Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON)

Jay N. Cohn, Marc A. Pfeffer, Jean Rouleau, Norman Sharpe, Karl Swedberg, Matthias Straub, Curtis Wiltse, Theressa J. Wright

Research output: Contribution to journalArticle

258 Citations (Scopus)

Abstract

Background: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. Methods: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II-IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. Findings: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (-18.8% from baseline) vs. placebo (+6.9%). Interpretation: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.

Original languageEnglish (US)
Pages (from-to)659-667
Number of pages9
JournalEuropean Journal of Heart Failure
Volume5
Issue number5
DOIs
StatePublished - Oct 1 2003

Fingerprint

moxonidine
Heart Failure
Mortality
Placebos
Imidazoline Receptors

Keywords

  • Chronic heart failure
  • Mortality
  • Moxonidine

Cite this

Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). / Cohn, Jay N.; Pfeffer, Marc A.; Rouleau, Jean; Sharpe, Norman; Swedberg, Karl; Straub, Matthias; Wiltse, Curtis; Wright, Theressa J.

In: European Journal of Heart Failure, Vol. 5, No. 5, 01.10.2003, p. 659-667.

Research output: Contribution to journalArticle

Cohn, Jay N. ; Pfeffer, Marc A. ; Rouleau, Jean ; Sharpe, Norman ; Swedberg, Karl ; Straub, Matthias ; Wiltse, Curtis ; Wright, Theressa J. / Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). In: European Journal of Heart Failure. 2003 ; Vol. 5, No. 5. pp. 659-667.
@article{2878df250e144e72906c98a318596ec9,
title = "Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON)",
abstract = "Background: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. Methods: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II-IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20{\%} reduction in mortality, which required a total of 724 deaths. Findings: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5{\%}) in the moxonidine SR group and 32 deaths (3.4{\%}) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (-18.8{\%} from baseline) vs. placebo (+6.9{\%}). Interpretation: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.",
keywords = "Chronic heart failure, Mortality, Moxonidine",
author = "Cohn, {Jay N.} and Pfeffer, {Marc A.} and Jean Rouleau and Norman Sharpe and Karl Swedberg and Matthias Straub and Curtis Wiltse and Wright, {Theressa J.}",
year = "2003",
month = "10",
day = "1",
doi = "10.1016/S1388-9842(03)00163-6",
language = "English (US)",
volume = "5",
pages = "659--667",
journal = "European Journal of Heart Failure",
issn = "1388-9842",
publisher = "Oxford University Press",
number = "5",

}

TY - JOUR

T1 - Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON)

AU - Cohn, Jay N.

AU - Pfeffer, Marc A.

AU - Rouleau, Jean

AU - Sharpe, Norman

AU - Swedberg, Karl

AU - Straub, Matthias

AU - Wiltse, Curtis

AU - Wright, Theressa J.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - Background: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. Methods: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II-IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. Findings: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (-18.8% from baseline) vs. placebo (+6.9%). Interpretation: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.

AB - Background: The association between sympathetic activation and mortality in chronic heart failure and the favorable effect of beta blocking drugs has raised the possibility of therapeutic efficacy for central sympathetic inhibition with sustained-release (SR) moxonidine, an imidazoline receptor agonist. Methods: A randomized double-blind, placebo-controlled trial was initiated in 425 centers in 17 countries with a plan to enter 4533 patients with New York Heart Association class II-IV heart failure and a reduced ejection fraction. Moxonidine SR or matching placebo was titrated to a target dose of 1.5 mg BID. The trial was powered to detect a 20% reduction in mortality, which required a total of 724 deaths. Findings: An early increase in death rate and adverse events in the moxonidine SR group led to premature termination of the trial because of safety concerns after 1934 patients were entered. Final analysis revealed 54 deaths (5.5%) in the moxonidine SR group and 32 deaths (3.4%) in the placebo group during the active treatment phase. Survival curves revealed a significantly (P=0.012) worse outcome in the moxonidine SR group. Hospitalization for heart failure, acute myocardial infarction and adverse events were also more frequent in the moxonidine SR group. Plasma norepinephrine was significantly decreased by moxonidine SR (-18.8% from baseline) vs. placebo (+6.9%). Interpretation: Early termination of the trial limited conclusions regarding the long-term effects of central sympathetic inhibition. Nonetheless, the excess early mortality and morbidity suggest the likelihood of an adverse effect of moxonidine SR and raise concerns regarding the efficacy of generalized sympathetic inhibition in heart failure.

KW - Chronic heart failure

KW - Mortality

KW - Moxonidine

UR - http://www.scopus.com/inward/record.url?scp=0346730904&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0346730904&partnerID=8YFLogxK

U2 - 10.1016/S1388-9842(03)00163-6

DO - 10.1016/S1388-9842(03)00163-6

M3 - Article

C2 - 14607206

AN - SCOPUS:0346730904

VL - 5

SP - 659

EP - 667

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

SN - 1388-9842

IS - 5

ER -