Transcript Slide 1

Effect of Aliskiren on Postdischarge
Outcomes Among Non-Diabetic Patients
Hospitalized for Heart Failure: Insights from
the ASTRONAUT Outcomes Trial
Aldo P. Maggioni, MD, FESC
Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy
On behalf of: Stephen J. Greene, MD; Gregg C. Fonarow, MD; Michael Böhm, MD; Faiez
Zannad, MD; Scott D. Solomon, MD; Eldrin F. Lewis, MD; Fabio Baschiera, PhD; Tsushung
A. Hua, PhD; Claudio R. Gimpelewicz, MD; Anastasia Lesogor, MD; Mihai Gheorghiade, MD;
for the ASTRONAUT Investigators and Coordinators
Presenter Disclosure Information
Dr. Maggioni:
 Serving in Committees of studies on Heart Failure
sponsored by: Bayer, Abbott Vascular, Cardiorentis,
Johnson & Johnson, Novartis Pharma AG
Study Organization
Study Executive Committee:
Central Endpoint Committee:
 Mihai Gheorghiade, MD; Chair
 Scott D. Solomon, MD; Chair
 Aldo P. Maggioni, MD; Co-Chair
 Eldrin F. Lewis, MD; Co-Chair
 Michael Böhm, MD
 Peter Finn, MD
 Gregg C. Fonarow, MD
 Howard Hartley, MD
 Faiez Zannad, MD, PhD
 Larry Weinrauch, MD
 Ebrahim Barkoudah, MD
Study Data Monitoring Committee:
 Karl Swedberg, MD, PhD; Chair
 Jeffrey S. Borer, MD
 Bertram Pitt, MD
 Stuart Pocock, PhD
 Jean Rouleau, MD
 Kayode Odutayo, MD
Study was funded by Novartis Pharma AG
Background and Rationale
 ASTRONAUT explored the effect of aliskiren, a direct
renin inhibitor, when added to standard therapy on the
rate of CV death or HF re-hospitalization among
hemodynamically stable hospitalized HF patients.1
 Pre-specified subgroup analyses suggested potential
heterogeneity in post-discharge outcomes with aliskiren in
patients with and without baseline diabetes mellitus (DM).
 The overall results were presented at the ACC 2013 and
ESC HF 2013 and published in JAMA1; the current
presentation is focused on the effects of aliskiren in
patients without DM (~60% of the study population).
1. Gheorghiade et al. JAMA. 2013;309(11):1125-35.
Objectives
Primary:
 CV death or HF re-hospitalization within 6 months
Key Secondary:
 CV death or HF re-hospitalization within 12 months
Secondary:
 All-cause mortality within 6 and 12 months
 Change in biomarkers from baseline (NT-proBNP, PRA,
plasma troponin I, and plasma aldosterone) at 1, 6 and 12
months of follow up
Selection Criteria
Inclusion criteria:
 Patients requiring hospitalization for worsening of chronic HF
 LVEF ≤40%
 BNP ≥400 pg/mL or NT-proBNP ≥1600 pg/mL
 SBP ≥110 mm Hg for at least 6 hours
 No use of IV vasodilators (except nitrates)/IV inotropes from the time of
hospital presentation to randomization
Exclusion criteria:
 Recent MI, cardiac surgery or stroke
 eGFR <40 mL/min/1.73 m2 or potassium >5.0 mEq/L
 Hyponatremia <130 mEq/L, and
 Comorbid conditions with expected survival <3 years
Study Design
Hospitalization
for worsening
chronic HF
Randomization
Aliskiren
150 mg
Aliskiren 300 mg
Placebo
Conventional therapy
Screening
median: 5 days
2 weeks
Follow-up period
median: 11.3 months
Patient Flow
2134
screened
Screening
495 excluded
1639 randomized
Randomization
Allocation
Primary
Analysis
Pre-specified
sub-group
with/without
DM
821 aliskiren
818 placebo
13 excluded
11 excluded
808
Efficacy analysis
807
Efficacy analysis
319/489
Subgroup analysis
343/464
Subgroup analysis
Study Endpoints by Baseline DM Status
Aliskiren
Placebo
Non-DM (n=489) Non-DM (n=464)
Interaction
HR
p-value
DM (n=319)
DM (n=343)
(95% CI)
(two-sided)
102 (20.9)
99 (31.0)
114 (24.6)
100 (29.2)
0.80 (0.61-1.04)
1.13 (0.86- 1.50)
0.08
CV death or HF re-hospitalization
Non-DM
DM
148 (30.3)
135 (42.3)
165 (35.6)
136 (39.7)
0.80 (0.64-0.99)
1.16 (0.91-1.47)
0.03
All-cause death
Non-DM
DM
72 (14.7)
72 (22.6)
91 (19.6)
57 (16.6)
0.69 (0.50-0.94)
1.64 (1.15-2.33)
<0.01
Primary End Point (6 months)
CV death or HF re-hospitalization
Non-DM
DM
Secondary End Points (12 months)
Baseline Characteristics of non-DM Patients
Aliskiren
(n = 489)
Placebo
(n = 464)
Age, mean (SD), years
64.1 (13.3)
63.4 (13.0)
Male, n (%)
394 (80.6)
345 (74.4)
Ischemic heart failure etiology, n (%)
287 (58.7)
248 (53.4)
28 (7.3)
27 (7.5)
SBP, mean (SD), mm Hg
123 (12.8)
123 (12.2)
Heart rate, mean (SD), bpm
77 (16.0)
78 (16.5)
68.5 (20.4)
67.0 (19.9)
NT-proBNP (pg/mL), median (IQR), Visit 1
4471 (2840-8540)
4472 (2715-8924)
NT-proBNP (pg/mL), median (IQR), Visit 2
2851 (1510-5344)
2651 (1555-5257)
BNP (pg/mL), mean (IQR), Visit 1
936 (592-1650)
842 (533-1570)
BNP (pg/mL), mean (IQR), Visit 2
466 (239-900)
437 (220-910)
LVEF, mean (SD), %
eGFR, mean (SD), mL/min/1.73 m2
Medical History and Background Therapies in
non-DM Patients
Aliskiren
N = 489, n (%)
Placebo
N = 464, n (%)
Hypertension
353 (72.2)
330 (71.1)
Coronary artery disease
240 (49.1)
203 (43.8)
Renal insufficiency
67 (13.3)
79 (17.0)
COPD
97 (19.8)
78 (16.8)
Diuretic (not including MRA)
469 (95.9)
445 (95.9)
ACEi
324 (66.3)
318 (68.5)
ARB
87 (17.8)
65 (14.0)
β-blocker
385 (78.7)
391 (84.3)
MRA
276 (56.4)
281 (60.6)
Medical history
Background therapies
Primary Endpoint in non-DM Patients
CV Death or HF Re-hospitalization Within 6 Months
30
Aliskiren (102/489 patients with events; 20.9%)
Placebo (114/464 patients with events; 24.6%)
Kaplan-Meier estimate of
cumulative event rate (%)
25
20
15
10
5
HR: 0.80 (95% CI: 0.61-1.04)
p = 0.11
0
0
Number of subjects
Aliskiren 489
Placebo 464
30
60
466
440
444
410
90
Time in study (days)
190
427
393
383
343
Aliskiren
n (%)
Placebo
n (%)
HR
(95% CI)
p-value
(two-sided)
CV death
42 (8.6)
49 (10.6)
0.73 (0.48-1.12)
0.14
HF re-hospitalization
74 (15.1)
86 (18.5)
0.77 (0.56-1.05)
0.10
Key Secondary Endpoint in non-DM Patients
CV Death or HF Re-hospitalization Within 12 Months
35
Aliskiren (148/489 patients with events; 30.3%)
Placebo (165/464 patients with events; 35.6%)
Kaplan-Meier estimate of
cumulative event rate (%)
30
25
20
15
10
5
HR: 0.80 (95% CI: 0.64-0.99)
p = 0.04
0
0
30
Number of subjects
Aliskiren 489
466
Placebo 464
440
60
444
410
90
427
393
190
Time in study (days)
365
383
343
134
113
Aliskiren
n (%)
Placebo
n (%)
HR
(95% CI)
p-value
(two-sided)
CV death
64 (13.1)
85 (18.3)
0.63 (0.45-0.87)
<0.01
HF re-hospitalization
104 (21.3)
116 (25.0)
0.79 (0.61-1.04)
0.09
All-Cause Death Within 12 Months in non-DM
Patients
25
Aliskiren (72/489 patients with events; 14.7%)
Placebo (91/464 patients with events; 19.6%)
Kaplan-Meier estimate of
cumulative event rate (%)
20
15
10
5
HR: 0.69 (95% CI: 0.50-0.94)
p = 0.02
0
0
30
Number of subjects
Aliskiren 489
480
Placebo 464
457
60
476
443
90
190
Time in study (days)
365
467
434
441
405
172
152
Changes in Biomarkers With Time in non-DM Patients
6
3,200
NT-proBNP (pg/mL)
2,800
**
5
NT-proBNP
2,600
PRA (ng/ml/L)
3,000
2,400
*
2,200
2,000
1,800
**
**
4
3
2
1,600
1
1,400
1,200
0
BL Month 1
Month 6
BL Month 1
Month 12
0.05
Troponin I
**
**
*
0.03
0.025
Aldosterone (pmol/L)
450
0.04
0.035
Month 6
Month 12
500
0.045
Troponin I (ng/L)
**
PRA
400
**
**
**
Aldosterone
350
300
250
200
150
100
0.02
50
0
BL Month 1
Month 6
Month 12
Aliskiren (N = 489)
BL, baseline; * p≤0.05; ** p≤0.01
BL Month 1
Placebo (N = 464)
Month 6
Month 12
Safety profile in Non-DM Patients
Aliskiren
N = 489
n (%)
Placebo
N = 465
n (%)
Aliskiren vs.
Placebo
relative risk
(95% CI)
16 (3.3)
10 (2.2)
1.52 (0.70-3.32)
P-value
(2-sided)
0.32
Rate of treatment
discontinuation due to AEs
Hyperkalemia
0.09
Renal impairment or renal
failure
19 (3.9)
9 (1.9)
2.01 (0.92-4.39)
Hypotension
18 (3.7)
9 (1.9)
1.90 (0.86-4.19)
0.12
Maximum or minimum
post-baseline values
Potassium ≥6 (mmol/L)
32 (6.5)
26 (5.6)
1.17 (0.71-1.93)
0.59
eGFR <30
46 (9.4)
42 (9.0)
1.04 (0.70-1.55)
0.91
(mL/min/1.73 m2)
Limitations
 The major limitation of this work is that these results are
based on a subgroup analysis. Therefore these results can
be considered hypothesis generating only.
 An additional limitation is the definition of DM used. The
presence or absence of underlying diabetes was
determined solely by the investigator and it was not
mandatory to use objective criteria.
Conclusions
 In the pre-specified subgroup of ASTRONAUT patients
without DM representing 60% of study population, the addition
of aliskiren to standard therapy appeared to improve postdischarge outcomes, serum biomarker profile and was
generally well tolerated.
 In contrast, diabetic patients appeared to have worse postdischarge outcomes with aliskiren.
 Results suggest the potential of aliskiren in hospitalized HF
patients without DM, where, despite of available therapies,
post-discharge event rate remains high.
 Future prospective investigations are encouraged to confirm
potential benefits of renin inhibition in the large cohort of
hospitalized HF patients without DM.
Publication
Aldo P. Maggioni and coauthors
Effect of Aliskiren on Postdischarge
Outcomes Among Diabetic and Non-diabetic
Patients Hospitalized for Heart Failure:
Insights from the ASTRONAUT Trial
Published online September 2nd, 2013
Available at www.
eurheartj.oxfordjournals.org