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)

Placebo

Non-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

Ka

pla

n-M

eie

r e

stim

ate

of

cum

ula

tive

eve

nt

rate

(%

)

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 365Time in study (days)

Number of subjectsAliskiren 489 466 444 427 383 134Placebo 464 440 410 393 343 113

Ka

pla

n-M

eie

r e

stim

ate

of

cum

ula

tive

eve

nt

rate

(%

)

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 90 190 365

Time in study (days)

Ka

pla

n-M

eie

r e

stim

ate

of

cum

ula

tive

eve

nt

rate

(%

)

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

2,600

2,400

2,200

2,000

1,800

1,600

1,400

1,200

3,000

3,200

BL Month 1 Month 6 Month 12

450

400

350

300

250

200

150

100

50

500

BL Month 1 Month 6 Month 12

BL Month 1 Month 6 Month 12

Aliskiren (N = 489) Placebo (N = 464)

NT-

pro

BN

P (

pg

/mL

)

PR

A (

ng/

ml/L

)A

ldo

ste

ron

e (

pm

ol/L

)

**

**

**

** ****

1

2

3

4

5

6

0

NT-proBNP

PRA

Aldosterone

BL, baseline; * p≤0.05; ** p≤0.01

*

**

Tro

pon

in 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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