CIBIS III trial

A beta blocker first strategy appears to be as safe and effective as an ACE inhibitor first strategy for the treatment of older patients with heart failure, and may confer an early survival advantage.

The trend toward better early survival with the beta blocker first sequence may be important considering that the risk of sudden cardiac death in these patients is particularly high during the first year of treatment, said Ronnie Willenheimer, MD, PhD, lead investigator of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III trial. The results from CIBIS III were presented at the European Society of Cardiology Congress 2005 in Stockholm, Sweden.

"Bisoprolol's pronounced inhibition of the sympathetic nervous system, not seen with the ACE inhibitor, may be of particular value at this critical time point when the risk of sudden death is greatest," he said. In contrast, patients who received bisoprolol first had a greater tendency to be hospitalized for worsening heart failure, especially early in the study.

CIBIS III included 1,010 patients with a mean age of 72 years. All patients had New York Heart Association (NYHA) Class II or III heart failure and a left ventricular ejection fraction ≤35%. They were randomized to bisoprolol (target dosage of 10 mg/d) or enalapril (target dosage of 10 mg twice daily) for 6 months, followed by their combination for 6 to 24 months.

The primary end point was the time to death or all-cause hospitalization. Non-inferiority of the bisoprolol first strategy was demonstrated in an intent-to-treat analysis in which the event rates were 35.2% in the bisoprolol first group and 36.8% in the enalapril first group.

The prespecified criterion for non-inferiority was not met in the per-protocol analysis, in which the event rates were 32.4% and 33.1% with the bisoprolol first and enalapril first strategies, respectively.

Because of the large number of protocol violations and withdrawals in the per-protocol sample, the per-protocol analysis had less statistical power than the intent-to-treat analysis, explained Dr Willenheimer, making the intent-to-treat analysis at least as relevant as the per-protocol analysis.

There were 65 deaths in the bisoprolol first group and 73 in the enalapril first group, corresponding to a nonsignificant 12% reduction with the bisoprolol first strategy. There were 151 hospitalizations in the bisoprolol first group and 157 in the enalapril first group (P=.66).

At the end of the monotherapy phase, 109 patients in the bisoprolol first group and 108 in the enalapril first group reached the primary end point (P=.90), with 23 deaths and 99 hospitalizations in the bisoprolol first group versus 32 deaths and 92 hospitalizations in the enalapril first group.

During the monotherapy phase, 6.9% of bisoprolol first patients permanently discontinued randomized treatment compared with 9.7% of patients treated with enalapril.

During the first year, the bisoprolol first strategy was associated with a 31% reduction in mortality, which did not quite reach statistical significance (P=.06).

"If patients survive the early phase, they will enjoy the benefits of multiple treatments," said Dr Willenheimer. "We can't start all of these treatments at once. We feel that it's important to know which drug is best to start with. CIBIS III clearly shows that if you start with bisoprolol rather than enalapril, patients won't do worse."