1. 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

2. © Copyright 2009 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

3. © 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 Introduction

4. © 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 Aims

5. © 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? Question

6. © 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 Studies

7. © 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 Participants

8. © 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? Questions

9. © Copyright 2009 by the American Association for Clinical Chemistry Correlations between aldosterone quartiles & clinical risk factors/biomarkers

10. © Copyright 2009 by the American Association for Clinical Chemistry 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.

11. © 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.

12. © 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.

13. © 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? Questions

14. © 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

15. © 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)

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