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(Circulation. 2000;101:1638.)
© 2000 American Heart Association, Inc.
Editorial |
Implantable Cardioverter Defibrillator Therapy
The Sickest Patients Benefit the Most
From the Heart Research Follow-up Program of the Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, NY.
Correspondence to Arthur J. Moss, MD, Heart Research Follow-up Program, Box 653, University of Rochester Medical Center, Rochester, NY 14642. E-mail heartajm{at}heart.rochester.edu
Key Words: Editorials • defibrillation • arrhythmia • heart failure
At times, our clinical intuition may lead us down the wrong path, but the scientific method helps direct us back to the proper course. In 1970, Mirowski et al1 published their first experience with the standby automatic defibrillator in animals, but their innovative approach to prevent sudden cardiac death was not initially accepted by the cardiac community. Concerns about the practicality of the implanted defibrillator to save lives stimulated Mirowski and colleagues to perform additional investigations; this culminated in their 1980 publication documenting life-saving internal defibrillation with an implantable device in 3 patients.2 The era of the clinical use of the implantable cardioverter defibrillator (ICD) therapy began just 20 years ago, and progress in the field since that time has been astounding.
A series of randomized ICD trials began in the early 1990s. When my colleagues and I were designing the Multicenter Automatic Defibrillator Implantation Trial (MADIT), the general attitude was that the ICD might prolong life for only a short time in patients with advanced coronary disease. Although the ICD had already been shown to be effective in terminating acute ventricular fibrillation, it was assumed that defibrillation in patients with chronic coronary disease would only be a temporizing measure, with early occurrence of death due to heart failure. This was not the case. The results of MADIT were published in 1996,3 and those of the Multicenter UnSustained Tachycardia Trial (MUSTT) in 1999.4 These 2 primary prevention trials substantiated improved survival with ICD therapy in coronary patients with nonsustained ventricular tachycardia. Two secondary prevention trials that focused on patients with aborted cardiac arrest or life-threatening cardiac arrhythmias have also been completed; these are the Antiarrhythmics Versus Implantable Defibrillators (AVID) study5 and the Canadian Implantable Defibrillator Study (CIDS).6 A similar survival benefit was achieved with ICD therapy when compared with amiodarone in both of these trials.
When these 4 trials were planned, it was thought that ICD therapy would be less effective in patients with more advanced left ventricular dysfunction. It was reasoned that the competing risk from nonarrhythmic death (heart failure) would dominate the mortality mechanism in patients with low ejection fractions, thereby limiting the effectiveness of ICD therapy in the sickest group of patients. Once again, our intuition was wrong. These 4 randomized trials (MADIT, MUSTT, AVID, and CIDS) all showed an improved benefit with ICD therapy in those patients having the highest mortality risk. This point is nicely highlighted in the article from the CIDS group by Sheldon et al,7 which is presented in this issue of Circulation.
The CIDS investigators retrospectively stratified the 659 study patients into 4 risk quartiles on the basis of reduced ejection fraction, advanced age, and poor New York Heart Association (NYHA) functional class. In the highest risk quartile, a 50% relative risk reduction in death occurred with ICD therapy when compared with amiodarone, with no evident benefit from ICD treatment over amiodarone in the 3 lower risk quartiles.7 Patients with the highest mortality risk received the greatest benefit from the ICD, with lower risk patients receiving little, if any, benefit. The implications of these findings regarding the clinical selection of patients for ICD therapy and the cost-effectiveness of using expensive ICD therapy primarily in the group at highest risk are self-evident.
These findings from the CIDS group are in excellent alignment with the
recent publication by Domanski et al from the AVID
investigators.8 The AVID data indicate that patients with
a relatively well-preserved ejection fraction (
0.35) do not
have better survival when treated with the ICD when compared with
antiarrhythmic drugs (mostly amiodarone). However, in patients
with a lower ejection fraction, the ICD was associated with improved
survival when compared with antiarrhythmic drugs. Kaplan-Meier survival
curves revealed improved survival with ICD therapy in patients with
ejection fractions in the range of 0.20 to 0.34, as well as in those
with ejection fractions <0.20. Thus, patients with moderate to very
severe left ventricular dysfunction achieved the greatest
benefit from ICD therapy.
These findings and the request for this editorial influenced me to
review the clinical experience with ICD therapy by ejection fraction
subsets in MADIT. The eligibility criterion for MADIT was an ejection
fraction 
0.35, and the median ejection fraction for the 196 enrolled
patients was 0.26. When the ejection fraction was divided at the median
value, the benefit from ICD therapy was concentrated almost exclusively
in those with an ejection fraction <0.26
(Figure
).
|
The findings from MADIT, AVID, MUSTT, and CIDS paint a very clear
picture—it is the sickest patients who benefit the most from ICD
therapy. In retrospect, these results are not surprising when effective
therapy is used. Similar results have been found with
ß-blocker therapy in postinfarction patients, with a greater benefit
achieved with ß-blockers than with placebo in those with left
ventricular dysfunction and frequent
ventricular ectopic beats.9 In patients with
chronic congestive heart failure (NYHA functional class II to IV and an
ejection fraction 0.40), controlled/extended release metoprolol was
associated with a significant reduction in all-cause mortality,
cardiovascular mortality, and sudden
death.10 In a similar vein, coronary artery bypass
graft surgery is associated with a better survival benefit in those
with severe coronary artery disease (ie, those with left main
coronary stenosis and those with 2 or 3-vessel
coronary disease plus associated left ventricular
dysfunction) than in those with milder forms of coronary
disease.11
The ejection fraction–ICD findings that have surfaced in recent
publications3 5 8 were known to the investigators during
the data analysis and manuscript preparation phase of these
studies, and these preliminary findings were the backbone for the
design decisions that were made in planning the recently initiated
MADIT-II12 and Sudden Cardiac Death–Heart Failure Trial
(SCD-HeFT) ICD studies. These 2 randomized trials will be evaluating
the survival benefit of ICD therapy in patients with left
ventricular dysfunction. The ejection fraction entry
criterion for MADIT-II is 0.30, whereas SCD-HeFT is using an ejection
fraction 0.35. Whether this minor difference in ejection fraction
eligibility is important will be determined when the results of these
studies become available in a few years. At this time, both studies
have enrolled 
50% of the target population, with an accumulation of
only 25% of the anticipated patient-months of risk exposure for ICD
and non-ICD therapy.
The ICD is not stand-alone therapy for the prevention of sudden cardiac death. The reduction of sudden death with ß-blockers9 10 13 and angiotensin-converting enzyme inhibitors14 in patients with heart failure is well substantiated, and hypolipidemic therapy may also contribute additional benefit in patients with heart failure due to coronary disease. These results are in sharp contrast to the increased mortality found with antiarrhythmic drug therapy in the Cardiac Arrhythmias Suppression Trial.15
The consistency of the ejection fraction/heart failure-ICD
findings3 4 5 6 7 8 9 has several important clinical implications.
In the future, ICD therapy will become increasingly targeted for
patients with more severe heart disease. It is likely that ICD therapy
will become an important adjunct to ß-blocker and afterload-reduction
drug therapy to improve survival in patients with advanced left
ventricular dysfunction and congestive heart failure. At
this time, insufficient data exist to determine if there is a lower
limit of the ejection fraction below which ICD therapy is not helpful.
Many patients with ejection fractions of 0.10 function at a level of
NYHA class II to III for many years, and I suspect these patients will
also benefit from ICD therapy. Improved cooperation is needed between
the arrhythmologists and the heart failure specialists to answer these
unresolved questions. Finally, better risk stratification will be
required to identify arrhythmically-prone patients with good
ventricular function who might benefit from ICD
therapy.
Acknowledgments
The author of this editorial was the principal investigator of the original MADIT and is the current principal investigator of the MADIT-II trial. These 2 trials were/are supported by research grants from Guidant Corp to the University of Rochester. Dr Moss holds no stock options or equity with Guidant Corp or any other implantable defibrillator manufacturer, and he is not a paid consultant or on any advisory board of companies that produce defibrillator devices.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1.
Mirowski M, Mower MM, Staewen WS, Tabatznik B,
Mendoloff AI. Standby automatic defibrillator: an approach to
prevention of sudden coronary death. Arch Intern
Med. 1970;126:158–161.
2. Mirowski M, Reid PR, Mower MM, Watkins L, Gott VL, Schauble JF, Langer A, Heilman MS, Kolenik S, Fischell RE, Weisfeldt M. Termination of malignant ventricular arrhythmias with an implanted automatic defibrillator in human beings. N Engl J Med. 1980;303:322–324.[Medline] [Order article via Infotrieve]
3.
Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL,
Klein H, Levine JH, Saksena S, Waldo AL, Wilber D, Brown MW, Heo M, for
the MADIT Investigators. Improved survival with an implanted
defibrillator in patients with coronary disease at high risk
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4.
Buxton AE, Lee KL, Fisher JD, Gold MR, Josephson ME,
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The Antiarrhythmics Versus Implantable Defibrillators
(AVID) investigators. A comparison of antiarrhythmic drug therapy with
implantable defibrillators in patients resuscitated from near-fatal
ventricular arrhythmias. N Engl J
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6.
Connolly SJ, Gent M, Roberts RS, Dorian P, Sheldon R,
Mitchell LB, Green M, Klein G, the CIDS investigators. Canadian
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Domanski MJ, Sakseena S, Epstein AE, Hallstrom AP,
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12. Moss AJ, Cannom DS, Daubert JP, Hall WJ, Higgins SL, Klein H, Wilber D, Zareba W, Brown MW, for the MADIT II investigators. Multicenter Automatic Defibrillator Implantation Trial II (MADIT II): design and clinical protocol. Ann Noninvas Electrocard. 1999;4:83–91.
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