Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation

Defibrillators in Nonischemic Cardiomyopathy
Treatment Evaluation
ALAN KADISH,* REBECCA QUICC,* ANDI SCHAECHTER,*
KELLEY P. ANDERSON,^ MARK ESTES**, and JOSEPH LEVINE++
From the *Division of Cardiology, Department of Internal Medicine, Northwestern University
Medical School, Chicago, Illinois, ^University of Pittsburgh Medical Center, Pittsburgh,
Pennsylvania, **New England Medical Center, Boston, Massachusetts, and ''"''St. Frances Hospital,
Roslyn, New York
KADISH, A., ET AL.: Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation. The Defibril-
lators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE) is a multicenter randomized
trial. Patients will have nonischemic cardiomyopathy (LVEE < 35%), a history of symptomatic heart failure and spontaneous arrhythmia (> 10 PVCs/hour or nonsustained ventricular tachycardia defined as
3-15 beats at a rate of > 120 beats/min) on Holter monitor or telemetry within the past 6 months. Patients
will be randomized to an implantable cardioverter defibrillator (ICD) versus no ICD. All patients will receive standard oral medical therapy for heart failure including angiotensin converting enzyme inhibitors
and p-blockers (if tolerated). Patients will be followed for 2-3 years. The primary endpoint will be total
mortality. Quality-of-life and pharmacoeconomics analyses will also be performed. A registry will track
patients who meet basic inclusion criteria but are not randomized. We estimate an annual total mortality
of 15% at 2 years in the treatment arm that does not receive an ICD. The ICD is expected to reduce mortality by 50%. Approximately 204 patients will be required in each treatment group. Twenty-five centers
will be included in a trial designed to last an estimated 4 years. (PACE 2000; 23:338-343)
nonischemic cardiomyopathy, ICD, nonsustained ventricular tachycardia
Introduction
Patients with systolic heart failure due to dilated cardiomyopathy have a poor survival rate as
a result of progressive heart failure or sudden cardiac death. Sudden cardiac death in patients with
heart failure is most often due to the development
of sustained ventricular tachyarrhythmias hut has
also heen reported to he caused hy bradyarrhythmias.^ A recent prospective study has confirmed
that implantable cardioverter defibrillator (ICD)
implantation decreases mortality in selected high
risk patients with left ventricular (LV) dysfunction
due to coronary artery disease.^ A retrospective,
uncontrolled study has also suggested that ICD
implantation may also benefit selected patients
with nonischemic dilated cardiomyopathy.^ Medical therapy also decreases mortality in patients
with LV dysfunction. Randomized trials of vasodilating agents have shown that angiotensinconverting enzyme (ACE) inhibitors improve survival in patients with systolic heart failure."*"^ In
addition, (S-blockers have heen shown to improve
survival in patients with systolic heart failure.^"^^
In contrast, although digoxin does improve symptoms, exercise capacity, and left ventricular ejec-.
tion fraction (LVEF) in patients with symptomatic
Supported by a grant from St. Jude's CRMD.
Address for reprints: Alan Kadish, M.D., Northwestern Memorial Hospital, 250 E. Superior Street, Suite 520, Chicago, IL
60611. Fax: (312) 908-6003; e-mail: a-kadish@nwu.edu
Received April 6, 1999; accepted July 20, 1999.
338
heart failure,^^ the recently reported Digoxin Survival Trial (DIC) demonstrated that digoxin had a
neutral effect on survival.^^ In addition, therapy
with most sodium and potassium channel-hlocking drugs for the primary prevention of sudden
death in patients with systolic heart failure has
not shown a beneficial effect on survival.^*'^^ The
results of studies evaluating the effect of amiodarone in patients with systolic heart failure have
demonstrated somewhat conflicting results.^^~^^
Thus, the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation (DEFINITE)
trial was designed to treat all randomized patients
with (B-blockers and ACE inhibitors but not
digoxin or antiarrhythmic agents unless necessary. Most studies of therapy for patients with systolic heart failure have included suhjects of any
etiology of LV dysfunction. However, recent studies have suggested that ventricular arrhythmia
mechanisms may differ in patients who have coronary artery disease or ischemic dilated cardiomyopathy compared to patients who have nonischemic etiologies of their cardiomyopathy.^" The
purpose of the present trial is to examine the ability of the ICD implantation to reduce mortality in
high risk patients with nonischemic dilated cardiomyopathy who are treated with the best available medical therapy.
Study Organization
The study organization includes the clinical
coordinating center, a data coordinating center, a
data safety monitoring hoard, an executive steering
March 2000
PACE, Vol. 23
DEFINITE
committee, and the investigational sites (Appendix
1). A contracting organization, Ovations (Highland
Park, IL), will perform cost analysis and quality-oflife analysis. In addition, the study will contain a
three-memher supervisory committee not including the principal investigations at Northwestern
University. All three members of the committee
have extensive experience with multicenter clinical trials and grant peer review at the National Institutes of Health (NIH) and the American Heart Association (AHA). In the event that the data safety
monitoring hoard has concerns regarding patient
enrollment or patient safety or it recommends discontinuation of the study because of either a positive or negative endpoint, the final decision regarding study status will made by the independent
supervisory committee at Northwestern University
rather than the steering committee or the principal
investigators. The study is funded by St. Jude's
CRMD. The data safety monitoring board and. principal investigators have disclosed potential conflicts of interest based on the AHA and American
College of Cardiology (ACC) guidelines.
Trial Design
Patients who meet inclusion criteria will be
randomized to one of two treatment arms.
1. Standard oral medical therapy for heart
failure including ACE inhihitors, 3-adrenergic
blockers (if tolerated), and, if necessary, digoxin
and diuretics to control sympyoms.
2. Oral medical therapy (as above) pins ICD
implantation.
No antiarrhythmic agents will be used in either treatment arm nnless indicated for the treatment of atrial fibrillation. Enrollment is projected
to occur over 2 1/2 years with a postenroUment
follow-up of 1 1/2 years.
Patient Population
Inclusion and exclusion criteria for the main
trial are shown in Table I. Basic inclusion criteria
inclnded an ejection fraction < 0.36 and the presence of ambient arrhythmias and nonischemic dilated cardiomyopathy. A history of symptomatic
heart failure is also reqnired for inclusion in the
study. If the ejection fraction is estimated to be between 0.30 and 0.35 by echocardiogram or biplane
cardiac catheterization, radionuclide angiography
is required to confirm the ejection fraction. The
presence of a single episode of nonsustained ventricular tachycardia on telemetry monitoring is acceptable for study inclnsion. An average of s 10
premature ventricular contractions (PVCs) per hour
or nonsustained ventricular tachycardia (3-15
beats at a rate of > 120 beats/min) on 24-hour
Holter monitoring or telemetry monitoring is also
acceptable for inclusion in the study. This arrhyth-
Table I.
Inclusion and Exclusion Criteria
Inclusion Criteria
1. Age 21-80 years
2. Nonischemic cardiomyopathy with left ventricular ejection fraction (LVEF) < 35% by any technique including
radionuclide angiography (MUGA), echocardiogram or left ventriculogram
3. History of symptomatic heart failure
4. Documented nonsustained ventricular tachycardia (NSVT, 3-15 beats) or > 10 premature ventricular contractions
(PVCS) per hour (or both) on Holter monitor or telemetry within the past 6 months.
5. Excluding coronary artery disease by the absence of a history of a Q wave myocardial infarction and
a. coronary angiography demonstrating > 50% proximal or > 75% distal luminal stenosis in one or more of the main
coronary arteries, or
b. stress testing with nuclear perfusion imaging or dobutamine echocardiography demonstrating any evidence of
ischemia
Exclusion Criteria
1. Symptomatic ventricular arrhythmias
2. Unexplained syncope within the past 6 months
3. Prior cardiac arrest, sustained ventricular tachycardia or ventricular fibrillation
4. New York Heart Association Class IV heart failure at the time of enrollment
5. Familial cardiomyopathy associated with sudden death, hypertrophic or restrictive cardiomyopathy, constrictive
pericarditis, clinically acute myocarditis or congenital heart disease
6. Permanent pacemaker
7. Electrophysiology study within the past 3 months
8. Patients in whom cardiac transplantation appears to be imminent or patients expected to undergo other cardiac
surgery within 1 year
PACE, Vol. 23
March 2000
339
KADISH, ET AL.
mia marker was selected primarily based on the Argentinean Cooperative (GESICA) trial, which suggested that the presence of this arrhythmia marker
conferred a relative risk of total mortality of 1.6-2.5
in patients with a nonischemic cardiomyopathy.^^
However since the trial was initiated, other studies
have not consistently confirmed this observation.^^'^^ The absence of significant coronary artery
disease as the etiology of the cardiomyopathy will
be confirmed by coronary angiography or by a negative stress imaging study. Some patients with a
nonischemic dilated cardiomyopathy may have
minimal coronary artery disease that is felt to be
unrelated to the primary etiology of heart failure
and, therefore, prognosis. Thus, the presence of a
proximal lesion < 50% or a distal lesion in one of
the main coronary arteries < 75% will not exclude
participation in the study. Small branch occlusions
will also not constitute exclusion criteria.
Patients with severe symptomatic Class IV
congestive heart failure or patients who are not candidates for ICD implantation will be excluded from
the study. Patients with recent unexplained syncope may have a significant adverse prognosis and
thus will not be included in the study. In addition,
patients who have undergone electrophysiologicai
testing within the last 3 months and patients with
permanent pacemakers will also be excluded.
dition, p-blocker therapy is required unless there
is demonstrated patient intolerance. An attempt
will be made to slowly titrate the ACE inhibitor
and p-blockers to the highest tolerated dose. We
expect to achieve a > 75% treatment rate with pblockers and ACE inhibitors, Digoxin and diuretics
may be used when necessary to manage clinical
symptoms. To avoid confounding factors that may
decrease the study power, antiarrhythmic drug use
is discouraged in the trial. However, it is recognized that some patients with LV dysfunction may
have symptomatic atrial fibrillation or supraventricular arrhythmias requiring treatment and will
not constitute an exclusion criteria. Any patient receiving antiarrhythmic drugs for ventricular arrhythmia will be excluded at the time of randomization and the use of any antiarrhythmic drug
including amiodarone during follow-up will require approval of the principal investigators.
Randomization
Patients will be randomized into two treatment groups in an unblinded fashion. Randomization will be stratified by center and for the use of
antiarrhythmic drugs for supraventricular arrhythmias at the time of randomization. Randomization will be performed centrally and randomization status will be assigned to investigational
sites only after patients have given signed consent
and inclusion criteria are confirmed,
Drug Therapy and Antiarrh)rthmic Drug Use
All patients will receive ACE inhibitors unless
contraindicated. If patients are unable to tolerate
ACE inhibitors, hydralazine and nitrates as a second level vasodilator therapy may be substituted.
Angiotensin II converting enzyme blocking agents
may be used at the investigator's discretion in drug
intolerant patients; however, because randomized
studies demonstrating prognostic benefit are not
yet convincing, they are to be reserved for those patients who do not tolerate first line therapy. In ad-
Follow-Up
All patients will be followed at 3-month intervals for evaluation of progression of heart failure,
vital status, and quality-of-life. In patients randomized to receive an ICD, follow-up will also include ICD interrogation. Additionally, a 6-minute
walk test, a standard 12-lead electrocardiogram,
signal-averaged electrocardiogram, and Holter
monitoring will be performed annually (Fig. 1).
Baseline
1
Vital Status
ICD Interrogation
Medications
Labs*
ECG
SAECG
Holter
Walk Test
QOL Questionnaires
NIPS
DFT
Adverse Events
3
6
9
12
Post Randomization (Months)
15 18 21 24 27 30
33
36
39
42
V V
V V V
V V V V V V
v
V V
V V
V V ^/
yj
V
V
V ^/
V
V
^/
V
V V
V
V*
V*
V
V
>/
V
* Laboratory testing as clinically indicated only
V V V
V V V V
• DFT testing is optional at 3 & 12 months
Figure 1. Follow-up schedule for the DEFINITE study. QOL = quality of life; DFT = defibrillator
testing; NIPS = noninvasive programmed stimulation.
340
March 2000
PACE, Vol. 23
DEFINITE
The primary endpoint of the study will he total mortality. Any recommendations regarding
early terminating of the study hy the data safety
and monitoring hoard will he hased on the primary endpoint. Secondary endpoints will include
quality-of-life, all-cause specific mortality, and
appropriate defihrillator shocks in patients randomized to ICD therapy (Tahle II]. Although inclusion in the study is primarily hased on the
presence of LV dysfunction and an arrhythmia
marker, the relationship of other variahles, including QT dispersion, arrhythmia density, heart
rate variahility, and 6-minute walk test, to patient
outcome also will he analyzed in a posthoc secondary analysis.
Quality-of-Life
This study will include a careful assessment
of the effects of ICD implantation and presence on
continued quality-of-life, and will he performed
using two assessment tools. The SF-12 Quality of
Life Questionnaire and the Minnesota Living with
Heart Failure Quality of life Questionnaire will he
completed at each follow-up visit.^^"^^ The mean
quality-of-life scores for the ICD and control
groups will he compared. In addition, in association with the therapeutic economics calculations,
the average quality-of-life and employment and
functional status in hoth groups will he examined
to estimate these "the quality of life" endpoints in
relationship to any determined mortality henefit.
Cost Effectiveness
Medical care costs for hoth groups will he estimated using a diagnosis-hased methodology. For
the initial hospitalization for ICD implant (in patients randomized to ICD) and for any suhsequent
hospitalizations or doctor visits the diagnosis,
CPT code, and DRC, if appropriate, will he ohtained. For all hospitalizations, length of stay will
Table II.
Endpoints
Primary:
Secondary:
Total mortality
Quality-of-life (QOL)
Cost effectiveness
Appropriate implantable cardioverter
defibrillator discharges for sustained
ventricular tachycardia or ventricular
fibrillation
Cardiac and sudden death mortality
Presence, length, and rate of nonsustained
ventricuiar tachycardia
Appropriate pacemaker backup to severe
brachycardia
PACE, Vol. 23
he calculated. This will apply to the initial hospitalization and any suhsequent hospitalizations. In
addition, all diagnostic tests performed on an outpatient hasis, with the exception of hlood work,
will he recorded. Based on these data, a model of
estimated medical costs for each suhject in each
group will he calculated. The estimated costs will
be hased on the standard Medicare reimhursement
rate for the individual testing procedure. This will
standardize charges across study centers. After an
average cost is estimated for the two groups per
patient year, it will he divided hy the expected patient year henefit hased on the survival difference
hetween the two groups. This will allow a calculation of dollar cost per life saved. The target hypothesis is that the ICD placement in this at risk
patient population will result in a cost henefit of <
$50,000/year of life saved.
ICD Discharges
If a significant mortality henefit is demonstrated in the ICD group, an attempt will he made
to determine to what degree the mortality henefit
is due to the hradycardia hackup support or antitachyarrhythmia conversion ahilities of the ICD.
Although ventricular fihrillation (VF) is presumed
to he the most common mechanism of sudden cardiac death in this patient population, some studies have suggested that hradycardia may he an important cause of mortality especially in patients
with heart failure.^ Each ICD discharge will he
classified hy the study site investigator as heing
appropriate or inappropriate hased on associated
symptoms and standard criteria from intracardiac
electrogram analysis. A data report form documenting symptoms associated with an ICD discharged and characteristics of the electrogram will
he completed. The analysis of each individual
episode will he verified at a core lahoratory.
Backup hradycardia pacing will he characterized
hased on recall analysis of episodes requiring
hradycardia pacing. The numher of subjects in the
ICD group who receive appropriate ICD discharges and who use hradycardia hackup will he
calculated to provide an estimate of potential
causes for the ohserved mortality difference hetween the ICD and control groups.
Cause Specific Mortality
Determinations of cause specific mortality
may he fraught with a numher of errors due to inahility to differentiate hetween death due to pump
failure and sudden cardiac death. Therefore, a system of evaluating cause specific mortality recently
descrihed hy Epstein et al.^'' will he used in the
present study. This scheme examines the prohahle
cause of death and the degree of certainty with
which the mortality mechanisms can he assigned.
March 2000
341
KADISH, ET AL,
Statistical Analysis
Estimating placebo and treatment event rates
in multicenter prospective studies remains a challenge wrhen other changes to standard therapy can
substantially effect mortality. An annual placebo
total mortality rate of 7.5% was estimated based
on available published data at the time of trial deg^gj^ 5,7,8,12,1^.21 -Yhis is lower than the placebo
mortality rate in earlier multicenter studies, but
was designed to correct for the expected characteristics of this study patient population and for
anticipated changes in survival with the use of pblockers. It has been shown that the percentage of
patients who experience sudden, as opposed to
nonsudden, cardiac death varies depending on the
severity of underlying heart failure. Not surprisingly, patients with more severe heart failure are
more likely to die of pump failure whereas those
with less severe degrees of heart failure are more
likely to experience a sudden cardiac arrhythmic
death.^ Thus, it was estimated that approximately
55% of the deaths in the current study would be
due to sudden tachyarrhythmic or bradyarrhythmic death. Estimating that 90 of these deaths will
be prevented by the ICD, a reasonable assumption
in patients without severe ischemia, we postulated a 50% total reduction in mortality in the ICD
treatment group. A modified two-sided triangular
design as described by Whitehead, used in the
Multicenter Automatic Defibrillator Trial (MADIT), was used for statistical calculations^^ and a
level of 0.05 was used. Based on these assumptions, it was estimated that 204 subjects would be
required in each group. Sample size calculations
in the present study are primarily event driven. If
the study hypothesis is correct, it will require 66
events to achieve the study endpoint with 85%
power. ^""^^
Appendix 1—Centers
Christine Albert, M.D., Liz Simpson, B.S.,
Massachusetts Ceneral, Boston, M/1; James Baker,
M.D., Janice Sensing, R.N., The Heart Croup,
Nashville, TiV; Anil Bhandari, M.D., Beverly Firth,
R.N., M.N., Cood Samaritan Hospital, Los Angeles, CA; Hugh Calkins, M.D,, Karen Braznell, R.N.,
fohns Hopkins Hospital, Baltimore, MD; Sergio
Cossu, M.D., Rosanne Dittenber, R.N., Intermedics
Health Center, Port Charlotte, EL; James P.
Daubert, M.D., Kris Kremer, R,N., University of
Rochester Medical Center, Rochester, ATY; Peter R.
Foster, M.D., Tanya Isaacs, R.N., Cardiology Consultants, Indianapolis, IN; Jeffrey Coldberger,
M.D., Merribeth Rose, R.N., B.S.N., Northwestern
University Medical School, Chicago, IL; Lewis L.
Horvitz, M.D., Ceri Schulte, R.N., Cardiovascular
Associates Deleware Valley, Cherry Hill, Nf;
Robert W. Hull, M.D., Cynthia Chapman, R.N., Ar342
rhythmia Consultants, Creenville, SC; Harry A.
Kopelman, M.D., Joni Miller, R.N,, Atlanta Cardiac Croup, Atlanta, CA; Robert Lemery, M.D.,
Rhode Island Hospital, Providence, RI; Joseph H.
Levine, M.D., Molly Nichols, R.N., B.S.N., St.
Erancis Hospital, Roslyn, NY; Thomas Mattioni,
M.D., Suzanne Welch, R.N., Arizona Heart Institute, Phoeniz, AZ; ]ohn P. McKenzie, M.D., Dodie
Wilson, R.N., California Cardiac Institute, Clendale, CA; William Miles, M.D., Diana Marshall,
R.N., Southwest Florida Heart Croup, Eort Myers,
EL; Andrea Natale, M.D., Laura Martin, R.N., University of Kentucky, Lexington, KY; Behzad B.
Pavri, M.D., Linda Coffredo, R.N., M.S.N., University of Pennsylvania Hospital, Philadelphia, PA;
Paul M. Popper, M.D., Denise Steele, R.N., Cardiology Consultants, Punta Corda, EL; Marc Roeike,
M.D., Yolanda Spicer, R.N., Newark Beth Israel
Medical Center, Newark, Nf; Mark Rosenthal,
M.D., Charlotte Paskman, R.N., Abington Medical,
Philadelphia, PA; Stephen Rothbart, M.D., Jackie
Matthews, R.N., Newark Beth Israel Medical Center, Newark, Nf; Philip T. Sager, M.D., Rosemary
Connelly, R.N., WLA VA Medical Center, Los Angeles, CA; Paul Wang, M.D., Barbara Fitzpatrick,
R.N., New England Medical Center, Boston, MA;
Raul Weiss, M.D., Doris Cavolich, R.N., Melanie
Turkel, R.N., University of Pittsburgh Medical
Center, Pittsburgh, PA; Stephen L. Winters, M.D.,
Jennifer Herik, R.N., Kim Wain, R.N., Morristown
Memorial Hospital, Morristown, Nf; Joseph
Zebede, M.D., Kimberly Vitale, R.N., Mount Sinai
Medical Center, Miami Beach, EL.
Appendix 2—Committees
Steering Committee:
Kelley Anderson, M.D., University of Pittsburgh Medical Center, Pittsburgh, PA; Mark Estes,
M.D., New England Medical Center, Boston, MA;
Joseph H. Levine, M.D., St. Erancis Hospital,
Roslyn, NY; Alan Kadish, M.D., Northwestern
University Medical School, Chicago, IL; Rebecca J.
Quigg, M.D., Northwestern University Medical
School, Chicago, IL.
Data Safety and Monitoring Board:
Andrew E. Epstein, M.D., University of Alabama, Birmingham, AL; Kirk Adams, M.D., University of North Carolina, Chapel Hill, NC; Cary
Cutter, Ph.D., Center for Research Methodology
and Biometrics, Denver, CO; Kenneth Ellenbogen,
M.D., Medical College of Virginia, Richmond, VA.
Publications Committee:
Alan Kadish, M.D., Northwestern University
Medical School, Chicago, IL; David Cannom,
M.D., Cood Samaritan Hospital, Los Angeles, CA;
Joseph H. Levine, M.D., St, Erancis Hospital,
March 2000
PACE, Vol, 23
DEFINITE
Roslyn, NY; William Miles, M.D., Southwest
Florida Heart Group, Fort Myers, FL; Paul Wang,
M.D., New England Medical Center, Boston, MA.
Events Committee:
James P. Daubert, M.D., University of
Rochester Medical Center, Rochester, NY; Srinivas Murali, M.D., University of Pittsburgh Medical
Center, Pittsburgh, PA; Behzad B. Pavri, M.D.,
University of Pennsylvania Hospital, Philadel-
phia, PA; Philip T. Sager, M.D., WLA VA Medical
Center, Los Angeles, CA; Stephen L. Winters,
M.D., Morristown Memorial Hospital, Morristown,
NJ.
Recruitment Committee:
Joseph H. Levine, M.D., St Francis Hospital,
Roslyn, NY; Anil Bhandari, M.D., Cood Samaritan
Hospital, Los Angeles, CA; Raul Weiss, M.D., University of Pittsburgh Medical Center, Pittsburgh, PA.
References
1, Luu M, Stevenson W, Stevenson L, Diverse mechanisms of unexpected cardiac arrest in advanced heart failure. Circulation 1989;
80:1675-1680,
2, Moss A, Hall W, Cannon D, Improved survival vi^ith an implanted
defibrillator in patients with coronary disease at high risk for ventricular arrhythmia, N Engl J Med 1996; 335:1933-1940,
3, Levine J, Waller T, Hoch D, et al, Implantable cardioverter defibrillator; Use in high asymptomatic individuals. Am Heart J 1996;
131:59-65,
4, Cohn J, Archibald D, Ziesche S, Effect of vasodilator therapy on
mortality in chronic congestive heart failure: Results of a Veterans
Administration cooperative study, N Engl J Med 1986;
314:1547-1552,
5, Cohn J, Johnson G, Ziesche S, A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic heart
failure (V-HeFt II—Veterans Health Failure Trial II), N Engl J Med
1991; 325:303-310,
6, Swedherg K, Kjekshus J, Effects of enalapril on niortality in severe
congestive heart failure: Results of the Cooperative North Scandanavian Enalapril Survival Study (CONSENSUS), Am J Cardiol
1988; 62;60A-66A,
7, Fonarow G, Chelimsky-FalUick C, Warner-Stevenson J, Effect of direct vasodilation with hydralizine versus angiotensin-converting
enzyme inhibition with captopril on mortality in advanced heart
failure: The Hy-C Trial, J Am Coll Cardiol 1992; 19;842-850,
8, Pfeffer M, Braunwald E, Moyee L, Effect of captopril on mortality
and morbidity in patients with left ventricular dysfunction after
myocardial infarction: Results of the survival and ventricular enlargement trial, N Engl J Med 1992; 327;699-677,
9, Waagstein F, Bristow M, Swedberg K, Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;
32:1441-1446,
10, Packer M, Bristow M, Cohn J, The effect of Carvedilol on morbidity and mortality in patients with chronic heart failure, N Engl J
Med 1996; 334:1349-1397,
11, Heidenreich P, Lee T, Massie B, Effect of beta-blockade on mortality in patients with heart failure: A meta-analysis of randomized
clinical trials, J Am Coll Cardiol 1997; 30:27-34,
12, Packer M, Gheorghiade M, Young J, Withdrawal of digoxin from
patients with chronic heart failure treated with angiotensin-converting-enzyme inhihitors. New Engl) Med 1993; 329:1-7,
13, The Digitalis Investigation Group: The effect of digoxin on mortality and morbidity in patients with heart failure, N Engl J Med 1997;
336:525-533,
14, Waldo A, Camm A, DeRuyter H, Effect of d-sotalol on mortality in
patients with left ventricular dysfunction and recent and remote
myocardial infarction. Lancet 1996; 348:7-12,
15, (CAST) Investigators Preliminary report: Effect of endainide and
flecainide on mortality in a randomized trial of arrhythmia sup-
PACE, Vol. 23
16,
17,
18,
19,
20,
21,
22,
23,
24,
25,
26,
27,
28,
29,
30,
31,
March 2000
pression after myocardial infarction, N Engl J Med 1989;
321:406-410,
Singh S, Fletcher R, Fisher S, Amiodarone in patients with congestive heart failure and asymptomatic ventricular arrhythmia, N
Engl J Med 1995; 333:77-82,
Doval H, Nul D, Grancelli H, Randomized trial of low-dose amiodarone in severe congestive heart failure. Lancet 1994; 1:493—498,
Doval H, Nul D, Grancelli H, Nonsustained ventricular tachycardia
in severe heart failure. Circulation 1996; 94:3198-3203,
Connolly S, Cairns J, Gent M, et al. Effects of prophylactic amiodarone on mortality after acute myocardial infarction and in congestive heart failure: Meta-analysis of individual data from 6,500
patients in randomized trials. Lancet 1997; 350:14,17-1424,
Pogwizd S, McKenzie J, Cain M, Mechanisms underlying spontaneous and induced ventricular arrhythmias in patients with idiopathic dilated cardiomyopathy. Circulation 1998; 98:2404-2414,
Singh S, Fisher S, Carsion P, et al. Prevalence and significance of
nonsustained ventricular tachycardia in patients with premature
ventricular contractions and heart failure treated with vasodilator
therapy, J Am Coll Cardiol 1998; 32:942-947,
Grimm W, Hoffmann J, Meni V, et al. Programmed ventricular
stimulation for arrhythmia risk prediction in patients with idiopathic dilated cardiomyopathy and nonsustained ventricular
tachycardia, J Am Coll Cardiol 1998; 32;739-745,
Rector T, Kubo S, Cohn J, Patients self-assessment of their congestive heart failure: Content, reliability and validity of a new measure, the Minnesota Living with Heart Failure Questionnaire,
Heart Failure 1987; 3:198-209,
Rector T, Cohn J, Assessment of patient outcome with the Minnesota Living with Heart Failure Questionnaire: Reliability and validity during a randomized, double-blind, placebo-controlled trial
of Pimobenden, Am Heart J 1992; 124:1017-1025,
Guyatt G, Nogradi S, Halcrow S, et al. Development and testing of
a new measure of health status for clinical trials in heart failure, J
Gen Intern Med 1989; 4:101-107,
Ware J, Sherbourne G, A 12-Item Short-form Health Survey: Construction of scales and preliminary tests of reliability and validity,
Med Care 1996; 34:220-233,
Epstein A, Carlson M, Fogoros R, et al. Classification of death in
antiarrhythmla trials, J Am Coll Cardiol 1996; 26:433^42,
Whitehead J, Stratton I, Group sequential trials with triangular
continuation regions. Biometrics 1983; 39:227-236,
Kim K, DeMets D, Design and analysis of group sequential tests based
on the type I error spending function, Biometrika 1987; 74:149-154,
Kim K, Tsiatis A, Study duration for clinical trials with survival response and early stopping rule. Biometrics 1990; 46:81-92,
Kim K, DeMets D, Sample size determination for group sequential
clinical trials with immediate response, Stat Med 1992;
11:1391-1399,
343