischemic heart disease was discussed earlier. An electrophysiology study to evaluate for the presence of sustained ventricular arrhythmias is indicated. Patients with advanced non-ischemic cardiomyopathy presenting with syncope also have a very high risk of SCD. A very small study done nearly 10 years ago examined patients with idiopathic dilated cardiomyopathy, unexplained syncope and a negative electrophysiology study. This cohort received an ICD and during, 50% of these patients had an appropriate shock by the device over a 2-year period. We believe that patients with unexplained syncope should be referred for electrophysiology study to assess their need for ICD despite the limited data regarding this question. T-wave alternans is a promising non-invasive risk stratifier that may be equivalent to or better than electrophysiology study when applied to high-risk populations. Its value in low-risk patients still needs to be validated in a large population study. Long QT and Brugada Syndrome The decision-making process for secondary prevention of SCD in these two conditions is very simple: an ICD is indicated. A similar approach should be used for the patient with sustained ventricular arrhythmias or recurrent syncope despite medical therapy. Implantation of an ICD in patients with long QT syndrome must not replace additional therapy with beta-blockers. The possible intensification of a sympathetic discharge induced by painful shocks can trigger a storm of torsade de pointes. A more difficult decision is the patient with electrocardiographic manifestation of Brugada or long QT in the absence of symptomatic arrhythmias and/or a family history of SCD. Currently, there is no single or uniform approach to these syndromes, but the threshold to proceed with ICD implantation is decreasing. An individual approach with participation in the final decision by a well-informed patient and family is indicated. Hypertrophic Cardiomyopathy As with long QT and Brugada syndromes, an ICD is indicated as secondary prevention of SCD. For primary prevention, all the screening tests used in other organic heart diseases for potentially lethal ventricular arrhythmias (electrophysiology study, signal-averaged ECG, heart rate variability, continuous ambulatory ECG monitoring, T-wave alternans) have a poor predictive value in hypertrophic cardiomyopathy. Consequently, there is a consensus that the low-risk patient does not need prophylactic therapy. Low risk is defined as an asymptomatic individual with no family history of sudden death, no ventricular arrhythmia, a normal blood pressure response to exercise and a septum 30 mm. The identification of high-risk patients is more problematic, but the presence of two or more of the following risk factors should prompt the decision for ICD placement: family history of sudden death, unexplained syncope, younger than 40 years of age, the presence of abnormal blood response during exercise, severe and diffuse left ventricular hypertrophy (particularly if the maximum wall thickness exceeds 30 mm). There have been attempts to classify patients on the basis of their genetic abnormality, but this approach is not yet fully defined nor is it widely available. Arrhythmogenic Right Ventricular Dysplasia Patients with arrhythmogenic right ventricular dysplasia who present with cardiac arrest, sustained VT, or unequivocal syncope must receive an ICD. For primary prevention, individuals with extensive myocardial disease, frequent episodes of nonsustained ventricular tachycardia, and/or a familial history of unexpected sudden death, should be also 79
offered ICD therapy. Finally, any patient with this uncommon diagnosis must be educated regarding his underlying risk and discuss the option of ICD implant as preventive therapy. Contraindications for an ICD The presence of syncope of undetermined etiology in a patient without documented or inducible sustained VT, who does not fit into one of the above categories, is not an indication for an ICD. Patients whose arrhythmias are due to a transient or reversible disorder, such as acute MI, drug ingestion or trauma have been thought not to have a very high risk of recurrence and should not receive an ICD. While recent data from the AVID trial have questioned the validity of that conclusion, the issue is not yet resolved. The presence of incessant VT or VF is a contraindication for ICD therapy. Drug therapy or catheter ablation are therapeutic options, possibly combined with an ICD. Patients with specific arrhythmias that have a definitive cure with catheter or surgical ablation (e.g., VT from right ventricular or left outflow tract, verapamil-sensitive ventricular tachycardia, Wolff-Parkinson-White syndrome, etc.) are generally not ICD candidates because they are thought to be cured by catheter ablation. Individuals with a projected life expectancy 6 months, including drug-refractory heart failure patients who are not candidates for cardiac transplantation, are not candidates for ICD therapy. Impact on Quality of Life by ICD The explanation of the risks and benefits of an ICD is particularly crucial when ICD implantation is offered as primary prevention. The fear of a shock, as well as lifestyle limitations, including driving restrictions in some patients, can outweigh the feeling of security from the ICD. The occurrence of inappropriate discharges for asymptomatic arrhythmias or sinus tachycardia, and the limited life of the device with the need for future procedures, should be discussed. Importantly, in the AVID trial, the quality of life in patients treated with drugs was the same as the ICD patients at 1 year. Summary The ICD, once called a device in search of a disease, has revolutionized the treatment of patients with life-threatening arrhythmias and ranks with the pacemaker as one of the most important therapeutic device advances for patients with life-threatening cardiac arrhythmias. Questions and Answers 1. A 35-year-old man undergoes a routine physical exam as part of a life insurance evaluation. An ECG reveals a pattern that could be consistent with Brugada syndrome. He denies any syncope or family history of sudden death. How would you proceed? A) He should receive an ICD. B) He should undergo an electrophysiology study to assess his risk of sudden death. C) There are not enough data to clearly define the strategy of his evaluation or to indicate ICD implantation at this time. 2. What is the mortality benefit from the use of ICD as secondary prevention therapy according to the AVID trial? A) There is an equal benefit between the use of ICD and antiarrhythmic drugs. B) At 3 years, ICD provided a 31% relative reduction in mortality. C) At 3 years, there was a relative reduction in mortality of 50% in the ICD group. 3. A 62-year-old woman presents to the Emergency Department with an acute myocardial infarction. She is being treated with thrombolytic therapy when she suffers cardiac arrest due to VF. She is appropriately treated and an echocardiogram before discharge indicates a normal LVEF. How would you manage this patient regarding her need for an ICD? A) This is a very high-risk patient for recurrence of SCD. An ICD should be implanted before discharge from the hospital. B) The patient should undergo an electrophysiology study to assess her need of an ICD. C) Her VF arrest was due to the presence of acute ischemia. There is no indication for an ICD. 4. A 22-year-old medical student presents with recurrent episodes of severe lightheadedness associated with palpitations. An echocardiogram ruled out the presence of organic heart disease, but a holter monitor recorded two episodes of sustained monomorphic VT with LBBB-pattern. A) The patient should be referred for electrophysiology study and possible ablation of his ventricular tachycardia. B) ICD is indicated. C) He should be started on amiodarone. If similar episodes recur on this therapy, ICD is the next option. 5. A 16-year-old presents with new onset of palpitations. During his evaluation at the Emergency Department, he is diagnosed with Wolff-Parkinson-White syndrome. He suddenly develops atrial fibrillation, inducing VF. He is resuscitated and referred to you for further management. A) The patient should undergo electrophysiology study for ablation of his accessory pathway. B) Genetic testing to rule out the presence of long QT syndrome is indicated. 80
C) An immediate conversation with his parents is necessary to explain his high mortality risk and obtain consent for ICD implantation. The correct answers are 1. C, 2. B, 3. C, 4. A, 5. A. Suggested Reading The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. N Engl J Med 1997;337: 1576 83. Bigger JT Jr. Prophylactic use of implanted cardiac defibrillators in patients at high risk for ventricular arrhythmias after coronary-artery bypass graft surgery. Coronary Artery Bypass Graft (CABG) Patch Trial Investigators. N Engl J Med 1997; 337:1569 75. Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med 1999;341:1882 90. Connolly SJ, Gent M, Roberts RS, et al. Canadian implantable defibrillator study (CIDS): A randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation 2000;101:1297 302. Gregoratos G, Cheitlin MD, Conill A, et al. ACC/AHA Guidelines for Implantation of Cardiac Pacemakers and Antiarrhythmia Devices: Executive Summary a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Pacemaker Implantation). Circulation 1998;97:1325 35. Kuck KH, Cappato R, Siebels J, Ruppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: The Cardiac Arrest Study Hamburg (CASH). Circulation 2000;102:748 54. Moss AJ, Hall WJ, Cannom DS, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med 1996;335:1933 40. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, Daubert JP, Higgins SL, Brown MW, Andrews ML. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346:877 83. Address correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, Indiana University School of Medicine, Methodist Hospital, Noyes Pavilion, 1800 North Capitol Ave., Indianapolis, IN 46202. 81