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Effect of Aliskiren on Postdischarge Outcomes Among Non-Diabetic Patients Hospitalized for Heart Failure: Insights from the ASTRONAUT
Outcomes Trial
Aldo P. Maggioni, MD, FESCAssociazione 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:· Mihai Gheorghiade, MD; Chair· Aldo P. Maggioni, MD; Co-Chair· Michael Böhm, MD· Gregg C. Fonarow, MD · Faiez Zannad, MD, PhD
Study Data Monitoring Committee:· Karl Swedberg, MD, PhD; Chair· Jeffrey S. Borer, MD· Bertram Pitt, MD· Stuart Pocock, PhD· Jean Rouleau, MD
Central Endpoint Committee:· Scott D. Solomon, MD; Chair· Eldrin F. Lewis, MD; Co-Chair· Peter Finn, MD· Howard Hartley, MD· Larry Weinrauch, MD· Ebrahim Barkoudah, MD· Kayode Odutayo, MD
Study was funded by Novartis Pharma AG
Background and Rationale
1. Gheorghiade et al. JAMA. 2013;309(11):1125-35.
· 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).
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
Screening 2 weeks
Randomization
Placebo
Aliskiren 300 mg
Conventional therapy
Aliskiren 150 mg
Follow-up period
Hospitalization for worsening
chronic HF
median: 5 days median: 11.3 months
Patient Flow
821 aliskiren 818 placebo
1639 randomized
Screening
Allocation
Pre-specified sub-group
with/without DM
Primary Analysis
2134 screened
Randomization
495 excluded
13 excluded 11 excluded
807 Efficacy analysis
808 Efficacy analysis
319/489Subgroup analysis
343/464Subgroup analysis
Study Endpoints by Baseline DM Status
Aliskiren Non-DM (n=489)
DM (n=319)
PlaceboNon-DM (n=464)
DM (n=343)HR
(95% CI)
Interaction p-value
(two-sided)
Primary End Point (6 months)
CV death or HF re-hospitalization Non-DM DM
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
Secondary End Points (12 months)
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
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)
LVEF, mean (SD), % 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)
eGFR, mean (SD), mL/min/1.73 m2 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)
Medical History and Background Therapies in non-DM Patients
Aliskiren N = 489, n (%)
Placebo N = 464, n (%)
Medical history
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)
Background therapies
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)
HR: 0.80 (95% CI: 0.61-1.04)p = 0.11
10
5
0
25
20
15
Kap
lan-
Mei
er e
stim
ate
of
cum
ulat
ive
even
t rat
e (%
)
Aliskiren (102/489 patients with events; 20.9%)Placebo (114/464 patients with events; 24.6%)
0 30 60 90 190
Number of subjectsAliskiren 489 466 444 427
383Placebo 464 440 410 393
343
Time in study (days)
Primary Endpoint in non-DM PatientsCV Death or HF Re-hospitalization Within 6 Months
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
30
Aliskiren (148/489 patients with events; 30.3%)Placebo (165/464 patients with events; 35.6%)30
25
10
0 0 30 60 90 190 365
Time in study (days)Number of subjectsAliskiren 489 466 444 427 383 134Placebo 464 440 410 393 343 113
Kap
lan-
Mei
er e
stim
ate
of
cum
ulat
ive
even
t rat
e (%
)
HR: 0.80 (95% CI: 0.64-0.99)p = 0.04
Key Secondary Endpoint in non-DM PatientsCV Death or HF Re-hospitalization Within 12 Months
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
20
15
5
35
Aliskiren (72/489 patients with events; 14.7%)Placebo (91/464 patients with events; 19.6%)20
10
0
0 30 60 90 190 365Time in study (days)
Kap
lan-
Mei
er e
stim
ate
of
cum
ulat
ive
even
t rat
e (%
)
HR: 0.69 (95% CI: 0.50-0.94)p = 0.02
Number of subjectsAliskiren 489 480 476 467 441 172Placebo 464 457 443 434 405 152
25
15
5
All-Cause Death Within 12 Months in non-DM Patients
Changes in Biomarkers With Time in non-DM Patients
2,800
2,6002,4002,200
2,0001,800
1,6001,400
1,200
3,0003,200
BL Month 1 Month 6 Month 12
450400350300250200
15010050
500
BL Month 1 Month 6 Month 12
BL Month 1 Month 6 Month 12
Aliskiren (N = 489) Placebo (N = 464)
NT-
proB
NP
(pg/
mL)
PR
A (n
g/m
l/L)
Ald
oste
rone
(pm
ol/L
)
****
**
** ****
1
2
3
4
5
6
0
NT-proBNP
PRA
Aldosterone
BL, baseline; * p≤0.05; ** p≤0.01
*
**
Trop
onin
I (n
g/L)
****Troponin I0.04
0.03
0.02
0.045
0BL Month 1 Month 6 Month 12
0.025
0.035
0.05
*
Safety profile in Non-DM Patients
AliskirenN = 489n (%)
Placebo N = 465n (%)
Aliskiren vs. Placebo
relative risk (95% CI)
P-value (2-sided)
Rate of treatment discontinuation due to AEs
Hyperkalemia 16 (3.3) 10 (2.2) 1.52 (0.70-3.32) 0.32
Renal impairment or renal failure 19 (3.9) 9 (1.9) 2.01 (0.92-4.39)
0.09
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
(mL/min/1.73 m2)
46 (9.4) 42 (9.0) 1.04 (0.70-1.55) 0.91
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 post-discharge outcomes, serum biomarker profile and was generally well tolerated.
· In contrast, diabetic patients appeared to have worse post-discharge 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-
diabeticPatients Hospitalized for Heart Failure:
Insights from the ASTRONAUT Trial
Published online September 2nd, 2013
Available at www. eurheartj.oxfordjournals.orgSna
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