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J Am Coll Cardiol, 2002; 40:491-498
© 2002 by the American College of Cardiology Foundation
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CLINICAL STUDY

Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure

Analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF)

John Wikstrand, MD, PhD*,*,1, Å. ke Hjalmarson, MD, PhD{dagger}, Finn Waagstein, MD, PhD{dagger}, B. jörn Fagerberg, MD, PhD*, Sidney Goldstein, MD{ddagger}, John Kjekshus, MD, PhD§, Hans Wedel, PhD|| MERIT-HF Study Group

* Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg, Sweden
{dagger} Department of Cardiology, Sahlgrenska University Hospital, Göteborg, Sweden
{ddagger} Henry Ford Heart and Vascular Institute, Henry Ford Hospital, Detroit, Michigan, USA
§ Section of Cardiology, Rikshospitalet, Oslo, Norway
|| Nordic School of Public Health, Göteborg, Sweden

Manuscript received December 28, 2001; revised manuscript received April 8, 2002, accepted April 30, 2002.

* Reprint requests and correspondence: Dr. John Wikstrand, Wallenberg Laboratory, Sahlgrenska University Hospital, SE 413 45 Göteborg, Sweden.
john.wikstrand{at}wlab.gu.se

OBJECTIVES: We performed a post-hoc subgroup analysis in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) with the aim of reporting on the heart rate (HR) response during the titration phase and clinical outcomes from the three-month follow-up visit to end of study in two dosage subgroups: one that had reached more than 100 mg of metoprolol CR/XL once daily (high-dose group; n = 1,202; mean 192 mg) and one that had reached 100 mg or less (low-dose group; n = 412; mean 76 mg).

BACKGROUND: Clinicians have questioned whether patients need to reach the target beta-blocker dose to receive benefit.

METHODS: Outcome (Cox-adjusted) was compared with all placebo patients with dose available at the three-month visit (n = 1,845).

RESULTS: Data indicated somewhat higher risk in the low-dose group compared with the high-dose group. Heart rate was reduced to a similar degree in the two dose groups, indicating higher sensitivity for beta-blockade in the low-dose group. The reduction in total mortality with metoprolol CR/XL compared with placebo was similar: 38% (95% confidence interval [CI], 16 to 55) in high-dose group (p = 0.0022) and also 38% (95% CI, 11 to 57) in the low-dose group (p = 0.010).

CONCLUSIONS: Risk reduction was similar in the high- and low-dose subgroups, which, at least partly, may be the result of similar beta-blockade as judged from the HR response. The results support the idea of an individualized dose-titration regimen, which is guided by patient tolerability and the HR response. Further research is needed to shed light on why some patients respond with a marked HR reduction and reduced mortality risk on a relatively small dose of a beta-blocker.

Abbreviations and Acronyms
  CI
  confidence interval
  CIBIS II
  Cardiac Insufficiency Bisoprolol Study
  COPERNICUS
  Carvedilol Prospective Randomized Cumulative Survival study
  CR/XL
  controlled-release/extended-release
  HF
  heart failure
  HR
  heart rate
  MERIT-HF
  Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure
  NYHA
  New York Heart Association




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Copyright © 2002 by the American College of Cardiology Foundation.