on June 9, 2003
Published online before print June 9, 2003, doi: 10.1161/01.CIR.0000077913.60364.D2
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© 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.).
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
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Abstract |
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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
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Introduction |
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Serum levels of tumor necrosis factor-
(TNF) are elevated in patients with heart failure, and the magnitude of the increase is directly correlated with the severity of disease.1,2 TNF is produced by the failing heart (possibly due to an increase in ventricular wall stress3,4) and may contribute directly to the evolution and progression of heart failure.5 TNF has established negative inotropic effects,6 and transgenic mice that overproduce myocardial TNF develop systolic dysfunction.7 In addition, TNF can cause pathological changes in the myocardium, including ventricular remodeling, interstitial fibrosis, and cardiomyocyte apoptosis,8,9 changes that are characteristic of those seen in the failing human heart. The hypothesis that TNF is a deleterious factor in heart failure is further supported by a preliminary clinical study with the TNF antagonist etanercept (a soluble p75 TNF receptor fusion protein).10 In this pilot trial, treatment with etanercept was reported to improve cardiac function and clinical status in patients with moderate-to-severe symptoms.
Infliximab is a recombinant immunoglobulin G1-
, human-murine chimeric monoclonal antibody that specifically and potently binds to and neutralizes the soluble TNF homotrimer and its membrane-bound precursor.11 It has been shown to be an effective treatment for moderate-to-severe Crohn’s disease when conventional therapies are inadequate12 and for active rheumatoid arthritis that is not responding adequately to methotrexate therapy.13 The ATTACH (Anti-TNF Therapy Against Congestive Heart failure) trial was designed to evaluate, in a preliminary fashion, whether TNF inhibition with infliximab could have favorable effects in patients with moderate-to-severe heart failure.
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Methods |
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Study Patients
One hundred fifty patients were enrolled at 32 US study centers between August 14, 2000, and April 20, 2001. Men and women at least 18 years old with stable New York Heart Association (NYHA) class III or IV heart failure associated with a radionuclide left ventricular ejection fraction ≤35% within 14 days before randomization were eligible for enrollment. Heart failure was considered stable if none of the following occurred within 2 weeks before screening: Change in NYHA functional class, hospitalization for heart failure, or administration of any intravenous medication for heart failure. Patients were required to have received treatment with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin II receptor blocker if intolerant of ACE inhibitors) for at least 85% of the time during the prior 3 months. ß-Blockers, digoxin, and spironolactone were allowed, provided that they were started ≥3 months before screening and were to be continued throughout the 28-week trial period; patients not receiving these medications at the time of screening were not to have received them within 3 months. Treatment with vasodilators or nitrates was permitted but not required. Doses of all cardiac medications were to be constant for at least 2 weeks before and during screening. Patients were required to have received adequate immunization against Streptococcus pneumoniae ≥2 weeks before randomization.
Patients were excluded if they had hemodynamically significant obstructive valvular disease, cor pulmonale, restrictive or hypertrophic cardiomyopathy, constrictive pericarditis, or congenital heart disease; had experienced an acute myocardial infarction or coronary revascularization procedure within 2 months; or were likely to undergo coronary revascularization or heart transplant during the anticipated duration of the study. Patients were not allowed to participate if they had been resuscitated from sudden death or had had a therapeutic discharge of an implanted implantable cardioverter defibrillator within 3 months or had received within 2 weeks or were likely to receive within the following 28 weeks any of the following: A class IC or III antiarrhythmic other than amiodarone; a calcium channel blocker other than amlodipine for hypertension or angina; a positive inotrope other than digoxin; or a nonsteroidal antiinflammatory drug other than aspirin. In addition, patients were not enrolled if they had experienced a serious infection within 2 months; had latent tuberculosis or had had tuberculosis within 3 years; had a documented human immunodeficiency virus infection; or had any other opportunistic infection within 6 months. Finally, patients who within 3 months had been treated with infliximab or other therapeutic agents that could interfere with the actions of TNF (eg, etanercept, pentoxifylline, thalidomide, or D2E7) were not allowed in the study.
Study Design
Informed consent was obtained from all patients according to institutional review board guidelines. Within 14 days before planned randomization, potential study candidates underwent a screening evaluation, including medical history and physical examination, assessment of NYHA class, routine laboratory tests, chest x-ray, 12-lead ECG, and determination of left ventricular ejection fraction by radionuclide ventriculography. Patients meeting all eligibility criteria underwent a repeat assessment of NYHA class just before randomization to reaffirm eligibility, and a baseline assessment of quality of life using the Minnesota Living With Heart Failure questionnaire was performed. Blood was collected for baseline measurements of inflammatory markers (TNF, interleukin-6 [IL-6], and C-reactive protein [CRP]). Eligible patients were randomly assigned in a double-blind fashion to receive infliximab 5 mg/kg, infliximab 10 mg/kg (to maximum of 1 g), or placebo immediately after randomization and again at 2 and 6 weeks after randomization. At each of the 3 visits, the study agent was administered as a 2-hour intravenous infusion.
Randomized patients underwent follow-up evaluations at 1, 2, 6, 10, 14, 20, and 28 weeks after randomization, whether the study agent was administered or was prematurely discontinued. At each visit, patients provided an overall assessment of their heart failure status, relative to baseline, using one of the following categories: Unchanged, mildly improved or worse, moderately improved or worse, markedly improved or worse (patient global assessment); NYHA class was assessed; blood samples were drawn for inflammatory markers and serum infliximab concentrations; and patients were queried about the occurrence of adverse effects, hospitalization, and other major clinical events. Repeat assessments of left ventricular ejection fraction and Minnesota Living With Heart Failure score were performed at 14 and 28 weeks after randomization. Every attempt was made to maintain background medication constant throughout the 28-week trial period, and patients were not allowed to receive open-label infliximab or etanercept during this time. The vital status of all patients was assessed at 1 year after randomization.
The primary endpoint of the study was the change in clinical status at 14 weeks. Clinical status was assessed by the clinical composite score, which categorized each patient as improved, worse, or unchanged using prespecified criteria.14 Patients were considered improved if they showed an improved NYHA class or moderate or marked improvement in the patient global assessment; to be improved, none of the criteria for worse clinical status could be present. Patients were considered worse if they died, were hospitalized for heart failure, or had worsening NYHA class or moderate or marked worsening of the patient global assessment. Patients who were neither improved nor worse were considered to be unchanged.
A patient was considered to have been hospitalized for heart failure if he/she was hospitalized at least overnight for or with worsening heart failure and received intravenous diuretics, vasodilators, or positive inotropic drugs within 24 hours of admission for the treatment of heart failure.
Secondary endpoints included change in inflammatory markers during the 28-week trial period, change in left ventricular ejection fraction at 14 and 28 weeks, the combined risk of death or hospitalization for worsening heart failure at 28 weeks, and the change in Minnesota Living With Heart Failure score at 14 and 28 weeks.
Assays
Serum TNF levels were measured from blood samples collected immediately before and after each infliximab or placebo infusion at weeks 0, 2, and 6, as well as at weeks 1, 10, 14, 20, and 28. Serum was separated and stored at -70°C until analyzed. TNF was assayed using a validated assay kit (R&D Systems Human TNF-/TNFSF2 QuantiGlo ELISA Kit).
IL-6 and CRP levels were measured from samples collected before and after the study agent infusion at week 0, before the study agent infusions at weeks 2 and 6, and at weeks 1, 10, 14, 20, and 28. IL-6 was assayed using the human IL-6 QuantiGlo Immunoassay Kit (R&D Systems Laboratories) and CRP, using the validated high sensitivity CRP assay method (rate nephelometry) from Quest Laboratories (Quest Diagnostics).
Serum infliximab levels were measured from blood samples collected immediately before and after each infliximab or placebo infusion at weeks 0, 2, and 6, as well as at weeks 1, 10, 14, 20, and 28, with the use of an enzyme-linked immunoassay. The lowest level of infliximab that could be reliably detected using the assay was 0.06 µg/mL.
Statistical Analyses
Patients were included in the analysis according to the intention-to-treat principle, whether or not they received the study drug at specified time points. Applying last observation carried forward for missing data, analysis of the primary efficacy endpoint used an ordered alternative Cochran Mantel-Haenszel Test15 with scores of 1, 2, and 3 for worse, unchanged, and improved, respectively. For the analysis of major clinical events, the Kaplan-Meier method was used to describe the occurrence of events, and the log- rank test and proportional hazards regression analysis were used to test for treatment-group differences. Between-treatment comparisons of changes in left ventricular ejection fraction and Minnesota Living With Heart Failure scores were carried out by using a nonparametric test using van der Waerden scores.16
This pilot study was powered to detect major differences between treatment groups. Assuming that the proportions of placebo patients with improved, unchanged, and worsened clinical status at week 14 were similar to those observed in the 47-patient etanercept trial (45%, 42%, and 13%, respectively), a sample size of 150 patients would have been sufficient to detect rates in the combined infliximab groups of 75%, 15%, and 10%, respectively, with a power of 80%.
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Results |
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Patient Disposition
Of the 150 patients enrolled, 49 were randomized to placebo, 50 to 5 mg/kg infliximab, and 51 to 10 mg/kg infliximab. The 3 treatment groups were similar in their baseline characteristics (Table 1).
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One patient in the placebo group was not treated with study medication. In addition, 8 patients did not receive all 3 infusions of the study drug (1 in the placebo group, 2 in the 5 mg/kg infliximab group, and 5 in the 10 mg/kg infliximab group); the most common reason for permanent discontinuation of the study medication was an adverse event (6 patients). One patient who was randomized to 10 mg/kg infliximab received 5 mg/kg infliximab at each of the 3 infusion visits but was included in the 10 mg/kg group for efficacy analyses, according to the intention-to-treat principle.
Effect of Infliximab on Clinical Status
Changes in clinical status in the patients randomized to either dose of infliximab were not significantly different than in those randomized to placebo, either at 14 weeks (the primary endpoint) or at 28 weeks (the end of the prespecified period of follow-up) (Table 2). However, patients in the 10 mg/kg infliximab group were more likely than those in the other 2 groups to experience worsening of their clinical status at both 14 weeks (22% versus 8% in the placebo group and 10% in the 5 mg/kg infliximab group) and at 28 weeks (31% versus 14% in placebo group and 16% in the 5 mg/kg infliximab group) (Table 2).
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Effect of Infliximab on Major Clinical Events
The increased risk of worsening clinical status in patients in the 10 mg/kg infliximab group was primarily related to an increased risk of major adverse clinical events in that group. Specifically, through 28 weeks, patients in the 10 mg/kg infliximab group were more likely to die or be hospitalized for heart failure than patients in the placebo group (hazard ratio 2.84, 95% confidence interval 1.01 to 7.97; nominal P=0.043 using log-rank test) (Table 3 and Figure 1). Patients in the 10 mg/kg infliximab group were more likely to be hospitalized for heart failure or for any reason than patients in the placebo or 5 mg/kg infliximab groups (Table 3 and Figure 1).
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Effect of Infliximab on Quality of Life
Median scores for the Minnesota Living With Heart Failure questionnaire at baseline were 52.0, 53.0, and 52.0 in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively. There were no significant changes in quality of life scores among the 3 treatment groups either at 14 weeks (-4.0, -6.5, and -4.0 for placebo, 5 mg/kg, and 10 mg/kg [P=0.829]) or at 28 weeks (0.0, -3.0, and -6.0 for placebo, 5 mg/kg, and 10 mg/kg, respectively [P=0.811]).
Serum Levels of Infliximab and Effect on Surrogate Markers
Median serum levels of infliximab rose immediately with each infusion of the drug and, for at least 14 weeks, remained above levels that have been associated with clinical benefit in patients with rheumatoid arthritis (Figure 2).17
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At baseline, median values for CPR were 6.2, 2.2, and 4.4 mg/L in the placebo, 5 mg/kg infliximab, and 10 mg/kg infliximab groups, respectively; values for IL-6 were 3.7, 3.2, and 3.8 pg/mL, respectively; and values for TNF were 6.0, 5.7, and 6.6 pg/mL respectively. Treatment with both doses of infliximab was associated with a reduction in serum levels of CRP and IL-6 within the first week; both markers remained below baseline for 14 weeks and gradually returned toward baseline levels by 28 weeks (Figure 3). Measured serum levels of TNF in the infliximab groups were also reduced immediately after each infusion but were elevated above baseline values at all other time points through the 28-week period (Figure 4). An in vitro bioactivity assay based on the WEHI cell viability method demonstrated an apparent lack of free biologically active TNF in samples that had increased levels of immunodetectable TNF.
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Changes in inflammatory markers were accompanied by changes in the left ventricular ejection fraction. At 14 weeks (when levels of CRP and IL-6 were suppressed), left ventricular ejection fraction increased in patients treated with infliximab (mean changes from baseline of 3.5% with 5 mg/kg infliximab, 2.1% with 10 mg/kg infliximab, and 0.8% with placebo, P=0.039 for placebo versus both infliximab groups combined). However, by 28 weeks (when levels of CRP and IL-6 had increased toward baseline), changes in left ventricular ejection fraction in the infliximab groups were no longer significantly different than in the placebo group (mean increases from baseline of 4.2%, 1.3%, and 3.4% in the 5 mg/kg infliximab, 10 mg/kg infliximab, and placebo groups, respectively).
Adverse Events
A similar proportion of patients in each of the 3 treatment groups reported 1 or more adverse events during the first 28 weeks of the study (Table 4). Dizziness, dyspnea, hypotension, and angina were reported more frequently in infliximab-treated patients. Serious adverse events were reported more frequently in the 10 mg/kg infliximab group than in the other 2 groups (44.0% versus 29.2% in the placebo group and 23.5% in the 5 mg/kg group), a finding that was primarily related to the higher frequency of reports of heart failure in that group (22.0% with 10 mg/kg versus 8.3% with placebo and 2.0% with 5 mg/kg). Other serious adverse events reported in greater than 2% of the combined infliximab groups included dyspnea (4.2%, 5.9%, and 6.9% in the placebo, 5 mg/kg, and 10 mg/kg groups, respectively); chest pain (0.0%, 2.0%, and 6.0%); and pneumonia (2.1%, 3.9%, and 2.0%). Serious infections occurred in 2.1%, 5.9%, and 8.0% of the placebo, 5 mg/kg, and 10 mg/kg infliximab groups.
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Of 96 infliximab-treated patients with serum samples evaluable for antibodies to infliximab, 16 (16.7%) had detectable antibodies, and titers were ≤1:20 in 15 of these patients.
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Discussion |
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Although the current study was designed as a pilot experience, the observations carried out during the course of this trial do not support the utility of TNF
antagonism with infliximab as a treatment for chronic heart failure in the doses utilized in this study. Patients treated with infliximab (at 5 mg/kg or at 10 mg/kg per infusion) did not show an improvement in any of a broad range of objective and subjective clinical assessments. Furthermore, treatment of patients with moderate-to-severe chronic heart failure with high doses of infliximab (10 mg/kg per infusion) was associated with worsening clinical status, an increased likelihood of hospitalization, and a high frequency of worsening heart failure reported as a serious adverse event. The increased risk of adverse clinical events associated with the use of high doses of infliximab was not only observed during treatment but also persisted for up to 5 months after the cessation of therapy.
Infliximab failed to produce clinical benefits in this study, even though the drug exerted its expected biological effects. Serum levels of CRP and IL-6 were suppressed in both infliximab groups relative to placebo for at least 14 weeks. The lack of benefit may have been related to the short duration of effective treatment (
14 weeks); this may have been particularly true for a drug that is believed to exert any benefit by altering fundamental processes that affect cardiac structure and function. However, previous trials have shown that improvements in physiological variables are not reliably translated into measurable clinical benefits, even when the treatment is sustained for long periods.18,19
The results of the current trial differ substantially from those reported with the use of TNF antagonists in experimental models of heart failure. Administration of the soluble TNF receptor etanercept attenuates adverse cardiac effects associated with the infusion of TNF in rats.20 The administration of both a soluble tumor necrosis factor encoding adenovirus and a monoclonal anti-TNF antibody similar to infliximab but biologically active in mice is associated with beneficial cardiac effects in genetically altered mice with heart failure secondary to overexpression of TNF,21,22 and suppression of TNF exerts favorable effects in rats with heart failure produced by coronary artery ligation.23 Unfortunately, favorable results with therapeutic agents in experimental models of heart failure have frequently not been replicated in controlled clinical trials.24,25
Despite the encouraging results of the small pilot trial with etanercept, the results of 2 large-scale, multicenter trials of this TNF antagonist in 2048 patients with moderate-to-severe heart failure did not demonstrate any clinical benefits associated with the use of etanercept and suggested that etanercept might adversely affect the courses of patients with chronic heart failure in a dose-dependent manner.26 The results of these definitive trials are consistent with the observations of the current study.
What might explain the tendency for TNF antagonism to adversely affect the clinical course of patients with heart failure in a dose-dependent manner? Some reports have suggested that treatment with available TNF antagonists might potentiate (rather than interfere with) the cardiac toxicity of TNF. By complexing with circulating TNF and thereby retaining it within the circulation, etanercept may prolong exposure of cardiac tissue to TNF27 and potentially lead to cardiac toxicity. Similarly, when exposed to cells expressing transmembrane TNF, infliximab can cause cell lysis in the presence of complement,28 an effect that would be undesirable if it occurred in cardiomyocytes in patients with heart failure. The toxicity of TNF might be also enhanced if treatment with infliximab caused circulating levels of TNF (which are immediately suppressed after administration of the drug) to rebound to levels substantially higher than those seen before the start of treatment (Figure 4). However, there is no direct evidence to suggest that any of these proposed mechanisms are operative in patients with heart failure. Biologically active TNF could not be detected in serum samples taken at the time of the hypothesized "TNF rebound" in the present study. This is consistent with the hypothesis that the assay used for the measurement of TNF detected not only free TNF but also partially saturated TNF–infliximab complexes, which are immunoreactive but biologically inactive. Fully saturated TNF homotrimers, which are formed immediately after each infusion when there is a large excess of infliximab, are undetectable. A similar pattern of serum TNF concentrations is seen in patients with Crohn’s disease who show sustained clinical benefits with infliximab.29
If treatment with TNF antagonists does not potentiate the toxicity of TNF, then what can explain the worsening of heart failure seen in studies with infliximab and etanercept? It has generally been assumed that the activation of cytokines plays a deleterious role in heart failure,30 but it is conceivable that increases in TNF play an adaptive role—similar to that hypothesized for natriuretic peptides. By enhancing the production of vascular nitric oxide, TNF may play an important role in enhancing the production of adrenomedullin and other endogenous vasodilators and maintaining peripheral blood flow inpatients with heart failure.31–33 Furthermore, TNF may prevent apoptosis in myocytes under stress,34 and by enhancing the production of myocardial nitric oxide, the cytokine may attenuate responsiveness to ß-adrenergic stimulation and thereby attenuate the toxicity associated with prolonged activation of the sympathetic nervous system.33,35–38 The existence of mechanisms by which cytokine activation may be beneficial (when taken together with the results of clinical trials with TNF antagonists) challenge the conventional wisdom that TNF acts as a deleterious factor in patients with chronic heart failure.
In conclusion, therapy with infliximab over a 6-week period did not produce clinical improvement in patients with moderate-to-severe heart failure followed for 14 to 28 weeks, and treatment with high doses (10 mg/kg) was associated with an increased risk of worsening heart failure. Although a similar risk was not observed with the 5 mg/kg doses of infliximab in the current study, an adverse effect at this lower dose (particularly during longer-term treatment) cannot be excluded. These findings raise unresolved questions about the role of TNF in heart failure and important concerns about the safety of using TNF antagonists (especially at high doses) for the treatment of noncardiac disorders in patients who also have moderate-to-severe heart failure. Whether infliximab can be used safely in patients with asymptomatic left ventricular dysfunction or mild symptoms of heart failure (NYHA class I/II) remains to be determined.
Investigators and Study Centers (in Descending Order of Number of Patients Enrolled)
Dean Kereiakes and Linda Martin, The Lindner Clinical Trial Center, Cincinnati, Ohio; Jerome L. Anderson and Carolyn Carter-Emmett, Cardiovascular Clinic, Oklahoma City, Okla; Ron Oren and Todd Jayden, University of Iowa, Iowa City, Iowa; Richard Gilmore and Myra Thomas, St Patrick Hospital, Lake Charles, La; Brian Jaski and Sue Harte, San Diego Cardiac Center, San Diego, Calif; Krishnaswami Vijayaraghavan and Debra Rothenbuehler, Arizona Heart Institute, Phoenix, Ariz; Martin R. Berk and Mary Ann Richards, Cardiology Research Institute of Dallas, Dallas, Tex; Norman Erenrich and Elizabeth Dagher, Cardiology Associates of Palm Beach, Atlantis, Fla; Sidney Gottlieb and Vicky Coombs, GBMC & St Joseph’s Medical Center, Towson, Md; Paul Hauptman (CORE [Collaborative Organization for Research Endeavors] investigator) and Mary Rawlings, Saint Louis University, St Louis, Mo; Thomas J. Heywood and Jennifer Connolly, Loma Linda University, Loma Linda, Calif; Dale Renlund and Barbara Daniels, LDS Hospital, Salt Lake City, Utah; David Hager and Mary Beth Barry, University of Connecticut Health Center, Farmington, Conn; Marc Litt and Mary Roberts, Jacksonville Heart Center, Jacksonville, Fla; Lawrence Miller and Mandy Hickman, Cardiovascular Group PC, Fairfax, Va; Daniel Levine and Noreen Gorham, University Cardiology Foundation, Providence, RI; Susan Bennett and Marie Burgett, Washington Hospital Center, Washington, DC; Richard Steingart and Maryellen Coglianese, Winthrop University Hospital, Mineola, NY; William Wickenmeyer and Lisa Kiley, Iowa Heart Center, Des Moines, Iowa; Alan Bank and Kathleen Mullen, St Paul Heart Clinic United Hospital, St Paul, Minn; Jeffrey Hosenpud and Maggie Miller, St Luke’s Hospital, Milwaukee, Wis; Richard Dickstein and Tracy Vogt, South Jersey Hospital, Elmer, NJ; David A. Henderson and Diane Martin, Cardiology Research Associates, Ormond Beach, Fla; Mitchell Greenspan and Gail Titus, Buxmont Cardiology Associates, Sellerville, Pa; Sayed Feghali (CORE [Collaborative Organization for Research Endeavors] investigator) and Mary Harlan, Texas Heart Institute, Houston, Tex; Alan Gradman and Michele Wagner, Western PA Hospital, Pittsburgh, Pa; Irmina Gradus-Pizlo (CORE [Collaborative Organization for Research Endeavors] investigator) and Linda Rohyans, Krannert Institute of Cardiology, Indianapolis, Ind; Thomas Hilton and Saralynn Duncan, Jacksonville Heart, Jacksonville Beach, Fla; Mark Milunski and Valerie Spier, Orlando Regional Hospital, Orlando, Fla; Frank Smart and Kim Drake, Tulane University, New Orleans, La; Dwayne A. Schmidt and Sharon Mears, Oklahoma Foundation for Cardiovascular Research, Oklahoma City, Okla; J. Robert McGhee and Veta Markland-Page, Cardiovascular Research Associates Inc, Ocala, Fla.
Operations Committee (Centocor)
Sanjay Batra, Catherine F. Cabot, Steven Carr, Judith Cooper, Lakshmi Damaraju, Lawrence Deckelbaum, Adedigbo Fasanmade, Leah Foster, Diane Licursi, Kim Hung Lo, Jennifer Toomey.
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Acknowledgments |
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This work was supported by a grant from Centocor, Inc.
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Footnotes |
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*The ATTACH Investigators and study centers are listed in the Appendix.
Dr Packer is a consultant to and Drs Lo and Fasanmade are employees of Centocor, Inc, which provided support for this study.
Guest editor for this article was Eugene Braunwald, MD, Harvard Medical School, Boston, Mass.
Received February 26, 2003; accepted May 6, 2003.
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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]
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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]
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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]
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M. Satoh, J. Iwasaka, M. Nakamura, T. Akatsu, Y. Shimoda, and K. Hiramori Increased expression of tumor necrosis factor-{alpha} converting enzyme and tumor necrosis factor-{alpha} in peripheral blood mononuclear cells in patients with advanced congestive heart failure Eur J Heart Fail, December 1, 2004; 6(7): 869 - 875. [Abstract] [Full Text] [PDF]
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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]
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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]
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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]
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G. W. Moe, J. Marin-Garcia, A. Konig, M. Goldenthal, X. Lu, and Q. Feng In vivo TNF-{alpha} inhibition ameliorates cardiac mitochondrial dysfunction, oxidative stress, and apoptosis in experimental heart failure Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1813 - H1820. [Abstract] [Full Text] [PDF]
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G. Torre-Amione, F. Sestier, B. Radovancevic, and J. Young Effects of a novel immune modulation therapy in patients with advanced chronic heart failure: Results of a randomized, controlled, phase II trial J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1181 - 1186. [Abstract] [Full Text] [PDF]
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J. Braun and J. Sieper Biological therapies in the spondyloarthritides--the current state Rheumatology, September 1, 2004; 43(9): 1072 - 1084. [Abstract] [Full Text] [PDF]
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J. Springer, D. O. Okonko, S. D. Anker, M. Li, C. Zheng, T. Kawada, M. Sugimachi, K. Sunagawa, and T. Sato Vagal Nerve Stimulation in Chronic Heart Failure: An Antiinflammatory Intervention? * Response Circulation, July 27, 2004; 110(4): e34 - e34. [Full Text] [PDF]
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R. Mills and D. L. Bhatt The yin and yang of arterial inflammation J. Am. Coll. Cardiol., July 7, 2004; 44(1): 50 - 52. [Full Text] [PDF]
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G F Ferraccioli and E Gremese Autoantibodies and thrombophilia in RA: TNF{alpha} and TNF{alpha} blockers Ann Rheum Dis, June 1, 2004; 63(6): 613 - 615. [Full Text]
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D. L. Mann, J. J.V. McMurray, M. Packer, K. Swedberg, J. S. Borer, W. S. Colucci, J. Djian, H. Drexler, A. Feldman, L. Kober, et al. Targeted Anticytokine Therapy in Patients With Chronic Heart Failure: Results of the Randomized Etanercept Worldwide Evaluation (RENEWAL) Circulation, April 6, 2004; 109(13): 1594 - 1602. [Abstract] [Full Text] [PDF]
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