The document describes the design and results of the ASCEND-HF trial, which evaluated the clinical effectiveness and safety of nesiritide compared to placebo for treatment of acute decompensated heart failure. The trial found no significant difference between nesiritide and placebo for the co-primary endpoints of 30-day mortality or heart failure rehospitalization. Nesiritide was associated with greater improvement in dyspnea at 6 and 24 hours compared to placebo.

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

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

6. Co-Primary objectives
To assess whether nesiritide vs placebo,
in addition to standard care provides:
• Reduction in rate of
HF rehospitalization 60
Markedly Better
Moderately Better
or all-cause mortality 40 Minimally Better
through Day 30
% Subjects
20 No Change
• Significant improvement
Minimally Worse
0
Moderately Worse
in self-assessed dyspnea 20
Markedly Worse
at 6 or 24 hrs 40
Placebo Nesiritide
using 7-point Likert scale

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. Study design and drug procedures
Nesiritide
Acute HF < 24 hrs
24–168 hrs Rx
from IV RX
Placebo
Co-primary Co-primary All-cause
endpoint: endpoint: mortality
Dyspnea relief 30-day death or at 180
at 6 and 24 hrs HF rehosp 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  Hypotension at baseline
IV treatment (SBP <100 mm Hg or SBP<110
mm Hg with IV vasodilator)
 Dyspnea at rest or with minimal
activity  Significant lung disease that could
interfere with interpretation of
 1 clinical sign: dyspnea
• Respiratory rate ≥ 20 breaths per
min  Acute coronary syndrome
• Rales >1/3 bases  Severe anemia or active bleeding
 1 objective measure:  Treatment with levosimendan or
• CXR with pulmonary edema milrinone
• BNP ≥400 pg/mL or  Unstable doses of IV vasoactive
NT-proBNP≥1000 pg/mL
medication within 3 hours
• Prior EF <40% within 12 months
• PCWP > 20 mmHg

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
0.045 significance level
• Dyspnea tested at 0.005 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%

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

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

13. Baseline characteristics
Placebo (n=3511) Nesiritide (n=3496)
Age (yrs) 67 (56, 76) 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) 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
Nesiritide (n=3496)
(n=3511)
Labs/Studies
LVEF <40% within 12 mths (%) 79.5 80.8
BNP (pg/mL) 989 994
(543, 1782) (544, 1925)
NT pro-BNP (pg/mL) 4461 4508
(2123, 9217) (2076, 9174)
Creatinine (mg/dL) 1.2 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. Co-Primary outcome: 30-day all-cause
mortality or HF rehospitalization
P=0.31 Hazard Ratio 0.93 (95% CI: 0.8,1.08)
12
10.1
10 9.4 Placebo
Nesiritide
8
6.1 6.0
% 6
4.0
4 3.6
2
0
30-day Death/HF 30-day Death HF Rehospitalization
Rehospitalization
Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)

16. 30 day death/HF readmission subgroups
All Subjects N=6836
< 123 N=3346
Baseline SBP (mmHg)
≥ 123 N=3490
Baseline Ejection Fraction <40 N=4362
(%) ≥ 40 N=1187
Renal function- MDRD GFR <60 N=3395
(mL/min/m2) ≥ 60 N=3093
No N=3092
History of CAD
Yes N=3742
No N=3923
History of Diabetes Mellitus
Yes N=2913
-10 -5 0 5 10
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 No N=6556
Randomization Yes N=280
None N=5889
Any IV Vasodilators N=942
Vasodilators
No IV Nitroglycerin N=5943
IV Nitroglycerin N=892
Diuretic Use from No N=691
Hospitalization to
Rand Yes N=6145
No N=2609
Study Drug Bolus
Yes N=4227
Time from Hosp to <15.5 N=3426
Rand (hrs) ≥15.5 N=3410
-10 -5 0 5 10
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% P=0.007 68.2%
60 P=0.030
60
50 42.1% 44.5% 50 27.5 30.4
40 40
13.4 15.0
% Subjects
% Subjects
30 30
20 20 38.6 37.8
28.7 29.5
10 10
0 0
10 10
32.8 22.1 21.2
34.1
20 20
9.5 8.6
30 30
40 20.3 40 3398 3371
21.7
50 Placebo Nesiritide
60
3444 3416
Placebo Nesiritide
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
6 hours 24 hours
All Subjects N=6860 N=6769
<123 N=3369 N=3314
SBP
≥123 N=3491 N=3455
<60 N=3494 N=3349
GFR
≥60 N=3121 N=3075
Ejection <40 N=4385 N=4335
Fraction ≥40 N=1186 N=1171
No N=3115 N=3082
CAD
Yes N=3743 N=3685
No N=3930 N=3887
Diabetes
Yes N=2930 N=2882
0 1 20 1 2
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
6 hours 24 hours
All Subjects N=6860 N=6769
No N=6574 N=6481
Inotropes
Yes N=286 N=288
None N=5912 N=5835
Any IV Vaso N=943 N=929
Vasodilators
No IV Nitro N=5965 N=5886
IV Nitro N=894 N=882
No N=691 N=679
Diuretics
Yes N=6169 N=6090
Study
Medication No N=2612 N=2564
Bolus Yes N=4248 N=4205
Time from
<15.5 N=3428 N=3369
Hosp to
≥15.5 N=3432 N=3400
Rand
0 1 2 0 1 2
OR <1: Favors Placebo; OR >1: Favors Nesiritide;
Odds Ratio of Markedly/Moderately vs. Other

21. Secondary endpoints
Placebo Nesiritide Difference P-
(n=3511) (n=3496) (95% CI) value
Persistent or worsening HF or
4.8% 4.2% -0.5
all-cause mortality through 0.30
(165) (147) (-1.5 to 0.5)
discharge
Days alive and outside of 0.2
20.7 20.9 0.16
hospital through Day 30 (-0.13 to 0.53)
CV death or CV rehosp 11.8% 10.9% -0.9
0.24
through Day 30 (402) (372) (-2.4 to 0.6)
Placebo Nesiritide
P-value
(n=3511) (n=3496)
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. Renal Safety
Placebo Nesiritide
Anytime Through Day 30 P-value Placebo Nesiritide
(n=3509) (n=3498)
>25% decrease eGFR 29.5% 31.4% 0.11
End of Treatment Creatinine Discharge or 10 day Creatinine
1.0 1.0
0.9 0.9
0.8 0.8
0.7 0.7
Cum Dist
Cum Dist
0.6 0.6
0.5 0.5
0.4 0.4
0.3 0.3
0.2 0.2
0.1 0.1
0 0
0 2 4 6 8 0 2 4 6 8
Creatinine (mg/dL) Creatinine (mg/dL)

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