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(Circulation. 1999;99:3224-3226.)
© 1999 American Heart Association, Inc.
Brief Rapid Communications |
Safety and Efficacy of a Soluble P75 Tumor Necrosis Factor Receptor (Enbrel, Etanercept) in Patients With Advanced Heart Failure
From the Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Administration Medical Center, and Baylor College of Medicine, Houston, Tex; and Immunex Corp, Seattle, Wash (F.A.H., C.B.).
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionReferences |
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Background—Although previous studies suggested that TNF may contribute to heart failure progression, it is unclear whether antagonizing TNF is beneficial in heart failure patients.
Methods and Results—Eighteen NYHA class III heart failure patients were randomized into a double-blind dose-escalation study to examine the safety and potential efficacy of etanercept, a specific TNF antagonist (Enbrel). Patients received placebo (6 patients) or an escalating dose (1, 4, or 10 mg/m2) of etanercept (12 patients) given as a single intravenous infusion. Safety parameters and patient functional status were assessed at baseline and at days 1, 2, 7, and 14. There were no significant side effects or clinically significant changes in laboratory indices. There was, however, a decrease in TNF bioactivity and a significant overall increase in quality-of-life scores, 6-minute walk distance, and ejection fraction in the cohort that received 4 or 10 mg/m2 of etanercept; there was no significant change in these parameters in the placebo group.
Conclusions—A single intravenous infusion of etanercept was safe and well tolerated in patients with NYHA class III heart failure. These studies provide provisional evidence that suggests that etanercept is sufficient to lower levels of biologically active TNF and may lead to improvement in the functional status of patients with heart failure.
Key Words: tumor necrosis factor • heart failure • etanercept
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Introduction |
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Since the original report of elevated levels of tumor necrosis factor (TNF) in patients with heart failure, there has been increasing speculation that TNF may contribute to the progression of heart failure by virtue of the direct toxic effects that this cytokine exerts on the heart and the circulation.1 For example, experimental studies have shown that pathophysiologically relevant peripheral and/or elevated intramyocardial levels of TNF are sufficient to mimic many aspects of the heart failure phenotype, including left ventricular (LV) dilation, LV dysfunction, and activation of fetal gene programs.2 3 Moreover, TNF can produce LV dysfunction, pulmonary edema, and cardiomyopathy in human subjects.1 Recent experimental studies from this laboratory have shown that a soluble p75 TNF receptor fusion protein (etanercept) that binds to TNF and functionally inactivates this cytokine is sufficient to reverse some of the deleterious cardiovascular effects of TNF in vitro and in vivo.2 To extend these early preclinical studies, we examined the safety and efficacy of etanercept in patients with advanced heart failure.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Study Population
We studied 18 NYHA class III heart failure patients who had an initial screening ejection fraction <35% and elevated circulating plasma levels of TNF >3.0 pg/mL (>2 SD above the mean TNF level for normal subjects4 ). The protocol was approved by the Baylor College of Medicine Institutional Review Board.
Study Protocol and Objectives
The study was a randomized, double-blind, placebo-controlled,
dose-escalation trial. The primary objectives were to evaluate the
safety of etanercept in patients with NYHA class III heart failure and
to assess clinical and laboratory indices for preliminary evidence of
improvement in LV ejection fraction, patient functional status, and TNF
bioactivity. The secondary objective was to evaluate the systemic
pharmacokinetics of a single intravenous dose of
etanercept. For safety purposes, the study was designed as a
dose-escalation study consisting of 3 patient cohorts. Each cohort
consisted of 6 patients, 2 of whom received placebo and 4 of whom
received etanercept. The order of drug delivery was random within each
cohort, such that the patient and investigators were blinded at the
time of study drug administration. The first group received 1
mg/m2, which was intended to serve as a
no-dose effect, whereas the second and third groups received 4 and 10
mg/m2 of etanercept, respectively, which were
anticipated to have biological effects.
The baseline evaluation consisted of a history and cardiopulmonary examination, a 2D echocardiogram for measurement of ejection fraction, routine laboratory tests, and patient functional status. Etanercept or placebo (diluent) was administered as a single intravenous infusion over 30 minutes. Repeated evaluations of blood pressure, heart rate, and clinical status were performed for the first 6 hours after administration of study drug to observe for side effects. All other data were obtained at baseline and on days 1, 2, 7, and 14.
Safety of Etanercept
Patients were evaluated for adverse events for 14 days,
including a serial assessment of heart rate and blood pressure,
hemoglobin/hematocrit, white blood cell count, platelet count,
serum electrolytes, and serum creatinine. Testing for
antibodies to etanercept was performed at baseline and on day 14, as
described.5
Systemic Levels and Biological Effects of Etanercept
To obtain an indirect assessment of the pharmacokinetics of a
single dose of etanercept, we measured circulating levels of the
soluble type 2 (p75) TNF receptor (sTNFR2) by ELISA (R&D Systems) at
baseline, at 6 hours, and on days 1, 2, 7, and 14. Etanercept contains
2 molecules of the extracellular portion of sTNFR2 linked to the Fc
portion of the IgG1 molecule. Hence, changes in circulating levels of
sTNFR2 by ELISA should largely reflect the presence of etanercept in
the circulation. To assess the effects of etanercept on TNF
bioactivity, we used an L929 assay.2 Changes in the
circulating plasma levels of interleukin-6 (IL-6) were determined by
ELISA (R&D Systems).4
Functional Effects of Etanercept
To assess the functional effects of etanercept, we assessed
changes in the quality of life using a visual analogue scale, the
distance walked during a 6-minute uncoached walk test, and the LV
ejection fraction, which was determined by
echocardiography using a modified Simpson's
rule to calculate LV volumes. All echocardiographic
analyses were performed by 1 experienced observer. Changes in
quality of life were measured by the visual analogue scale in which
the patient assesses his or her overall feeling of well-being on
an ordinal scale ranging from 0 to 100, with 100 as the best possible
score.
Statistical Analysis
Data are expressed as mean±SEM. A Student's t test
or Fisher's exact test was used to test for differences in baseline
characteristics. A factorial repeated-measures ANOVA was used to assess
changes between each of the 4 groups (placebo and 1, 4, and 10
mg/m2 etanercept). A 1-way repeated-measures
ANOVA was used to assess changes in quality of life, 6-minute walk
distance, ejection fraction, TNF bioactivity, and safety
parameters within individual groups; post hoc ANOVA testing
was performed when appropriate. Factorial repeated-measures ANOVA was
also used to assess changes in safety parameters between
the placebo and etanercept groups.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Patient Demographics
Table 1
shows the baseline
characteristics of the patients who received placebo and the 12
patients who received etanercept. There was no significant difference
in age, cause of heart failure, ejection fraction, or
peripheral TNF levels between groups. All of the patients
received ACE inhibitors, 94.4% received digoxin, 11%
received ß-blockers, and 11% received amlodipine; there was no
significant difference between groups with respect to medication
use.
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Safety of Etanercept
None of the patients developed side effects after the infusion of
etanercept, nor were there any significant differences in heart rate,
blood pressure, or hematological and serum chemical
parameters between the placebo and etanercept groups (data
not shown). No antibodies to etanercept were detected.
Peripheral Levels and Biological Effects of
Etanercept
Figure 1B shows the changes in the
plasma levels of sTNFR2 (which should predominantly reflect changes in
the circulating level of etanercept) in the patients who received
etanercept. The peripheral levels were highest at 6 hours
after administration and then declined thereafter (P<0.001
by ANOVA), but they were still elevated at day 7 compared with baseline
values (P<0.05). There was no significant change in the
level of sTNFR2 in the patients who received diluent alone (data not
shown). Figure 1A shows that circulating levels of biologically
active TNF decreased by 
50% in the patients who received etanercept
(P=0.04 by ANOVA); moreover, these levels remained
significantly depressed at day 14 (P<0.05). Figure 1C shows that there was a small but significant decrease in IL-6
levels in the etanercept group (P=0.003 by ANOVA).
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Functional Effects of Etanercept
Table 2 shows the values for quality
of life, 6-minute walk distance, and ejection fraction at baseline and
on days 1, 2, 7, and 14 for patients who received placebo and the
entire cohort of patients who received etanercept. When
analyzed by a factorial repeated-measures ANOVA, there was no
significant difference in these parameters between the 4
groups of patients who received either placebo or 1, 4, or 10
mg/m2 of etanercept except for ejection fraction,
for which the difference was of borderline significance
(P=0.04). Because of the relatively small sample size (n=4
for each dose of etanercept), we next tested for differences within
individual groups. Although there were no significant changes from
baseline in any parameter for the placebo group, there was
a significant improvement in the quality-of-life score in the patients
who received etanercept (P=0.003) and a small but
statistically significant increase in the ejection fraction
(P<0.01). There was, however, no significant change in the
6-minute walk distance in the etanercept group. Because the
1-mg/m2 dose was included in the study design as
a "no-dose" effect, we also repeated the above analyses
after excluding the 4 patients who received 1
mg/m2. As shown in Figure 1D
, 1E, and 1F, respectively, there was a significant overall improvement in
the quality-of-life score (P=0.001), 6-minute walk distance
(P=0.01), and ejection fraction (P=0.03) for the
patients who received 4 or 10 mg/m2 of
etanercept.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Although previous preclinical studies have supported a role for TNF in the pathogenesis of heart failure,2 3 the clinical experience with TNF antagonism in heart failure patients is limited. The results of this study, as well as a previous study with pentoxifylline in patients with dilated cardiomyopathy,6 support the concept that TNF is a potentially important therapeutic target in heart failure patients. In this study, we show that a single intravenous infusion of etanercept was safe and well tolerated in patients with NYHA class III heart failure. Moreover, a single intravenous infusion of etanercept was sufficient to lower levels of biologically active TNF (Figure 1A
) and lead to
improvements in the functional status of patients (Figure 1D and 1E). Although the results of this phase 1 study must be regarded as
provisional because of the relatively small numbers of patients and the
relatively short duration of follow-up, this study does show that
etanercept can be given safely to heart failure patients. Whether the
effects that were observed with etanercept in the present study can
be sustained when etanercept is given repeatedly over longer periods of
time and in larger patient populations will be addressed in the planned
multicenter Randomized Etanercept
North AmerIcan Strategy to
Study AntagoNism of
CytokinEs (RENAISSANCE).
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Acknowledgments |
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This research was supported by research funds from the NIH (P50-HL-O6H) and Immunex Corp. The authors gratefully acknowledge the spirited technical assistance of Dorellyn Lee-Jackson, Pamela Samuels, and Debbie Smith.
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Footnotes |
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Reprint requests to Douglas L. Mann, MD, Cardiology Research (151C), VA Medical Center, 2002 Holcombe Blvd, Houston, TX 77030. E-mail dmann@bcm.tmc.edu
Guest Editor for this article was Michael R. Bristow, MD, PhD, University of Colorado Health Science Center, Denver.
Received February 12, 1999; revision received April 8, 1999; accepted April 29, 1999.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Seta Y, Shan K, Bozkurt B, Oral H, Mann DL. Basic mechanisms in heart failure: the cytokine hypothesis. J Cardiac Failure. 1996;2:243–249.[Medline] [Order article via Infotrieve]
2.
Bozkurt B, Kribbs S, Clubb FJ Jr, Michael LH,
Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL.
Pathophysiologically relevant concentrations of
tumor necrosis factor-
promote progressive left
ventricular dysfunction and remodeling in rats.
Circulation. 1998;97:1382–1391.
3.
Kubota T, McTiernan CF, Frye CS, Slawson SE, Koretsky
AP, Demetris AJ, Feldman AM. Dilated cardiomyopathy
in transgenic mice with cardiac specific overexpression of tumor
necrosis factor-. Circ Res. 1997;81:627–635.
4. Torre-Amione G, Kapadia S, Benedict CR, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol. 1996;27:1201–1206.[Abstract]
5.
Moreland LW, Baumgartner SW, Schiff MH, Tindall EA,
Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K,
Widmer MB, Blosch CM. Treatment of rheumatoid arthritis with a
recombinant human tumor necrosis factor receptor (p75)-Fc fusion
protein. N Engl J Med. 1997;337:141–147.
6. Sliwa K, Skudicky D, Candy G, Wisenbaugh T, Sareli P. Randomised 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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M. Rauchhaus, W. Doehner, D. P. Francis, C. Davos, M. Kemp, C. Liebenthal, J. Niebauer, J. Hooper, H.-D. Volk, A. J. S. Coats, et al. Plasma Cytokine Parameters and Mortality in Patients With Chronic Heart Failure Circulation, December 19, 2000; 102(25): 3060 - 3067. [Abstract] [Full Text] [PDF]
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 J. Schumann, D. Wolf, A. Pahl, K. Brune, T. Papadopoulos, N. van Rooijen, and G. Tiegs Importance of Kupffer Cells for T-Cell-Dependent Liver Injury in Mice Am. J. Pathol., November 1, 2000; 157(5): 1671 - 1683. [Abstract] [Full Text] [PDF]
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 P.J. Pugh, K.M. English, T.H. Jones, and K.S. Channer Testosterone: a natural tonic for the failing heart? QJM, October 1, 2000; 93(10): 689 - 694. [Full Text] [PDF]
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K. M. Mohler, K. M. Murray, D. L. Mann, and G. Francis Use of Targeted Anticytokine Treatments in Heart Failure Circulation, August 29, 2000; 102 (9): e65 - e65. [Full Text] [PDF]
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E. J. Birks, V. J. Owen, P. B. J. Burton, A. E. Bishop, N. R. Banner, A. Khaghani, J. M. Polak, and M. H. Yacoub Tumor Necrosis Factor-{alpha} Is Expressed in Donor Heart and Predicts Right Ventricular Failure After Human Heart Transplantation Circulation, July 18, 2000; 102(3): 326 - 331. [Abstract] [Full Text] [PDF]
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P. Elliott CARDIOMYOPATHY: Diagnosis and management of dilated cardiomyopathy Heart, July 1, 2000; 84(1): 106 - 106. [Full Text] [PDF]
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L. L. Lequier, H. Nikaidoh, S. R. Leonard, J. L. Bokovoy, M. L. White, P. J. Scannon, and B. P. Giroir Preoperative and Postoperative Endotoxemia in Children With Congenital Heart Disease Chest, June 1, 2000; 117(6): 1706 - 1712. [Abstract] [Full Text] [PDF]
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 M. Okuyama, S. Yamaguchi, M. Yamaoka, J. Nitobe, S. Fujii, T. Yoshimura, and H. Tomoike Nitric Oxide Enhances Expression and Shedding of Tumor Necrosis Factor Receptor I (p55) in Endothelial Cells Arterioscler Thromb Vasc Biol, June 1, 2000; 20(6): 1506 - 1511. [Abstract] [Full Text] [PDF]
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T. Kubota, G. S. Bounoutas, M. Miyagishima, T. Kadokami, V. J. Sanders, C. Bruton, P. D. Robbins, C. F. McTiernan, and A. M. Feldman Soluble Tumor Necrosis Factor Receptor Abrogates Myocardial Inflammation but Not Hypertrophy in Cytokine-Induced Cardiomyopathy Circulation, May 30, 2000; 101(21): 2518 - 2525. [Abstract] [Full Text] [PDF]
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P.P. Davey and H. Ashrafian New therapies for heart failure: is thalidomide the answer? QJM, May 1, 2000; 93(5): 305 - 311. [Abstract] [Full Text] [PDF]
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G. Z. Feuerstein and P. R. Young Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways Cardiovasc Res, February 1, 2000; 45(3): 560 - 569. [Abstract] [Full Text] [PDF]
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M. N. Sack, R. M. Smith, and L. H. Opie Tumor necrosis factor in myocardial hypertrophy and ischaemia -- an anti-apoptotic perspective Cardiovasc Res, February 1, 2000; 45(3): 688 - 695. [Full Text] [PDF]
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J. B. Young Angiotensin-converting enzyme inhibitors and cytokines in heart failure: dose and effect? J. Am. Coll. Cardiol., December 1, 1999; 34(7): 2068 - 2071. [Full Text] [PDF]
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 A New Therapy for CHF Journal Watch (General), July 13, 1999; 1999(713): 3 - 3. [Full Text]
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 Y. Abu-Amer, J. Erdmann, L. Alexopoulou, G. Kollias, F. P. Ross, and S. L. Teitelbaum Tumor Necrosis Factor Receptors Types 1 and 2 Differentially Regulate Osteoclastogenesis J. Biol. Chem., August 25, 2000; 275(35): 27307 - 27310. [Abstract] [Full Text] [PDF]
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A. Amadou, A. Nawrocki, M. Best-Belpomme, C. Pavoine, and F. Pecker Arachidonic acid mediates dual effect of TNF-alpha on Ca2+ transients and contraction of adult rat cardiomyocytes Am J Physiol Cell Physiol, June 1, 2002; 282(6): C1339 - C1347. [Abstract] [Full Text] [PDF]
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