Scott D. Solomon, MD, FACC, Sung Hee Shin, MD, Amil Shah, MD, Lars
Kober, MD, Aldo P. Maggioni, MD, Jean Rouleau, MD, FACC, John J. V.
McMurray, MD, FACC, Roxzana Kelly, Allen Hester, Marc A. Pfeffer, MD,
PhD, FACC for the Aliskiren Study in Post-MI Patients to Reduce
Remodeling (ASPIRE) investigators
Brigham and Women’s Hospital, Boston, MA; Rigshospitalet Copenhagen
University Hospital, Copenhagen, Denmark; ANMCO Research Center, Firenze,
Italy; University of Montreal, Montreal, Canada; Western Infirmary, Glasgow,
Scotland; Novartis Pharmaceuticals, East Hanover, NJ

• Dr. Solomon, Kober, Maggioni, Rouleau,
McMurray and Pfeffer have received research support from and have consulted for Novartis.
• Ms. Kelly and Dr. Hester are employees of Novartis
• The ASPIRE trial was funded by Novartis.

• Despite major therapeutic advances acute myocardial infarction (AMI) remains associated with high morbidity and mortality
• In post-MI patients, reduced left ventricular (LV) systolic function is associated with increased risk of LV remodeling, heart failure and mortality
• Angiotensin converting enzyme inhibitors (ACEi) decrease the risk of death or chronic HF in patients with AMI 1,2,3 and angiotensin receptor blockers (ARB) are an established alternative to
ACE-i 4
1 Pfeffer et al. SAVE Invest. NEJM 1992; 2 AIRE Invest. Lancet 1993; 3 TRACE Invest. NEJM 1995
4 Pfeffer et al. VALIANT invest NEJM 2003

The direct renin inhibitor aliskiren blocks the RAAS proximally and may attenuate ACE or ARB induced compensatory rise in PRA and further RAAS activation
Angiotensinogen
Non-ACE Pathways
(e.g., chymase)
Negative Feedback
 Vasoconstriction
 Cell growth
 Na/H
2
O retention
 Sympathetic activation
Aliskiren renin
Cough,
Angioedema
Benefits?
Angiotensin I ARBs AT
1
Angiotensin II
ACE-Inhibitors

ACE
Bradykinin
Aldosterone
Inactive
Fragments
AT
2
 Vasodilation
 Antiproliferation
(kinins)
Gradman et al. Circulation , 2006; McMurray et al. Circulation, 2004

Adding aliskiren to standard therapy, including a proven inhibitor of the
RAAS, would result in greater attenuation of adverse LV remodeling in patients after high risk acute myocardial infarction

• International multicenter, randomized, double-blind, placebocontrolled trial
• Primary Endpoint: Change in LVESV (baseline to week 36)
• 80% power, alpha=0.05, to detect 3.1mL difference in LVESV reduction: Estimated sample size ~ 800 patients
•
•
•
•
•
Key Secondary endpoints:
CV death, hospitalization for heart failure, or a reduction in ejection fraction greater than 6 units
CV death, hospitalization for heart failure, recurrent myocardial infarction, stroke or resuscitated sudden death overall safety and tolerability in combination with standard therapy in patients post acute myocardial infarction other echocardiographic assessments of cardiac size and function

•
•
•
•
Inclusion criteria
>18 years-old
AMI and LV systolic dysfunction within 7-42 days
Stable doses for 2 weeks of: antiplatelet, statin, beta-blocker, ACE-i or
ARB
Qualifying echo: quality, LVEF< 45%, infarct size>20%
Key exclusion criteria
•
•
•
•
•
On both ACE-I and ARB
Severe refractory hypertension
Cardiogenic shock eGFR<
30ml/min/1.73m2
K > 5.0 mEq

Background Rx: antiplatelet, statin, beta-blocker, ACE-I or ARB
75 mg 150 mg aliskiren 300 mg once daily
75 mg 150 mg placebo 300 mg once daily
2-8 weeks
1 week 1 week
Total Follow-up: 36 weeks
Echocardiograms evaluated in core laboratory
Endpoints adjudicated by blinded central committee

ASPIRE Patient Flow
Patients Screened Post MI N=1074
Enrolled/Randomized N= 820
Placebo n=397
Aliskiren n=423
Received Aliskiren n=422
Died (8), withdrew consent (10), Echo of insufficient quality or other (50)
Paired Evaluable
Echocardiograms n=329
Paired Evaluable
Echocardiograms n=343
Died (17), withdrew consent (11), echo of insufficient quality or other (52)

Characteristic
Male Gender (% )
Age (Years ± SD)
Age ≥65 years
Baseline eGFR
(mL/min/1.73m^2) eGFR< 60
Diabetes
Hypertension
Prior MI
Prior HF
Q wave MI
Anterior MI
Killip Class ≥ 2
Reperfusion Therapy
Placebo
N=397
85%
59 ± 12
34%
81 ± 19
13%
22%
50%
18%
4%
71%
79%
42%
76%
Aliskiren
N=423
81%
61 ± 12
40%
80 ± 20
17%
23%
55%
22%
6%
68%
79%
45%
73%
P value
0.22
0.26
0.13
0.58
0.17
0.93
0.27
0.27
0.23
0.36
0.91
0.85
0.36

Concomitant Medications at Baseline
Baseline Meds
Anti-platelet agents
ACE-i
ARB
“Optimal” dose ACE-i or ARB*
Beta-Blocker
Statin
Aldosterone Blocker
Placebo
N=397
98%
91%
9%
43%
95%
98%
24%
Aliskiren
N=423
98%
89%
10%
44%
96%
97%
29%
•Optimal dose of ACE-I or ARB defined as daily doses of captopril 150mg, enalapril 20mg, lisinopril 20mg, perindopril 8mg, ramipril
10mg, candesartan 32mg, valsartan 320mg, losartan 100mg, irbesartan 300mg
P value
0.72
0.62
0.17
0.72
0.45
0.57
0.12

LVESV (mL)
LVEDV (mL)
LVEF (%)
Infarct Length (%)
WMSI placebo
N=374
86.1 ± 29.9
135.7 ± 36.2
37.5 ± 5.8
25.0 ± 10.6
1.8 ± 0.2
aliskiren
N=403
P value
82.4 ± 26.0
0.03
130.5 ± 32.9
37.6 ± 5.3
25.7 ± 10.6
1.8 ± 0.2
0.02
0.57
0.46
0.99

140
130
120
110
100
90
80
70
60
50
40
Placebo
Aliskiren
Placebo 124.2 ± 14.9
Aliskiren 122.4 ± 16.3
Placebo 76.5 ± 9.4
Aliskiren 74.2 ± 9.3
2 4 6
Visit
8 10

LVESV
(mL)
86,0
Primary Outcome:
Left Ventricular End-Systolic Volume at Baseline and Final Echo visit
Baseline and Final LVESV Delta LVESV placebo aliskiren
84,0
84,4
82,0
82,4
80,9
80,0
78,0
76,0
78,0
Baseline LVESV Final LVESV
Difference
0.90 (-1.6, 3.4)
P = 0.44

Placebo
N= 329
LVESV(mL)
LVEDV (mL)
Baseline Change
84.2 ± 25.5
133.5 ± 31.6
-3.5 ±
16.3
-1.7 ±
19.6
LVEF (%)
Infarct
Length (%)
EF drop >
6%
37.8 ± 5.5
2.3 ± 4.1
Aliskiren
N=343
Baseline
82.5 ± 26.6
131.2 ± 33.9
Change
-4.4 ±
16.8
-3.2 ±
19.3
24.5 ± 10.4
-4.8 ± 9.5
25.0 ± 10.4
-5.6 ± 9.0
0.27
2 (0.6%)
37.9 ± 5.1
6 (1.8%)
P
0.44
0.26
2.5 ± 4.5
0.80
0.17

Secondary Efficacy Variables: composite endpoints of echo and adjudicated outcomes
Secondary endpoints
Placebo
N=397 n (%)
Aliskiren
N=423 n (%)
HR 95% CI
Composite of CV death, hospitalization for HF, LVEF reduction by>6 units
Composite of CV death, hospitalization for HF, recurrent MI, stroke, resuscitated sudden death
24 (6%) 29 (7%) 1.06
(0.60, 1.8)
34 (9%) 39 (9%) 1.01
(0.62, 1.63)
P-value
0.85
0.98
All cause death 8 (2%) 17 (4%) 1.83
(0.79, 4.3) 0.16

Endpoint
CV Death
Resuscitated Sudden Death
HF Hospitalization
Myocardial Infarction
Stroke
Any of the above
Placebo n=397 n (%)
6 (1.5)
4 (1.0)
17 (4.3)
16 (4.0)
2 (0.5)
34 (8.6)
Aliskiren n=423 n (%)
13 (3.1)
1 (0.2)
12 (2.8)
11 (2.6)
7 (1.7)
39 (9.2)
No Significant between group differences

Posthoc Subgroup Analysis:
Difference in primary endpoint (delta LVESV) between placebo and aliskiren
P for interaction
Male (n=565)
Female (n=107)
No DM (n=524)
DM (n=148)
No HTN (n=327)
HTN (n=345) age<65 (n=427) age>65 (n=245)
No Aldo Blockers (n=499)
Aldo Blockers (n=173)
LVEF<35% (n=495)
LVEF>35% (n=177)
0.77
0.06
0.60
0.82
0.91
0.93
-6 -4 -2 0 2 4 6 8 10 12
Difference in change in LVESV (placebo - aliskiren) placebo favors aliskiren

Total AEs and SAEs
AEs
SAEs
Placebo (n = 397) Aliskiren (n = 422*)
268 (67.5)
92 (23.2)
316 (74.9)
107 (25.4)
Renal Dysfunction
AEs
SAEs
Hypotension
AEs
SAEs
Hyperkalemia†
AEs
SAEs
3 (0.8)
1 (0.3)
18 (4.5)
3 (0.8)
5 (1.3)
0 (0)
10 (2.4)
2 (0.5)
37 (8.8)
1 (0.2)
22 (5.2)
0 (0)
Based on MEDRA codes * Based on safety set
† reported only, not based on laboratory values p-value
0.02
0.51
0.09
>0.99
0.02
0.36
0.001
-

Biochemical abnormalities
Urea
 > 14.3 mmol/L (40mg/dL)
Placebo n=397 n (%)
18 (4.5)
Creatinine
 > 176 & <265  mol/L (> 2 & < 3 mg/dL)
 > 265  mol/L (3 mg/dL)
Potassium
 < 3.5 mmol/L
 >5.5 &< 6.0 mmol/L
 ≥ 6.0 mmol/L
4 (1.0)
1 (0.3)
11 (2.8)
16 (4.0)
10 (2.5)
Aliskiren n=422 n (%)
52 (12.3)
13 (3.1)
2 (0.5)
10 (2.4)
32 (7.6)
23 (5.5)

• In high risk post-MI patients with LV systolic dysfunction, the addition of aliskiren to a standard optimal medical regimen, including an ACE-I or an ARB, did not result in benefit with respect to ventricular remodeling compared to placebo and was associated with more adverse events
• Although ASPIRE utilized a surrogate endpoint, and was not powered to assess hard clinical outcomes, these results do not provide support for testing the use of aliskiren in a morbidity and mortality trial in the high-risk post-MI population
• Ongoing outcomes trials with aliskiren in patients with heart failure and diabetic kidney disease are well underway and will further assess the role for direct renin inhibition in these populations