Data Monitoring Experience in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure: Potentially High-Risk Treatment in High-Risk Patients

  • Jan Feyzi
  • Desmond G. Julian
  • John Wikstrand
  • Hans Wedel


The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) was a double-blind, randomized, placebo-controlled trial in 3,991 patients with New York Heart Class II–IV heart failure and LVEF ≤0.40. The two primary objectives were to determine the effect of metoprolol CR/XL on all-cause mortality and on the combined endpoint of all-cause mortality or all-cause hospitalizations (time to first event). There was a two-week placebo run-in period. after which patients were randomized to either metoprolol CR/XL at a dose of 12.5 mg (NYHA III–IV) or 25mg (NYHA II) once daily or matching placebo. The randomized treatment was titrated up to 200 mg once daily or to the highest tolerated dose over an eight-week titration phase. The trial was designed to follow patients for a total mean follow-up of 2.4 years. The Data and Safety Monitoring Board (DSMB) had two tasks. The first was to review all reported Serious Adverse Events (SAEs) on a monthly basis and produce a short report to the sponsor aimed for regulatory agencies. This was done because the sponsor had received a waiver for expedited reporting of SAEs from regulatory agencies including the U.S. Food and Drug Administration (FDA). The second was to perform three pre-specified interim analyses of total mortality. After the second interim analysis, at the point of observing one-half of the targeted number of deaths, the trial was stopped early by the International Steering Committee on recommendation of the DSMB (mean follow-up time 1 year). Final results showed that all-cause mortality was lower in the metoprolol CR/XL group compared to the placebo group (145 deaths, corresponding to 7.2% per patient-year of follow-up for the metoprolol CR/XL group versus 217 deaths, 11.0% per patient-year of follow-up for the placebo group, p = 0.0062 adjusted for interim analyses, p = 0.00009 nominal). The second primary endpoint of all-cause mortality combined with all-cause hospitalizations was also lower for the metoprolol CR/XL group (641 events) compared to placebo (767 events), p = 0.00012 nominal. The procedures developed by the DSMB to implement the required intense safety follow-up will be described.


Chronic Heart Failure Interim Analysis Executive Committee Systolic Heart Failure Severe Chronic Heart Failure 
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  1. 1.
    The International Steering Committee on behalf of the MERIT-HF Study Group. 1997. Rationale, design, and organization of the metoprolol CR/XL randomized trial in heart failure (MERIT-HF). Am J Cardiol 80:54–58J.CrossRefGoogle Scholar
  2. 2.
    MERIT-HF Study Group. 1999. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 353:2001–2007.CrossRefGoogle Scholar
  3. 3.
    Hjalmarson A, Goldstein S, Fagerberg B,Wedel H,Waagstein F, Kjekshus J, et al. 2000. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure:The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF). JAMA 283:1295–2007.CrossRefGoogle Scholar
  4. 4.
    Cohn, JN. 1996. The management of chronic heart failure. N Engl J Med 335: 490–498CrossRefGoogle Scholar
  5. 5.
    MattsonJack EpiOnline database accessed on 21.03.02 at Scholar
  6. 6.
    Senni M,Tribouilloy CM, Rodeheffer RJ, et al. 1999. Congestive heart failure in the community.Trends in incidence and survival in a 10-year period. Arch Intern Med 159:29–34.CrossRefGoogle Scholar
  7. 7.
    McMurray J, Hart W, Rhodes G. 1993. An evaluation of the economic cost of heart failure to the National Health Service in the United Kingdom. Br J Med Econ 6:99–110Google Scholar
  8. 8.
    Task Force on Heart Failure of the European Society of Cardiology. 1995. Guidelines for the diagnosis of heart failure. Eur Heart J 16:741–751.Google Scholar
  9. 9.
    The CONSENSUS Trial Study Group. 1987. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 316:1429–1435.CrossRefGoogle Scholar
  10. 10.
    Garg R,Yusuf S. Collaborative group on ACE Inhibitor Trials. 1995. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 273:1450–1456CrossRefGoogle Scholar
  11. 11.
    Goldstein, S. 1997. Clinical studies on beta-blockers and heart failure preceding the MERIT-HF trial. Am J Cardiol 80(9B):50J–53J.CrossRefGoogle Scholar
  12. 12.
    Waagstein F, Hjalmarson Å, Varnauskas, Wallentin I. 1975. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. BMJ 37:1022–1036.Google Scholar
  13. 13.
    CIBIS-II Investigators and Committees. 1999.The cardiac insufficiency bisoprolol study II (CIBIS II), Lancet 353:9–13.CrossRefGoogle Scholar
  14. 14.
    Packer M, Coats AJS, Fowler MB, et al. 2001. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344:1651–1658.CrossRefGoogle Scholar
  15. 15.
    Lan KKG, DeMets DL. 1983. Discrete sequential boundaries for clinical trials. Biometrika 70:649–653.MathSciNetCrossRefGoogle Scholar
  16. 16.
    Peto R, Pike MC, Armitage P, et al. 1976. Design and analysis of randomized clinical trials requiring prolonged observations of each patient. I. Introduction and design. Br J Cancer 34:585–612.CrossRefGoogle Scholar
  17. 17.
    Wedel H, DeMets D, Deedwania P, Fagerberg B, Goldstein S, Gottlieb S, Hjalmarson A, Kjekshus J,Waagstein F,Wikstrand J on behalf of the MERIT-HF Study Group: 2001 Challenges of subgroup analyses in multinational clinical trials: Experiences from the MERIT-HF trial. Am Heart J 143:502–511.CrossRefGoogle Scholar

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© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • Jan Feyzi
    • 1
  • Desmond G. Julian
    • 2
  • John Wikstrand
    • 3
    • 4
  • Hans Wedel
    • 5
  1. 1.Department of Biostatistics and Medical InformaticsUniversity of WisconsinMadison
  2. 2.University of Newcastle-upon-TyneLondonEngland
  3. 3.Wallenberg Laboratory for Cardiovascular ResearchSahlgrenska University HospitalGöteborg
  4. 4.Clinical ScienceAstra Zeneca R&DMölndalSweden
  5. 5.Epidemiology and BiostatisticsNordic School of Public HealthGöteborgSweden

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