Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study.
BACKGROUND
Despite clear guidelines recommendations, most patients with heart failure and reduced ejection-fraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers.


RESULTS
BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centres in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n = 151) and patients with a LVEF > 40% (n = 242) were excluded. Median follow up was 21 months. We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05).


CONCLUSIONS
Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%.
Department of Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
W
W
Ouwerkerk
Department of Cardiology, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
A A
AA
Voors
Innovative Clinical Trials, Department of Cardiology & Pneumology, University Medical Center Göttingen (UMG), Robert-Koch-Straße 40 37075, Göttingen, Germany.
S D
SD
Anker
National Heart & Lung Institute, Royal Brompton & Harefield Hospitals, Imperial College, Sydney St, Chelsea, London SW3 6NP, UK.
J G
JG
Cleland
University of Bergen, 5007 Bergen, Norway.
K
K
Dickstein
Stavanger University Hospital, Gerd-Ragna Bloch Thorsens Gate 8, 4011 Stavanger, Norway.
G
G
Filippatos
Department of Cardiology, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
P
P
van der Harst
Department of Cardiology, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
H L
HL
Hillege
National and Kapodistrian University of Athens, School of Medicine & Department of Cardiology, Heart Failure Unit, Athens University Hospital Attikon, 1, Rimini Str, Haidari, 124 62 Athens, Greece.
C C
CC
Lang
Department of Cardiology, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
J M
JM
Ter Maaten
School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, UK.
L L
LL
Ng
Department of Heart Diseases, Wroclaw Medical University, Poland and Cardiology Department, Military Hospital, 50-981 Wroclaw, Poland.
P
P
Ponikowski
School of Medicine Centre for Cardiovascular and Lung Biology, Division of Molecular and Clinical Medicine, University of Dundee, Ninewells Hospital & Medical School, Dundee, DD1 9SY, UK.
N J
NJ
Samani
Department of Cardiology, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
D J
DJ
van Veldhuisen
Department of Heart Diseases, Wroclaw Medical University, Poland and Cardiology Department, Military Hospital, 50-981 Wroclaw, Poland.
F
F
Zannad
Institute of Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health; University of Brescia, Piazza del Mercato, 15, 25121 Brescia, Italy.
M
M
Metra
Department of Epidemiology, Biostatistics & Bioinformatics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
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AH
Zwinderman
D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage*; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005060:Europe / Q000453:epidemiology; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D011446:Prospective Studies; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors
ACE-inhibitor; ARB; Beta-blocker; Heart failure; Uptitration