Comparison of treatment initiation with bisoprolol vs. enalapril in chronic heart failure patients: rationale and design of CIBIS‐III

Abstract

Background: Angiotensin-converting-enzyme (ACE) inhibitors and b-blockers are standard therapy for chronic heart failure (CHF). b-blockers are recommended to be initiated after ACE-inhibitors, but this order is not evidence based. The initiation order may be important since many, especially elderly CHF patients cannot tolerate target doses of both. Data suggest that b-blockers may be more important to CHF patients than ACE-inhibitors, especially in early stages of CHF. Aims: To compare the effect on combined death or hospitalisation of initial monotherapy with either bisoprolol or enalapril, followed by combination therapy. Methods: One-thousand CHF patients without ACE-inhibitor, b-blocker or angiotensin-receptor-blocker therapy will be randomised 1:1 to monotherapy with either enalapril or bisoprolol for 6 months, followed by combined therapy for 6-18 months. The primary objective is to show non-inferiority for bisoprolol-first vs. enalapril-first regarding combined death or hospitalisation. If that is shown, superiority for bisoprolol-first will be tested. Conclusions: If the trial shows non-inferiority for bisoprolol-first vs. enalaprilfirst, the first CHF therapy may be chosen based on individual judgement in each patient. If bisoprolol-first is superior to enalapril-first, a b-blocker should be given prior to an ACE-inhibitor in CHF, and the paradigm of testing CHF compounds against a background of ACE-inhibitor therapy will be challenged.

Effect on Survival and Hospitalization of Initiating Treatment for Chronic Heart Failure With Bisoprolol Followed by Enalapril, as Compared With the Opposite Sequence

“…25 Two interim analyses of safety were performed. Given that the study could not be stopped prematurely because of between-group differences with regard to the primary end point or other efficacy end points, no adjustment of probability values for the primary end point or other efficacy end points was necessary.…”

“…The design and protocol of CIBIS III have been described previously. 25 After initial physician screening, patients were randomized, via random numbers produced by a dynamic balancing algorithm, 26 at the independent statistical center and were stratified according to NYHA class (II or III). Treatment was allocated by telephone from the statistical center.…”

Angiotensin-Converting Enzyme Inhibitors or β-Blockers in Heart Failure

“…The lack of blinding could have lowered the threshold to hospitalize for heart failure but not for other reasons in the bisoprolol-first group (as was seen) and could have had an impact on the small difference in the numbers of deaths between groups. Although the authors address this problem, noting that blinding of the end points committee limits bias, 18 such blinding does not eliminate bias.…”

Response to Ryan and Parwani: Heart Failure Patients With Low Blood Pressure: How Should We Manage Neurohormonal Blocking Drugs?

“…Recent data, however, suggest that it may be safe to initiate β-blockers before ACEI. 3 With this in mind, therapy may be individualized in challenging patients with low BP. In patients with active ischemia, recent acute coronary syndrome, tachyarrhythmias, or certain cardiomyopathies, initiation of β-blockers may precede initiation of ACEI.…”