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 (Ps0.012) 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 (y18.8% from baseline) vs. placebo (q6.9%). 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.

Continuous Autonomic Assessment in Patients With Symptomatic Heart Failure

“…16 The recent MOXonidine CONgestive heart failure (MOXCON) trial demonstrated harm in patients who had central inhibition of sympathetic outflow even though plasma norepinephrine levels declined dramatically. 17 In dogs with ischemic left ventricular dysfunction, sympathetic activation only occurred in a group at high risk for sudden death despite similar degrees of left ventricular injury in the low-risk animals. 18 Therefore, the autonomic response to heart failure represents a complex pathophysiology with mechanisms that have proved difficult to study over time, especially with regard to other hormonal influences on heart rate control.…”

Treatment of Chronic Heart Failure With β-Adrenergic Receptor Antagonists

“…The failed attempts to improve on ␤-blocker therapy include the use of compounds with ISA in isolated or intact human heart, 110,179 the addition of PDE3 inhibitors, 122,124 the use of ␤-blockers with ␤ 3 -agonist activity, 79,80 and the use of pure sympatholytic agents. 180 As-yet untested possible new approaches are the addition of a ␤ 2 -agonist to a ␤ 1 -blocker, 109 the use of pharmacogenetics to modulate the effects of sympatholytics into a more ideal, mild NE-lowering range, 116 CaMKII inhibition 130,131 added to ␤-blockade, the addition to ␤-blockade of agents that dephosphorylate receptors and restore receptor function, 146,147 and prospective pharmacogenetic targeting of ␤-blockers that distinguish between different genetic variants of ␤ 1 -ARs. 116,117,163 Although it is likely that one or more of these approaches will be successful, the fact that it has proved difficult to improve on single agent ␤-blockade is a powerful testament to the effectiveness of this form of heart failure therapy.…”

The Management of Co-Morbidities in Patients with Heart Failure – Hypertension

“…These include Moxonidine, alpha receptor antagonists, diltiazem and verapamil, although the latter two are probably safe in HFpEF, because the concern in HFrEF is their negative inotropic effect which is of less concern in true HFpEF. Moxonidine increased mortality in patients in the MOXCON trial in HFrEF [11] and there are concerns of the risk in HFrEF patients of neurohormonal activation, fluid retention and worsening HF with alphaadrenoceptor antagonists. [12][13][14] Lastly in the setting of acute heart failure (AHF) i.v.…”