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(Circulation. 2001;103:1044.)
© 2001 American Heart Association, Inc.
Brief Rapid Communications |
Results of Targeted Anti–Tumor Necrosis Factor Therapy With Etanercept (ENBREL) in Patients With Advanced Heart Failure
From the Winters Center For Heart Failure Research, Department of Medicine, Veterans Administration Medical Center, and the Methodist Hospital, and Baylor College of Medicine, Houston, Tex (B.B., G.T.-A., D.L.M.); the Cardiovascular Institute of the University of Pittsburgh Medical Center Health System, Pittsburgh, Pa (O.Z.S., A.M.F.); and Immunex Corporation, Seattle, Wash (M.S.W., J.W.).
Correspondence to Douglas L. Mann, MD, Winters Center for Heart Failure Research (151C), Houston VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann{at}bcm.tmc.edu
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionConclusionReferences |
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Background—Previously, we showed that tumor necrosis factor (TNF) antagonism with etanercept, a soluble TNF receptor, was well tolerated and that it suppressed circulating levels of biologically active TNF for 14 days in patients with moderate heart failure. However, the effects of sustained TNF antagonism in heart failure are not known.
Methods and Results—We conducted a randomized, double-blind, placebo-controlled, multidose trial of etanercept in 47 patients with NYHA class III to IV heart failure. Patients were treated with biweekly subcutaneous injections of etanercept 5 mg/m2 (n=16) or 12 mg/m2 (n=15) or with placebo (n=16) for 3 months. Doses of 5 and 12 mg/m2 etanercept were safe and well tolerated for 3 months. Treatment with etanercept led to a significant dose-dependent improvement in left ventricular (LV) ejection fraction and LV remodeling, and there was a trend toward an improvement in patient functional status, as determined by clinical composite score.
Conclusion—Treatment with etanercept for 3 months was safe and well-tolerated in patients with advanced heart failure, and it resulted in a significant dose-dependent improvement in LV structure and function and a trend toward improvement in patient functional status.
Key Words: heart failure • myocardial contraction • growth substances • cytokines • tumor necrosis factor
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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Recent experimental studies have shown that etanercept (ENBREL), a recombinant human tumor necrosis factor (TNF) receptor that binds to TNF and functionally inactivates this cytokine, is sufficient to reverse some of the deleterious effects of TNF in vitro and in vivo.1 2 3 Recently, we reported that a single intravenous infusion of etanercept was safe and well tolerated and led to a decrease in biologically active levels of TNF, as well as to an improvement in the functional status of heart failure patients.4 To extend these studies, we conducted a randomized, multidose study with etanercept to further characterize the safety and potential efficacy of TNF antagonism in patients with advanced heart failure.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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Study Cohort
We studied 47 patients with stable New York Heart Association (NYHA) functional class III to IV heart failure. Patients were eligible if their screening left ventricular (LV) ejection fraction was <35%; they were receiving stable doses of an angiotensin-converting enzyme (ACE) inhibitor, digoxin, and oral diuretics for 30 days before enrollment; and they were able to walk
100 meters during a 6-minute walk test. ACE-intolerant patients were
on hydralazine/isosorbide or losartan. The use of ß-blockers was
permitted (but not required) as long as the patient was on stable doses
of ß-blockers for 3 months before enrollment. The study was conducted
at Baylor College of Medicine (Methodist Hospital and the Houston
Veterans Affairs Medical Center) and the University of Pittsburgh, and
it was approved by the Institutional Review Boards at both
centers.
Study Protocol and Objectives
This study was a randomized, double-blind,
placebo-controlled, multidose trial of etanercept, a soluble TNF
receptor. The primary objective was to evaluate the safety and
tolerability of etanercept. The secondary objective was to assess the
clinical and laboratory indices for evidence of improvement in (1) LV
function and structure and (2) patient functional and clinical status,
as measured by a clinical composite score. Patients were randomized to
receive 5 mg/m2 or 12
mg/m2 etanercept SC twice weekly for 3
months. The etanercept doses were based on data from a previous dose
escalation study with etanercept in heart failure and studies with
etanercept in rheumatoid
arthritis.4 Baseline
evaluations consisted of a history and cardiopulmonary examination,
echocardiography with Doppler, routine laboratory tests, and the
assessment of patient functional status. Data were recorded at baseline
and then on days 1, 30, 60, and 90 after study drug
administration.
Safety and Tolerability of Etanercept
Patients were evaluated for adverse events
throughout the study. In addition to serially monitoring heart rate and
blood pressure, we also assessed hemoglobin/hematocrit, white blood
cell count, platelet count, serum electrolytes, and serum creatinine.
Assessment for antibodies to etanercept were performed as described
previously4 at baseline and
at the end of 3 months of blinded therapy.
Effect of Etanercept on LV Structure
and Function
Two-dimensional and Doppler echocardiography
were used to measure LV ejection fraction and LV end-diastolic and LV
end-systolic volumes using the modified Simpson’s rule. LV mass was
determined using the area-length method. All 2D and Doppler
echocardiographic readings were performed at baseline and after 3
months of therapy, and they were interpreted by a single qualified
reader who was blinded to the treatment protocol.
Effect of Etanercept on Clinical Status
To assess the effects of etanercept on clinical
functional status, we employed a clinical composite score that
classified patients as better, worse, or unchanged at the end of 3
months of blinded therapy (see Data Supplement for
details).
Statistical Analysis
Data are expressed as mean±SD. The likelihood
ratio 
2 test was used to test for
differences in baseline categorical and nominal variables, including
the clinical composite score. Given the small sample sizes and because
the data were generally not normally distributed, nonparametric tests
were used to compare the groups on quantitative variables, including
measures of LV function and structure. The Kruskal-Wallis test was used
to test for differences among the 3 groups, and the Wilcoxon rank sum
test was used to make pair-wise treatment comparisons for these
variables. All statistical analyses were performed using the last
observation carried forward in the presence of missing data. All
probability values are
2-tailed.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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Patient Demographics
Table 1
shows the baseline characteristics of the study
population. There was no significant difference in age, sex, race, NYHA
class, LV ejection fraction, cause of heart failure (ischemic
versus nonischemic), or circulating levels of TNF between the 3 groups
of patients. All patients were on stable drug therapy, including
digoxin, diuretics, and ACE inhibitors. An equal number of patients in
each group were taking ß -blockers. There was no significant
difference in medication use between the treatment groups.
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Of the 31 patients who received etanercept, 27 completed 3 months of therapy (75% in the 5 mg/m2 group and 100% in the 12 mg/m2 group); all of the patients in the placebo group finished 3 months of blinded therapy. The reasons for discontinuation from the study were as follows: 1 patient with a history of sustained ventricular tachycardia who refused an implantable cardiac defibrillator died, 1 patient requested to be withdrawn for worsening heart failure during the second week after enrollment, 1 patient declined to continue after developing pneumonia, and 1 patient was lost to follow-up.
Safety and Tolerability of Etanercept
Etanercept was safe and well tolerated when
administered twice weekly using subcutaneous doses of 5 or 12
mg/m2. There were no dose-limiting
toxicities observed in the etanercept groups. The adverse events were
equally distributed among the 3 groups and were mild in intensity
(Table 2). The overall frequency of injection site reactions
was 
10%, and the reactions were considered mild or moderate in
intensity; none required treatment. Abnormal laboratory results were
infrequent and were not clinically significant (data not shown). There
were no significant changes in heart rate or blood pressure (see Data
Supplement), and there were no significant changes in hematological or
serum chemical parameters between the placebo and etanercept groups
during 3 months. Serological tests for antibodies against etanercept
were negative at the end of 3 months of blinded therapy, as well as at
the 30- and 90-day follow-up after the end of blinded
therapy.
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Effect of Etanercept on LV
Structure and LV Function
Figure 1A shows that there was a dose-dependent
increase in LV ejection fraction for the patients who received
etanercept, whereas there was a small decrease in LV ejection fraction
for the patients who received placebo.
Figures 1B through 1D show, respectively, that the
improvement in LV ejection performance in the etanercept treatment
group was accompanied by a dose-dependent decrease in LV end-diastolic
volume, LV end-systolic volume, and LV mass. The changes in LV ejection
fraction and LV end-diastolic and end-systolic volumes were
statistically significant
(P=0.01,
P=0.04, and
P=0.02, respectively) when
compared with placebo. However, the dose-dependent reduction in LV mass
in the etanercept treatment groups did not reach statistical
significance
(P=0.3).
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Effect of Etanercept on Functional
Status
There was a trend
(P=0.20) toward improvement in
the clinical composite score after 3 months of therapy with 12
mg/m2 etanercept. At the end of 3 months of
treatment, 44% of the placebo-treated patients, 56% of the 5
mg/m2 etanercept–treated patients, and 67%
of the 12 mg/m2 etanercept–treated patients
were scored as improved. Importantly, there was no significant
difference (P=0.96) in the
number of patients who were considered worse after 3 months of therapy
with etanercept.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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In the present study, twice-weekly subcutaneous injections of etanercept were safe and well tolerated when administered to patients with advanced heart failure for 3 months (Table 2
). Furthermore, treatment with etanercept led to a
significant dose-dependent improvement in LV function and LV remodeling
(Figures 1A through 1C), consistent with prior experimental
studies, which showed that etanercept reversed the untoward biological
effects of pathophysiologically relevant concentrations of TNF in vitro
and in vivo.1 2
Finally, although this study was designed to assess safety and was
therefore not sized to detect statistically significant changes in
patient functional status, there was a trend toward improvement in the
clinical composite score after 3 months of therapy with etanercept
(Figure 2), whereas there was no worsening of clinical status
at the end of 3 months of therapy. Moreover, there was a consistent
treatment effect in patients who were and who were not receiving
ß-blockers (data not shown).
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Conclusion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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This study is consistent with previous clinical studies which have suggested that cytokine antagonism may be beneficial in patients with heart failure.4 5 Although, this study must be regarded as provisional because of the modest numbers of patients and the modest duration of follow-up, the results do suggest that it is safe and potentially efficacious to use etanercept in conjunction with existing conventional therapies for heart failure. Indeed, the lack of untoward hemodynamic effects with etanercept allows physicians to add this biological response modifier to existing strategies of ACE inhibitors, ß-blockers, and diuretics, without the untoward consequences that often occur when traditional vasoactive neurohormonal antagonists are used in combination. Whether the salutary effects that were observed with etanercept in the present study can be sustained over longer periods of time and in larger patient populations will be addressed in the following 3 ongoing multicenter trials: Randomized Etanercept North AmerIcan Strategy to Study AntagoNism of CytokinEs (RENAISSANCE), Research into Etanercept CytOkine antagonism in VEntriculaR dysfunction (RECOVER), and Randomized EtaNErcept Worldwide evALuation (RENEWAL).
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Acknowledgments |
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This research was supported by the National Institutes of Health (P50 HL-O6H) and Immunex Corporation. We gratefully acknowledge the technical assistance of Carolyn Thibodeaux, B.J. Schneider, and Dorellyn Lee-Jackson, and we thank Dr Andrew I. Schafer for past and present support and guidance.
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Footnotes |
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Dr Mann serves as an unpaid consultant to Immunex Corporation; Dr Feldman is an Immunex Corporation stockholder.
Guest Editor for this article was William W. Parmley, MD, University of California at San Francisco.
Supplementary material to this article can be found Online Only at www.circulationaha.org
Received September 5, 2000; revision received January 11, 2001; accepted January 12, 2001.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
|---|
1. Kapadia S, Torre-Amione G, Yokoyama T, et al. Soluble tumor necrosis factor binding proteins modulate the negative inotropic effects of TNF-
in
vitro. Am J Physiol. 1995;37:H517–H525.
2.
Bozkurt B,
Kribbs S, Clubb FJ Jr, et al. Pathophysiologically relevant
concentrations of tumor necrosis factor- promote progressive left
ventricular dysfunction and remodeling in rats.
Circulation. 1998;97:1382–1391.
3.
Kubota T,
Bounoutas GS, Miyagishima M, et al. Soluble tumor necrosis factor
receptor abrogates myocardial inflammation but not hypertrophy in
cytokine-induced cardiomyopathy.
Circulation. 2000;101:2518–2525.
4.
Deswal A,
Bozkurt B, Seta Y, et al. A phase I trial of tumor necrosis factor
receptor (p75) fusion protein (TNFR:Fc) in patients with advanced heart
failure. Circulation. 1999;99:3224–3226.
5. Sliwa K, Skudicky D, Candy G, et al. Randomized investigation of effects of pentoxifylline on left ventricular performance in idiopathic dilated cardiomyopathy. Lancet. 1998;351:1091–1093. [Medline] [Order article via Infotrieve]
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