Beta-blockers in HFrEF (CIBIS-II, COPERNICUS, US Carvedilol HF study, MERIT-HF)

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CIBIS-II: The cardiac insufficiency bisoprolol study II (CIBIS-II): A randomised trial. Lancet 1999;353:9-13.

US Carvedilol HF Study: Packer M, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure: U.S. Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55.

COPERNICUS: Packer M, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651-8.

MERIT-HF: Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001-7.

Bottom line: Bisoprolol, carvedilol & extended-release metoprolol all reduced death in HFrEF (NNT ~10-20 @ 1 year). When evaluated, these beta-blockers also reduced hospitalizations to a similar degree.

 

Issues with internal validity?

  • No: All 4 were randomized, allocation-concealed, double-blind trials with <1% loss-to-follow-up analyzed using the intention-to-treat population
    • All 4 RCTs were stopped early during interim analyses due to overwhelming evidence of a mortality benefit from the beta-blocker
  • 2 trials had a run-in period:
    • US carvedilol study: 2-week open-label run-in phase where all patients received carvedilol 6.25 mg PO BID. Those who could tolerate this dose (94% of patients) were randomized.
  • MERIT-HF: 2-week run-in period with placebo, after which those who took >75% of doses were randomized.

Patients

Interventions & co-interventions

  • I: Beta-blocker
    • CIBIS 2: Bisoprolol started at 1.25 mg PO daily, increased weekly (-> 2.5 -> 5), then monthly (-> 7.5 -> 10) to a maximum tolerated dose of up to 10 mg PO daily
      • Achieved dose: 1.25-2.5 mg/d (33%), 5-7.5 mg/d (25%), 10 mg/d (42%)
    • US Carvedilol HF Study: After the run-in where patients initially received carvedilol 6.25 mg PO BID, the dose was increased to 12.5 mg PO BID, then incrementally up to 50 mg PO BID as tolerated
      • Mean dose achieved during study 45 mg/d (80% achieved target dose)
    • COPERNICUS: Carvedilol started at 3.125 mg PO BID x2 weeks, then doubled q2 weeks as tolerated to a target dose of 25 mg PO BID
      • As necessary, other drugs could be titrated or carvedilol titration frequency could be modified
      • Mean dose achieved @ 4 months: 37 mg/d 
    • MERIT-HF: Metoprolol extended-release 25 mg PO once daily (12.5 mg for NYHA III-IV at baseline), doubled q2 weeks as tolerated to a target dose of 200 mg PO daily
      • Mean dose achieved @ 6 months: 160 mg (64% achieved target dose)
  • C: Matching placebo

Results

  • Subroup analyses in the individual trials did not demonstrate any difference in relative benefit differences based on age, sex, HF etiology, NYHA functional class, or LVEF.
  • In all trials, the mortality benefit from beta-blockers stemmed from a reduction in both progression of HF & sudden cardiac death.

Other studies

  • The COMET trial is the largest RCT comparing different beta-blockers in HFrEF. It demonstrated a lower risk of death (NNT 17) over 4.8 years with carvedilol at a target dose of 25 mg PO BID versus metoprolol tartrate at a target dose of 50 mg PO BID
    • The benefit of carvedilol in this trial may be a result of an unfair comparison rather than a true benefit. The short-acting metoprolol tartrate was used in this trial instead of the once-dialy long-acting succinate salt proven to reduce mortality in MERIT-HF. Additionally, the target metoprolol was half the target dose in MERIT-HF. The carvedilol dose and formulation were the same as in the landmark trials demonstrating benefit over placebo.