Transcript ASPIRE

EFFECT OF THE DIRECT RENIN INHIBITOR
ALISKIREN ON LEFT VENTRICULAR REMODELING
FOLLOWING MYOCARDIAL INFARCTION WITH
LEFT VENTRICULAR DYSFUNCTION
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
Disclosures
• 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.
Background
• 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 (ACE-
i) decrease the risk of death or chronic HF in
patients with AMI1,2,3 and angiotensin receptor
blockers (ARB) are an established alternative to
ACE-i4
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
Non-ACE Pathways




(e.g., chymase)
Negative Feedback
Angiotensinogen
renin
Vasoconstriction
Cell growth
Na/H2O retention
Sympathetic activation
ARBs
Angiotensin I
AT1
Angiotensin II
Aliskiren
Cough,
Angioedema
Benefits?
ACE-Inhibitors
ACE
Bradykinin
Aldosterone
Inactive
Fragments
AT2
 Vasodilation
 Antiproliferation
(kinins)
Gradman et al. Circulation, 2006; McMurray et al. Circulation, 2004
Hypothesis
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
Methods
• International multicenter, randomized, double-blind, placebo-
controlled 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
Methods
Inclusion criteria
Key exclusion criteria
• >18 years-old
• On both ACE-I and ARB
• AMI and LV systolic
• Severe refractory
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%
hypertension
• Cardiogenic shock
• eGFR<
30ml/min/1.73m2
• K > 5.0 mEq
Design and titration
Randomization
2-8 weeks
75 mg
150 mg
aliskiren 300 mg once daily
75 mg
150 mg
placebo 300 mg once daily
1 week
1 week
Total Follow-up: 36 weeks
Endpoints adjudicated by blinded central committee
Visit 10
final
echo
Echocardiograms evaluated in core laboratory
Visit 2
Baseline
echo
Qualifying MI
Background Rx: antiplatelet, statin, beta-blocker, ACE-I or ARB
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)
Died (17), withdrew
consent (11), echo
of insufficient
quality or other (52)
Paired Evaluable
Echocardiograms
n=329
Paired Evaluable
Echocardiograms
n=343
Baseline Demographics
Placebo
N=397
Aliskiren
N=423
P value
Male Gender (% )
85%
81%
0.22
Age (Years ± SD)
59 ± 12
61 ± 12
0.26
34%
40%
0.13
81 ± 19
80 ± 20
0.58
eGFR< 60
13%
17%
0.17
Diabetes
22%
23%
0.93
Hypertension
50%
55%
0.27
Prior MI
18%
22%
0.27
Prior HF
4%
6%
0.23
Q wave MI
71%
68%
0.36
Anterior MI
79%
79%
0.91
Killip Class ≥ 2
42%
45%
0.85
Reperfusion Therapy
76%
73%
0.36
Characteristic
Age ≥65 years
Baseline eGFR
(mL/min/1.73m^2)
Concomitant Medications at Baseline
Placebo
N=397
Aliskiren
N=423
P value
Anti-platelet agents
98%
98%
0.72
ACE-i
91%
89%
0.62
ARB
9%
10%
0.17
“Optimal” dose ACE-i or ARB*
43%
44%
0.72
Beta-Blocker
95%
96%
0.45
Statin
98%
97%
0.57
Aldosterone Blocker
24%
29%
0.12
Baseline Meds
•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
Baseline Echo parameters
placebo
N=374
aliskiren
N=403
P value
LVESV (mL)
86.1 ± 29.9
82.4 ± 26.0
0.03
LVEDV (mL)
135.7 ± 36.2
130.5 ± 32.9
0.02
LVEF (%)
37.5 ± 5.8
37.6 ± 5.3
0.57
Infarct Length (%)
25.0 ± 10.6
25.7 ± 10.6
0.46
1.8 ± 0.2
1.8 ± 0.2
0.99
WMSI
Mean Sitting Blood Pressure
Throughout Trial
Blood Pressure (mm Hg)
140
Placebo 124.2 ± 14.9
Aliskiren 122.4 ± 16.3
130
120
110
Placebo
100
Aliskiren
90
Placebo 76.5 ± 9.4
Aliskiren 74.2 ± 9.3
80
70
60
50
40
2
4
6
Visit
8
10
Primary Outcome:
Left Ventricular End-Systolic Volume
at Baseline and Final Echo visit
Baseline and Final LVESV
LVESV
(mL)
86.0
Delta LVESV
placebo
aliskiren
84.0
84.4
82.0
82.4
80.9
80.0
78.0
78.0
76.0
Baseline LVESV
Final LVESV
Difference
0.90 (-1.6, 3.4)
P = 0.44
Echocardiographic Measures
Placebo
N= 329
Aliskiren
N=343
P
Baseline
Change
Baseline
Change
LVESV(mL)
84.2 ± 25.5
-3.5 ±
16.3
82.5 ± 26.6
-4.4 ±
16.8
0.44
LVEDV (mL)
133.5 ± 31.6
-1.7 ±
19.6
131.2 ± 33.9
-3.2 ±
19.3
0.26
LVEF (%)
37.8 ± 5.5
2.3 ± 4.1
37.9 ± 5.1
2.5 ± 4.5
0.80
Infarct
Length (%)
24.5 ± 10.4
-4.8 ± 9.5
25.0 ± 10.4
-5.6 ± 9.0
0.27
EF drop >
6%
2 (0.6%)
6 (1.8%)
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
P-value
Composite of CV
death, hospitalization
for HF, LVEF reduction
by>6 units
24 (6%)
29 (7%)
1.06
(0.60, 1.8)
0.85
Composite of CV
death, hospitalization
for HF, recurrent MI,
stroke, resuscitated
sudden death
34 (9%)
39 (9%)
1.01
(0.62, 1.63)
0.98
All cause death
8 (2%)
17 (4%)
1.83
(0.79, 4.3)
0.16
Cardiovascular Outcomes
Endpoint
Placebo
n=397
n (%)
Aliskiren
n=423
n (%)
CV Death
6 (1.5)
13 (3.1)
Resuscitated Sudden Death
4 (1.0)
1 (0.2)
HF Hospitalization
17 (4.3)
12 (2.8)
Myocardial Infarction
16 (4.0)
11 (2.6)
Stroke
2 (0.5)
7 (1.7)
Any of the above
34 (8.6)
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)
0.77
No DM (n=524)
DM (n=148)
0.06
No HTN (n=327)
HTN (n=345)
0.60
age<65 (n=427)
age>65 (n=245)
0.82
No Aldo Blockers (n=499)
Aldo Blockers (n=173)
0.91
LVEF<35% (n=495)
LVEF>35% (n=177)
0.93
-6
-4
-2
0
2
4
6
8
10
12
Difference in change in LVESV (placebo - aliskiren)
placebo
favors
aliskiren
Adverse Events
Placebo (n = 397)
Aliskiren (n = 422*)
268 (67.5)
92 (23.2)
316 (74.9)
107 (25.4)
p-value
Total AEs and SAEs
AEs
SAEs
0.02
0.51
Renal Dysfunction
AEs
SAEs
Hypotension
AEs
3 (0.8)
1 (0.3)
10 (2.4)
2 (0.5)
0.09
>0.99
18 (4.5)
37 (8.8)
0.02
SAEs
3 (0.8)
1 (0.2)
0.36
AEs
SAEs
5 (1.3)
0 (0)
22 (5.2)
0 (0)
0.001
-
Hyperkalemia†
Based on MEDRA codes
* Based on safety set † reported only, not based on laboratory values
Biochemical abnormalities
Biochemical abnormalities
Placebo
n=397
n (%)
Aliskiren
n=422
n (%)
Urea
 > 14.3 mmol/L (40mg/dL)
18 (4.5)
52 (12.3)
Creatinine
 > 176 & <265mol/L (> 2 & < 3 mg/dL)
 > 265 mol/L (3 mg/dL)
4 (1.0)
1 (0.3)
13 (3.1)
2 (0.5)
Potassium
 < 3.5 mmol/L
 >5.5 &< 6.0 mmol/L
 ≥ 6.0 mmol/L
11 (2.8)
16 (4.0)
10 (2.5)
10 (2.4)
32 (7.6)
23 (5.5)
Conclusions
• 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