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
© Copyright 2009 by the American Association for Clinical Chemistry
IntroductionIntroduction
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
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
IntroductionIntroduction
© Copyright 2009 by the American Association for Clinical Chemistry
To determine if early, more complete renin-angiotensin-aldosterone 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
AimsAims
© Copyright 2009 by the American Association for Clinical Chemistry
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?
QuestionQuestion
© Copyright 2009 by the American Association for Clinical Chemistry
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
Materials and Methods: Laboratory StudiesMaterials and Methods: Laboratory Studies
© Copyright 2009 by the American Association for Clinical Chemistry
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
Materials and Methods: Study ParticipantsMaterials and Methods: Study Participants
© Copyright 2009 by the American Association for Clinical Chemistry
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?
QuestionsQuestions
© Copyright 2009 by the American Association for Clinical ChemistryCorrelations between aldosterone quartiles & clinical risk factors/biomarkers
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Table 2. Change in serum aldosterone by treatment group. Absolute changes are least-squares 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.
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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© 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
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?
QuestionsQuestions
© Copyright 2009 by the American Association for Clinical Chemistry
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
Conclusions Conclusions
© Copyright 2009 by the American Association for Clinical Chemistry
…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
Conclusions (continued)Conclusions (continued)