1. Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure
Adrian F. Hernandez, MD
On behalf of the ASCEND-HF Committees, Investigators and Study Coordinators 1

2. Disclosure Information
Adrian F. Hernandez, MD ASCEND-HF Trial
FINANCIAL DISCLOSURE:
Trial Sponsor: Scios Inc
Research funding from Johnson & Johnson
Honorarium from Amgen, Corthera
Full listing of disclosures at dcri.org
UNLABELED or UNAPPROVED USE: None

3. Study organization Executive Committee Sponsor Scios Inc.
Chair: Rob Califf
Chris O’Connor (Co-PI), Randy Starling (Co-PI)
Paul Armstrong, Kenneth Dickstein, Michel Komajda, Barry Massie, John McMurray, Markku Nieminen, Jean Rouleau, Karl Swedberg, Vic Hasselblad
Sponsor
Scios Inc.
Independent DSMB
Chair: Sidney Goldstein
Salim Yusuf, David DeMets, Milton Packer,
John Kjekshus
Clinical Event Committee
Chair: John McMurray
International Steering Committee
North America
Academic Consortium:
(DCRI, C5, Jefferson, Henry Ford, Canadian VIGOUR Centre)
ROW: Johnson & Johnson Global Clinical Operations
Coordinating center: DCRI
Adrian Hernandez, Craig Reist,
Gretchen Heizer
>800 Investigators and Study Coordinators at 398 Sites

4. Background
Acute heart failure is a major health problem responsible for several million hospitalizations worldwide each year.
Standard therapy has not changed since 1970s and includes diuretics and variable use of vasodilators or inotropes.
In 2001, nesiritide was approved by the FDA to reduce PCWP and improve dyspnea, based on efficacy at 3 hrs.
However, in 2005 two meta-analyses raised concerns regarding the risks of mortality and renal injury.
Subsequently, an independent panel* was convened by Scios Inc and recommended that a clinical trial be conducted to definitively answer the question of nesiritide’s safety and efficacy.
*chaired by Eugene Braunwald

5. Design of ASCEND-HF: Guiding principles
Independent framework
Pragmatic trial model
Focused
Efficient study design
Streamlined procedures
Simple follow-up
Permissive enrollment criteria for broad population
Meaningful outcomes
Standard of care per local practice (“real world”)

6. Co-Primary objectives
To assess whether nesiritide vs placebo, in addition to standard care provides:
Reduction in rate of HF rehospitalization or all-cause mortality through Day 30
Significant improvement in self-assessed dyspnea at 6 or 24 hrs using 7-point Likert scale 60 40 20
% Subjects
Markedly Better
Minimally Worse
Moderately Better
Moderately Worse
Minimally Better
Markedly Worse
No Change

7. Secondary and safety objectives
Secondary endpoints:
Overall well-being at 6 and 24 hours
Persistent or worsening HF and all-cause mortality from randomization through discharge
Number of days alive and outside of the hospital
Cardiovascular rehospitalization and cardiovascular mortality
Safety endpoints:
All cause mortality
Renal: 25% decrease in eGFR at any time from study drug initiation through Day 30
Hypotension: As reported by investigator as symptomatic or asymptomatic

8. Dyspnea relief at 6 and 24 hrs All-cause mortality at 180 days
Study design and drug procedures
Nesiritide
Acute HF < 24 hrs from IV RX
24–168 hrs Rx
Placebo
Co-primary endpoint:
Dyspnea relief at 6 and 24 hrs
Co-primary
endpoint:
30-day death or
HF rehosp
All-cause mortality at 180 days
Double – blind placebo controlled
IV bolus (loading dose) of 2 µg/kg nesiritide or placebo
Investigator’s discretion for bolus
Followed by continuous IV infusion of nesiritide 0.01 µg/kg/min or placebo for up to 7 days
Usual care per investigators including diuretics and/or other therapies as needed
Duration of treatment per investigator based on clinical improvement

9. Inclusion and exclusion criteria
Key inclusion criteria
Key exclusion criteria
Hospitalized for ADHF <24 hrs from IV treatment
Dyspnea at rest or with minimal activity
1 clinical sign:
Respiratory rate ≥ 20 breaths per min
Rales >1/3 bases
1 objective measure:
CXR with pulmonary edema
BNP ≥400 pg/mL or NT-proBNP≥1000 pg/mL
Prior EF <40% within 12 months
PCWP > 20 mmHg
Hypotension at baseline (SBP <100 mm Hg or SBP<110 mm Hg with IV vasodilator)
Significant lung disease that could interfere with interpretation of dyspnea
Acute coronary syndrome
Severe anemia or active bleeding
Treatment with levosimendan or milrinone
Unstable doses of IV vasoactive medication within 3 hours

10. Statistical methods
Study population: modified intention-to-treat based on receiving study drug
Primary analysis:
Co-primary endpoints tested using Bonferroni approach
Composite of HF rehospitalization and all-cause mortality tested at significance level
Dyspnea tested at level using Hochberg method:
Significant if both 6- and 24-hr assessment P values ≤0.005; or
If either 6- or 24-hr assessment P values ≤0.0025
Sample size determination:
Based on composite endpoint: 89% power with 7000 patients using chi-square test, assuming a placebo event rate of 14% and a relative risk reduction of 18.6%
Dyspnea: >90% power to detect a 13% greater likelihood of reporting improvement for nesiritide compared to placebo

11. >800 Investigators and Study Coordinators
Enrollment
7141 patients
30 Countries & 398 Sites
Western Europe = 7%
35 sites
North America = 45%
214 sites
Central Europe = 14%
48 sites
Asia-Pacific = 25%
62 sites
Latin America = 9%
39 sites
>800 Investigators and Study Coordinators

12. Study population Randomized (n=7141) Placebo MITT=3511
Placebo (n=3577)
  Did not receive study drug (n=66)
Hypotension (n=28)
Exclusion criteria (n=8)
Physician decision (n=6)
Participant withdrew consent (n=14)
Other reason (n=10)
Nesiritide MITT=3496
Nesiritide (n=3564)
Did not receive study drug (n=68)
Hypotension (n=26)
Exclusion criteria identified (n=9)
Participant withdrew consent (n=16)
Other reason (n=11)

13. Baseline characteristics
Placebo (n=3511)
Nesiritide (n=3496)
Age (yrs)
67 (56, 76)
Female (%)
34.9
33.4
Black or African American
15.0
14.7
Systolic Blood Pressure (mmHg)
124 (110, 140)
123 (110, 140)
Heart rate (beats/min)
82 (72, 95)
Respiratory rate (breaths/min)
24 (21,26)
23 (21, 26)
Medical History (%)
Ischemic heart disease
60.8
59.5
Hypertension
72.6
71.8
Atrial fibrillation
37.7
37.4
Chronic respiratory disease
16.6
16.3
Diabetes
42.9
42.3
Continuous variables as median (IQR 25th, 75th); MITT population

14. Baseline characteristics
Placebo (n=3511)
Nesiritide (n=3496)
Labs/Studies
LVEF <40% within 12 mths (%)
79.5
80.8
BNP (pg/mL)
989
(543, 1782)
994
(544, 1925)
NT pro-BNP (pg/mL)
4461
(2123, 9217)
4508
(2076, 9174)
Creatinine (mg/dL)
1.2
(1.0, 1.6)
(1.0, 1.5)
Pre-randomization treatment (%)
Loop diuretics
95.3
94.9
Inotropes
4.4
4.3
Vasodilators
14.1
15.7
Continuous variables as median (IQR 25th, 75th); MITT population

15. 30-day Death/HF Rehospitalization
Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization
P=0.31
Hazard Ratio 0.93 (95% CI: 0.8,1.08)
9.4
3.6
6.0 12
10.1
4.0
6.1 10
Placebo
Nesiritide 8 % 6 4 2
30-day Death/HF Rehospitalization
30-day Death
HF Rehospitalization
Risk Diff (95 % CI) (-2.1; 0.7) (-1.3; 0.5) (-1.2; 1.0)

16. 30 day death/HF readmission subgroups
All Subjects
N=6836
Baseline SBP (mmHg)
< 123
≥ 123
N=3346
N=3490
Baseline Ejection Fraction (%)
<40
≥ 40
N=4362
N=1187
Renal function- MDRD GFR (mL/min/m2)
<60
≥ 60
N=3395
N=3093
History of CAD No
Yes
N=3092
N=3742
History of Diabetes Mellitus
N=3923
N=2913
Risk Difference <0: Favors Nesiritide;
Risk Difference >0: Favors Placebo
Difference (%) and 95% Confidence Interval

17. 30 day death/HF readmission subgroups
All Subjects
N=6836
Inotrope Use at Randomization No
Yes
N=6556
N=280
Vasodilators
None
Any IV Vasodilators
No IV Nitroglycerin
IV Nitroglycerin
N=5889
N=942
N=5943
N=892
Diuretics
N=691
N=6145
Study Drug Bolus
N=2609
N=4227
Time from Hosp to Rand (hrs)
<15.5
≥15.5
N=3426
N=3410
Risk Difference <0: Favors Nesiritide;
Risk Difference >0: Favors Placebo
Difference (%) and 95% Confidence Interval

18. Co-Primary Endpoint: 6 and 24 hour dyspnea
6 Hours
24 Hours 70 70
66.1%
3371
Nesiritide
30.4
37.8
21.2
P=0.007
8.6
68.2% 60
P=0.030
3416
Nesiritide
15.0
29.5
32.8
20.3 60
3398
Placebo
27.5
38.6
22.1
9.5 50
42.1%
44.5% 50 40
3444 Placebo
13.4
28.7
34.1
21.7 40 30 30
% Subjects 20
% Subjects 20 10 10 10 10 20 20 30 30 40 40 50 60
Markedly Better
Moderately Better
Minimally Better
No Change
Minimally Worse
Moderately Worse
Markedly Worse

19. Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement
All Subjects
N=6860
N=6769
SBP
<123
≥123
N=3369
N=3491
N=3314
N=3455
GFR
<60
≥60
N=3494
N=3121
N=3349
N=3075
Ejection Fraction
<40
≥40
N=4385
N=1186
N=4335
N=1171
CAD No
Yes
N=3115
N=3743
N=3082
N=3685
Diabetes
N=3930
N=2930
N=3887
N=2882
OR <1: Favors Placebo; OR >1: Favors Nesiritide;
Odds Ratio of Markedly/Moderately vs. Other

20. Dyspnea at 6 and 24 Hours Odds for Marked-Moderate Improvement
All Subjects
N=6860
N=6769
Inotropes No
Yes
N=6574
N=286
N=6481
N=288
Vasodilators
None
Any IV Vaso
No IV Nitro
IV Nitro
N=5912
N=943
N=5965
N=894
N=5835
N=929
N=5886
N=882
Diuretics
N=691
N=6169
N=679
N=6090
Study Medication Bolus
N=2612
N=4248
N=2564
N=4205
Time from Hosp to Rand
<15.5
≥15.5
N=3428
N=3432
N=3369
N=3400
OR <1: Favors Placebo; OR >1: Favors Nesiritide;
Odds Ratio of Markedly/Moderately vs. Other

21. Secondary endpoints Placebo (n=3511) Nesiritide (n=3496)
Difference (95% CI)
P-value
Persistent or worsening HF or all-cause mortality through discharge
4.8%
(165)
4.2%
(147)
-0.5
(-1.5 to 0.5)
0.30
Days alive and outside of hospital through Day 30
20.7
20.9
0.2
(-0.13 to 0.53)
0.16
CV death or CV rehosp through Day 30
11.8%
(402)
10.9%
(372)
-0.9
(-2.4 to 0.6)
0.24
Placebo
(n=3511)
Nesiritide
(n=3496)
P-value
Well Being at 6 hours*
40.3%
41.4%
0.32
Well Being at 24 hours*
63.7%
65.7%
0.02
*Combined response for moderately/markedly better

22. End of Treatment Creatinine Discharge or 10 day Creatinine
Renal Safety
Anytime Through Day 30
Placebo
(n=3509)
Nesiritide
(n=3498)
P-value
>25% decrease eGFR
29.5%
31.4%
0.11
End of Treatment Creatinine
Creatinine (mg/dL)
Cum Dist 2 4 6 8
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Discharge or 10 day Creatinine
Nesiritide
Placebo

23. Hypotension Placebo (n=3509) Nesiritide (n=3498) Risk Difference
(95% CI)
P- value
Any hypotension
(Through Day 10/discharge)
15.3%
(538)
26.6% (930)
11.3
(9.4 to 13.1)
<.001
Asymptomatic Hypotension
12.4%
(436)
21.4%
(748)
9.0
(7.2 to 10.7)
Symptomatic Hypotension
4.0%
(141)
7.1%
(250)
3.1
(2.1 to 4.2)

24. 30-day mortality meta-analysis
Odds Ratio (95% CI)
Mills (N=163)
0.38 (0.05, 2.74)
Efficacy (N=127)
1.24 (0.23, 6.59)
Comparative (N=175)
1.43 (0.50, 4.09)
PRECEDENT (N=147)
0.59 (0.18, 2.01)
VMAC (N=498)
1.63 (0.77, 3.44)
PROACTION (N=237)
6.93 (0.89, 53.91)
COMBINED 30 day w/out ASCEND
1.28 (0.73, 2.25)
ASCEND-HF (N=7007)
0.89 (0.69, 1.14)
COMBINED with ASCEND
1.00 (0.76, 1.30)
0.1 1 10

25. Conclusions
Nesiritide did not reduce the rate of recurrent heart failure hospitalization or death at 30 days.
Nesiritide reduced dyspnea to a modest degree, consistent with previous findings but did not meet pre-specified protocol criteria for statistical significance at 6 and 24 hours.
Nesiritide did not affect 30-day all cause mortality nor did it worsen renal function as had been suggested by prior meta-analyses of smaller studies.

26. Implications
Nesiritide can now be considered a safe therapy in patients with acute heart failure.
Further analysis of ASCEND-HF is likely to permit better understanding of acute heart failure and patient profiles that may potentially benefit from nesiritide.
Our results from this large randomized trial emphasize both the challenges of making therapeutic decisions on inadequate evidence as well as the urgent need for large, well-conducted trials capable of informing clinical practice

27. Steering Committee
North America: Kirkwood F. Adams Jr MD; Javed Butler, MD;Maria Rosa Costanzo, MD; Mark E. Dunlap, MD; Justin A. Ezekowitz, MBBCh, MSc; David Feldman, MD, PhD; Gregg C. Fonarow, MD; Stephen S. Gottlieb, MD, MHS; James A. Hill, MD, MS; Judd E. Hollander, MD; Jonathan G. Howlett, MD; Michael Hudson, MD; Mariell L. Jessup, MD; Serge Lepage, MD; Wayne C. Levy, MD; Naveen Pereira, MD; W.H. Wilson Tang, MD; John R. Teerlink, MD; David J. Whellan, MD; Clyde W. Yancy, MD Europe: Stefan D. Anker, MD, PhD; Dan Atar, MD; Alexander Battler, MD; Ulf Dahlstrom, MD, PhD; Aleksandras Laucevicius, MD; Marco Metra, MD; Alexander Parkhomenko, MD; Piotr Ponikowski, MD, PhD; Jindrich Spinar, MD; Svetla Torbova, MD; Filippos Triposkiadis, MD;Vyacheslav Mareev, MD; Adriaan A. Voors, MD, PhD; Faiez Zannad, MD, PhD Latin America: Rodrigo Botero, MD; Nadine Clausell, MD; Ramón Corbalán, MD; Rafael Diaz, MD; Gustavo Méndez Machedo Asia Pacific: Ping Chai, MD; Wen-Jone Chen, MD; Henry Krum, MBBS, PhD; Sanjay Mittal, MD; Byung Hee Oh, MD; Supachai Tanomsup, MD; Richard W. Troughton, MD, PhD; YueJin Yang, MD;