Circulation. 2003;107:3133-3140
Published online before print June 9, 2003, doi: 10.1161/01.CIR.0000077913.60364.D2
Published online before print June 9, 2003, doi: 10.1161/01.CIR.0000077913.60364.D2
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2003;107:3133.)
© 2003 American Heart Association, Inc.
Clinical Investigation and Reports |
Randomized, Double-Blind, Placebo-Controlled, Pilot Trial of Infliximab, a Chimeric Monoclonal Antibody to Tumor Necrosis Factor-
, in Patients With Moderate-to-Severe Heart Failure
Results of the Anti-TNF Therapy Against Congestive Heart failure (ATTACH) Trial
From The Lindner Center and Ohio Heart Health Center, Cincinnati, Ohio (E.S.C.); the Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, New York, NY (M.P.); Cardiac, Vascular, and Pulmonary Clinical Research and Development, Centocor, Malvern, Pa (K.H.L., A.A.F.); the Department of Medicine, University of Texas Health Science Center and Texas Heart Institute, Houston (J.T.W.); and the Collaborative Organization for Research Endeavors (CORE) (J.T.W., M.P.).
Correspondence to Eugene S. Chung, MD, The Lindner Center for Research and Education, 2123 Auburn Ave, Suite 424, Cincinnati, OH 45219. E-mail chunge{at}ohioheart.org
Background– Preclinical and preliminary clinical data have suggested that tumor necrosis factor-
(TNF) may play a role in the evolution and progression of heart failure and that inhibition of TNF may favorably modify the course of the disease. We evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNF, in patients with moderate-to-severe heart failure.
Methods and Results– One hundred fifty patients with stable New York Heart Association class III or IV heart failure and left ventricular ejection fraction ≤35% were randomly assigned to receive placebo (n=49), infliximab 5 mg/kg (n=50), or infliximab 10 mg/kg (n=51) at 0, 2, and 6 weeks after randomization and were followed-up prospectively for 28 weeks. Neither dose of infliximab improved clinical status at 14 weeks, the primary endpoint of the study, despite suppression of inflammatory markers (C-reactive protein and interleukin-6) and a modest increase in ejection fraction in the patients receiving 5 mg/kg (P=0.013). Furthermore, after 28 weeks, 13, 10, and 20 patients were hospitalized for any reason in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. The combined risk of death from any cause or hospitalization for heart failure through 28 weeks was increased in the patients randomized to 10 mg/kg infliximab (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal P=0.043).
Conclusions– Short-term TNF antagonism with infliximab did not improve and high doses (10 mg/kg) adversely affected the clinical condition of patients with moderate-to-severe chronic heart failure.
Key Words: heart failure • proteins • antibodies
This article has been cited by other articles:
 |
|
 |
|
  S. M. Dunlay, S. A. Weston, M. M. Redfield, J. M. Killian, and V. L. Roger Tumor Necrosis Factor-{alpha} and Mortality in Heart Failure: A Community Study Circulation, August 5, 2008; 118(6): 625 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C Parish and J. D Evans Inflammation in Chronic Heart Failure Ann. Pharmacother., July 1, 2008; 42(7): 1002 - 1016. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-M. Kang, Z.-H. Zhang, B. Xue, R. M. Weiss, and R. B. Felder Inhibition of brain proinflammatory cytokine synthesis reduces hypothalamic excitation in rats with ischemia-induced heart failure Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H227 - H236. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Leuschner, J. Li, S. Goser, L. Reinhardt, R. Ottl, P. Bride, J. Zehelein, G. Pfitzer, A. Remppis, E. Giannitsis, et al. Absence of auto-antibodies against cardiac troponin I predicts improvement of left ventricular function after acute myocardial infarction Eur. Heart J., June 13, 2008; (2008) ehn268v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. R. Kompa, F. See, D. A. Lewis, A. Adrahtas, D. M. Cantwell, B. H. Wang, and H. Krum Long-Term but Not Short-Term p38 Mitogen-Activated Protein Kinase Inhibition Improves Cardiac Function and Reduces Cardiac Remodeling Post-Myocardial Infarction J. Pharmacol. Exp. Ther., June 1, 2008; 325(3): 741 - 750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. D Sin and W D. Reid Is inflammation good, bad or irrelevant for skeletal muscles in COPD? Thorax, February 1, 2008; 63(2): 95 - 96. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hori and K. Nishida Toll-Like Receptor Signaling: Defensive or Offensive for the Heart? Circ. Res., February 1, 2008; 102(2): 137 - 139. [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Witteles and M. B. Fowler Insulin-Resistant Cardiomyopathy: Clinical Evidence, Mechanisms, and Treatment Options J. Am. Coll. Cardiol., January 15, 2008; 51(2): 93 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Freeling, K. Wattier, C. LaCroix, and Y.-F. Li Neostigmine and pilocarpine attenuated tumour necrosis factor {alpha} expression and cardiac hypertrophy in the heart with pressure overload Exp Physiol, January 1, 2008; 93(1): 75 - 82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H.R.S. Girn, N.M. Orsi, and S. Homer-Vanniasinkam An overview of cytokine interactions in atherosclerosis and implications for peripheral arterial disease Vascular Medicine, November 1, 2007; 12(4): 299 - 309. [Abstract] [PDF]
|
|
|
|
 |
|
 W G Dixon and D P M Symmons What effects might anti-TNF{alpha} treatment be expected to have on cardiovascular morbidity and mortality in rheumatoid arthritis? A review of the role of TNF{alpha} in cardiovascular pathophysiology Ann Rheum Dis, September 1, 2007; 66(9): 1132 - 1136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Maki-Petaja, A. D. Booth, F. C. Hall, S. M.L. Wallace, J. Brown, C. M. McEniery, and I. B. Wilkinson Ezetimibe and Simvastatin Reduce Inflammation, Disease Activity, and Aortic Stiffness and Improve Endothelial Function in Rheumatoid Arthritis J. Am. Coll. Cardiol., August 28, 2007; 50(9): 852 - 858. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Monden, T. Kubota, T. Inoue, T. Tsutsumi, S. Kawano, T. Ide, H. Tsutsui, and K. Sunagawa Tumor necrosis factor-{alpha} is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H743 - H753. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D'Haens Risks and benefits of biologic therapy for inflammatory bowel diseases Gut, May 1, 2007; 56(5): 725 - 732. [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. Rennard, C. Fogarty, S. Kelsen, W. Long, J. Ramsdell, J. Allison, D. Mahler, C. Saadeh, T. Siler, P. Snell, et al. The Safety and Efficacy of Infliximab in Moderate to Severe Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., May 1, 2007; 175(9): 926 - 934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Monden, T. Kubota, T. Tsutsumi, T. Inoue, S. Kawano, N. Kawamura, T. Ide, K. Egashira, H. Tsutsui, and K. Sunagawa Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction Cardiovasc Res, March 1, 2007; 73(4): 794 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. K. Khush, D. D. Waters, V. Bittner, P. C. Deedwania, J. J.P. Kastelein, S. J. Lewis, and N. K. Wenger Effect of High-Dose Atorvastatin on Hospitalizations for Heart Failure: Subgroup Analysis of the Treating to New Targets (TNT) Study Circulation, February 6, 2007; 115(5): 576 - 583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Skyschally, P. Gres, S. Hoffmann, M. Haude, R. Erbel, R. Schulz, and G. Heusch Bidirectional Role of Tumor Necrosis Factor-{alpha} in Coronary Microembolization: Progressive Contractile Dysfunction Versus Delayed Protection Against Infarction Circ. Res., January 5, 2007; 100(1): 140 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Linde, D. Mosier, F. Blecha, and T. Melgarejo Innate immunity and inflammation - New frontiers in comparative cardiovascular pathology Cardiovasc Res, January 1, 2007; 73(1): 26 - 36. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Hoare, E. J. Birks, C. Bowles, N. Marczin, and M. H. Yacoub In vitro endothelial cell activation and inflammatory responses in end-stage heart failure J Appl Physiol, November 1, 2006; 101(5): 1466 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bellahcene, S. Jacquet, X. B. Cao, M. Tanno, R. S. Haworth, J. Layland, A. M. Kabir, M. Gaestel, R. J. Davis, R. A. Flavell, et al. Activation of p38 Mitogen-Activated Protein Kinase Contributes to the Early Cardiodepressant Action of Tumor Necrosis Factor J. Am. Coll. Cardiol., August 1, 2006; 48(3): 545 - 555. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kaur, A. K. Sharma, and P. K. Singal Significance of changes in TNF-{alpha} and IL-10 levels in the progression of heart failure subsequent to myocardial infarction Am J Physiol Heart Circ Physiol, July 1, 2006; 291(1): H106 - H113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Jankowska, P. Ponikowski, M. F. Piepoli, W. Banasiak, S. D. Anker, and P. A. Poole-Wilson Autonomic imbalance and immune activation in chronic heart failure - Pathophysiological links Cardiovasc Res, June 1, 2006; 70(3): 434 - 445. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Rizzello, G. Liuzzo, S. Brugaletta, A. Rebuzzi, L. M. Biasucci, and F. Crea Modulation of CD4+CD28null T Lymphocytes by Tumor Necrosis Factor-{alpha} Blockade in Patients With Unstable Angina Circulation, May 16, 2006; 113(19): 2272 - 2277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E Morley, D. R Thomas, and M.-M. G Wilson Cachexia: pathophysiology and clinical relevance. Am. J. Clinical Nutrition, April 1, 2006; 83(4): 735 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Zochling, D van der Heijde, M Dougados, and J Braun Current evidence for the management of ankylosing spondylitis: a systematic literature review for the ASAS/EULAR management recommendations in ankylosing spondylitis Ann Rheum Dis, April 1, 2006; 65(4): 423 - 432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J Zochling, D van der Heijde, R Burgos-Vargas, E Collantes, J C Davis Jr, B Dijkmans, M Dougados, P Geher, R D Inman, M A Khan, et al. ASAS/EULAR recommendations for the management of ankylosing spondylitis Ann Rheum Dis, April 1, 2006; 65(4): 442 - 452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zheng, A. Chin, I. Duignan, K.-H. Won, M. K. Hong, and J. M. Edelberg Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H525 - H530. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D D Sin and S F P Man Skeletal muscle weakness, reduced exercise tolerance, and COPD: is systemic inflammation the missing link? Thorax, January 1, 2006; 61(1): 1 - 3. [Full Text] [PDF]
|
|
|
|
 |
|
 F. C. Hall and N. Dalbeth Disease modification and cardiovascular risk reduction: two sides of the same coin? Rheumatology, December 1, 2005; 44(12): 1473 - 1482. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Van Doornum, G. McColl, and I. P. Wicks Tumour necrosis factor antagonists improve disease activity but not arterial stiffness in rheumatoid arthritis Rheumatology, November 1, 2005; 44(11): 1428 - 1432. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Grundmann, I. Hoefer, S. Ulusans, N. van Royen, S. H. Schirmer, C. K. Ozaki, C. Bode, J. J. Piek, and I. Buschmann Anti-tumor necrosis factor-{alpha} therapies attenuate adaptive arteriogenesis in the rabbit Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1497 - H1505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Sarzi-Puttini, F Atzeni, A Doria, L Iaccarino, and M Turiel Tumor necrosis factor-a, biologic agents and cardiovascular risk Lupus, September 1, 2005; 14(9): 780 - 784. [Abstract] [PDF]
|
|
|
|
|
|
Z. Kassiri, G. Y. Oudit, O. Sanchez, F. Dawood, F. F. Mohammed, R. K. Nuttall, D. R. Edwards, P. P. Liu, P. H. Backx, and R. Khokha Combination of Tumor Necrosis Factor-{alpha} Ablation and Matrix Metalloproteinase Inhibition Prevents Heart Failure After Pressure Overload in Tissue Inhibitor of Metalloproteinase-3 Knock-Out Mice Circ. Res., August 19, 2005; 97(4): 380 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. van der Vaart, G. H. Koeter, D. S. Postma, H. F. Kauffman, and N. H. T. ten Hacken First Study of Infliximab Treatment in Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., August 15, 2005; 172(4): 465 - 469. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. B. Suhler, J. R. Smith, M. S. Wertheim, A. K. Lauer, D. E. Kurz, T. D. Pickard, and J. T. Rosenbaum A Prospective Trial of Infliximab Therapy for Refractory Uveitis: Preliminary Safety and Efficacy Outcomes Arch Ophthalmol, July 1, 2005; 123(7): 903 - 912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Gurantz, A. Yndestad, B. Halvorsen, O. V. Lunde, J. H. Omens, T. Ueland, P. Aukrust, C. D. Moore, J. Kjekshus, and B. H. Greenberg Etanercept or intravenous immunoglobulin attenuates expression of genes involved in post-myocardial infarction remodeling Cardiovasc Res, July 1, 2005; 67(1): 106 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Burkhoff and S. A. Ben-Haim Nonexcitatory electrical signals for enhancing ventricular contractility: rationale and initial investigations of an experimental treatment for heart failure Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2550 - H2556. [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Kittleson, K. M. Minhas, R. A. Irizarry, S. Q. Ye, G. Edness, E. Breton, J. V. Conte, G. Tomaselli, J. G. N. Garcia, and J. M. Hare Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure Physiol Genomics, May 11, 2005; 21(3): 299 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Bernatsky, M. Hudson, and S. Suissa Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis Rheumatology, May 1, 2005; 44(5): 677 - 680. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mpofu, F. Fatima, and R. J. Moots Anti-TNF-{alpha} therapies: they are all the same (aren't they?) Rheumatology, March 1, 2005; 44(3): 271 - 273. [Full Text] [PDF]
|
|
|
|
|
|
S. Kyle, D. Chandler, C. E. M. Griffiths, P. Helliwell, J. Lewis, I. McInnes, S. Oliver, D. Symmons, N. McHugh, and on behalf of the British Society for Rheumatology Guideline for anti-TNF-{alpha} therapy in psoriatic arthritis Rheumatology, March 1, 2005; 44(3): 390 - 397. [Full Text] [PDF]
|
|
|
|
|
|
P J Mease and C E Antoni Psoriatic arthritis treatment: biological response modifiers Ann Rheum Dis, March 1, 2005; 64(suppl_2): ii78 - ii82. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Tachikawa, M. Kodama, K. Watanabe, T. Takahashi, M. Ma, T. Kashimura, M. Ito, S. Hirono, Y. Okura, K. Kato, et al. Amiodarone Improves Cardiac Sympathetic Nerve Function to Hold Norepinephrine in the Heart, Prevents Left Ventricular Remodeling, and Improves Cardiac Function in Rat Dilated Cardiomyopathy Circulation, February 22, 2005; 111(7): 894 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Ledingham, C. Deighton, and on behalf of the British Society for Rheumatology Update on the British Society for Rheumatology guidelines for prescribing TNF{alpha} blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001) Rheumatology, February 1, 2005; 44(2): 157 - 163. [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Yan, R. T. Yan, and P. P. Liu Narrative Review: Pharmacotherapy for Chronic Heart Failure: Evidence from Recent Clinical Trials Ann Intern Med, January 18, 2005; 142(2): 132 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Ziegelstein Prescribing Antitumor Necrosis Factor Drugs to Patients With Heart Failure Arch Intern Med, January 10, 2005; 165(1): 118 - 119. [Full Text] [PDF]
|
|
|
|
 |
|
 N Wisniacki, W Taylor, M Lye, and J P H Wilding Insulin resistance and inflammatory activation in older patients with systolic and diastolic heart failure Heart, January 1, 2005; 91(1): 32 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J.V. McMurray and M. A. Pfeffer The year in heart failure J. Am. Coll. Cardiol., December 21, 2004; 44(12): 2398 - 2405. [Full Text] [PDF]
|
|
|
|
|
|
K L Hyrich, A J Silman, K D Watson, and D P M Symmons Anti-tumour necrosis factor {alpha} therapy in rheumatoid arthritis: an update on safety Ann Rheum Dis, December 1, 2004; 63(12): 1538 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. C. Sharma, S. Pokharel, T. J. van Brakel, J. H. van Berlo, J. P.M. Cleutjens, B. Schroen, S. Andre, H. J.G.M. Crijns, H.-J. Gabius, J. Maessen, et al. Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction Circulation, November 9, 2004; 110(19): 3121 - 3128. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Agnoletti, S. Curello, F. Malacarne, P. Airò, A. Cargnoni, M. Valgimigli, and R. Ferrari Immune activation in severe heart failure: Does etiology play a role? Eur. Heart J. Suppl., November 1, 2004; 6(suppl_F): F22 - F29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bourraindeloup, C. Adamy, G. Candiani, M. Cailleret, M.-C. Bourin, T. Badoual, J. B. Su, S. Adubeiro, F. Roudot-Thoraval, J.-L. Dubois-Rande, et al. N-Acetylcysteine Treatment Normalizes Serum Tumor Necrosis Factor-{alpha} Level and Hinders the Progression of Cardiac Injury in Hypertensive Rats Circulation, October 5, 2004; 110(14): 2003 - 2009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Madjid, A. Zarrabi, S. Litovsky, J. T. Willerson, and W. Casscells Finding Vulnerable Atherosclerotic Plaques: Is It Worth the Effort? Arterioscler. Thromb. Vasc. Biol., October 1, 2004; 24(10): 1775 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. W. Moe, J. Marin-Garcia, A. Konig, M. Goldenthal, X. Lu, and Q. Feng In vivo TNF-{alpha} inhibition ameliorates cardiac mitochondr |