Heart Failure and Implantable Cardioverter Defibrillator (ICD) Therapy: Update and Perspective on Current Primary Prevention Trials

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1 Journal of Cardiac Failure Vol. 8 No Perspectives Heart Failure and Implantable Cardioverter Defibrillator (ICD) Therapy: Update and Perspective on Current Primary Prevention Trials LESLIE A. SAXON, MD San Francisco, California ABSTRACT Background: Recently completed studies have evaluated the role ofthe Implantable Cardioverter Defibrillator (ICD) in extending life in the letting of left ventricular dysfunction. Methods and Results: All major primary prevention ICD trials performed in the United States are reviewed. Conclusions: Data to date supports the use ofthe ICD for primary prevention ofsudden death in the setting of ischemic left ventricular dysfunction. Data is lacking in an advanced heart failure population and in patients with nonischemic cardiomyopathy. Key Words: Heart failure, ICD. Primary prevention ofdeath in patients with left ventricular dysfunction, prior infarct scar and nonsustained ventricular tachycardia with an implantable cardioverter-defibrillator (ICD) versus antiarrhythmic drug therapy or no therapy has been investigated in three large trials. 1-3 These include the Multicenter Automatic Defibrillator Implantation Trial (MADIT), Multicenter Unsustained Tachycardia Trial (MUSTT), and Coronary Artery Bypass Graft Patch Trial (CABG PATCH) Trial. These studies used either invasive electrophysiologic From the Cardiac Electrophysiology Department, University of California, San Francisco Manuscript received April 2, 2002; revised manuscript received April 12, 2002; revised manuscript accepted April 16, Reprint requests: Leslie A Saxon, MD, UCSF Cardiac Electrophysiology, 500 Parnassus Avenue, Room MU 433 East Tower, San Francisco, CA Copyright 2002, Elsevier Science (USA). All rights reserved /02/ $35.00/0 doi: /jcaf studies or signal averaged electrocardiogram (ECG) to identify high-risk patients eligible for randomization. Using inducible ventricular tachycardia as a marker of risk, the MADIT and MUSTT trials identified a mortality benefit in ICD-treated patients. The CABG PATCH trial, which assessed the benefit ofthe ICD in patients with a positive signal, averaged ECG undergoing elective coronary artery bypass surgery, found no decrease in mortality in ICD-treated patients. These early studies, viewed from our current perspective of what constitutes optimal pharmacologic therapy for patients with left ventricular dysfunction, limit their applicability to patients with symptomatic heart failure. Patients were enrolled in the early 1990s, a minority was treated with beta-receptor blocking agents, and less than 20% had advanced symptom class heart failure. The next generation primary prevention ICD trials, initiated in the late 1990s, target patients with more advanced left ventricular dysfunction or symptomatic heart failure. 4-7 There are two outstanding features of 161

2 162 Journal of Cardiac Failure Vol. 8 No. 3 June 2002 these study designs: (1) patients are not screened by invasive testing to identify a group at higher risk of experiencing a life threatening ventricular arrhythmia and (2) entry criteria are in place to ensure that patients are treated with those medical therapies shown to improve survival (Table 1). The objectives ofthis briefreview are: (1) to summarize the results ofthe one recently completed trial and the status ofthree ongoing trials and (2) to discuss the significance and potential importance ofthese trials in the care ofthe patients with symptomatic heart failure resulting from systolic dysfunction. Multicenter Automatic Defibrillator Implantation Trial II The first ofthe trials to conclude, the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) was recently published and the results presented at the American College ofcardiology 51st Annual Scientific Sessions. 4,5 The MADIT II trial evaluated the efficacy of the ICD versus standard medical therapy in patients with prior myocardial infarction and left ventricular ejection fraction of0.30 or less. A total of1,232 patients were randomized in a 3:2 ratio to receive an ICD or conventional medical therapy. The clinical characteristics ofthe patients are listed in Table 2. It is important to note that two-thirds ofenrolled patients had New York Heart Association (NYHA) Functional Class (FC) II or III heart failure. Medical therapy did not differ between groups, with a high percentage ofpatients taking angiotensin-converting enzyme inhibitor, beta-blocker, and lipid-lowering statin therapies. The ICD reduced the rate ofdeath by 12% at 1 year and 28% at 2 years (P.007) and follow-up averaged 20 months (range 6 days-53 months). The absolute mortality was 105/742 (14.2%) in the ICD arm and 97/490 (19.8%) in the conventional medical therapy arm (hazard ratio 0.69). Several findings ofthis trial deserve comment. Unlike MADIT I, in which the mortality benefit ofthe ICD was apparent within the first few months of ICD implant 1 ; the ICD did not confer mortality benefit in MADIT II for 9 months. This may be due to the fact that screening tests identifying patients at high risk for arrhythmia were not used to determine treatment arms. It may also reflect the improved outcomes ofpatients with increasing use of beta-blocker therapy. The use ofbeta blockers was more common in MADIT II than MADIT I. 1,5 The increase in use ofbeta-blocker therapy coupled with the lack of screening studies to identify a high-risk patient for an arrhythmia, may also explain the higher hazard ratio found in MADIT II compared to MADIT I (0.69 versus 0.46). 1,5 Interestingly, the incidence ofnew or worsened heart failure was higher in the ICD-treated patients (19.9% versus 14.9% for no ICD). The reasons for this finding are unclear. It may be that patients who were rescued from a potentially life-threatening arrhythmia went on to develop heart failure at a higher rate. Another possibility is that a subset ofthe ICD-treated patients required pacing and that RV pacing induced left bundle branch block resulted in worsened heart failure because of dyssynchrony. Prolongation ofthe QRS duration 120 milliseconds was present in 50% ofpatients randomized. The mortality benefit demonstrated in MADIT II was observed in the presence ofexcellent background medical therapies for heart failure. Although absolute survival benefits were modest, over the relatively short-term 20-month follow-up interval, the benefits may be more pronounced over the 4- to 5-year life of the ICD. 8 There are also other potential benefits to having an implantable device that are more difficult to measure. For instance, devices provide the ability to support atrial rate, allowing for upward titration of rate slowing medical therapies, such as beta blocking agents. The current generation ICDs can record, store in the memory, and treat episodes ofatrial fibrillation before the development ofsymptoms or disabling sequelae such as stroke. These types of potential benefits are rarely considered and may be particularly important, given the cost implications of widespread use ofthe ICD as prophylaxis in this patient population. Cost analyses performed on other ICD trials Table 1: Primary Prevention: ICD Trials in Patients with Left Ventricular Dysfunction MADIT II SCD-HeFT DEFINITE COMPANION Etiology CAD CAD ICM ICM CAD ICM No. ofpatients 1,232* 2,251* 480* 1,470 LVEF (%) Therapy OPT/ICD Amio/ICD OPT OPT/ICD OPT/CRT CRT ICD *completed enrollment ICD, implantable cardioverter defibrillator; CAD, coronary artery disease; ICM, idiopathic cardiomyopathy; OPT, optimized heart failure drug therapy; Amio, low-dose amiodarone; CRT, chronic resynchronization therapy.

3 Characteristic Primary Prevention of Sudden Death in Heart Failure O Saxon 163 Table 2: MADIT II Clinical Characteristics Defibrillator Group (N 742) Conventional-Therapy Group (N 490) Age (yr) Male sex (%) NYHA functional class (%) I II III IV 5 4 Treatment for hypertension (%) Diabetes (%) Interval of> 6 mo between most recent myocardial infarction and enrollment (%) Cardiac findings at enrollment (%) Blood urea nitrogen > 25 mg/dl ( mmol/l) Atrial fibrillation 9 8 QRS interval 0.12 sec Nonspecific conduction defect Right bundle-branch block 9 7 Left bundle-branch block Left ventricular ejection fraction Medications at last contact (%) Amiodarone Angiotensin-converting enzyme inhibitors Beta blockers Calcium-channel blockers 9 9 Class I antiarrhythmic agents 3 2 Digitalis Diuretics Lipid-lowering statin drugs MADIT, Multicenter Automatic Defibrillator Implantation Trial II; NYHA, New York Heart Association. to date 9 indicate that the most favorable cost/benefit ratio is found in patients with left ventricular ejection fraction (LVEF) <.30 and symptomatic heart failure. This group is well represented in MADIT II. Ongoing ICD Trials We asked the principal investigators ofthe Prevention ofsudden Cardiac Death in Patients with Congestive Heart Failure Trial and Defibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation trials, Drs. Gust Bardy and Alan Kadish to provide trial updates. We specifically asked them to address the issue ofhow these trial results will interact with completed studies showing symptom status benefit with resynchronization therapy. Prevention of Sudden Cardiac Death in Patients with Congestive Heart Failure Trial Prepared by Gust H. Bardy, MD The central hypothesis in the Prevention ofsudden Cardiac Death in Patients with Congestive Heart Failure Trial (SCD-HeFT) is that amiodarone or an ICD will improve survival compared to placebo in patients with NYHA Class II and Class III congestive heart failure (CHF) and reduced left ventricular ejection fraction ( 35%) from either ischemic cardiomyopathy or nonischemic dilated cardiomyopathy. The study has enrolled 2,521 patients from 148 sites in the United States, Canada, and New Zealand. Patients were randomly allocated in equal proportions to three different treatment arms. The first arm ofthe study is a control arm that consists of conventional heart failure therapy and placebo. Placebo therapy is a critical aspect ofthis trial implemented to prevent bias in favor of active therapy. Conventional CHF therapy will require the use ofappropriate dose angiotensin-converting enzyme (ACE) inhibitors and beta-blocker therapy. The second arm ofthe study combines conventional therapy with the use ofamiodarone. Placebo and amiodarone are used in a double-blind fashion. The third arm ofthe study employs conventional therapy together with a single lead, pectoral ICD inserted on an outpatient basis programmed to shock-only or to treat marked bradycardia. Treatment arms will be compared using an intention-to-treat analysis. Secondary specific aims include comparisons ofarrhythmic and nonarrhythmic cardiac and noncardiac mortality; cardiac morbidity, defined as all-cause mortality and rehospitalization for CHF; health-related quality

4 164 Journal of Cardiac Failure Vol. 8 No. 3 June 2002 of life; and incremental cost-effectiveness ratios for the two intervention arms. We also intend to determine the incidence ofventricular tachycardia/fibrillation (VT/VF) and profound bradyarrhythmias (rates 34 bpm) in CHF patients in the ICD arm via the ICD memory log. As ofjanuary 16, 2002, minimum follow-up has been only 6 months and average follow-up, 18 months. Patients with ischemic cardiomyopathy constitute 51% ofthe population and 49% have nonischemic cardiomyopathy. Women make up 23% ofthose enrolled. Minority enrollment has also been strong at 23%. This study will provide new insights into the management ofwomen and minorities; populations generally not studied prospectively in amiodarone and ICD trials. The results ofthe trial likely will be available in Regarding the use ofscd-heft to assess the value of biventricular pacing therapy combined with ICD therapy, it is this author s opinion that one can not use the SCD-HeFT results, be they positive or negative for any particular therapy, to argue either for or against biventricular pacing as an adjunct to ICD therapy. This is the case whether a significant portion ofthe SCD-HeFT population has a wide QRS or not. Combination therapies, as demonstrated in the drug realm numerous times, can either be additive and beneficial or surprisingly harmful compared to the value of either therapy when used in isolation. Consequently, no assumptions should be made regarding the value ofscd-heft in supporting biventricular pacing therapies regardless ofoutcome. Defibrillators In Non-Ischemic Cardiomyopathy Treatment Evaluation Prepared by Dr. Alan Kadish, MD The Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Trial was designed to test the hypothesis that ICD implantation will improve survival relative to standard therapy for congestive heart failure in patients with non ischemic dilated cardiomyopathy. Inclusion criteria are ejection fraction less than 0.36, the presence ofeither nonsustained ventricular tachycardia or more than 10 premature ventricular contractions per hour on a Holter monitor and a history of class II or greater heart failure. The absence of coronary disease is documented by coronary angiography or a negative imaging stress test. All patients were treated with beta blockers and ACE inhibitors, iftolerated. More than 85% ofpatients have received beta-blocker and ACE inhibitor therapy. Patients randomized to ICD underwent implantation ofa St. Jude approved implantable defibrillator with transvenous leads. The trial will complete enrollment of408 patients in a projected sample size in December Follow-up will continue for additional 18 months. Background therapy for heart failure has changed in the past several years, potentially complicating the interpretation ofresults oficd trials. Based on preliminary available at the time that DEFINITE was designed, aggressive beta-blocker use was incorporated in the original study design for all patients who can tolerate it. Ofthe close to 400 patients enrolled thus far, 85% of patients in each ofthe randomized groups have been treated with beta blockers. Thus the DEFINITE trial will compare ICD therapy to best medical therapy. Although biventricular pacing may provide symptomatic advantage to some ofthe patients in class III heart failure, there is no evidence yet that biventricular pacing affects survival. Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure Prepared by Leslie A. Saxon, MD The purpose ofthe Comparison ofmedical Therapy, Pacing, and Defibrillation in Heart Failure (COMPAN- ION) Trial, initiated in 2000, is to determine whether combined mortality and hospitalization in heart failure patients receiving optimal pharmacologic therapy can be reduced by combining optimal pharmacologic therapy and (1) biventricular pacing therapy alone or (2) biventricular pacing therapy with defibrillation (ICD). Patients are randomized in a 1:2:2 design to optimal medical therapy versus a resynchronization device alone versus a resynchronization device with an ICD (Fig. 1). Patients may have heart failure resulting from ischemic or nonischemic etiology. The COMPANION trial is better defined as a heart failure rather than device trial. Compared to the trials mentioned previously, inclusion criteria for enrollment in COMPANION require patients to have NYHA FC III heart failure in addition to a heart failure hospitalization within 1 year ofenrollment. This is the only trial that will provide hard endpoint data to determine how resynchronization therapy interacts with ICD therapy for primary prevention ofsudden death. Because all patients randomized to device therapy are treated with resynchronization, entry criteria also include a QRS duration > 120 milliseconds. The COMPANION trial requires 2,200 patients to meet the primary outcome ofall-cause mortality plus all-cause hospitalization. To date, 1,470 patients have been randomized. However, enrollment has slowed because ofmarket release ofa resynchronization device and the publication ofthe MADIT II results. The availability ofa market-released resynchronization device, which gained U.S. Food and Drug Administration approval on the basis ofdata showing improvement in functional endpoints of heart failure status, has resulted in reluctance on the part ofpatients and physicians to

5 Primary Prevention of Sudden Death in Heart Failure O Saxon 165 Fig. 1. COMPANION trial randomization scheme. accept the possibility ofrandomization in a clinical trial. This is true even though patients meeting an endpoint in COMPANION, such as hospitalization for worsening heart failure, are able to receive a market-approved resynchronization device. Based on review ofthe MA- DIT II data, approximately 20% ofenrolled MADIT II patients would have qualified for the COMPANION trial, so that the overlap ofpatients is not great. Comments One large mortality trial, MADIT II, offers compelling data in support ofthe ICD in the setting ofoptimized pharmacologic therapy for prolonging survival in patients with depressed LV function after myocardial infarction. Although absolute survival benefit is modest over an average follow-up of less than 2 years, these patients are also unlikely to succumb to progressive pump dysfunction over that same interval, and serious consideration should be give to ICD implantation. The results ofthe SCD-HeFT trial will be helpful in corroborating these findings and comparing the ICD to low dose amiodarone. The role ofthe ICD in prolonging survival in patients with nonischemic etiologies ofheart failure, particularly in comparison to low-dose amiodarone, will be addressed in the recently completed SCD-HeFT trial. One completed trial comparing amiodarone to the ICD, although lacking a control arm, did not show benefit in ICD-treated patients. 10 The DEFINITE study will also help evaluate the role ofthe ICD in this population. A recently published European trial with a similar design to the DEFINITE trial was terminated before completion because oflow event rates. Nonetheless, it did not show benefit with the ICD compared to standard medical therapy. 11 Further, the evidence for low-dose amiodarone to improve mortality is strongest in patients with nonischemic etiologies ofheart failure. 12 The COMPANION trial will help identify the role of resynchronization therapy, in addition to resynchronization therapy coupled with an ICD, in patients with advanced symptom stage heart failure and QRS delay. The completion ofthis trial is essential as many patients initially undergoing ICD implantation under MADIT II criteria may eventually be indicated for resynchronization as heart failure progresses. The results ofthe entirety ofdata from these studies are essential from a scientific and a cost perspective. Based solely on MADIT II trial data, there may be upwards of3 million Americans who are now eligible for ICD therapy. 8 The cost to Medicare and insurance companies will be enormous ifthe results ofthis trial become the standard of care. In fact, device therapies for heart failure may represent the most substantial challenge to Medicare funding in the past two decades. At the present time, it is unclear how they will respond to the fiscal challenge. References 1. Moss AJ, Jackson Hall W, Cannom DS, Daubert JP, Higgins SL, Klein H, Levine JH, Saksena S, Waldo AL,

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