Published online before print March 25, 2002, doi: 10.1161/01.CIR.0000014212.04920.62
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(Circulation. 2002;105:1797.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Effects of Sustained-Release Moxonidine, an Imidazoline Agonist, on Plasma Norepinephrine in Patients With Chronic Heart Failure
From the Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden (K.S.); Division of Cardiology, University Hospital, University of Colorado Health Sciences Center, Denver (M.R.B.); Cardiovascular Division, University of Minnesota Medical School, Minneapolis (J.N.C.); MRC Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow, UK (H.D.); Solvay Pharmaceuticals, Hanover, Germany (M.S.); and Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Ind (C.W., T.J.W.).
Correspondence to Karl Swedberg, MD, Department of Medicine, Göteborg University, Sahlgrenska University Hospital/Östra, S-416 85 Göteborg, Sweden. E-mail karl.swedberg{at}hjl.gu.se
Background— In chronic heart failure, sympathetic activation is increased. Moxonidine acts on central nervous system receptors to decrease sympathetic activation. We investigated the dose-response relationship of a new sustained-release (SR) preparation of moxonidine and the plasma concentration of norepinephrine in patients with chronic heart failure.
Methods and Results— A total of 268 patients with chronic heart failure in NYHA functional class II to IV on optimal standard therapy were randomized to placebo or 1 of 5 doses of moxonidine SR: 0.3, 0.6, 0.9, 1.2, or 1.5 mg BID. After a dose-titration phase (7 weeks), patients were followed up for another 12 weeks at their maximally tolerated dose. Blood samples for plasma norepinephrine were collected at baseline and weekly during the initial 7 weeks, at week 19, and at the end of the study. At baseline and 7 and 19 weeks, sampling was also done 4 hours after the dose. After the active phases of the study, plasma norepinephrine was evaluated for an additional 3 days. A marked, statistically significant dose-related decrease in plasma norepinephrine was observed for predose levels as well as 4 hours after the dose at week 19. At the highest dose (1.5 mg BID), the trough reduction in norepinephrine was 52%. These reductions were accompanied by a modest decrease in heart rate, a modest increase in left ventricular ejection fraction, and a dose-related increase in adverse events.
Conclusions— Plasma norepinephrine was markedly reduced in a dose-related manner by moxonidine SR. This reduction was accompanied by evidence of reverse remodeling, but also by an increase in adverse events.
Key Words: heart failure • norepinephrine • nervous system, sympathetic • drugs
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