Effects
of Carvedilol on the Renin-Angiotensin-Aldosterone System in Patients
with Ischaemic Left Ventricular Systolic Dysfunction
J
GF Cleland
Authors: G Murray; P W Macfarlane; D J Pennell; A Lahiri; S Ray;
J Dalle Mule; Z Vered; J G Cleland
Background: Beta-blockers, in synergy
with ACE inhibitors, are an effective therapy for patients with
heart failure secondary to left ventricular (LV) systolic dysfunction
but the mechanism(s) of action remain unclear. Part of their benefits
may be due to suppression of renin, thereby enhancing the efficacy
of ACE inhibitors. We measured changes in renin and aldosterone
in response to carvedilol in the CHRISTMAS (The Carvedilol Hibernation
Reversible Ischaemia Trial; Marker of Success) study.
Methods: Patients with chronic
heart failure of ischaemic aetiology were screened by echo for
systolic dysfunction (corresponding to a LVEF of <=39%). Eligible
patients were further assessed by myocardial perfusion imaging,
radionuclide ventriculography and measurement of renin activity
and aldosterone. Hibernation was defined as a regional mismatch
of impaired echo wall motion with preserved myocardial perfusion.
All imaging data were assessed in a blinded fashion by core laboratories.
Patients were then randomised to receive placebo or carvedilol
in a double-blind fashion, titrated to a target dose of 25 mg
bid (50 mg bid if >=85 kg) or matching placebo. Patients were
reassessed approximately 6 months after randomisation.
Results: 305 patients were randomised
and included in the intention to treat population, of whom 242
had renin activity and 188 had aldosterone measured. Baseline
levels of renin and aldosterone were similar on carvedilol and
placebo and in patients designated as hibernators and non-hibernators.
Mean LVEF rose on carvedilol compared to placebo (+2.8±0.7% v
-0.4±0.7%; p=0.0001). Plasma renin activity tended to fall on
carvedilol compared to placebo (median change and [inter-quartile
range](-38µU/mL[-165 to -1] v +2µU/mL[-48 to 76];
p=0.054 but not aldosterone (-0.05nmol/L[-0.17 to +0.06] v 0.0nmol/L[-0.12
to +0.09].
Conclusions: Carvedilol may reduce
plasma renin activity when administered to patients with heart
failure and LV systolic dysfunction treated with ACE inhibitors
but this does not lead to a further suppression of aldosterone.
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