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Inhibition of the Renin-Angiotensin System
Reduces the Rise in Serum Aldosterone in
ACS Patients with Preserved Left
Ventricular Function: Observations from
the AVANT GARDE-TIMI 43 Trial
J.A. Udell, D.A. Morrow, E. Braunwald, K. Swedberg,
C. Bode, N. Rifai, P.C. Brunel, M.F. Prescott, F. Ren,
E.B. Hoffman, and B.M. Scirica
June 2013
www.clinchem.org/content/59/6/959.full
© Copyright 2013 by the American Association for Clinical Chemistry
Introduction
 Aldosterone
 The major mineralocorticoid hormone secreted by
the adrenal cortex
 Key modulator of neurohormonal hemodynamic
regulation
 In acute coronary syndrome (ACS), adverse
cardiovascular remodeling is mediated in part by
aldosterone
 Plays a deleterious role to worsen cardiac function,
leading to left ventricular (LV) dysfunction, heart
failure, and cardiovascular death
© Copyright 2009 by the American Association for Clinical Chemistry
Introduction
 Clinical Benefit of Aldosterone Inhibition
 Survival benefit of renin-angiotensin-aldosterone system
(RAAS) inhibition with angiotensin-converting-enzyme
(ACE) inhibitors, angiotensin receptor blockers (ARB), or
aldosterone blockade after ACS appears to be greatest in
patients with large myocardial infarctions and depressed
LV function via afterload reduction and improved
myocardial remodeling
 The AVANT GARDE-TIMI 43 trial specifically excluded
those types of patients to focus on patients in whom the
benefit of early RAAS inhibition remains unproven
 A potential mechanism of clinical benefit from RAAS
inhibition may be by reducing aldosterone post-ACS
© Copyright 2009 by the American Association for Clinical Chemistry
Aims
 To determine if early, more complete renin-angiotensinaldosterone system (RAAS) inhibition would result in a
graded reduction in aldosterone concentrations in post-ACS
patients without reduced left ventricular function or heart
failure, a group in which a benefit of inhibition of RAAS
remains uncertain
 To explore whether high or low baseline concentrations of
plasma N-amino terminal fragment of the prohormone brain
natriuretic peptide (NT-proBNP) may modify treatment effects
on aldosterone concentrations
© Copyright 2009 by the American Association for Clinical Chemistry
Question
 Describe the strengths and weaknesses of evaluating the
relationship between RAAS inhibition therapy and
aldosterone concentrations in an observational study as
compared to a randomized controlled trial
 Which approach is most informative when designing a study
of the effect of RAAS inhibition on aldosterone
concentrations as a potential mechanism for improved
clinical outcomes?
© Copyright 2009 by the American Association for Clinical Chemistry
Materials and Methods: Laboratory Studies
 Laboratory Analysis
 Serum aldosterone was measured using a Coat-A-Count
radioimmunoassay from Diagnostics Products
 Serum renin activity, BNP, and NT-proBNP biomarkers were also
measured
 Statistical Analysis
 Efficacy analyses were performed on an intention-to-treat basis,
consisting of patients with a baseline and follow-up aldosterone
 Temporal change in serum aldosterone from baseline was
evaluated using an analysis of covariance (ANCOVA) model with a
test for linear trend across treatment groups and pairwise
comparisons between treatment groups and placebo or other
therapies
 Further evaluation was tested by stratifying patients above vs.
below median baseline NT-proBNP
© Copyright 2009 by the American Association for Clinical Chemistry
Materials and Methods: Study Participants
 AVANT GARDE-TIMI 43 Trial
 1101 patients with ACS, without left ventricular systolic dysfunction
or clinical heart failure but increased concentration of a natriuretic
peptide measured 3-10 days after their qualifying event
 BNP had to be ≥80 ng/L or NT-proBNP ≥400 ng/L
 Randomized to aliskiren, valsartan, their combination, or placebo
 Study Procedures
 Study drug was titrated up over an 8-week duration to a goal dose
 Combination therapy started at week 4 when aliskiren added to
valsartan and up-titrated over the next 4 weeks
 Endpoints
 Change in serum aldosterone concentration between baseline ad
end of study
© Copyright 2009 by the American Association for Clinical Chemistry
Questions
 In a randomized controlled trial, is it critical to include
the baseline aldosterone concentration in a statistical
model testing the relationship between treatment and
follow-up aldosterone concentration?
 In a randomized controlled trial, is it critical to include
other baseline covariates in this statistical model?
© Copyright 2009 by the American Association for Clinical Chemistry
Correlations between aldosterone quartiles
clinical
risk Association
factors/biomarkers
© Copyright &
2009
by the American
for Clinical Chemistry
Table 2. Change in serum aldosterone by treatment group. Absolute changes are leastsquares mean changes from baseline until follow-up week 8 from ANCOVA model (95% CI). P
values for treatment relative change compared to placebo by t-test for continuous aldosterone
concentration. P value for linear trend across treatment groups = 0.008. To convert aldosterone
concentrations in ng/dL to pmol/L, multiply by 27.74.
© Copyright 2009 by the American Association for Clinical Chemistry
Figure 1. Comparison of absolute change in serum aldosterone according to treatment
groups. Absolute changes are least-squares mean changes from baseline until follow-up week 8
from ANCOVA model (95% CI). *P<0.05 for treatment relative change compared to placebo by t-test
for continuous aldosterone concentration. † P value for linear trend across treatment groups. To
convert aldosterone concentrations in ng/dL to pmol/L, multiply by 27.74.
© Copyright 2009 by the American Association for Clinical Chemistry
Table 3. Change in serum aldosterone by treatment group and baseline NT-proBNP. See
Table 2 footnote for model definition. P value for linear trend across treatment groups = 0.008
for NT-proBNP ≤ median and 0.65 for > median. To convert aldosterone concentrations in
ng/dL to pmol/L, multiply by 27.74.
© Copyright 2009 by the American Association for Clinical Chemistry
Questions
 What are the implications of a rise in aldosterone
concentration in placebo ACS patients with preserved
LV function but evidence of hemodynamic stress based
on elevated BNP?
 What are the implications of mitigating the increase in
aldosterone with early, more complete RAAS
inhibition?
 Why might patients with lower baseline NT-proBNP
concentrations demonstrate most of the benefit?
© Copyright 2009 by the American Association for Clinical Chemistry
Conclusions
 AVANT GARDE-TIMI 43 represents the largest randomized
controlled trial to demonstrate that aldosterone
concentrations rise early after an uncomplicated ACS…
 Higher baseline aldosterone concentrations observed
than in other post-MI or stable CAD studies
 A nearly 20% rise in aldosterone over 8 weeks in placebo
patients was observed; the mechanism leading to this
rise is unclear but is unrelated to poor LV function or
cardiac output and more likely related to neurohormonal
activation
 Prior reports observed that aldosterone peaked soon
after an index MI and decreased substantially thereafter
© Copyright 2009 by the American Association for Clinical Chemistry
Conclusions (continued)
 …and that early, more complete RAAS inhibition
significantly mitigates the increase in aldosterone when
initiated within 3-10 days after ACS
 Suggesting aldosterone is a modifiable target of therapy
 The potential application of aldosterone to risk-stratify
patients post-ACS and target those patients with more
complete RAAS inhibition remains unknown but warrants
confirmation in large clinical trials
 May translate into a clinically meaningful improvement in
cardiovascular events in this patient population
© Copyright 2009 by the American Association for Clinical Chemistry
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© Copyright 2009 by the American Association for Clinical Chemistry