This document summarizes the EMPHASIS-HF clinical trial which evaluated the addition of the aldosterone antagonist eplerenone to standard heart failure therapy in patients with mild symptoms. The trial randomized over 2700 patients with systolic heart failure, NYHA class II symptoms, and elevated BNP levels to eplerenone or placebo on top of background ACE/ARB and beta-blocker therapy. The primary outcome was a composite of cardiovascular death or heart failure hospitalization. The trial found that eplerenone reduced the risk of the primary outcome compared to placebo, providing evidence that aldosterone antagonism benefits patients with mild symptomatic heart failure.

1. Aldosterone Antagonists in Mild
Heart Failure
Harsha Nagarajarao
June, 2012

2. Medicine
Evidence Based Surgery - 2012

3. Objectives
• Learn Patho-physiology of RAS pathway in heart
failure
• Analysis of EMPHASIS-HF trial
• Brief overview of other trials looking on aldosterone
antagonism in heart failure

4. Myocardial Damage
Fluid Restriction
Myocardial Failure Inotropic Agents
Low-sodium Diet
Diuretics
Venodilators
Cardiac Output
Ventricular Filling
Arterial Dilators Pressures
Preload Afterload
Complementary Mechanisms
Vasopressin
Na+/H2O Retention Renin/angiotensin/aldosterone
Venoconstriction Systemic Vascular Sympathetic Activity
Resistance
ACE Inhibitors
? Beta-blockers
ARB
Aldosterone Antag

6. Aldosterone

7. New Biology of Aldosterone
For a long time Adrenal Cortex was thought off as a single source of Aldosterone
• Aldosterone synthesis is widespread in the body outside of the adrenal
cortex
• Aldosterone receptors are widespread in the body as well as traditional
renal receptors
• Aldosterone produces endothelial vascular dysfunction
• Aldosterone produces tissue injury and fibrosis—seen in the myocardium, kidney,
fibrosis
and cerebral tissues
• Aldosterone produces baroreceptor dysfunction

8. Aldosterone Receptor
• Stimulated equally both by gluco-corticoids and mineralo-corticoids
• But in-vivo only aldosterone can effectively activate the receptor
• This is due to proximity of 11ß hydrosterone dehydrogenase – which is
juxta-posed to aldosterone receptor and rapidly inactivates cortisol

9. Genomic and Non-Genomic Actions
• Aldosterone acts via traditional genomic transcription
pathway which takes about 1-2 hours to reach its peak
stimulation
• But some actions are also immediate not involving
transcription of new genes – what cause there immediate
effects is still under debate

10. Aldosterone
• In vitro studies showed first that aldosterone reduced nitric oxide
production in response in inflammatory stimuli.
• In experimental animals in vivo, aldosterone was then found to produce a
vascular inflammatory response with increased expression of cytokines
such as osteopontin
• Aldosterone blockade reduces both tissue injury and tissue fibrosis this
protection is seen even when aldosterone blockade is given at a dose too
low to alter blood pressure—that is, the tissue protective effect of
aldosterone blockade in experimental models is not simply due to its
antihypertensive effect.

11. Tissue Level Effect of Aldostorone
• Aldosterone may reduce NO bioactivity by increasing NADH
oxidase induced free radical production which in turn
degrades NO.

12. Aldosterone activates NFkB

14. Aldosterone Induced Myocardial Fibrosis

16. Aldosterone Escape
Defined in two different Contexts:
3.Escape from the sodium-retaining effects of excess aldosterone (or other
mineralocorticoids) in primary hyperaldosteronism, manifested by volume
and/or pressure natriuresis.
•The inability of ACE inhibitor therapy to reliably suppress aldosterone
release, for example, in patients with heart failure or diabetes, usually
manifested by increased salt and water retention. This latter sense may
rather be termed refractory hyperaldosteronism.
hyperaldosteronism

17. Aldosterone Escape
• The importance of aldosterone in congestive heart
failure has been overlooked in recent years because
ACE-inhibitor–related reductions in angiotensin were
thought to eliminate aldosterone production.
• Such suppression of circulating aldosterone,
however, is transient, as exemplified by the term
“escape” used to describe the phenomenon.

19. Aldosterone Escape
Brevity of Aldosterone suppression is explained by:
-Potent stimuli for Aldosterone suppression may
counter-act ACEI due to often used low dosage of
medications secondary to limitations like hypotension
and renal failure.
•E.g.: upright posture, physical activity, and excessive
restriction of dietary sodium (to less than 3 g per day).

20. Aldosterone Escape Contd..
• Some aldosterone synthesis is also independent of angiotensin
concentration
• For example, potassium-dependent aldosterone secretion is independent
of angiotensin concentrations and is integral to intravascular volume
regulation.
• This mechanism comes into play when sodium intake is excessively
restricted, the use of loop diuretics leads to substantial urinary sodium
losses, and potassium supplementation is used to counteract kaliuresis
related to the use of loop diuretics.
• Finally, the role of reduced metabolic clearance of aldosterone and the
biologic activity of its metabolites cannot be overlooked.

21. Aldosterone Escape

22. CHF and Aldosterone
• In patients with congestive heart failure,
plasma aldosterone concentrations may reach
20 times the normal level.
• Two pathophysiologic mechanisms contribute
to the increased concentrations.

23. Aldosterone in CHF
• The first is an increase in the rate of aldosterone production by the adrenal
glands due to activation of RAS.
• The second, and not widely recognized, mechanism is a decreased rate of
hepatic aldosterone clearance = causes plasma aldosterone concentrations
to triple or quadruple.
• The primary determinant of aldosterone metabolism is hepatic blood flow.
In patients with congestive heart failure, the rate of aldosterone clearance
by the liver falls to 25 to 50 percent of the normal rate.

24. Aldosterone Hypothesized to be Causing
Myocardial Fibrosis

25. ACEI in Near Normal Hearts
All Cause Mortality
Perindopril
Trandalopirl Primary end point NOT met.
Ramipril
Enalapril
Ramipril – Post MI
Captopril – post MI
Enalapril
Trandalopirl Post MI

26. AREA-IN-CHF

27. AREA-IN-CHF

28. Background
• Context
– CHF is the most common reason for hospital admission
– ACEI/ARB and Mineralocorticoid antagonists improve
survival in:
• NYHA Class III/IV patients with systolic HF (RALES trial)
• Patients post acute-MI with LV dysfunction/CHF (EPHESUS
trial)
– Current standard of care: add mineralocorticoid to
class III/IV systolic HF pt already on BB + ACEI
– What about my clinic CHF patient with only mild
symptoms?

29. “EMPHASIS-HF Trial”

30. RALES Trial

31. EMPHASIS-HF

33. Clinical Question
• Population: patients with systolic heart failure
(EF ≤ 35%) and mild sxs (NYHA Class II)
• Intervention: eplerenone (up to 50mg daily) +
standard therapy (ie BB, ACEI)
• Comparison: placebo + standard therapy
• Outcome: death, hospitalization rates

35. Study Oversight
• The executive steering committee designed and
oversaw the conduct of the trial and data analysis in
collaboration with representatives of the study
sponsor (Pfizer).
• The trial was monitored by an independent data and
safety monitoring committee.
• Data were collected, managed, and analyzed by the
sponsor according to a predefined statistical analysis
plan, and the analyses were replicated by an
independent academic statistician.

37. Study Design
• Setting: 278 centers, 29 countries
• Participants :
– 2737 patients, age ≥55
– NYHA Class II, EF ≤30% or ≤35% if QRS>130
– already on maximized ACE or ARB + BB
– hospitalization within 6 months OR ↑BNP
– Excluded: baseline K >5.0, GFR <30
• Placebo vs. 25mg eplerenone daily
– Both placebo and eplerenone were uptitrated
– Lab checks with any dose adjustment
– Decrease/stopped study med for hyperK

38. Dose was lower for GFR between 30 and 49 (provided potassium levels were less than
- Started at 25 mg every other day and then went up to 25 mg daily

39. Procedures
• Follow up every 4 months
• Investigators were asked to stop the drug if k
was > 6 and decrease the dose if between 5 to
5.9
• Potassium was re-measured with in 72 hours
in those with k > 6 and only re-started if
repeat levels were < 5

40. Outcomes
• The primary outcome was a composite of
death from cardiovascular causes or a first
hospitalization for heart failure.
• The pre specified secondary outcomes were
hospitalization for heart failure or death from
any cause, death from cardiovascular causes,
hospitalization for any reason

41. Statistics
• The initial assumptions were that, with 2584 patients
and an annual event rate of 18% in the placebo group
(based on data from a subgroup analysis of the
Candesartan in Heart Failure: Assessment of Reduction in
Mortality and Morbidity– Added trial [CHARM-Added])
• It was estimated that trial would require 813 patients with a
primary outcome occurring within 48 months to achieve 80%
power to detect an 18% relative reduction in the risk of the
primary outcome in the eplerenone group as compared with
the placebo

42. Statistics
• The data and safety monitoring committee’s charter
specified interim analyses of the primary outcome after
approximately 271 and 542 events had occurred, with a
statistical stopping guideline for an overwhelming benefit
(two-sided P<0.001 in favor of eplerenone).
• In May 6, 2010, after the second interim analysis, the data
and safety monitoring committee reported that the
prespecified stopping boundary for an overwhelming
benefit had been crossed.
• The full executive committee was informed, decided to
stop the trial

43. Statistics
• Two study groups was assessed by means of a
two-sample t-test, for continuous variables, or
Fisher’s exact test, for categorical variables.
• Primary and secondary outcomes were
conducted on data from all patients who had
undergone randomization, according to the
intention-to-treat principle, with the use of
Kaplan–Meier estimates and Cox proportional-
hazards models

46. Study Population
• A total of 45 patients (3.3%) in the eplerenone group and 51
patients (3.7%) in the placebo group were enrolled on the
basis of a QRS duration > 130 msec. (with EF b/n 30-35%)
• 195 patients (14.3%) in the eplerenone group and 190
patients (13.8%) in the placebo group were enrolled on the
basis of the BNP or N-terminal pro-BNP criterion (with no IP
admission over past 180 days)
• About 50% had history of MI (all > 30 days prior)

47. Study Details
• Eight patients (four in each study group) did not start the
study medication and were not included in the safety analysis
• After completion of the dose-adjustment phase, at 5 months,
60.2% of patients who had been assigned to receive
eplerenone were taking the higher dose (50 mg daily)
• The corresponding proportion in the placebo was 60.5%
• The mean doses in each group was 39.1±13.8 mg and
40.8±12.9 mg respectively

48. Study Details
• At the trial cutoff date, the study drug had been discontinued
in 222 patients (16.3%) receiving eplerenone and 228 patients
(16.6%) receiving placebo.
• At the trial cutoff date, 17 patients (1.2%) in the eplerenone
group and 15 patients (1.1%) in the placebo group were lost
to follow-up.
• The median duration of follow-up among all patients was 21
months, with 4783 patient-years of follow-up.

49. Outcomes

50. Results

51. Results

52. NNT
• The estimated number of patients who would
need to be treated to prevent one primary
outcome from occurring, per year of follow-
up, was 19 (95% CI, 15 to 27)
• The estimated number needed to treat to
postpone one death, per year of follow-up,
was 51 (95% CI, 32 to 180).

53. Safety
• During the course of the study, 188 patients
(13.8%) receiving eplerenone and 222 patients
(16.2%) receiving placebo discontinued the
study drug because of an adverse event (P =
0.09) – Analyzed numbers are in the next
table.

54. Adverse Events

55. Review of Terms
• Event rate: # of people experiencing an event
as a fraction of the total at-risk population
ex: 15% rate of MI in control group (CER)
5% rate of MI in experimental group (EER)
• Relative risk: likelihood of the event happening in the
experimental group as compared to the control group
(Ideally, experimental or therapy group should have lower
risk of event than control, ie ratio <1.0)
ex: 5% therapy group/15% control group = 0.333
Therapy pts have 1/3 the risk of MI as control patients

56. Review of Terms
• RRR: difference between control and experimental event rates
in relative terms – ie what proportion of risk reduction does the
therapy contribute as compared to baseline risk?
ex: 15%-5%/15% = 0.6666
therapy pts have a 66% reduction in baseline rate of MI
• ARR: subtracted difference between experimental and control
event rates
ex: 15% - 5% = 10% absolute risk reduction
• NNT: How many pts need to receive the therapy to prevent one
event? (ie not all pts that take the medication will benefit)
ex: 1/10% = 10 pts treated to prevent one MI

57. One Caveat…In Population where Event Rate Is Low
RRR: 66% 66%
ARR: 10% 1.33%
NNT: 10 75

58. Number Needed to Harm!!!
Control Exper Relative RRR ARR NNT
OUTCOME event Event Rate Risk (CER-EER) CER-EER 1/ARR
Rate (%) (%) EER/CER CER (95% CI) (95% CI)
Death by 15.5% 12.5% 0.81 0.19 3% 33
any cause
Death by 13.5% 10.8% 0.80 0.20 2.7% 37
CV cause
CHF cause 18.4% 12% 0.65 0.35 6.4% 16
hospitaliz
HyperK 3.7% 8% n/a n/a 4.3% 23
(increase) (NNH)

59. Are the Results Meaningful?
• Very clinically relevant outcomes
– Easily applicable, meaningful to patients
• AKI, hyperkalemia, hypotension considered &
reported

60. Can I Apply the Results to Patient Care?
Are the study patients similar to my patients? YES
Is the intervention feasible in my practice setting? YES
Are the benefits worth the harms and costs? YES*

61. Cautions
• Composite primary outcome – confusing to apply clinically
• Pharma funded (Pfizer, maker of eplerenone)
– Eplerenone: $113/month
– Spironolactone: $14/month
• NNH for hyperkalemia lower than NNT for reducing death.. However
no deaths from hyperkalemia, no difference in hyperK
hospitalization rates

62. Bottom Line
• Addition of eplerenone to maximized CHF regimen
(BB + ACEI/ARB) in Class II systolic HF patients
reduced all-cause mortality and decreased CHF
hospitalizations with a statistically significant, though
probably acceptable, risk of hyperkalemia.
– Extrapolate to spironolactone?
– Choose reliable patients (given hyperK issues)
– Recommendation not yet incorporated into CHF guidelines

76. HFSA - 2012

78. Study Validity
Criteria
Were pts randomized? YES
Was randomization concealed? YES
Were pts similar on important variables? YES
Was “intention to treat” analysis done? YES**
Were pts aware of group allocation? YES
Were outcome assessors aware of allocation? ?
Complete and long enough follow-up? YES

79. Management of Systolic Heart Failure
Transplantation
Inotropes
Nitrates, hydralazine
Aldosterone Antagonists
Digoxin
Beta-blockers
ACE inhibitors or AII Blockers
Diuretics Combinations
Na+ restriction, alchohol abstinence, activity counseling, weight monitoring
NYHA I NYHA II NYHA III NYHA IV
Asymptomatic Mild Moderate Severe
symptoms symptoms symptoms
Massie, B.M., Cardiology 2001;Section 5:p. 14.

80. EMPHASIS-HF

81. TOPCAT
TOPCAT is a multi-center, international, randomized, double blind placebo-controlled
trial of the aldosterone antagonist, spironolactone, in 3,445 adult subjects with heart
failure and left ventricular ejection fraction of at least 45%, recruited internationally from
over 200 clinical centers in the US, Canada, Russia, Republic of Georgia, Argentina,
and Brazil.

82. Thank You