Secondary prevention of sudden cardiac death

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1 Secondary prevention of sudden cardiac death Balbir Singh, MD, DM; Lakshmi N. Kottu, MBBS, Dip Card, PGPCard Department of Cardiology, Medanta Medcity Hospital, Gurgaon, India Abstract All randomised secondary prevention of sudden death trials have shown ICD therapy is superior to anti-arrythmic drug therapy. Salvage rate for patients with sudden cardiac arrest is <2% in general population, so it makes sense to use defibrillators for preventing sudden cardiac death (SCD). The patient group likely to benefit from ICD therapy are (1) Survivors of cardiac arrest caused by VT/VF, (2) VT with syncope, (3) Asymptomatic VT with LVEF less than 35%, (4) Genetic syndromes that predisposes to sustained VT/VF including long QT, short QT syndromes, Brugada syndrome, Catecholaminergic polymorphic VT, Idiopathic VF. ICD therapy remains the only known effective method for protection of patients at this high risk. Key Words Secondary prevention Sudden cardiac death ICD AVID DUTCH CASH CIDS trials Introduction Despite numerous efforts in recent years, preventing sudden cardiac death (SCD) still remains a challenge in modern cardiology. It remains one of the most important causes of death. No exact data on the real incidence of cardiac arrest exist, and reported values vary between /00 population per year. This variability can be explained by the different methods used to gather data and by the difficulty in classifying sudden death.two thirds of these deaths occur out of hospital, the rhythm observed in victims of out-of-hospital cardiac arrest depends on the time elapsed between collapse and the first ECG recording, and ventricular fibrillation (VF) accounts for 95% of 2 cardiac arrests if this interval is <4 min. In most cases SCD occurs in patients with structural heart 3,4 disease. Coronary artery disease (CAD) undoubtedly represents the most frequent cause of cardiac arrest, responsible for 80% of the cases. About 20% of CAD have cardiac arrest as the first clinical manifestation which otherwise can occur during the course of the patient s clinical history. The most important independent predictive factor for SCD in these patients is left ventricular dysfunction. The present review focuses on secondary prevention of sudden death which means the patient has already had a cardiac arrest or aborted sudden death or ventricular tachycardia or unexplained syncope with an underlying substrate for sudden death. Secondary prevention Received: ; Revised: ; Accepted: Disclosures: This article has not received any funding and has no vested commercial interest Acknowledgements: None Patients resuscitated out of cardiac arrest Patients resuscitated from cardiac arrest are at very high 667

2 Singh B, et al risk of SCD, with a mortality rate of 45% at 2 years. In the 1980s, ICD therapy was used with caution because there was some concern that the ICD would simply change the mode of death without modifying survival. Trials subsequently demonstrated the superiority of ICDs with respect to standard medical treatment in reducing both SCD and total mortality. The first trial to investigate the use of ICDs in secondary 5 prevention was the DUTCH study which began to enroll patients in It included 60 patients who survived SCD following a documented ventricular tachycardia (VT)/VF; they were randomized to either conventional drug treatment or ICD therapy. A 63% reduction of mortality was observed in the group of patients treated with an ICD. The enrollment in another secondary prevention trial, 6 CASH (Cardiac Arrest Study Hamburg), began in Patients who had survived cardiac arrest caused by a documented ventricular arrhythmia were randomized to receive either an ICD or one of the three drugs considered the most effective in prevention of SCD propafenone, metoprolol, and amiodarone. The primary end point was all cause mortality, and the secondary end points were SCD and cardiac arrest. After 5 years, the surveillance committee of the study recommended the interruption of the propafenone arm because of significant excess of mortality (29%) and cardiac arrests compared to the ICD arm. The results demonstrated that in patients treated with an ICD there was a 23% reduction of total mortality at 2 years with respect to patients treated with metoprolol or amiodarone (statistically borderline). The secondary end point of freedom from SCD was significantly greater in patients assigned to ICD therapy than in those assigned to drug treatment, with a 61% reduction of SCD in the ICD group. 7 CIDS (Canadian Implantable Defibrillator Study) enrolled patients with cardiac arrest caused by VF; it also included patients with sustained VT causing syncope, patients with poorly tolerated VT and left ventricular ejection fraction (LVEF) of 40% or less, and patients with syncope and inducible or monitored VT. A total of 659 patients were enrolled and randomized to ICD or amiodarone treatment. The results showed a 20% relative risk reduction of all-cause mortality and a 33% reduction of arrhythmic mortality with ICD therapy compared to amiodarone treatment; this reduction did not reach statistical significance but it came very close (p = 0.09). The analysis of the cause specific mortality in this study supports the presumed mechanism of action of ICD therapy which is to prevent deaths caused by ventricular arrhythmia. A multivariate analysis of the CIDS data was carried out in order to identify those patients who would 668 most likely benefit from treatment with an ICD. Considering the three variables which were significant predictors of all-cause mortality in the amiodarone treated group [increasing age, decreasing LVEF, and New York Heart Association (NYHA) functional class], patients were divided into four equally sized quartiles of ascending risk of death. The principal finding of this analysis was that patients most likely to benefit from ICD therapy are those at highest risk of death, with at least two of the following characteristics: age >70 years, LVEF (35%, and presence of NYHA class III or IV. In this group of patients ICD 8 determined a 50% relative risk reduction of mortality. The biggest trial on secondary prevention of SCD, comparing ICD and drug treatment (amiodarone, sotalol) is the AVID (Antiarrhythmics versus Implantable 9 Defibrillators) trial which enrolled 1,016 patients. It included patients with cardiac arrest caused by VF/VT, patients with VT and syncope, and patients with VT and LVEF <40%. After a mean (SD) follow-up of 18.2 (12.2) months, the study was interrupted prematurely because of a significant reduction of mortality in the ICD arm (39% at 1 year). Again, the greatest benefit was observed in patients with low ejection fractions (LVEF 35%), whereas similar benefits were observed in patients with either VF or VT as index arrhythmia. Further data were obtained from the AVID registry which included all 4,595 patients screened and registered, regardless of whether they were randomized or not. Of the patients screened, only those with a reasonable likelihood of being eligible to receive antiarrhythmic drug treatment, ICD therapy, or both were registered. The registered patients were divided into six groups according to the presenting arrhythmia: VF, VT with syncope, symptomatic VT, asymptomatic VT, VT/VF of transient/correctable cause, and unexplained syncope with inducible VT. A high mortality rate was noted for all six groups, with 2 year survival rates ranging from 76% in patients presenting with syncopal VT to 84% in patients with unexplained syncope. The surprisingly high and similar mortality across the arrhythmia subgroups were not explained by multivariate analysis looking at baseline risk predictors, such as ejection fraction or antiarrhythmic treatment. Another analysis of the AVID registry compared patients with stable ventricular tachycardia, who were felt to be at low risk and not subsequently randomized in the AVID trial, with patients with unstable VT. The mortality in 440 patients with stable VT tended to be greater than that observed in 29 patients presenting with unstable VT [33.6% vs 27.6% at 3 years; relative risk (RR) 1.22; p = 0.97]. After adjustment for baseline and treatment differences, the relative risk was little changed (RR = 1.25, p = 0.06). These data suggest that patients with stable VT

3 Secondary prevention of SCD are still at high risk for SCD and may benefit from ICD therapy. Conclusions The main clinical trials on secondary prevention of SCD are summarized in Table 1 and Figure 1. The patient groups likely to benefit from ICD therapy are the following: Survivors of cardiac arrest caused by VT/VF: In practice, this group is very small since even with the best ambulance services very few survive, automatic external defibrillators (AED) are being promoted so that more patients could receive timely therapy for this deadly event, but have limitations in wide scale applicability. VT with syncope: Syncope during VT usually happens when ventricular function is poor or VT is rather rapid and is generally associated with poor prognosis. However, it must be clearly understood that even an idiopathic VT.which is VT with a normal heart, can sometimes cause syncope but is generally very amenable to radiofrequency ablation therapy which can offer a cure in vast majority of patients and ICD therapy would thus be avoided in this group of patients. Asymptomatic VT: This group is some what controversial since a hemodynamic stable VT in the setting of structural heart disease or otherwise responds well to ablation, it is felt by most experts that ICD should be reserved for only those with LVEF less than 35% with or with out ablation. VT/VF due to a reversible cause: Electrolyte disturbances or ischemia are truly most important reversible causes in this setting, all tests must be carried including coronary angiography. Specific disease states and secondary prevention of sudden death The majority of patients included in the above prospective randomized trials of patients resuscitated from cardiac arrest have had coronary artery disease with impaired ventricular function. Patients with other types of structural heart disease constitute a minority of patients in the secondary prevention trials. However, supplemental observational and registry data support the ICD as the preferred strategy over antiarrhythmic drug therapy for secondary prevention for patients resuscitated from cardiac arrest due to VT or fibrillation with coronary artery disease and other underlying structural heart disease. Coronary artery disease (CAD) Evidence strongly supports a survival benefit in such patients with an ICD compared with other therapy options.patients experiencing cardiac arrest due to VF that occurs more than 48 hours after a myocardial infarction (MI) may be at risk for recurrent cardiac arrest. It is recommended that such patients be evaluated and optimally treated for ischemia. Nonischemic dilated cardiomyopathy (DCM) Patients with nonischemic DCM and prior episodes of VF or sustained VT are at high risk for recurrent cardiac arrest. Empirical antiarrhythmic therapy or drug therapy guided by electrophysiological testing has not been demonstrated to improve survival in these patients.. On the basis of these data, the ICD is the preferred treatment for patients with nonischemic DCM resuscitated from prior cardiac arrest from VF or VT. Hypertrophic cardiomyopathy (HCM) HCM is an inherited heart muscle disease that affects approximately 1 out of every 500 persons in the general population and is the most common cause of cardiac arrest in individuals younger than 40 years of age. HCM should be suspected as the cause of cardiac arrest in young individuals during exertion, because exercise increases the risk of life-threatening ventricular arrhythmias with this condition. A history of prior cardiac arrest indicates a substantial risk of future VT or VF with this condition. In those patients with HCM resuscitated from prior cardiac arrest, there is a high frequency of subsequent ICD therapy Table 1: Trials in secondary prevention of SCD Trial Year No. of pts Enrollment criteria Results AVID DUTCH CASH CIDS Survivor of VT/VF, H/O syncope or VT with EF <40% Survivor of VT/VF and MI >4wks old Cardiac arrest due to VT/VF Survivor of VT/VF, H/O syncope or VT with EF <40% 31% mortality reduction 63% mortality reduction 23% mortality reduction 20% mortality reduction 669

4 Singh B, et al 50 Death 50 Death Amio 20 ICD Number at risk Years ICD: Amio: Amio ICD Years Figure 1 Meta-analysis of AVID/CASH/CIDS trials Cumulative risk of fatal events or the amiodarone(...) and ICD ( ) treatment arms. for life-threatening ventricular arrhythmias. On the basis of these data, the ICD is the preferred therapy for such patients with HCM resuscitated from prior cardiac arrest. Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/C) is a genetic condition characterized by fibrofatty infiltration of the RV and less commonly the LV. It usually manifests clinically with sustained monomorphic VT with left bundle morphology in young individuals during exercise. There are no prospective randomized trials of pharmacological therapy versus ICD therapy in patients with ARVD/C for secondary prevention of SCD; however, observational reports from multiple centers consistently demonstrate a high frequency of appropriate ICD use for life-threatening ventricular arrhythmias and a very low rate of arrhythmic death in patients with ARVD/C treated with an ICD. Genetic arrhythmia syndromes Genetic syndromes that predispose to sustained VT or VF include the long- and short-qt syndromes, Brugada syndrome, idiopathic VF, and catecholaminergic polymorphic VT. These primary electrical conditions typically exist in the absence of any underlying structural heart disease and predispose to cardiac arrest. Although controversy still exists with regard to risk factors for sudden death with these conditions, there is consensus that those with prior cardiac arrest or syncope are at very high risk for recurrent arrhythmic events. On the basis of the absence of any clear or consistent survival benefit of pharmacological therapy for those individuals with these genetic arrhythmia syndromes, the ICD is the preferred therapy for those with prior episodes of sustained VT or VF and may also be considered for primary prevention for some patients with a very strong family history of early mortality. Syncope with inducible sustained ventricular tachycardia Patients with syncope of undetermined origin in whom c l i n i c a l l y r e l e v a n t V T / V F i s i n d u c e d a t electrophysiological study should be considered candidates for ICD therapy. In these patients, the induced arrhythmia is presumed to be the cause of syncope. In patients with hemodynamically significant and symptomatic inducible sustained VT, ICD therapy can be a primary treatment option. Antiarrhythmic and non-antiarrythmic drugs for sudden cardiac prevention Only a few antiarrythmic drugs and non-antiarrythmic drugs play an important role in the prevention of SCD. Class I drugs should not be used to prevent VT/VF because they increase the risk of SCD and all-cause mortality. β- blockers prevent SCD in CAD and CHF. Carvedilol may have advantages over other β-blockers in this setting. Class III drugs treat and prevent VT/VF with a variable effect on SCD and all-cause mortality. Amiodarone has been demonstrated to decrease the risk or, at least, it has a neutral effect on the risk of SCD. Class IV drugs have a limited use in prevention of SCD. Class I, II, and III AADs are used for acute management VT/VF. Class III drugs are preferred to prevent recurrent ICD shocks. Most patients who have a propensity to VT/VF should receive a β-blocker. Statins, ACE inhibitors, ARBs, and aldosterone blockers have delayed or indirect antiarrhythmic effects that are 670

5 Secondary prevention of SCD expressed predominantly by a decrease in the rate of SCD and all-cause mortality in patients who have structural heart disease. Statins should be used in patients who have CAD. Recent evidence suggests that fish oil may not prevent SCD. The role of chronic AAD therapy alone, for primary and secondary prevention of SCD, is less than desired. Therefore, these drugs should be used judiciously so that the benefits of AAD therapy will outweigh risks of proarrhythmia and other adverse effects. References 1. Becker LB, Smith DW, Rhodes KV. Incidence of cardiac arrest: A neglected factor in evaluating survival rates. Ann Emerg Med. 1993;22: Myerburg RJ, Castellanos A. Cardiac arrest and sudden death. In: Braunwald E, ed. Heart disease: A textbook of cardiovascular medicine. Philadelphia: WB Saunders, pp Yap Y, Duong T, Bland M, et al. Left ventricular ejection fraction in the thrombolytic era remains a powerful predictor of long-term but not short term all cause, cardiac and arrhythmic mortality after myocardial infarction- a secondary meta-analysis of 2828 patients. Heart. 2000;83: Wever EFD, Hauer RNW, van Capelle FJL, Tijssen JGP, Crijns HJGM, Algra A, et al. Randomized study of implantable defibrillator as first-choice therapy versus conventional strategy in post infarct sudden death survivors. Circulation. 1995;91: Kuck KH, Cappato R, Siebels JH, Rüppel R. Randomized comparison of antiarrhythmic drugs therapy with implantable defibrillators in patients resuscitated from cardiac arrest. The Cardiac Arrest Study Hamburg (CASH). Circulation. 2000;2: Connolly SJ, Gent M, Roberts RS, Dorian P, Roy D, Sheldon RS, et al. Canadian Implantable Defibrillator Study (CIDS): A randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000;1: Sheldon R, Connolly S, Krahn A, Roberts R, Gent M, Gardner M. Identification of patients most likely to benefit from implantable cardioverter-defibrillator therapy: the Canadian Implantable Defibrillator Study. Circulation. 2000;1: A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators. N Engl J Med. 1997;337: The Sicilian gambit. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. Task Force of the Working Group on Arrhythmias of the European Society of Cardiology. Circulation. 1991;84: Das MK, Zipes DP. Antiarrhythmic and nonantiarrhythmic drugs for sudden cardiac death prevention. J Cardiovasc Pharmacol. 20;55: Address for correspondence Dr. Balbir Singh: drbalbirs@gmail.com 671