A Dose-Dependent Increase in Mortality with Vesnarinone Among Patients with Severe Heart Failure

Cohn, Jay N.; Greenberg, Barry; Lorell, Beverly H.; Bourge, Robert C.; Jaski, Brian E.; Gottlieb, Sidney O.; McGrew, Frank; DeMets, David L.; White, Bill G.

doi:10.1097/00132586-199910000-00011

Cited by 109 publications

(130 citation statements)

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“…Although there are multiple prognostic markers in heart failure, including ejection fraction (151,152), predicting time of death is notoriously challenging, especially given the cyclical nature of the disease. Recent technological advances have led to increased complexity of care and decision-making at the end of life.…”

Section: Practical Tipsmentioning

confidence: 99%

Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management

Arnold¹,

Liu²,

Demers³

et al. 2006

Canadian Journal of Cardiology

363

256

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Section: Practical Tipsmentioning

confidence: 99%

Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management

Arnold¹,

Liu²,

Demers³

et al. 2006

Canadian Journal of Cardiology

363

256

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“…) is a synthetic quinolinone derivative with inotropic effects, used clinically for the treatment of chronic congestive heart failure (CHF) 3 (1). This agent exhibits potent immunomodulatory activity, as indicated by the suppression of NK cell activity (2,3), endotoxin-induced production of inflammatory cytokines (4 -10), and nitric oxide synthase from macrophages (11,12) and cardiac myocytes (11,13), and it abrogate E-selectin expression in endothelial cells (5).…”

Section: -Piperazinyl]-2(1h)-quinolinone; Also Called Opc-8212mentioning

confidence: 99%

Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

Manna

Aggarwal

2000

The Journal of Immunology

161

180

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Vesnarinone, a synthetic quinolinone derivative used in the treatment of cardiac failure, exhibits immunomodulatory, anti-inflammatory, and cell growth regulatory properties. The mechanisms underlying these properties are not understood, but due to the critical role of nuclear transcription factor NF-κB in these responses, we hypothesized that vesnarinone must modulate NF-κB activation. We investigated the effect of vesnarinone on NF-κB activation induced by inflammatory agents. Vesnarinone blocked TNF-induced activation of NF-κB in a concentration- and time-dependent manner. This effect was mediated through inhibition of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. The effects of vesnarinone were not cell type specific, as it blocked TNF-induced NF-κB activation in a variety of cells. NF-κB-dependent reporter gene transcription activated by TNF was also suppressed by vesnarinone. The TNF-induced NF-κB activation cascade involving TNF receptor 1-TNF receptor associated death domain-TNF receptor associated factor 2 NF-κB-inducing kinase-IKK was interrupted at the TNF receptor associated factor 2 and NF-κB-inducing kinase sites by vesnarinone, thus suppressing NF-κB reporter gene expression. Vesnarinone also blocked NF-κB activation induced by several other inflammatory agents, inhibited the TNF-induced activation of transcription factor AP-1, and suppressed the TNF-induced activation of c-Jun N-terminal kinase and mitogen-activated protein kinase kinase. TNF-induced cytotoxicity, caspase activation, and lipid peroxidation were also abolished by vesnarinone. Overall, our results indicate that vesnarinone inhibits activation of NF-κB and AP-1 and their associated kinases. This may provide a molecular basis for vesnarinone’s ability to suppress inflammation, immunomodulation, and growth regulation.

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“…2 Increasing evidence indicates that routine administration of inotropic agents may heighten mortality risk in patients with ADHF. [3][4][5][6][7][8][9][10][11][12] Consequently, the European Society of Cardiology recommends that inotropic agents be prescribed only for patients with peripheral hypoperfusion with or without congestion or pulmonary edema that is refractory to diuretics and vasodilators at optimum dosages. 1 Despite concerns regarding inotropics, these agents remain a common therapeutic strategy and are prescribed for about 11% of hospitalized patients.…”

mentioning

confidence: 99%

Outcomes Associated with Vasoactive Therapy in Patients with Acute Decompensated Heart Failure

et al. 2006

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Study Objectives. To describe the clinical management of acute decompensated heart failure (ADHF) in patients receiving intravenous treatment with dobutamine, milrinone, or nesiritide, and to evaluate differences, based on treatment received, in the in-hospital mortality rate, length of stay (LOS), total health care costs, and 30-day hospital readmission rate. according to the vasoactive therapy received. To evaluate baseline characteristics, 2 analysis was used; logistic regression was employed to assess the relationships between drug therapy and in-hospital mortality rates, and multivariate linear regression was used to assess whether drug therapy was related to LOS and total health care costs. All regression analyses controlled for age, sex, race, region of the United States where the hospital was located, primary payer for the hospital stay, UHC patient severity class, and chronic renal failure. In-hospital mortality rates were 10.2%, 7.9%, and 2.9% in the dobutamine, milrinone, and nesiritide groups, respectively. This resulted in an adjusted odds ratio for death of 3.5 (95% confidence interval [CI] 1.8-6.8) for dobutamine and 3.9 (95% CI 1.8-8.3) for milrinone (p<0.0001). Compared with inotropic therapy (dobutamine and milrinone), mean LOS in the hospital and the intensive care unit were lower with nesiritide (p<0.001). Total health care costs were lowest with nesiritide, but this reached statistical significance only when compared with milrinone (p<0.001). Thirty-day hospital readmission rates with dobutamine, milrinone, and nesiritide were 5.0%, 9.5%, and 3.9%, respectively (p=NS). Conclusion. Nesiritide therapy was associated with a lower in-hospital mortality rate and shorter LOS compared with dobutamine and milrinone. In addition, total health care costs with nesiritide were decreased compared with milrinone. These observations need to be validated by a randomized controlled trial.

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A Dose-Dependent Increase in Mortality with Vesnarinone Among Patients with Severe Heart Failure

Cited by 109 publications

References 0 publications

Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management

Canadian Cardiovascular Society consensus conference recommendations on heart failure 2006: Diagnosis and management

Vesnarinone Suppresses TNF-Induced Activation of NF-κB, c-Jun Kinase, and Apoptosis

Outcomes Associated with Vasoactive Therapy in Patients with Acute Decompensated Heart Failure

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