 |
 |
|
20 May 2003 | Volume 138 Issue 10 | Pages 807-811
Background: Etanercept and infliximab are U.S. Food and Drug Administration–approved tumor necrosis factor (TNF) antagonists.
Objective: To describe adverse event reports of heart failure after TNF antagonist therapy.
Design: Case series.
Setting: The U.S. Food and Drug Administration's MedWatch program.
Patients: 47 patients who developed new or worsening heart failure during TNF antagonist therapy.
Measurements: Clinical and laboratory reports.
Results: After TNF antagonist therapy, 38 patients developed new-onset heart failure and 9 patients experienced heart failure exacerbation. Of the 38 patients with new-onset heart failure, 19 (50%) had no identifiable risk factors. Ten patients younger than 50 years of age developed new-onset heart failure after receiving TNF antagonists. After TNF antagonist therapy was discontinued and heart failure therapy was started in these 10 patients, 3 had complete resolution of heart failure, 6 improved, and 1 died.
Conclusion: In a fraction of patients, TNF antagonists might induce new-onset heart failure or exacerbate existing disease.
Contribution
Implications
–The Editors
More than a decade ago, Levine and colleagues (1) demonstrated increased serum levels of tumor necrosis factor (TNF) in patients with advanced heart failure. Torre-Amione and colleagues (2) later showed that TNF levels correlated with the severity of heart failure. Other experimental findings (3, 4) supported the role of TNF in heart failure, and early clinical studies of blocking TNF in patients with heart failure demonstrated promising results (5-7). However, large-scale randomized, placebo-controlled trials of etanercept for treatment of heart failure were stopped early because they failed to demonstrate an improvement in clinical heart failure or mortality (8). A phase II trial in 150 patients (101 taking infliximab and 49 taking placebo) who had New York Heart Association class III to IV heart failure showed excess mortality (7 deaths vs. 0 deaths) and hospitalization for worsening heart failure in the infliximab group (9).
At the time of our study, two TNF antagonists, etanercept and infliximab, were approved for use in the United States. Etanercept (Amgen, Thousand Oaks, California) is a recombinant, soluble TNF type 2 receptor that binds and inhibits TNF and is used to treat rheumatoid, juvenile rheumatoid, and psoriatic arthritis. Infliximab (Centocor, Malvern, Pennsylvania) is a chimeric monoclonal antibody against TNF-BRIEF COMMUNICATION
Case Reports of Heart Failure after Therapy with a Tumor Necrosis Factor Antagonist
Editors' Notes
Top
Editors' Notes
Methods
Results
Discussion
Author & Article Info
References
Context
and is used to treat Crohn disease and, in combination with methotrexate, rheumatoid arthritis. Neither product is indicated for the prevention or treatment of heart failure. As of July 2001, 104 000 patients had been treated with etanercept and 170 000 patients had been treated with infliximab worldwide (10). Because controlled trials in patients with heart failure showed no benefit of TNF antagonists and, in the case of the infliximab trial, suggested worse outcome, we examined spontaneous adverse event reports to the U.S. Food and Drug Administration (FDA)'s MedWatch system for evidence that TNF antagonists can exacerbate heart failure or promote new-onset heart failure.
Methods
Top
Editors' Notes
Methods
Results
Discussion
Author & Article Info
References
The FDA's MedWatch program receives reports of adverse events related to FDA-licensed products after the products are marketed to the general population (11). Adverse event reports are submitted by manufacturers, physicians, other health care workers, consumers, and others. Except for manufacturers, reporting is voluntary, and the proportion of all adverse events reported to MedWatch is unknown (12). Using the high-level group term heart failures from the Medical Dictionary for Regulatory Activities, we searched MedWatch records for adverse event reports of heart failure among patients receiving etanercept or infliximab from the time of licensure through February 2002. We included both patients with new-onset heart failure and patients with exacerbation of preexisting heart failure after administration of a TNF antagonist. We excluded heart failure reports that were temporally associated with other heart failure–inciting events (such as myocardial infarction, infection, pulmonary embolism, or atrial fibrillation). A cardiologist reviewed each report and determined that the available evidence supported the diagnosis of heart failure. Since patients younger than 50 years of age are relatively unlikely to develop heart failure due to traditional risk factors (that is, coronary artery disease, hypertension, and valvular abnormalities), we contacted reporting physicians of patients younger than 50 years of age to collect information on predisposing factors, tests of left ventricular function (for example, echocardiography), and clinical course and outcome. The funding sources had no role in the design, conduct, or reporting of this study.
Results
Top
Editors' Notes
Methods
Results
Discussion
Author & Article Info
References
Forty-seven patients had heart failure after receiving TNF antagonists. Thirty-eight (81%) developed new-onset heart failure, and 9 (19%) experienced heart failure exacerbations (Table 1). The median age was 62 years (range, 19 to 87 years) for patients with new-onset heart failure and 70 years (range, 57 to 74 years) for patients with heart failure exacerbation. Twenty-eight of 38 patients who developed new-onset heart failure (74%) were age 50 years or older. Twenty-nine of 38 patients with new-onset heart failure (76%) and all patients with heart failure exacerbation were receiving a TNF antagonist for rheumatoid arthritis. Of the 38 patients who reported new-onset heart failure, 19 (50%) had no identifiable traditional risk factor for heart failure (previous myocardial infarction, coronary heart disease, hypertension, or diabetes). The median interval from the first dose of TNF antagonist to a diagnosis of new-onset heart failure or heart failure exacerbation was 3.5 months (range, 24 hours to 24 months) and 4 months (range, 24 hours to 20 months), respectively.
|
All 10 patients younger than 50 years of age (range, 19 to 48 years of age) developed new-onset heart failure after receiving TNF antagonists. Table 2 provides clinical summaries of these cases. Six patients received infliximab, and 4 patients received etanercept. Echocardiography data were obtained in 9 of 10 patients and demonstrated decreased ejection fraction, with a median ejection fraction of 0.2 (range, 0.1 to 0.45); the remaining patient was included on a clinical basis alone. Three patients reported an underlying risk factor for heart failure: Two taking etanercept had diabetes, and 1 taking infliximab had hypertension. The median time to heart failure diagnosis in patients younger than 50 years of age was 3.5 months (range, 24 hours to 6 months) for those who received infliximab and 8.5 months (range, 5 months to 17 months) for those who received etanercept.
|
Nine of these 10 patients were reported to have discontinued TNF antagonist therapy after heart failure diagnosis. It was not known whether TNF antagonist therapy was discontinued in the remaining patient. Following heart failure treatment, 3 patients reported complete resolution of heart failure, 6 patients reported improvement, and 1 patient died. Three of the 6 patients whose heart failure improved had documented risk factors for heart failure.
Discussion
|
|---|
|
TopEditors' NotesMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
Our understanding of the pathophysiology of chronic heart failure has evolved over the past two decades. Although originally thought to be due primarily to hemodynamic derangement, it is now considered a syndrome mostly influenced by activation of the sympathetic nervous system and neurohormonal axis (renin–angiotensin system). Neurohormonal activation initially provides appropriate compensatory mechanisms for an acute decrease in cardiac output, but its long-term consequences are maladaptive.
Inflammatory cytokines, such as TNF, are also overproduced in chronic heart failure and are thought to correspond to a similarly maladaptive inflammatory process (1, 2). However, although elevated circulating TNF levels are noted in patients with severe heart failure and this overproduction appears to be largely cardiac in origin (13), heart failure, unlike arthritis and Crohn disease, is not principally an inflammatory process. The syndrome of heart failure and the systemic response to myocardial injury are complex, with noninflammatory features particularly prominent. The recent failures of infliximab and etanercept (9, 14) to demonstrate benefit in heart failure illustrate this complexity.
It is rare for inflammatory bowel diseases to have cardiac effects. However, cardiovascular disease is a recognized extra-articular complication of rheumatoid arthritis, usually due to an increase in premature coronary atherosclerosis or, more rarely, active vasculitis (15). Although we excluded cases of new or worsening heart failure with concomitant myocardial infarction, underlying rheumatoid arthritis or other comorbid conditions may have contributed to heart failure in some older patients.
Finally, it is possible that some of these reported heart failure events occurred by chance. In the general U.S. population, the prevalence of heart failure is reported to be 2% among persons age 40 to 59 years and more than 5% among persons age 60 to 69 years (16). Given the number of persons exposed to TNF antagonist therapy, these prevalence figures suggest that coincidental heart failure among TNF antagonist recipients is a possibility. Nevertheless, the resolution or improvement of heart failure after withdrawal of TNF antagonists and administration of heart failure treatment in 9 younger patients (<50 years of age) shows that there may be a causal connection.
Given the underreporting common in spontaneous reporting systems, the cases outlined here may represent only a fraction of actual heart failure events following therapy with TNF antagonists. The FDA continues to solicit reports of this and other adverse drug events from physicians and health care providers, even if causality is uncertain. Care providers can easily report directly to the FDA through the MedWatch program. The form for reporting, available at http://www.fda.gov/medwatch, is brief and takes approximately 10 to 15 minutes to complete. Timely and complete reports of heart failure in patients receiving TNF antagonists will be important in assessing the extent of this problem.
This case series has important pragmatic implications. Clinicians should be aware that new-onset heart failure or exacerbation of preexisting heart failure may occur in patients who begin TNF antagonist therapy.
Author and Article Information
|
|---|
|
TopEditors' NotesMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
Acknowledgments: The authors thank Ellis Unger, MD, and Jeffrey N. Siegel, MD, for their help and advice in reviewing the manuscript.
Grant Support: In part by Dr. Kwon's appointment to the Research Fellowship Program at the Center for Biologics Evaluation and Research, administered by Oak Ridge Associated Universities through a contract with the U.S. Food and Drug Administration.
Potential Financial Conflicts of Interest:Consultancies: M.S. Cuffe (Wyeth); Honoraria: M.S. Cuffe (Wyeth).
Requests for Single Reprints: Hyon J. Kwon, PharmD, MPH, Division of Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Suite 200S, HFM-224, Rockville, MD 20852; e-mail, kwon{at}cber.fda.gov.
Current Author Addresses: Drs. Kwon, Coté, and Braun: Division of Epidemiology, Center for Biologics Evaluation and Research, Food and Drug Administration, 1401 Rockville Pike, Suite 200S, HFM-224, Rockville, MD 20852.
Dr. Cuffe: Duke University Medical Center, Box 3850, Durham, NC 27710.
Dr. Kramer: Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715.
Author Contributions: Conception and design: H.J. Kwon, M.S. Cuffe, M.M. Braun.
Analysis and interpretation of the data: H.J. Kwon, T.R. Coté, M.S. Cuffe, J.M. Kramer, M.M. Braun.
Drafting of the article: H.J. Kwon, M.S. Cuffe.
Critical revision of the article for important intellectual content: H.J. Kwon, T.R. Coté, M.S. Cuffe, J.M. Kramer, M.M. Braun.
Final approval of the article: H.J. Kwon, T.R. Coté, M.S. Cuffe, J.M. Kramer, M.M. Braun.
Administrative, technical, or logistic support: H.J. Kwon.
Collection and assembly of data: H.J. Kwon.
References
|
|---|
|
TopEditors' NotesMethodsResultsDiscussionAuthor & Article InfoReferences |
|---|
1. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure N Engl J Med. 1990;323:236-41. [PMID: 2195340].[Abstract]
2. Torre-Amione G, Kapadia S, Benedict C, 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;27:1201-6. [PMID: 8609343].[Abstract]
3. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, et al. Dilated cardiomyopathy in transgenic mice with cardiac-specific overexpression of tumor necrosis factor- Circ Res. 1997;81:627-35. [PMID: 9314845].
4. Bryant D, Becker L, Richardson J, Shelton J, Franco F, Peshock R, et al. Cardiac failure in transgenic mice with myocardial expression of tumor necrosis factor- Circulation. 1998;97:1375-81. [PMID: 9577949].
5. 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;351:1091-3. [PMID: 9660578].[Medline]
6. Deswal A, Bozkurt B, Seta Y, Parilti-Eiswirth S, Hayes FA, Blosch C, et al. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure Circulation. 1999;99:3224-6. [PMID: 10385494].
7. Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure Circulation. 2001;103:1044-7. [PMID: 11222463].
8. Louis A, Cleland JG, Crabbe S, Ford S, Thackray S, Houghton T, et al. Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001 Eur J Heart Fail. 2001;3:381-7. [PMID: 11378012].[Medline]
9. Dear Healthcare Professional [Letter]. Malvern, PA: Centocor; 23 October 2001.
10. Cush JJ, Matteson EL, eds. FDA Advisory Committee Reviews Safety of TNF Inhibitors. Accessed at http://www.rheumatology.org/research/hotline/0901tnf.html on 7 November 2001.
11. Kessler DA. Introducing MEDWatch. A new approach to reporting medication and device adverse effects and product problems JAMA. 1993;269:2765-8. [PMID: 8492403].
12. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs JAMA. 1999;281:824-9. [PMID: 10071004].
13. Feldman AM, Combes A, Wagner D, Kadakomi T, Kubota T, Li YY, et al. The role of tumor necrosis factor in the pathophysiology of heart failure J Am Coll Cardiol. 2000;35:537-44. [PMID: 10716453].
14. European Society of Cardiology's Heart Failure Update. RENEWAL trial: no improvement in CHF with etanercept. Accessed at http://www.theheart.org/documents/page.cfm?from = 590001200&doc_id = 3053 on 10 July 2002.
15. Manzi S, Wasko MC. Inflammation-mediated rheumatic diseases and atherosclerosis Ann Rheum Dis. 2000;59:321-5. [PMID: 10784507].
16. Congestive Heart Failure in the United States: A New Epidemic. National Heart, Lung, and Blood Institute Data Fact Sheet. Accessed at http://www.nhlbi.nih.gov/health/public/heart/other/CHF.htm on 7 November 2001.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Facebook 
Reddit 
Technorati 
Twitter What's this?
Related articles in Annals:
This article has been cited by other articles:
|
|
 |
|
  J. R. Curtis, J. M. Kramer, C. Martin, K. G. Saag, N. Patkar, D. Shatin, M. Burgess, A. Xie, and M. M. Braun Heart failure among younger rheumatoid arthritis and Crohn's patients exposed to TNF-{alpha} antagonists Rheumatology, November 1, 2007; 46(11): 1688 - 1693. [Abstract] [Full Text] [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]
|
|
|
|
 |
|
 J. S. Borer, H. Pouleur, E. Abadie, F. Follath, J. Wittes, M. A. Pfeffer, B. Pitt, and F. Zannad Cardiovascular safety of drugs not intended for cardiovascular use: need for a new conceptual basis for assessment and approval Eur. Heart J., August 1, 2007; 28(15): 1904 - 1909. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Hyrich, D Symmons, K Watson, A Silman, BSRBR Control Centre Consortium, and on behalf of the British Society for Rheumatology Baseline comorbidity levels in biologic and standard DMARD treated patients with rheumatoid arthritis: results from a national patient register Ann Rheum Dis, July 1, 2006; 65(7): 895 - 898. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Claassen, E. Dwyer, S. Maybaum, and M.S.V. Elkind Rheumatoid leptomeningitis after heart transplantation Neurology, March 28, 2006; 66(6): 948 - 949. [Full Text] [PDF]
|
|
|
|
|
|
R Fleischmann, S W Baumgartner, M H Weisman, T Liu, B White, and P Peloso Long term safety of etanercept in elderly subjects with rheumatic diseases Ann Rheum Dis, March 1, 2006; 65(3): 379 - 384. [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. 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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 F. R. Pasternack, L. P. Fox, and D. E. Engler Silicone Granulomas Treated With Etanercept Arch Dermatol, January 1, 2005; 141(1): 13 - 15. [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]
|
|
|
|
|
|
D E Furst, F C Breedveld, J R Kalden, J S Smolen, G R Burmester, J W J Bijlsma, M Dougados, P Emery, E C Keystone, L Klareskog, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2004 Ann Rheum Dis, November 1, 2004; 63(suppl_2): ii2 - ii12. [Full Text] [PDF]
|
|
|
|
 |
|
 W J Sandborn and W A Faubion Biologics in inflammatory bowel disease: how much progress have we made? Gut, September 1, 2004; 53(9): 1366 - 1373. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 O. Adolfsson, S. N. Meydani, and R. M Russell Yogurt and gut function Am. J. Clinical Nutrition, August 1, 2004; 80(2): 245 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
M. Cesari, B. W.J.H. Penninx, A. B. Newman, S. B. Kritchevsky, B. J. Nicklas, K. Sutton-Tyrrell, S. M. Rubin, J. Ding, E. M. Simonsick, T. B. Harris, et al. Inflammatory Markers and Onset of Cardiovascular Events: Results From the Health ABC Study Circulation, November 11, 2003; 108(19): 2317 - 2322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D E Furst, F C Breedveld, J R Kalden, J S Smolen, G R Burmester, M Dougados, P Emery, A Gibofsky, A F Kavenaugh, E C Keystone, et al. Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003) Ann Rheum Dis, November 1, 2003; 62(90002): ii2 - 9. [Full Text] [PDF]
|
|
|
|
|
|
E C Keystone Advances in targeted therapy: safety of biological agents Ann Rheum Dis, November 1, 2003; 62(90002): ii34 - 36. [Full Text] [PDF]
|
|
|
|
 |
|
 I. Malik JournalScan Heart, October 1, 2003; 89(10): 1279 - 1280. [Full Text] [PDF]
|
|
|
|
 |
|
 Tumor Necrosis Factor Antagonists Associated with Heart Failure Journal Watch Cardiology, August 8, 2003; 2003(808): 7 - 7. [Full Text]
|
|
|
|
 |
|
 Tumor Necrosis Factor Antagonists Associated with Heart Failure Journal Watch Dermatology, June 25, 2003; 2003(625): 7 - 7. [Full Text]
|
|
Article
