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The new england journal of medicine Alan Kadish, M.D., Alan Dyer, Ph.D., James P. Daubert, M.D., Rebecca Quigg, M.D., N.A. Mark Estes, M.D., Kelley P. Anderson, M.D., Hugh Calkins, M.D., David Hoch, M.D., Jeffrey Goldberger, M.D., Alaa Shalaby, M.D., William E. Sanders, M.D., Andi Schaechter, B.S.N., R.N., and Joseph H. Levine, M.D., for the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators* b a c k g r o u n d
Patients with nonischemic dilated cardiomyopathy are at substantial risk for sudden From the Clinical Cardiology Trials Office, death from cardiac causes. However, the value of prophylactic implantation of an im- Medicine, Northwestern University Medi- plantable cardioverter–defibrillator (ICD) to prevent sudden death in such patients is cal School, Chicago (A.K., A.D., R.Q., J.G.,unknown.
A. Schaechter); the University of RochesterMedical Center, Rochester, N.Y. (J.P.D.);New England Medical Center, Boston (N.A.M.E.); Marshfield Clinic, Marshfield, We enrolled 458 patients with nonischemic dilated cardiomyopathy, a left ventricular Wisc. (K.P.A.); Johns Hopkins Hospital, Bal- timore (H.C.); St. Francis Hospital, Roslyn, ejection fraction of less than 36 percent, and premature ventricular complexes or non- N.Y. (D.H., J.H.L.); the University of North sustained ventricular tachycardia. A total of 229 patients were randomly assigned to re- Carolina at Chapel Hill, Chapel Hill (W.E.S.);ceive standard medical therapy, and 229 to receive standard medical therapy plus a sin- and the Veterans Affairs Pittsburgh Health- care System, Pittsburgh (A. Shalaby). Ad- dress reprint requests to Dr. Kadish at 251E. Huron, Feinberg 8-536, Chicago, IL 60611, or at [email protected]
Patients were followed for a mean (±SD) of 29.0±14.4 months. The mean left ventric- *Participants in the DEFINITE trial are ular ejection fraction was 21 percent. The vast majority of patients were treated with an- giotensin-converting–enzyme (ACE) inhibitors (86 percent) and beta-blockers (85 percent). There were 68 deaths: 28 in the ICD group, as compared with 40 in the stan- Copyright 2004 Massachusetts Medical Society. dard-therapy group (hazard ratio, 0.65; 95 percent confidence interval, 0.40 to 1.06;P=0.08). The mortality rate at two years was 14.1 percent in the standard-therapy group(annual mortality rate, 7 percent) and 7.9 percent in the ICD group. There were 17 sud-den deaths from arrhythmia: 3 in the ICD group, as compared with 14 in the standard-therapy group (hazard ratio, 0.20; 95 percent confidence interval, 0.06 to 0.71; P=0.006).
c o n c l u s i o n s
In patients with severe, nonischemic dilated cardiomyopathy who were treated withACE inhibitors and beta-blockers, the implantation of a cardioverter–defibrillator sig-nificantly reduced the risk of sudden death from arrhythmia and was associated with anonsignificant reduction in the risk of death from any cause.
Downloaded from www.nejm.org on October 21, 2009 . For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine pharmacologic agents.2,3 The implantable cardio- cardiomyopathy often die suddenly.1 Al- verter–defibrillator (ICD) prevents sudden death in pthough therapy with angiotensin-convert- patients who have had an episode of ventricular ing–enzyme (ACE) inhibitors and beta-blockers has tachycardia or cardiac arrest,4 as well as in selectedincreased survival in clinical trials of patients with patients who have coronary disease and left ventric-left ventricular dysfunction due to nonischemic and ular dysfunction.5-7 However, no large-scale studiesischemic cardiomyopathies, such patients still have have examined the role of the ICD in the primarya substantial risk of sudden death from cardiac prevention of sudden death in patients with nonis-causes despite receiving adequate doses of both chemic cardiomyopathy. Therefore, we tested the hypothesis that an ICD will reduce the risk of deathin patients with nonischemic cardiomyopathy and Table 1. Baseline Characteristics of the Patients.*
moderate-to-severe left ventricular dysfunction.
Standard-
All Patients
ICD Group
Characteristic
t r i a l d e s i g n
The Defibrillators in Non-Ischemic Cardiomyop- athy Treatment Evaluation (DEFINITE) trial was aprospective, randomized, investigator-initiated study based on observational data8 and was funded by St. Jude Medical, which did not have access to the data. Data collection and analysis were indepen- dently performed at Northwestern University under the supervision of the statistical primary investiga- tor. The investigators had full access to the data and History of atrial fibrillation — no. (%) Patients were randomly assigned to receive either standard oral medical therapy for heart failure or standard oral medical therapy plus an ICD. The pri- mary end point of the study was death from any cause. Sudden death from arrhythmia was a pre- The study was initially designed to have a statis- tical power of 85 percent based on a one-sided test, assuming two-year mortality rates of 15 percent in the standard-therapy group and 7.5 percent in the ICD group and the enrollment of 458 patients, with 56 deaths. In order to report results with the use of two-sided tests and 85 percent statistical power, we extended follow-up to include 68 deaths. Interim analyses were performed after 22, 34, 45, 50, and 56 deaths. The critical values for the interim and fi- nal analyses assumed an O’Brien–Fleming type of spending function.10-12 For patients’ safety, bound- aries for stopping the study in favor of the null hy- pothesis of no effect of the ICD on the risk of death at each interim analysis were also defined accord-ing to the work of Whitehead and Stratton.13 No * ICD denotes implantable cardioverter–defibrillator, NYHA New York Heart As- sociation, NSVT nonsustained ventricular tachycardia, PVCs premature ven- boundaries were crossed at any of the five interim tricular complexes, and LVEF left ventricular ejection fraction.
analyses. Hence, this report presents the results of † Race and ethnic group were self-reported by the patients.
the final analysis at the time of the 68th death. The ‡ P=0.04 for the comparison with the ICD group.
P value required for significance at the final analy- Downloaded from www.nejm.org on October 21, 2009 . For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. p r o p h y l a c t i c d e f i b r i l l a t o r s a n d n o n i s c h e m i c d i l a t e d c a r d i o m y o p a t h y sis was 0.041, on the basis of a two-sided test. The atrial fibrillation or supraventricular arrhythmias re-first patient underwent randomization on July 9, quiring treatment with amiodarone, and these con-1998, and the 458th patient underwent randomiza- ditions did not constitute exclusion criteria. No oth-tion on June 6, 2002. The 68th death occurred on er antiarrhythmic drugs were used.
May 25, 2003.
The trial received annual approval from the in- randomization and follow-up
stitutional review board of Northwestern Universi- Patients were randomly assigned to one of twoty as well as each of the study centers. Written in- treatment groups, with 229 patients in each group.
formed consent was obtained from all patients.
Randomization was stratified according to centerand to the use or nonuse of amiodarone for su- p a t i e n t p o p u l a t i o n
praventricular arrhythmias. Patients who were ran- Inclusion criteria were a left ventricular ejection frac- domly assigned to the ICD group received a single-tion of less than 36 percent, the presence of ambi- chamber device approved by the Food and Drugent arrhythmias,14 a history of symptomatic heart Administration (St. Jude Medical). The ICDs werefailure, and the presence of nonischemic dilated car- programmed to back up VVI pacing at a rate of 40diomyopathy. Ambient arrhythmias were defined by beats per minute and to detect ventricular fibrilla-an episode of nonsustained ventricular tachycardia tion at a rate of 180 beats per minute. All patientson Holter or telemetric monitoring (3 to 15 beats were evaluated at three-month intervals. Accordingat a rate of more than 120 beats per minute) or an to prespecified criteria, patients who were random-average of at least 10 premature ventricular com- ly assigned to standard therapy received an ICD ifplexes per hour on 24-hour Holter monitoring. The they had a cardiac arrest or an episode of unex-absence of clinically significant coronary artery dis- plained syncope that was consistent with the occur-ease as the cause of the cardiomyopathy was con- rence of an arrhythmic event.
firmed by coronary angiography or by a negative For patients who died, the cause of death was de- stress imaging study. Patients were excluded if they termined by an events committee (see the Appendix)had New York Heart Association (NYHA) class IV whose members were unaware of patients’ treat-congestive heart failure, were not candidates for the ment assignments. The blinding process includedimplantation of a cardioverter–defibrillator, had editing any information from progress notes or lab-undergone electrophysiological testing within the oratory reports that could have identified the pres-prior three months, or had permanent pacemakers. ence of an ICD. The cause of death was determinedPatients in whom cardiac transplantation appearedto be imminent, those with familial cardiomyopathyassociated with sudden death, and patients with Table 2. Pharmacologic Therapy.*
acute myocarditis or congenital heart disease werealso excluded.
Standard-
All Patients
ICD Group
p h a r m a c o l o g i c t h e r a p y
All patients received ACE inhibitors unless they were contraindicated. Patients who were unable to tolerate ACE inhibitors received hydralazine or ni- trates15 or angiotensin II–receptor blockers. In ad- dition, beta-blocker therapy was required unless pa- tients were unable to tolerate it. Carvedilol was the beta-blocker of choice on the basis of data available when the study was designed.16 The doses of ACE inhibitors and beta-blockers were adjusted to the levels recommended for patients with heart failure or to the highest tolerated doses. Digoxin and di-uretics were used when necessary to manage clini- cal symptoms. The use of antiarrhythmic drugs such * ICD denotes implantable cardioverter–defibrillator, and ACE angiotensin-con- as amiodarone was discouraged. However, it was recognized that some patients had symptomatic Downloaded from www.nejm.org on October 21, 2009 . For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine as suggested by Epstein et al.17 In this classification, groups, and the Cox proportional-hazards modelpatients who had pump failure with progressive was used to adjust for covariates and to estimate thesymptomatic deterioration who died of terminal hazard ratio for death and corresponding 95 percentventricular fibrillation were not considered to have confidence interval in the ICD group as comparedhad sudden death from arrhythmia.
with the standard-therapy group.18 All analyseswere conducted according to the intention to treat.
s t a t i s t i c a l a n a l y s i s
Data on patients who received a heart transplant The baseline characteristics of the two groups were were censored at the time of transplantation, ascompared with the use of two-sample t-tests for specified in the study protocol. The duration of fol-continuous variables and chi-square tests for cate- low-up was computed from the time of randomiza-gorical variables. The log-rank test was used to tion to death for patients who died, and to the datecompare Kaplan–Meier survival curves in the two of the 68th death for patients who did not die. All A Death from Any Cause
Follow-up lasted a mean (±SD) of 29.0±14.4 months. Baseline characteristics were similar in thetwo groups, except for the duration of heart failure (3.27 years in the standard-therapy group and 2.39 years in the ICD group, P=0.04) (Table 1).
Probability of Survival
The types of pharmacologic therapy used for heart failure are shown in Table 2. The majority of pa- tients were treated with beta-blockers and ACE in- Survival (yr)
hibitors. Of the 229 patients in the ICD group, 227received a functioning ICD system. Two patients de- B Sudden Death from Arrhythmia
clined to undergo implantation of the ICD after pro- viding consent and undergoing randomization. Inaddition, in response to the patients’ requests, one patient had the ICD explanted and one patient hadthe device inactivated. All four patients were includ- ed in the ICD group according to the intention totreat.
There were three complications (1.3 percent) Probability of Survival
during the implantation of the ICD: one hemotho- rax, one pneumothorax, and one cardiac tampon- ade. There were no procedure-related deaths, and Survival (yr)
all complications resolved with medical therapy or No. at Risk
drainage. There were 10 complications during fol- low-up (4.4 percent): 6 lead dislodgements or lead fractures, 3 cases of venous thrombosis, and 1 in-fection. Thirteen patients received ICD upgrades Figure 1. Kaplan–Meier Estimates of Death from Any Cause (Panel A) and
during follow-up; 2 received dual-chamber ICDs Sudden Death from Arrhythmia (Panel B) among Patients Who Received
owing to the development of sinus-node dysfunc- Standard Therapy and Those Who Received an Implantable Cardioverter–
tion, and 11 received biventricular devices for NYHA Defibrillator (ICD).
class III or IV heart failure and a prolonged QRS In the ICD group, as compared with the standard-therapy group, the hazard interval. Of the 229 patients who were randomly ratio for death from any cause was 0.65 (95 percent confidence interval, 0.40 to 1.06) and the hazard ratio for sudden death from arrhythmia was 0.20 assigned to standard therapy, 23 (10.0 percent) (95 percent confidence interval, 0.06 to 0.71).
received ICDs during follow-up, primarily for syn-cope or heart failure with a prolonged QRS interval.
Downloaded from www.nejm.org on October 21, 2009 . For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. p r o p h y l a c t i c d e f i b r i l l a t o r s a n d n o n i s c h e m i c d i l a t e d c a r d i o m y o p a t h y There were 3 sudden deaths from arrhythmia in Fewer patients died in the ICD group than in the the ICD group, as compared with 14 deaths in thestandard-therapy group (28 vs. 40), but the differ- standard-therapy group (hazard ratio, 0.20; 95 per-ence in survival was not significant (P=0.08 by the cent confidence interval, 0.06 to 0.71; P=0.006)log-rank test) (Fig. 1). The unadjusted hazard ratio (Fig. 1). There were 11 deaths due to heart failure infor death among patients who received an ICD, as the standard-therapy group and 9 in the ICD group.
compared with those who received standard thera- One death in the standard-therapy group waspy, was 0.65 (95 percent confidence interval, 0.40 to thought to be from cardiac causes, but the events1.06). The hazard ratio was unchanged (0.65) after committee could not distinguish between arrhyth-adjustment for the duration of heart failure. On the mic and nonarrhythmic causes on the basis of thebasis of Kaplan–Meier survival curves, the rate of available information. Of the 26 deaths that weredeath from any cause at one year was 6.2 percent in classified as noncardiac, 10 were due to cancer, 7 tothe standard-therapy group and 2.6 percent in the pneumonia, 5 to stroke, and 1 each to a drug over-ICD group. At two years, it was 14.1 percent in the dose, suicide, liver failure, and renal failure. With re-standard-therapy group and 7.9 percent in the ICD spect to the other four deaths (two in each group),group.
there was not enough information to determine the An analysis according to treatment actually re- cause of death. Some of these deaths could have ceived was also performed. The resulting hazard been due to arrhythmia.
ratio was 0.66 (95 percent confidence interval, 0.40 During the follow-up period, 41 patients received 91 appropriate ICD shocks. In addition, 49 patients Variable
No. of Patients
Relative Risk of Death from Any Cause
ICD Better
Standard Therapy Better
Figure 2. Subgroup Analysis of the Relative Risk of Death from Any Cause among Patients Who Received an Implantable
Cardioverter–Defibrillator (ICD), as Compared with Those Who Received Standard Therapy.

The dashed line indicates the hazard ratio for the overall population. None of the differences between subgroups were significant. LVEF denotes left ventricular ejection fraction, and NYHA New York Heart Association.
Downloaded from www.nejm.org on October 21, 2009 . For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. The new england journal of medicine received inappropriate ICD shocks, primarily for in a reduction in the risk of death from any causeatrial fibrillation or sinus tachycardia.
that approached but did not reach statistical signif-icance (hazard ratio, 0.65; P=0.08).
s u b g r o u p a n a l y s i s
As in prior trials, the ICD was highly effective at Although the study was not powered to detect dif- preventing sudden death from cardiac causes.4-7ferences within subgroups, several prespecified The difference in mortality between the standard-analyses were performed regarding variables that therapy group and the ICD group was almost entire-could affect survival (Fig. 2). A Cox proportional- ly due to a difference in the incidence of death fromhazards model was used to analyze differences in cardiac arrhythmia. On the basis of data available atsurvival in predefined subgroups. Men had a rela- the time the study was designed, more than 50 per-tive risk of death from any cause of 0.49 (95 percent cent of the deaths were expected to be due to ar-confidence interval, 0.27 to 0.90; P=0.018) after the rhythmia, and thus, the trial was powered to detectimplantation of an ICD. Patients with NYHA class a 50 percent difference in the rates of death from anyIII heart failure had a relative risk of death of 0.37 cause. However, only approximately one third of the(95 percent confidence interval, 0.15 to 0.90; P= deaths in the standard-therapy group were due to0.02) after receiving an ICD (Fig. 3).
arrhythmia. Eighty-five percent of the patients inthis study were treated with ACE inhibitors and beta-blockers — a higher compliance rate than in other studies.4-7 The lower-than-expected rate of sudden Our results indicate that patients with left ventricu- death from arrhythmia may have been due to thelar dysfunction due to nonischemic cardiomyopathy high rate of use of beta-blockers and ACE inhibi-have an annual rate of death from any cause of about tors19-23 and may thus have resulted in the nonsig-7 percent when treated with standard medical ther- nificant reduction in deaths from any cause. Sub-apy for heart failure. Therapy with an ICD signifi- group analyses revealed that the implantation of ancantly reduced the risk of sudden death from ar- ICD significantly reduced the risk of death amongrhythmia (hazard ratio, 0.20; P=0.006) and resulted patients who had NYHA class III heart failure and among men. However, further studies will be re-quired to determine whether these findings are clin-ically important.
Prior large-scale studies evaluating the effect of prophylactic implantation of an ICD for the preven-tion of sudden death have focused on patients with coronary disease.5-7 Our trial was designed to eval-uate the effect of an ICD on the risk of death among patients with nonischemic cardiomyopathy who Probability of Survival
were receiving standard therapy, usually including ACE inhibitors and beta-blockers. The second Mul- ticenter Automatic Defibrillator Implantation Trial (MADIT II) reported a decrease in the relative risk of Survival (yr)
death from any cause of 31 percent among patients No. at Risk
who received an ICD — which was similar to our Two recent small studies have examined the use of ICDs in patients with nonischemic dilated cardio- Figure 3. Kaplan–Meier Survival Curves among Patients with New York Heart
myopathy.24,25 Each of these studies randomly as- Association Class III Heart Failure, According to Whether They Received Stan-
signed only approximately 100 patients and failed dard Therapy or an Implantable Cardioverter–Defibrillator (ICD).
to show a benefit of the ICD. However, the sample As compared with patients who received standard therapy, patients who re- size of these studies was too small to show even a ceived an ICD had a relative risk of death from any cause of 0.37 (95 percent moderate effect of the ICD on the risk of death.24,25 Our study design did not include a group of pa- tients who were treated with amiodarone. Several Downloaded from www.nejm.org on October 21, 2009 . For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. p r o p h y l a c t i c d e f i b r i l l a t o r s a n d n o n i s c h e m i c d i l a t e d c a r d i o m y o p a t h y previous studies have suggested that amiodarone On the basis of our results, the routine implanta- therapy slightly reduces the risk of death, especial- tion of a cardioverter–defibrillator cannot be recom-ly in patients with nonischemic cardiomyopathy.26 mended for all patients with nonischemic cardio-However, those data alone cannot be used to sup- myopathy and severe left ventricular dysfunction.
port the use of amiodarone as standard therapy in However, our findings of a reduction in suddenthis patient population.25-27 Since the data support- death from arrhythmia and an apparent benefit ofing the use of beta-blockers to improve survival were ICDs in subgroup analyses suggest that the use ofclear at the time our study was designed, the use of these devices should be considered on a case-by-amiodarone was specifically discouraged owing to case basis.
concern that its use would limit the ability to titrate Funded by a grant from St. Jude Medical.
beta-blockers to therapeutic doses. Aldosterone an- Dr. Daubert reports having received consulting fees from Medtronic and Biosense-Webster and lecture fees from Medtronic tagonists were not used as standard therapy in this and Guidant; Dr. Kadish, lecture fees from Guidant and St. Judestudy, since no survival benefit of these agents had Medical; Dr. Estes, lecture fees from St. Jude Medical; and Dr. Gold-been demonstrated in patients with NYHA class I, berger, consulting fees from Guidant and owning equity in and hav- ing received lecture fees from Guidant, Medtronic, and St. Jude II, or III heart failure due to nonischemic cardiomy- Medical.
opathy.28,29 a p p e n d i x
The following investigators and centers participated in the study: F. Abi-Samra, E. Faranceware, Alton Ochsner Medical Foundation, New Orleans;
C. Albert, B. Kelly, Massachusetts General Hospital, Boston; A. Bhandari, B. Firth, Heart Institute, Good Samaritan Hospital, Los Angeles; B. Belhassen,
Ichilov Hospital, Tel Aviv, Israel; H. Calkins, J. Bolt, Johns Hopkins Hospital, Baltimore; T. Chow, J. Everett, Linder Clinical Trial Center, Cincinnati; J.
Conti, D. Leach, University of Florida, Gainesville; J. Cook, J. Provencher, Baystate Medical Center, Springfield, Mass.; S. Cossu, K. Mullinax, Charlotte
Heart Group, Port Charlotte, Fla.;
R. Damle, L. Stoune, South Denver Cardiology, Littleton, Colo.; J.P. Daubert, G. Head, University of Rochester Medical
Center, Rochester, N.Y.;
M. Eldar, Sheba Medical Center, Tel Hashomer, Israel; N.A.M. Estes III, S. Galvin, New England Medical Center, Boston; N. Freed-
berg, Haemek Medical Center, Afula, Israel; J. Goldberger, K. Acker, Northwestern University, Chicago; C. Gottlieb, F. Hoffman, Abington Medical Spe-
cialists, Abington, Pa.;
M. Hazday, L. Jopperi, Orlando Regional Medical Center, Orlando, Fla.; B. Hook, L. Pimenta, New England Heart Institute,
Manchester, N.H.;
G. Horvath, E. Healy, Berkeley Cardiovascular Medical Group, Berkeley, Calif.; L.L. Horvitz, M. Cole-Ferry, Cardiovascular Associates
of the Delaware Valley, Cherry Hill, N.J.;
L. Kanter, P. Farrar, Virginia Beach General Hospital, Virginia Beach; A. Katz, Soroka Medical Center, Beer Sheva,
Israel;
S. Klein, D. Ricks, LeBauer Cardiovascular Research Foundation, Greensboro, N.C.; H.A. Kopelman, C. Griffith, American Cardiovascular Research
Institute, Atlanta;
C.S. Kuo, L. Withrow, University of Kentucky Divison of Cardiovascular Medicine, Lexington; J.H. Levine, M. Ferrara, Cardiac Arrhyth-
mia and Pacemaker Center of St. Francis Hospital, Roslyn, N.Y.;
D. Man, B. Gardner, S. Gable, Associated Cardiologists/Pinnacle Health Hospitals, Harris-
burg, Pa.;
F. Marchlinski, G. Schott, Hospital of the University of Pennsylvania, Philadelphia; D. Martin, N. Todd, Lahey Hitchcock Medical Center, Bur-
lington, Mass.;
T. Mattioni, S. Welch, Arizona Arrhythmia Consultants, Phoenix; R. McCowan, C. Tignor, Charleston Cardiology Group, Charleston,
W.V.;
J.P. McKenzie, III, N. Magno, California Cardiac Institute, Glendale; J. Merrill, T. Dicken, The Heart Center, Cardiovascular Associates, Kingsport,
Tenn.;
W. Miles, M. Barr, Southwest Florida Heart Group, Fort Myers; A. Natale, D. Holmes, Cleveland Clinic Foundation, Cleveland; B. Pavri, K. Henry,
Thomas Jefferson University Hospital, Philadelphia; J. Pennington III, L. Bittner, Christiana Health Care Systems, Newark, Del.; E. Rashba, M. Mclane,
University of Maryland School of Medicine, Baltimore; S. Rothbart, J. McCarthy, Newark Beth Israel Medical Center, Newark, N.J.; D. Rubenstein, C.
Bell, Arrhythmia Consultants, Greenville, S.C.; S. Saba, D. Parkinson, University of Pittsburgh Medical Center, Pittsburgh; W.E. Sanders, C.A. Sueta,
M.C. Herbst, University of North Carolina at Chapel Hill, Chapel Hill; A. Shalaby, K. Hickey, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh; J.
Szwed, J. Jackson, The Care Group, Indianapolis; T. Talbert, L. Wright, Diagnostic Center, Chattanooga, Tenn.; R.K. Thakur, L. Blaske, Thoracic and
Cardiovascular Healthcare Foundation, Lansing, Mich.;
S.L. Winters, K. Wain, Morristown Memorial Hospital, Morristown, N.J.; J. Zebede, S. Tong,
Mt. Sinai Hospital, Miami Beach, Fla.; Events Committee — J.P. Daubert, University of Rochester Medical Center, Rochester, N.Y.; S. Murali, University
of Pittsburgh Medical Center, Pittsburgh;
B. Pavri, Hospital of the University of Pennsylvania, Philadelphia; S.L. Winters, Morristown Memorial Hospital,
Morristown, N.J.

r e f e r e n c e s
apy with implantable defibrillators in pa- tients resuscitated from near-fatal ventricu- phylactic implantation of a defibrillator in heart failure: results from Prospective Ran- patients with myocardial infarction and re- duced ejection fraction. N Engl J Med 2002; Study II (CIBIS-II): a randomised trial. Lan- domized study of the prevention of sudden S, Goldberger J, Kadish A. Implantable car- death in patients with coronary artery dis- dioverter defibrillator: use in patients with ease. N Engl J Med 1999;341:1882-90. [Er- heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Fail- ure (MERIT-HF). Lancet 1999;353:2001-7.
proved survival with an implanted defibrilla- Anderson KP, Estes M, Levine J. Defibrilla- tor in patients with coronary disease at high tors in nonischemic cardiomyopathy treat- able Defibrillators (AVID) Investigators.
risk for ventricular arrhythmia. N Engl J Med ment evaluation. Pacing Clin Electrophysiol A comparison of antiarrhythmic-drug ther- Downloaded from www.nejm.org on October 21, 2009 . For personal use only. No other uses without permission. Copyright 2004 Massachusetts Medical Society. All rights reserved. p r o p h y l a c t i c d e f i b r i l l a t o r s a n d n o n i s c h e m i c d i l a t e d c a r d i o m y o p a t h y 10. Kim K, DeMets DL. Design and analysis
18. Kalbfleish JD, Prentice RL. The statisti-
mary prevention of sudden cardiac death in of group sequential tests based on the type I cal analysis of failure time data. New York: idiopathic dilated cardiomyopathy: the Car- diomyopathy Trial (CAT). Circulation 2002; 19. Waagstein F, Bristow MR, Swedberg K,
11. Kim K, Tsiatis AA. Study duration for
et al. Beneficial effects of metoprolol in idio- 25. Strickberger SA, Hummel JD, Bartlett
clinical trials with survival response and ear- pathic dilated cardiomyopathy. Lancet 1993; ly stopping rule. Biometrics 1990;46:81-92.
cardioverter-defibrillator: randomized trial 12. Kim K, Demets DL. Sample size deter-
20. Heidenreich PA, Lee TT, Massie BM. Ef-
in patients with nonischemic dilated cardio- mination for group sequential clinical trials fect of beta-blockade on mortality in pa- tients with heart failure: a meta-analysis of ventricular tachycardia — AMIOVIRT. J Am randomized clinical trials. J Am Coll Cardiol 13. Whitehead J, Stratton I. Group sequen-
26. Effect of prophylactic amiodarone on
tial trials with triangular continuation re- 21. Grimm W, Hoffmann JJ, Muller HH,
mortality after acute myocardial infarction Maisch B. Implantable defibrillator event and in congestive heart failure: meta analy- 14. Doval HC, Nul DR, Grancelli HO, et al.
rates in patients with idiopathic dilated car- sis of individual data from 6500 patients in Nonsustained ventricular tachycardia in se- vere heart failure: independent marker of in- tachycardia on Holter and a left ventricular creased mortality due to sudden death. Cir- ejection fraction below 30%. J Am Coll Car- 27. Singh SN, Fletcher RD, Fisher SG, et al.
15. Cohn JN, Archibald DG, Ziesche S, et al.
22. Poole-Wilson PA, Swedberg K, Cleland
heart failure and asymptomatic ventricular Effect of vasodilator therapy on mortality in JG, et al. Comparison of carvedilol and met- arrhythmia. N Engl J Med 1995;333:77-82.
chronic congestive heart failure: results of a 28. Pitt B, Remme W, Zannad F, et al.
Veterans Administration Cooperative Study.
with chronic heart failure in the Carvedilol Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction 16. Packer M, Bristow MR, Cohn JN, et al.
randomised controlled trial. Lancet 2003; after myocardial infarction. N Engl J Med The effect of carvedilol on morbidity and mortality in patients with chronic heart fail- 23. Rankovic V, Karha J, Passman R, Kadish
AH, Goldberger JJ. Predictors of appropriate 29. Pitt B, Zannad F, Remme WJ, et al. The
17. Epstein AE, Carlson MD, Fogoros RN,
implantable cardioverter-defibrillator thera- effect of spironolactone on morbidity and Higgins SL, Venditti FJ Jr. Classification of py in patients with idiopathic dilated cardio- mortality in patients with severe heart fail- death in antiarrhythmia trials. J Am Coll myopathy. Am J Cardiol 2002;89:1072-6.
24. Bansch D, Antz M, Boczor S, et al. Pri-
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Exploring the link between organizational values and human resource certification

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / h u m r e sExploring the link between organizational values and humanresource certificationThe Eli Broad Graduate School of Management, Michigan State University, N475 North Business Complex, East Lansing, MI 48824‐1122, United StatesWe contribute to the discussion of human resource (HR) certification by iden

Inverse gradient.qxp

Corona® CAD® - Charged Aerosol Detector Comparable Response Between AnalytesDuring Gradient Elution HPLC Using A Make-upInverse Gradient The response of nebulization-based detectors A ilent 12 typically varies as a function of mobile phasevolatility. An increase in the organic content ofthe eluent leads to more efficient nebulization,an increase in the percentage of analyte reac

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