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Sudden Cardiac Death: The Problem, Data, Economics, ......

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  • Sudden Cardiac Death: The Problem, Data, Economics, ......

    Originally posted by ebstoltz May 6th, 2003 in a different forum, moved for topic consistency:

    Sudden Cardiac Death: The Problem, Data, Economics, and Solution Disclosures

    Eric N. Prystowsky, MD

    Sudden cardiac death (SCD) is a major epidemiologic problem for the United States, and the most recent data from the Centers for Disease Control and Prevention suggest it is not getting any better.[1] In 1999, SCD accounted for 462,340 (63.4%) of the 728,743 cardiac deaths that occurred in the United States. However, even among this large majority of deaths classified as cardiac and sudden, this is still a wide spectrum of etiologies. Coronary artery disease (CAD) is the most common pathologic finding in victims of SCD, but the cause is not always obvious. For example, some patients with previous myocardial damage from CAD may develop ventricular tachycardia (VT) or ventricular fibrillation (VF) unrelated to any ischemia, whereas in others, an acute ischemic event, even in a patient without previous evidence of CAD, results in VT or VF and SCD. Some other conditions associated with SCD include dilated and hypertrophic cardiomyopathy. Finally, a minority of these patients have primary electrical disorders of the myocardium, for example, long QT syndrome or Brugada syndrome.

    If we were able to reach and rescue victims of cardiac arrest quickly and efficiently enough that a great number of them could be successfully defibrillated with a normal neurologic status, then a "wait and respond" approach might be reasonable. Unfortunately, survival rates for out-of-hospital cardiac arrest in most communities are lower than 10% to 15%, thus precluding such an approach. The growing access to the automated external defibrillator will likely yield a small increase in survival from cardiac arrest, but if a major breakthrough is to occur, this will certainly require efforts to reduce the prevalence of CAD in the population. Until this can be achieved, our efforts need to be directed at identifying and applying the best methods for primary and secondary prevention of SCD.

    The Data
    Decades of research have resulted in our current approach to risk stratification and treatment for patients at high risk for SCD.[2-4] The research milestones of that journey will be reviewed briefly below.

    Drug Therapy
    The earliest attempts to prevent SCD centered on antiarrhythmic drugs to suppress so-called "warning arrhythmias" or malignant premature ventricular contractions (PVCs). This likely was influenced by the work of Lown and Wolf,[5] who developed a classification for varieties of PVCs that theoretically identified patients at risk for SCD. It followed that suppression of these arrhythmias might lead to a better outcome. Although the classification scheme was shown by other authors to have many shortcomings, the "PVC suppression" hypothesis took on a life of its own, and for years this was the "standard" approach for many physicians.

    In retrospect, analysis of the many small and large trials that were conducted using different antiarrhythmic agents to suppress PVCs in patients after MI shows that there was actually a trend toward increased mortality in patients receiving antiarrhythmic drugs. This issue was clarified in 1989 by the results of CAST (Cardiac Arrhythmia Suppression Trial),[6] a large randomized, placebo-controlled study that assessed and compared the effects of encainide or flecainide vs placebo in asymptomatic or mildly symptomatic post-MI patients. The trial was stopped prematurely when it was found that although encainide or flecainide markedly reduced PVCs, patients receiving these drugs had a significantly higher mortality rate than those in the placebo group. The results of a subsequent study, CAST II[7] using moricizine, also failed to show a survival benefit. Thus, the CAST trials appeared to destroy the "myth" of the PVC suppression hypothesis, and certainly changed the prescription patterns of antiarrhythmic drug use for this purpose in the United States.

    During the 1980s, the various antiarrhythmic drugs were categorized into a schema known as the Singh-Vaughan Williams Classification, and the consensus developed that the drugs grouped as class 1 were ineffective, or indeed potentially lethal, for treating arrhythmias. Attention turned to the "class 3" drugs, of which the most promising example appeared to be amiodarone.

    Amiodarone prescribed empirically, not by monitoring PVC suppression, seemed to provide the answer for those physicians who still felt antiarrhythmic drug therapy was useful in the primary prevention of SCD. Smaller studies suggested that when given to high-risk post-MI patients, amiodarone could reduce mortality. Two large, randomized, placebo-controlled trials were designed to test this hypothesis. EMIAT (European Myocardial Infarction Amiodarone Trial)[8] enrolled 1486 patients with left ventricular ejection fraction (LVEF) </= 0.40 after MI, and CAMIAT (Canadian Myocardial Infarction Amiodarone Trial)[9] entered 1202 patients after MI who had more than 10 PVCs per hour. However, neither EMIAT nor CAMIAT demonstrated a statistically significant reduction in all-cause mortality in the amiodarone-treated patients.

    Two additional trials in the mid-1990s evaluated the effect of empiric amiodarone therapy to reduce mortality in patients with congestive heart failure (CHF), yielding conflicting results. Doval and colleagues[10] showed a modest survival benefit in the amiodarone-treated group of patients, most of whom had nonischemic cardiomyopathy. By contrast, Singh and colleagues[11] studied a cohort of patients, the majority of whom had ischemic cardiomyopathy, and found no survival benefit to patients receiving amiodarone.

    Since that time, there have been no new positive antiarrhythmic drug results, and at the present time, my interpretation of these trials is that empiric amiodarone treatment has no role in the primary prevention of SCD in patients with CAD. More data are needed to define its role in patients with CHF and nonischemic cardiomyopathy.

    The Implantable Cardioverter Defibrillator (ICD)
    In contrast to antiarrhythmic drugs, the ICD has had a very different track record. In fact, in multiple large, well-controlled, randomized clinical trials, the ICD has consistently been shown to treat successfully life-threatening ventricular arrhythmias and prevent SCD. Three randomized, prospective, controlled trials addressed the issue of primary prevention of SCD.

    MUSTT (Multicenter Unsustained Tachycardia Trial) evaluated the hypothesis that antiarrhythmic therapy guided by electrophysiologic (EP) testing could reduce risk of cardiac arrest and SCD.[12] Eligible patients had CAD, nonsustained VT, and LVEF </= 0.40, and had to have sustained VT induced at EP study. Patients were randomized to antiarrhythmic therapy or to a true control group (no antiarrhythmic therapy). Of the patients randomized to EP-guided antiarrhythmic therapy, those receiving an ICD had significantly reduced total mortality and arrhythmic deaths compared to those receiving antiarrhythmic drugs, including amiodarone. The 5-year mortality rate was 24% and 55% for patients receiving an ICD or antiarrhythmic drug, respectively.

    Another study, MADIT (Multicenter Automatic Defibrillator Implantation Trial) enrolled patients who had CAD, nonsustained VT, and LVEF </= 0.35.[13] Eligible patients had to have sustained VT induced at EP study that was not suppressed with intravenous procainamide, in which case they were randomized to receive an ICD or conventional therapy that was left to the discretion of the investigator. Many of the latter subjects received empiric amiodarone treatment. Importantly, the ICD group had a 56% reduction in mortality compared with the conventional medical treatment group.

    Subsequently, MADIT II enrolled 1132 patients with CAD and LVEF </= 0.30, but with no requirement for either nonsustained VT or for VT inducible at EP study.[14] Patients were randomized to ICD or conventional therapy. The results showed mortality rates of 19.8% vs 14.2% for the conventional and ICD groups, respectively, a highly significant mortality advantage for the ICD. In summary, the ICD has provided the clinician with a powerful tool to prevent SCD in high-risk patients with CAD post MI.

    The ICD is also the winning therapy in the secondary prevention of SCD in patients who have demonstrated the ability to survive a life-threatening arrhythmia, eg, those with sustained VT or resuscitated from cardiac arrest. The AVID (Antiarrhythmics Versus Implantable Defibrillators) trial enrolled cardiac arrest survivors and those with sustained VT and syncope or LVEF </= 0.40 with sustained VT who had hypotension, chest pain, or presyncope.[15] Patients were randomized to either an ICD or amiodarone (although a few received sotalol). AVID demonstrated that the ICD reduced overall mortality by 39%, 27%, and 31% compared with amiodarone at 1, 2, and 3 years, respectively.

    Two other trials, CASH (Cardiac Arrest Study Hamburg)[16] and CIDS (Canadian Implantable Defibrillator Study),[17] showed a nonsignificant reduction in overall mortality among the ICD-treated patients, consistent with AVID. Taken together, these data provide strong support for the ICD as the preferred therapy for secondary prevention of SCD.

    The Economics
    On a data basis alone, the ICD should be the treatment of choice for secondary prevention of SCD and in high-risk subgroups of patients for primary prevention of SCD. The ACC/AHA/NASPE 2002 Guideline Update for ICD indications lists a Class I recommendation (conditions for which there is evidence and/or general agreement that a given procedure or treatment is useful and effective) for ICD therapy in patients who have:

    Survived a cardiac arrest;
    Spontaneous sustained VT with heart disease;
    Syncope with sustained VT at EP study;
    MADIT/MUSTT-like characteristics with sustained VT at EP study;
    Sustained VT with normal heart not amenable to other therapy.
    A Class IIa recommendation (conflicting evidence and/or a divergence of opinion, but weight of evidence/opinion is in favor of usefulness/efficacy) is given for the MADIT II type of patient. The ICD is costly therapy, and I have seen a variety of estimates that the expense of primary prevention for all patients with the MADIT II indication would be in the range of up to $1 billion annually in the United States alone. While few deny that the primary analyses of the 3 ICD trials showed superiority of the ICD for secondary prevention of SCD, subsequent subgroup analyses have focused on potential ways to reduce costs by searching for patients that might do reasonably well with amiodarone treatment. Overall, the group identified comprises those with LVEF > 0.35.[18,19]

    One must use caution in interpreting data that require prospective testing for confirmation, however. Further, the data to date are for the relatively short term, although a recent 11-year follow-up of one center's patients in CIDS showed that most of amiodarone-treated patients died, had recurrences, or developed side effects over time.[20]

    The Solution
    If we want to reduce the incidence of SCD, then we need to use the therapy that has been shown in randomized, prospective trials to be the most effective, and for the primary prevention of SCD for the MUSTT/MADIT and MADIT II patient subgroups discussed above, this is the ICD. There is no reasonable alternative other than simply not providing protective treatment to these patients. The largest insurance company in the United States, Medicare, will reimburse for the cost of an ICD in the MUSTT/MADIT-I patients. However, the Centers for Medicare and Medicaid (CMS) has not agreed to reimburse for the MADIT II indication, even though the Medicare Coverage Advisory Committee assembled to consider this question recommended that they do so (February 2003). In fact, CMS Acting Chief Clinical Officer, Sean Tunis, MD, has reportedly said that he is struggling with the issue of whether the ICD is more likely than not going to help people with this indication (The Gray Sheet, March 31, 2003).

    This seemingly endless delay by CMS to reimburse for the US Food and Drug Administration-approved MADIT II indication is creating a difficult situation for physicians who want to implant the ICD to save lives but do not wish to put their patients at significant financial risk if payment is denied. Hopefully, this will be resolved soon. Excellent patient care also dictates that the cardiologists trained to implant and program ICDs, ie, electrophysiologists, be involved in the decision and implant procedure, and not merely physicians with pacemaker implantation skills. The training required for ICD implantation is clearly documented in the American College of Cardiology Task Force on this issue.

    Regarding therapy for patients with proven sustained VT and heart disease and patients resuscitated from cardiac arrest, nothing is as effective as the ICD for patients with LVEF </= 0.35, and the ICD needs to be given to these patients unless other mitigating circumstances are present. While some would argue that, primarily for financial reasons, amiodarone is acceptable treatment for patients with LVEF > 0.35, I would ask: What you would do for your own family member? Would you truly give your mother, father, brother, sister, or spouse amiodarone rather than an ICD? If not, then please treat others with the same regard; I, for one, would certainly choose an ICD, while acknowledging that for societies that have economic constraints on the use of ICDs, amiodarone may be the best alternative for these patients with higher LVEFs.

    Glossary
    AVID = Antiarrhythmics Versus Implantable Defibrillators
    CAD = coronary artery disease
    CAMIAT = Canadian Myocardial Infarction Amiodarone Trial
    CASH =Cardiac Arrest Study HamburgCAST = Cardiac Arrhythmia Suppression Trial
    CIDS = Canadian Implantable Defibrillator Study
    CMS = Centers for Medicare and Medicaid
    EMIAT = European Myocardial Infarction Amiodarone Trial
    EP = electrophysiology
    ICD = implantable cardioverter defibrillator
    LVEF = left ventricular ejection fraction
    MI = myocardial infarction
    MADIT = Multicenter Automatic Defibrillator Implantation Trial
    MUSTT = Multicenter Unsustained Tachycardia Trial
    PVC = premature ventricular contraction
    SCD = sudden cardiac death
    VF = ventricular fibrillation
    VT = ventricular tachycardia

    References
    State-specific mortality from sudden cardiac death--United States, 1999. MMWR Morb Mortal Wkly Rep. 2002;51:123-126.
    Cannom DS, Prystowsky EN. Management of ventricular arrhythmias: detection, drugs, and devices. JAMA. 1999;281:172-179.
    Prystowsky EN. Primary and secondary prevention of sudden cardiac death: the role of the implantable cardioverter defibrillator. Rev Cardiovasc Med. 2001;2:197-205.
    Exner DV, Klein GJ, Prystowsky EN. Primary prevention of sudden death with implantable defibrillator therapy in patients with cardiac disease: Can we afford to do it? (Can we afford not to?). Circulation. 2001;104:1564-1570.
    Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation. 1971; 44:130-142.
    Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators. N Engl J Med. 1989;321:406-412.
    Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. The Cardiac Arrhythmia Suppression Trial II Investigators. N Engl J Med. 1992;327:227-233.
    Schwartz PJ, Camm AJ, Frangin G, Janse MJ, Julian DG, Simon P. Does amiodarone reduce sudden death and cardiac mortality after myocardial infarction? The European Myocardial Infarct Amiodarone Trial (EMIAT). Eur Heart J. 1994;15:620-624.
    Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet. 1997;349:675-682.
    Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R. Randomised trial of low-dose amiodarone in severe congestive heart failure. Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA). Lancet. 1994;344:493-498.
    Singh SN, Fletcher RD, Fisher SG, et al. Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia. Survival Trial of Antiarrhythmic Therapy in Congestive Heart Failure. N Engl J Med. 1995;333:77-82.
    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;341:1882-1890.
    Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H. 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;335:1933-1940.
    Moss AJ, Zareba W, Hall WJ, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883.
    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;337:1576-1583.
    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;102:748-754.
    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;101:1297-1302.
    Domanski MJ, Sakseena S, Epstein AE, Hallstrom AP, Brodsky MA, Kim S, et al. Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias. AVID Investigators. Antiarrhythmics Versus Implantable Defibrillators. J Am Coll Cardiol. 1999;34:1090-1095.
    Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg . Canadian Implantable Defibrillator Study. Eur Heart J. 2000;21:2071-2078.
    Bokhari FA, Newman D, Korley V, Greene M, Dorian P. Implantable cardioverter defibrillator vs. amiodarone: eleven years follow up of the Canadian Implantable Defibrillator Study. Circulation. 2002;106:II-497. Abstract 2456.

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