Implantable Cardioverter Defibrillator Therapy for Prevention of Death in Patients With Cardiomyopathy

Albert A Del Negro, MD

Disclosures

October 20, 2004

Editorial Collaboration

Medscape &

One of the timeliest and, some say controversial, topics in clinical cardiac electrophysiology today is the proper role of the implantable cardioverter-defibrillator (ICD) in the treatment of patients with heart disease. Cardiostim 2004, held June 16-19 in Nice, France, featured several symposia that covered this very timely topic, since, just within the last 2 years, 2 important and much-anticipated studies were reported on the issue of the prophylactic use of ICD therapy. The results of both studies were consistent with prior studies and demonstrated that the use of an ICD reduced all-cause mortality as well as sudden cardiac death (SCD) in patients with cardiomyopathy of either ischemic or idiopathic morphology.

Such favorable results stimulated clinical decision making to liberalize the use of ICD therapy and apply it to a potentially enormous population. The economic implications of acting on these and other supportive studies gave pause to clinicians internationally and dampened their enthusiasm for following the logical conclusions derived from these studies.

MADIT-II

The well-known Second Multicenter Automatic Defibrillator Implantation Trial (MADIT-II)[1] examined the use of ICD therapy in patients with coronary artery disease, prior myocardial infarction (MI), and an ejection fraction (EF) < 30%. Admittedly a high-risk group, the patients enrolled were randomized in a 2:3 ratio to optimal medical therapy (OMT) or OMT plus ICD therapy. Reported in The New England Journal of Medicine in 2002, this study enrolled 1232 patients in the United Sates and Europe, and there was no arrhythmia qualifier for enrollment. Low EF and coronary artery disease with prior MI were the only qualifiers for enrollment; patients enrolled did not require an electrophysiologic study (EPS). Not all the patients were required to have congestive heart failure to enter the study, but any patient with New York Heart Association (NYHA) class IV heart failure symptoms was excluded. Coronary artery bypass surgery within 3 months was also an exclusion criterion. Both the ICD group (n = 742) and the control group (n = 490) were well matched for age, sex, location of infarction, and numbers of patients with NYHA class > II. OMT, consisting of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) where appropriate, spironolactone, and statin agents were also well balanced between the 2 groups.

The results of MADIT-II add to the growing body of evidence documenting the survival benefits associated with ICD therapy. In the trial, all-cause mortality in the medication alone group was 19.8% vs 14.2% in the ICD group. Arrhythmic deaths were more common among the medication alone group (9.4% vs 3.6%) while cardiac deaths were more common in the ICD group. Even despite the higher rate of nonarrhythmic deaths in the ICD group, the use of ICDs was associated with a 31% reduction in the relative risk of death compared with patients treated with OMT alone.

SCD-HeFT

The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)[2] was another highly anticipated ICD trial. Presented at the 2004 American College of Cardiology Annual Scientific Session in New Orleans, Louisiana, SCD-HeFT was a 3-arm study that compared placebo plus OMT vs OMT plus amiodarone (or d,l-sotalol) vs OMT plus ICD therapy in a total of 2521 patients.

Whereas congestive heart failure was not a requirement for study entry in MADIT-II, the 2521 patients enrolled in SCD-HeFT had to have ischemic or nonischemic heart failure with NYHA class II-III symptoms. Another difference between the 2 trials was that EF in SCD-HeFT was ≤ 35% and in MADIT-II, EF ≤ 30%. Importantly, neither MADIT-II nor SCD-HeFT had arrhythmia qualifiers for entry.

All 3 patient groups in SCD-HeFT were matched for age, sex, prior MI, prior bypass surgery, diabetes, and use of beta-blockers, ACE inhibitors, and spironolactone. It is worth noting that the use of all background medical therapy was extremely high; 96% of patients were on active ACE inhibitor or ARB treatment at baseline and 69% of patients were on beta-blocker therapy. The majority of patients were NYHA class II (70%); the remaining 30% of patients were class III. The distribution of ischemic vs nonischemic cardiomyopathy patients was also well balanced (52% vs 48%).

SCD-HeFT investigators reported that at the conclusion of the study (mean follow-up 3.8 years), ICDs were associated with a 23% reduction in mortality. The fact that mortality was significantly reduced within the ICD group is perhaps expected given the especially high sudden death rate of cardiomyopathy patients in general.

SCD-HeFT was powered to demonstrate a 25% survival benefit, but the survival in the medical group was better than expected. Of interest was the fact that amiodarone conferred no benefit whatsoever; the rate of death in the amiodarone plus OMT group was nearly identical to the rate of death reported in the placebo group. That there should be no benefit to prophylactic amiodarone, in the past considered a reasonable option for such patients, makes ICD therapy results all the more impressive.

As reported by Gust Bardy, MD, at Cardiostim, 27% of patients in the amiodarone group discontinued use of the drug because of side effects, and 22% of patients in the control group discontinued placebo therapy because of "perceived" side effects. In addition, crossovers from no drug to the ICD group (13%) and from ICD to drug group (11.2%) were similar.

We must be extremely cautious when considering the results of subgroup analyses. Instead of making clear-cut conclusions, we must consider them only as hypothesis-generating. That being said, the number of deaths reported in patients with nonischemic heart failure was approximately half the number of deaths among ischemic heart failure patients. Despite this numerical difference, investigators reported that the ICD conferred a comparable survival benefit in both subgroups, and both rates were lower than those reported in non-ICD-treated patients. Subgroup analysis by NYHA class found that class II patients fared better than class III patients -- a result that was unexpected given that in MADIT-II, class III patients achieved the greatest survival benefit.

Reaction Among Attendees

The overall reaction among experts attending Cardiostim was cautious optimism. Some said that the fiscal implications of using an expensive alternative to medical treatment for the sake of prolonging life is daunting in the face of limited resources. Heart failure experts especially expressed concern about the addition of ICD therapy to OMT specifically because of the cost of such therapy. At the time of the publication of the MADIT-II study, a similar discussion occurred within the United States.

Extrapolating from the MADIT-II study, it takes 11 ICD implants to save 1 patient life. Thus, there was considerable attention paid to better risk stratification to improve patient selection for ICD therapy.

Determining Degree of Risk in Patients With Hypertrophic and Dilated Cardiomyopathy

The importance of identifying candidates for ICD therapy remains an ongoing debate for many clinicians and was the subject of one of the sessions at the meeting. Determining the risk of SCD in patients with hypertrophic cardiomyopathy (HCM) is especially difficult. As reported by A. Oto from Ankaka, Turkey, patients with HCM comprise a relatively high-risk group. The annual mortality for HCM patients is about 1%, and half of these deaths are sudden. HCM is the most common cause of SCD in the young. Prof. Oto identified clues to the vulnerability of this population to SCD, including the fact that they tend to have syncope (especially on exertion), history of a prior cardiac arrest, and nonsustained ventricular tachycardia (NSVT) on ambulatory monitoring. Outflow tract gradients of 30 mm Hg at rest as well as exercise-induced fall in blood pressure may also predict increased risk of SCD. Unfortunately, all of these features have a low positive predictive value.

Prof. Oto also noted that other clinical investigations have identified the presence of abnormal QT dispersion on electrocardiogram in HCM patients. While present in some HCM patients who suffer SCD, abnormal QT dispersion also has a low positive predictive value. The use of T-wave alternans has shown some promise in HCM patients, but has a positive predictive value of only 39%, and an EPS that induces polymorphous VT with triple extrastimulation has a similar predictive value of 40%. It was suggested that the association of 2 or more such abnormalities in HCM patients was associated with a 35% risk of SCD and in such a situation, ICD therapy may be appropriate. The only certainty is that a survivor of SCD definitely should undergo ICD therapy.

For patients with dilated cardiomyopathy, the same low positive predictive value of many of these noninvasive markers exists. Combining low EF and such variables as NSVT and syncope may improve positive predictive value for arrhythmic death to nearly 80%. Late potentials in coronary disease patients with cardiomyopathy have value in selecting patients for diagnostic testing, and in that population, EPS has good sensitivity to identify candidates for SCD as well as to exclude them. Unfortunately, the same is not true for the nonischemic patient, in whom the sensitivity as well as the specificity of EPS are low.

The Marburg Cardiomyopathy Study,[3] for example, evaluated EF < 30%, NSVT, and T-wave alternans as predictors of arrhythmia vulnerability in patients with idiopathic dilated cardiomyopathy. The conclusion of this study was that a low EF (< 30%) was the single best predictor of SCD and that EPS was not useful as a strategy to predict vulnerability to SCD in idiopathic patients. This finding is consistent with the outcomes of the MADIT-II and SCD-HeFT studies, which investigated treatment strategies based on low EF alone. Until better ways to select patients for prevention of sudden arrhythmic death have been identified, EF will remain the cornerstone of identification for this important cohort of patients.

References
  1. Moss AJ, Zareba W, Hall WJ, et al, for the Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346:877-883.

  2. Bardy GH. The Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Late Breaking Clinical Trials. Presented at the American College of Cardiology 2004 Scientific Sessions; March 7-10, 2004; New Orleans, Louisiana.

  3. Grimm W, Christ M, Bach J, Müller H-H, Maisch B. Noninvasive arrhythmia risk stratification in idiopathic dilated cardiomyopathy: results of the Marburg Cardiomyopathy Study. Circulation. 2003;108:2883-2891.

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