1) The study examined outcomes in patients with heart failure who were at high risk, finding that at 6 months their risk was approximately 3.8 times higher. 2) Baseline characteristics were similar between the eplerenone and placebo groups, including average age of 64, 72% males, mean ejection fraction of 33%, and 32% with diabetes. 3) For the primary endpoints of total mortality and cardiovascular mortality or hospitalization, eplerenone demonstrated a 15% and 13% reduced risk respectively compared to placebo.

1. Six Month Outcome in Patients
With Heart Failure at Admission
On Admission
At 6 months,
risk approximately
3.8-fold
HR: 3.8 [95% CI 3.33-4.36]

2. Who Are High Risk Patients ?
USIK 1995 and USIC 2000
Risk reduction No risk reduction p
1,05
Age 0,001
0,61
Reperfusion 0,001
1,57
MI history 0,001
1,49
Diabetes 0,001
Arteriopathy 1,55 0,001
history 3,63
Killip>1 0,001
1,36
Anterior infarction 0,002
0,68
Statins 0,005
0,78
Hyperlipidemia 0,003
1,32
Tobacco 0,048
0 0,5 1 1,5 2 2,5 3 3,5 4 4,5

3. LVEF and Post-MI Prognosis
LVEF and 1 year prognosis after MI
1,00
0,95 LVEF = 51 % (n = 466)
0,90
Survival
41 % = LVEF < 51 % (n = 241)
0,85
0,80
p < 0,0001 LVEF = 40 % (n = 265)
0,75
0,70
0,65
0
0 50 150 250 350
time (days)

4. EPHESUS™
Study Design
AMI, LVEF ≤40%, CHF
Standard therapy
6632 Patients
3-14 Days
Post-AMI
Eplerenone
Placebo
25 mg - 50 mg qd
(n=3313)
(n=3319)
1012 Deaths
•Primary End Points: • Total mortality
• CV mortality/CV hospitalizations
•Secondary End Points: • CV mortality
• Total mortality/total hospitalizations

5. EPHESUS™
Patient Population
• Acute MI complicated by
• Impaired LV systolic function NYHA Class*
(EF ≤40%), with a mean LVEF
of 33%
• Diabetes mellitus
• Clinical congestive heart
failure during hospitalization
(whether persistent or not)
• Rales, S3 gallop, or
pulmonary venous congestion
on x-ray
• 65% of patients were Killip
∗ 1 week post-randomization.
Class II
• 91% of patients were started
on INSPRA® (eplerenone) in
the hospital

6. EPHESUS™
Baseline Characteristics
Eplerenone Placebo
n = 3319 n = 3313
Age (yrs) 64 64
Males 72% 70%
Caucasian 90% 90%
Blood pressure (mm Hg) 119 / 72 119 / 72
Ejection fraction 33% 33%
Body mass index (kg/m2) 28 27
Serum creatinine (mg/dL) 1.1 1.1
Serum potassium (mmol/L) 4.3 4.3
Hx of diabetes 32% 32%
Days from MI to randomization 7.3 7.3
Hx of HTN 60% 61%
Hx of HF 14% 15%
Hx of AMI 27% 27%

7. Patient Stratification by Killip Class
Eplerenone Placebo Total
(n=3319) (n=3313) (n=6632)
Group n (%) n (%) n (%)
Killip class I 507 (15) 505 (15) 1012 (15)
Killip class II 2143 (65) 2134 (64) 4277 (65)
Killip class III 544 (16) 551 (17) 1095 (17)
Killip class IV 106 (3) 101 (3) 207 (3)
Killip class 19 (0.6) 22 (0.7) 41 (0.6)
unknown

8. Effect of Eplerenone in Post-MI LVD & HF:
EPHESUS™ Primary End Points
Total Mortality CV Mortality/CV Hospitalization
20 40
Cumulative Incidence (%)
Cumulative Incidence (%)
30
10 20
RR=0.85 (95% CI, 0.75-0.96) 10 RR=0.87 (95% CI, 0.79-0.95)
P=0.008 P=0.002
0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Months Since Randomization Months Since Randomization
Placebo (N=3313)
Eplerenone (N=3319)

9. Relative Risks of Primary and Selected
Secondary End Points in EPHESUS™
All-cause mortality P=.008
CV mortality/CV hospitalization P=.002
All-cause mortality/any hospitalization P=.02
CV mortality P=.005
Sudden cardiac death P=.03
HF mortality P=.10
CV hospitalization P=.09
HF hospitalization P=.03
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
Risk ratio ± 95% CI
Eplerenone Better Placebo Better

10. Effect of Eplerenone on Sudden
Cardiac Death: EPHESUS™
All Patients Patients with Baseline
10 16 Ejection Fraction ≤ 30%
9
14
8
12
7
Placebo Placebo
6 10
5 8
Eplerenone Eplerenone
4
6
3
4
2
RR = 0.79 (95% CI, 0.64-0.97) RR = 0.67 (95% CI, 0.50-0.91)
1 P = 0.03 2 P = 0.009
0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 0 3 6 9 12 15 18 21 24 27 30 33 36
Months Since Randomization

11. Relative Risks of Mortality and Morbidity in
EPHESUS™ Patients With LVEF ≤30%
All-cause mortality P=.012
CV mortality/CV P=.001
hospitalization
Sudden cardiac death P=.01
HF mortality/HF hospitalization P=.005
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
Risk ratio ± 95% CI
Eplerenone Better Placebo Better

12. Relative Risk of All-Cause Mortality Long-
Term and at 30 Days Post-Randomization
16-Month Follow-Up1 30 Days Post-Randomisation2
40 5
Cumulative Incidence (%)
Risk Ratio=0.85 Risk Ratio=0.69 Placebo
Cumulative Incidence (%)
35 (95% CI, 0.75-0.96) (95% CI, 0.54-0.89)
P=0.008 4 P=0.004
30
Placebo
25 3
20
15 2 Eplerenone
Eplerenone
10
1
5
0 0
0 6 12 18 24 30 0 10 20 30
Months Since Days Since Randomisation
Randomisation

13. EPHESUS™ : Eplerenone Survival
Benefits at 30 Days
Eplerenone
13%
Placebo
12
Cumulative Incidence (%)
9.9
10
8.6
8
31% 32%
6
4.6 4.6
4 3.2 3.3
2
0
All-Cause Mortality CV Mortality/CV CV Mortality
RR=0.69 (95% CI, 0.54-0.89) Hospitalization RR=0.68 (95% CI, 0.53-0.88)
RR=0.87 (95% CI, 0.74-1.01)

14. EPHESUS™ : Eplerenone Reduced Sudden
Cardiac Death by 37% at 30 Days
1.6
1.4
1.4 37%
Cumulative Incidence (%)
1.2
1.0 0.9
Eplerenone
0.8
Placebo
0.6
0.4
0.2
0
Sudden Cardiac Death
RR=0.63 (95% CI, 0.40-1.00)

15. Relative Risks of Mortality and Morbidity 30
Days Post-Randomization in EPHESUS™
All-cause mortality P=.004
CV mortality/CV hospitalization P=.074
CV mortality P=.003
Sudden cardiac death P=.051
HF mortality/HF hospitalization P=.106
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
Risk ratio ± 95% CI
Eplerenone Better Placebo Better

16. Relative Risk of End Points in High-Risk
Subgroups in EPHESUS™ at 27 Months
History of Hypertension P Values
All-Cause Mortality P=0.001
Cardiovascular Mortality/Hospitalisation P=0.002
Sudden Cardiac Death P=0.022
History of Diabetes
All-Cause Mortality P=0.127
Cardiovascular Mortality/Hospitalisation P=0.03
Sudden Cardiac Death P=0.641
LVEF ≤30%
All-Cause Mortality P=0.012
Cardiovascular Mortality/Hospitalisation P=0.001
Sudden Cardiac Death P=0.01
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8
Eplerenone Better Placebo Better

17. Relative Risk of End Points in Each
Subgroup at 30 Days
History of Hypertension P Values*
All-cause Mortality P=0.017
Cardiovascular Mortality P=0.015
Cardiovascular Mortality/Hospitalisation P=0.138
Sudden Cardiac Death P=0.139
History of Diabetes
All-cause Mortality P=0.066
Cardiovascular Mortality P=0.057
Cardiovascular Mortality/Hospitalisation P=0.062
Sudden Cardiac Death P=0.136
LVEF ≤30%
All-cause Mortality P=0.002
Cardiovascular Mortality P=0.002
Cardiovascular Mortality/Hospitalisation P=0.006
Sudden Cardiac Death P=0.01
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8
Eplerenone Better Placebo Better

18. All-Cause Mortality at 30 Days,
by Subgroup
PBO, LVEF ≤30%
Cumulative Incidence (%)
6 PBO, Hx Diabetes
PBO, Hx HTN
EPL, LVEF ≤30%
4 EPL, Hx Diabetes
EPL, Hx HTN
2
0
0.0 0.2 0.4 Month 0.6 0.8 1.0
EPL=eplerenone; HTN=hypertension; Hx=history; PBO=placebo.

19. Incidence of Hypokalemia and
Hyperkalemia
Overall EPHESUS Patients
Eplerenone (n=3319) Placebo (n=3313)
14 P<.001 P=.002
12 13.1%
Incidence (%)
10
8
8.4%
6
5.5%
4
3.9%
2
0
Hypokalemia Hyperkalemia
Hypokalemia = K + <3.5 mmol/L.
Hyperkalemia = K + >6.0 mmol/L.

20. Incidence of Hyperkalemia and
Hypokalemia at 30 Days, by Subgroup
History of History of LVEF ≤ 30%
5 Hypertension Diabetes
4
P=0.005 P=0.051 P=0.008 P=0.229 P=0.016 P=0.105
Incidence (%)
3 3.3%
2.8% 2.8%
2.3% 2.4%
2 2.2%
2.0%
1.9%
1.7%
1
1.1%
0.7% 0.7%
0
Hypokalemia Hyperkalemia Hypokalemia Hyperkalemia Hypokalemia Hyperkalemia
Hypokalemia = K + <3.5 mmol/L. Eplerenone Placebo
Hyperkalemia = K + >5.5 mmol/L.