Effect on mode of death of heart failure treatment started with bisoprolol followed by Enalapril, compared to the opposite order: results of the randomized CIBIS III trial.
BACKGROUND
Mode of death in chronic heart failure (CHF) may be of relevance to choice of therapy for this condition. Sudden death is particularly common in patients with early and/or mild/moderate CHF. β-Blockade may provide better protection against sudden death than ACE inhibition (ACEI) in this setting.


METHODS
We randomized 1010 patients with mild or moderate, stable CHF and left ventricular ejection fraction ≤35%, without ACEI, β-blocker or angiotensin-receptor-blocker therapy, to either bisoprolol (n = 505) or enalapril (n = 505) for 6 months, followed by their combination for 6-24 months. The two strategies were blindly compared regarding adjudicated mode of death, including sudden death and progressive pump failure death.


RESULTS
During the monotherapy phase, 8 of 23 deaths in the bisoprolol-first group were sudden, compared to 16 of 32 in the enalapril-first group: hazard ratio (HR) for sudden death 0.50; 95% confidence interval (CI) 0.21-1.16; P= 0.107. At 1 year, 16 of 42 versus 29 of 60 deaths were sudden: HR 0.54; 95% CI 0.29-1.00; P= 0.049. At study end, 29 of 65 versus 34 of 73 deaths were sudden: HR 0.84; 95% CI 0.51-1.38; P= 0.487. Comparable figures for pump failure death were: monotherapy, 7 of 23 deaths versus 2 of 32: HR 3.43; 95% CI 0.71-16.53; P= 0.124, at 1 year, 13 of 42 versus 5 of 60: HR 2.57; 95% CI 0.92-7.20; P= 0.073, at study end, 17 of 65 versus 7 of 73: HR 2.39; 95% CI 0.99-5.75; P= 0.053. There were no significant between-group differences in any other fatal events.


CONCLUSIONS
Initiating therapy with bisoprolol compared to enalapril decreased the risk of sudden death during the first year in this mild systolic CHF cohort. This was somewhat offset by an increase in pump failure deaths in the bisoprolol-first cohort.
Departments of Epidemiology and Preventive Medicine and Medicine, Monash University, Alfred Hospital, Melbourne, Australia  Thoraxcenter, Department of Cardiology, University Hospital Groningen, The Netherlands  UPMC - AP-HP - INSERM CIC9304, Department of Pharmacology, Pitié-Salpêtrière Hospital, Paris, France  Department of Cardiology, University of Pavia and Policlinico di Monza, Italy  Department of Pharmacology & Therapeutics, Trinity Centre, St James' Hospital, Dublin, Ireland  Medizinische Klinik III, University of Cologne, Germany  Medicine A, University Hospital Zürich, Switzerland  Department of Heart Diseases, Medical University, Wroclaw, Poland  Worldwide Clinical Trials, Nottingham, UK  Merck KGaA, Darmstadt, Germany  Service de Pharmacologie, Hopital Pitié-Salpetriere, Paris, France  Lund University and Heart Health Group, Malmö, Sweden.
Henry
H
Krum
Dirk J
DJ
van Veldhuisen
Christian
C
Funck-Brentano
Emilio
E
Vanoli
Bernard
B
Silke
Erland
E
Erdmann
Ferenc
F
Follath
Piotr
P
Ponikowski
Michael
M
Goulder
Wilfried
W
Meyer
Philippe
P
Lechat
Ronnie
R
Willenheimer
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D017298:Bisoprolol / Q000008:administration & dosage*; D002908:Chronic Disease; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000008:administration & dosage*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality; D006760:Hospitalization; D006801:Humans; D008297:Male
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D017298:Bisoprolol