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


RESULTS
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%).


CONCLUSIONS
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.
Cohn
Jay N
JN
Cardiovascular Division, Mayo Mail Code 508, University of Minnesota Medical School, 420 Delaware Street SE, Minneapolis, MN 55455, USA. cohnx001@umn.edu
Pfeffer
Marc A
MA
Rouleau
Jean
J
Sharpe
Norman
N
Swedberg
Karl
K
Straub
Matthias
M
Wiltse
Curtis
C
Wright
Theressa J
TJ
D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000097:blood; D012449:Safety; D015996:Survival Rate; D013564:Sympathetic Nervous System / Q000187:drug effects; D013565:Sympatholytics / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*
D003692:Delayed-Action Preparations; D007093:Imidazoles; D013565:Sympatholytics; C043482:moxonidine; D009638:Norepinephrine