Cost-Effectiveness of Implantable Cardioverter Defibrillators Relative to Amiodarone for Prevention of Sudden Cardiac Death

Sudden cardiac death struck approximately 360 000 persons in the United States in 1990 [1, 2]. Defined as death that occurs within 1 hour of the onset of symptoms, sudden cardiac death accounts for about one half of all deaths from heart disease [2]. Sudden cardiac death occurs primarily in patients who have an established history of heart disease, particularly those with a history of severe congestive heart failure, myocardial infarction, or sustained ventricular arrhythmia [3]. The therapeutic alternatives are treatment with antiarrhythmic drugs or treatment with an implantable cardioverter defibrillator (ICD) [4]. Type Ia antiarrhythmic agents (for example, procainamide) were previously a mainstay of pharmacologic therapy, but recent evidence has raised concern about their effectiveness and potential toxicity [5-8]. In 1991, it was found that the type Ic agents encainide and flecainide increased mortality when used to suppress ventricular ectopy after myocardial infarction. This unexpected finding further limited the choice of antiarrhythmic drugs [9]. Amiodarone is one of the most promising pharmacologic alternatives [10-14]. However, amiodarone therapy is complicated by lengthy loading regimens; persistence of the drug in adipose tissue for long periods; and severe adverse effects, including pulmonary fibrosis and thyroid abnormalities [15, 16]. With the development of ICDs that can be implanted without thoracotomy (and possibly during an outpatient procedure), use of an ICD is now a practical therapeutic alternative to antiarrhythmic drug therapy [4]. Although ICDs are remarkably effective in terminating ventricular arrhythmias [17-20], they are expensive ($40 000 to $60 000 for implantation), and the extent to which they extend life is unknown [21]. Ongoing or planned randomized, controlled trials [19, 20, 22-27] will clarify the role of ICDs and drug therapy for the prevention of sudden cardiac death, but their results will not be available for several years. Economic analyses have suggested that ICDs have favorable cost-effectiveness ratios [28-32], but these analyses were based on controversial assumptions about efficacy in improving survival [28, 30, 31]; compared the implantation of an ICD with an expensive alternative, such as electrophysiologically guided therapy [29, 31, 32]; or limited the use of ICDs to extremely high-risk patients [28-32]. In this study, we used data from ongoing randomized trials and data on the costs of third-generation ICDs to evaluate the cost-effectiveness of treatment with an ICD (implanted without thoracotomy) relative to empirical therapy with amiodarone. We determined the reduction in total mortality that ICD use would have to confer to reach specified cost-effectiveness ratios. Because the indications for ICD use may expand the use of this therapy into new patient populations, we evaluated how the cost-effectiveness of treatment with an ICD varies when the device is used in a population that has a lower risk for sudden cardiac death than do survivors of cardiac arrest. Methods We used a decision model to estimate the quality-adjusted length of life and expenditures for a population of patients who received amiodarone or an ICD. We used the perspective of society and incorporated benefits and costs accordingly. We examined three treatment strategies (Figure 1). Patients who received the ICD-only regimen began treatment with an ICD and continued to receive this therapy regardless of subsequent arrhythmic events. Patients who received amiodarone only began treatment with amiodarone and continued to receive this drug as sole therapy regardless of subsequent arrhythmic events. They crossed over to receive an ICD only if they had intolerable side effects as a result of amiodarone use. Patients who received the amiodarone-to-ICD therapy began treatment with amiodarone and crossed over to ICD if they were subsequently resuscitated from ventricular fibrillation (all survivors) or from ventricular tachycardia (50% of survivors) or if severe drug toxicity occurred. We did not evaluate treatment strategies that used ICD and amiodarone simultaneously because evidence was not sufficient to assess the efficacy of this combined therapy. We discounted health benefits and costs using a 3% annual discount rate, as recommended by a panel on cost-effectiveness analysis in health care [33], and we did sensitivity analyses on all model variables. Figure 1. Schematic representation of the decision model. Decision Model We developed a Markov model [34, 35] (Figure 1, Appendix) using SMLTree software (version 2.9, J. Hollenberg, New York, New York); the model tracked a hypothetical cohort of patients over time. Each cohort began receiving one of the three therapeutic regimens: ICD only, amiodarone only, or amiodarone-to-ICD. Each month, a patient was at risk for ventricular fibrillation, ventricular tachycardia, nonarrhythmic cardiac death, noncardiac death, and illness or death from drug toxicity (the latter was applicable only to patients who received amiodarone). Patients who had an ICD were also at risk for perioperative death. If a patient had ventricular fibrillation or ventricular tachycardia, the patient either died, survived with neurologic impairment, or survived without neurologic impairment (Figure 2). The model included a decrement in quality of life for patients who survived an arrhythmic event with neurologic sequelae [36-39]. Patients who were treated with amiodarone were at risk for acute drug toxicity (Figure 2). Figure 2. Decision model subtrees. Top. Upper middle. Lower middle. Bottom. Quality of Life The Markov model incorporated adjustments for quality of life associated with current health, ICD or amiodarone therapy, arrhythmic events, ICD discharges (shocks), and amiodarone toxicity. We used the time-tradeoff technique to calculate quality-adjusted life-years [40, 41]. In the base-case analysis, we assumed that the quality of life of current health was 0.75 [39], and we assumed that quality of life did not change as a result of ICD or amiodarone therapy. In sensitivity analyses, we evaluated the importance of changes in quality of life caused by ICD or amiodarone therapy. Effectiveness of Implantable Cardioverter Defibrillators We assumed that treatment with an ICD did not affect the frequency of arrhythmias but did increase the chance for surviving an arrhythmic event if one occurred. Evidence from randomized trials and patient registries indicates that ICDs successfully treat life-threatening ventricular arrhythmias. In a registry that contained more than 600 patients with third-generation ICDs [17], ventricular tachycardia was terminated successfully in 98.7% of cases and ventricular fibrillation was converted in 98.9% of cases. The Cardiac Arrest Survivors in Hamburg (CASH) study, a randomized trial that compared ICD with pharmacologic therapy in survivors of cardiac arrest, reported a cardiac death rate of 0% at 1 year among 59 patients treated with an ICD [16, 19, 20, 42]. Other studies [18, 43-46] have also reported low rates of sudden cardiac death in ICD recipients. In our base-case analysis, we assumed that ICDs successfully terminated arrhythmias at rates similar to those reported in the patient registry [17] (Table 1). Table 1. Input Variables and Sources* The effect of ICD use on total mortality is less clear [67-70]. At approximately 1 year of follow-up, total mortality rates in the CASH study were 14.3% in the group that received ICDs and 14.7% in the group that received amiodarone; the difference between the groups was not statistically significant [16]. However, this trial is incomplete and relatively small: Each treatment group contained fewer than 60 patients. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT), 196 patients who had a history of previous Q-wave infarction, documented nonsustained ventricular tachycardia, an ejection fraction of 0.35 or less, and inducible sustained ventricular tachycardia (shown on electrophysiologic testing) that could not be suppressed by the infusion of procainamide were randomly assigned to receive either an ICD or conventional pharmacologic care [25]. The trial was stopped early because 15 deaths occurred in the ICD group and 39 occurred in the usual care group, producing a hazard ratio for total mortality of 0.46 (95% CI, 0.26 to 0.82). This corresponds to Kaplan-Meier survival rates of 87% in the ICD group and 65% in the usual care group at approximately 2 years (Moss AJ for the MADIT Investigators. Multicenter Automatic Implantable Defibrillator Trial [MADIT]. 17th Annual Scientific Session of the North American Society of Pacing and Electrophysiology. Seattle; 1996). The risk reduction found in MADIT may particularly favor ICD because selected patients were not suppressed by drug therapy and because the trial was discontinued early. Other large randomized trials of ICD treatment are still ongoing and have not reported any results. Cost-effectiveness studies [28, 30, 31] (with one exception [32]) have assumed that patients who receive ICDs have substantial survival advantages. This assumption has been based on the results of nonrandomized trials, which are subject to selection bias because healthier patients may have had ICD implantation. Such bias precludes definitive inferences about the effect of ICDs on total mortality [21, 71]. For our base-case analysis, therefore, we assumed that ICD use would reduce total mortality at 1 year by 20% to 40% relative to amiodarone therapy in patients who survive ICD implantation. This reduction was approximately constant over time. In sensitivity analyses, we examined reductions in total mortality by ICDs compared with amiodarone that varied from 5% to 60%. A reduction in total mortality of 30% is a reasonable point estimate, given the current evidence. We assumed that the implantation of an ICD was associated with a perioperative mortality rate of 1.