Published Online
on August 30, 2004

A more recent version of this article appeared on September 14, 2004

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Submitted on April 23, 2003
Revised on March 23, 2004
Accepted on April 29, 2004

Effect of Baseline or Changes in Adrenergic Activity on Clinical Outcomes in the -Blocker Evaluation of Survival Trial

M. R. Bristow MD, PhD^*, H. Krause-Steinrauf MS, R. Nuzzo PhD, Cheng-Seng Liang MD, J. Lindenfeld MD, B. D. Lowes MD, B. Hattler MD, W. T. Abraham MD, L. Olson MD, S. Krueger MD, S. Thaneemit-Chen MS, J. M. Hare MD, H. S. Loeb MD, M. J. Domanski MD, E. J. Eichhorn MD, R. Zelis MD, and P. Lavori PhD

From the University of Colorado Health Sciences Center, Division of Cardiology, Denver, Colo (M.R.B., J.L., B.D.L., B.H., E.J.E.); National Heart, Lung, and Blood Institute, Palo Alto, Calif (H.K.-S., M.J.D.); Division of Cardiology, Stanford University, Stanford, Calif (R.N.); Cardiology, University of Rochester, Rochester, NY (C.-S.L.); Physiology and Cell Biology, Ohio State University, Columbus (W.T.A.); Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, Rochester, Minn (E.O.); Bryan Memorial Hospital, Lincoln, Neb (S.K.); Data Coordinating Center, VA Cooperative Clinical Trials Program, Palo Alto, Calif (S.T.-C., P.L.); Cardiobiology, Johns Hopkins University, Baltimore, Md (J.M.H.); Veterans Affairs Hospital, Department of Medicine, Hines, Ill (H.S.L.); and Penn State University, College of Medicine, Hershey, Pa (R.Z.).

^* To whom correspondence should be addressed. E-mail: michael.Bristow{at}uchsc.edu.

Background--Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent.

Methods and Results--Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the -Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the -blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months.

Conclusions--In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation -blocker.

Key words: nervous system, sympathetic • mortality • risk factors • heart failure

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