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

Disclosure Information

Adrian F. Hernandez, MD

ASCEND-HF Trial

FINANCIAL DISCLOSURE: Trial Sponsor: Scios Inc

Research funding from Johnson & Johnson Honorarium from Amgen, CortheraFull listing of disclosures at dcri.org

UNLABELED or UNAPPROVED USE: None

International Steering Committee

Executive CommitteeChair: 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

SponsorScios Inc.

Independent DSMBChair: Sidney Goldstein

Salim Yusuf, David DeMets, Milton Packer, John Kjekshus

Study organization

North AmericaAcademic 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

Clinical Event Committee

Chair: John McMurray

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

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”)

Design of ASCEND-HF: Guiding principles

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

Co-Primary objectives

60

40

20

0

20

40

% S

ub

ject

s

Markedly Better

Minimally Worse

Moderately Better

Moderately Worse

Minimally Better

Markedly Worse

No Change

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

Secondary and safety objectives

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

Study design and drug procedures

Nesiritide

Placebo

24–168 hrs RxAcute HF < 24 hrs from IV RX

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

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

Key inclusion criteria Key exclusion criteria

Inclusion and exclusion criteria

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%

Statistical methods

Enrollment

North America = 45%214 sites

Latin America = 9%39 sites

Asia-Pacific = 25%62 sites

Central Europe = 14%48 sites

Western Europe = 7%35 sites

7141 patients 30 Countries & 398 Sites

>800 Investigators and Study Coordinators

Randomized (n=7141)

Study population

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)

Physician decision (n=6)

Participant withdrew consent (n=16)

Other reason (n=11)

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

Baseline characteristics

Continuous variables as median (IQR 25th, 75th); MITT population

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)

1.2 (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

Co-Primary outcome: 30-day all-cause mortality or HF rehospitalization

10.1

4.0

6.1

Hazard Ratio 0.93 (95% CI: 0.8,1.08)

9.4

3.6

6.0

Placebo

Nesiritide

HF Rehospitalization30-day Death/HF Rehospitalization

30-day Death0

2

4

6

8

10

12

Risk Diff (95 % CI) -0.7 (-2.1; 0.7) -0.4 (-1.3; 0.5) -0.1 (-1.2; 1.0)

%

P=0.31

All Subjects N=6836

Baseline SBP (mmHg)< 123≥ 123

N=3346N=3490

Baseline Ejection Fraction (%)

<40≥ 40

N=4362N=1187

Renal function- MDRD GFR (mL/min/m2)

<60≥ 60

N=3395N=3093

History of CADNoYes

N=3092 N=3742

History of Diabetes MellitusNoYes

N=3923N=2913

30 day death/HF readmission subgroups

Difference (%) and 95% Confidence Interval

Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo

All Subjects N=6836

Inotrope Use at Randomization

NoYes

N=6556N=280

Vasodilators

NoneAny IV VasodilatorsNo IV NitroglycerinIV Nitroglycerin

N=5889N=942N=5943N=892

Diuretics NoYes

N=691N=6145

Study Drug Bolus NoYes

N=2609N=4227

Time from Hosp to Rand (hrs)

<15.5≥15.5

N=3426N=3410

30 day death/HF readmission subgroups

Difference (%) and 95% Confidence Interval

Risk Difference <0: Favors Nesiritide; Risk Difference >0: Favors Placebo

70

60

50

40

30

20

10

0

10

20

30

40%

Su

bje

cts

24 Hours

Markedly Better

Minimally Worse

Moderately Better

Moderately Worse

Minimally Better

Markedly Worse

No Change

Co-Primary Endpoint: 6 and 24 hour dyspnea

70

60

50

40

30

20

10

0

10

20

30

40

% S

ub

ject

s

50

60

6 Hours

3444Placebo

13.4

28.7

34.1

21.7

P=0.030

3416Nesiritide

15.0

29.5

32.8

20.3 3398Placebo

27.5

38.6

22.1

9.5

3371Nesiritide

30.4

37.8

21.2

P=0.007

8.6

42.1% 44.5%

66.1% 68.2%

All Subjects N=6860 N=6769

SBP<123≥123

N=3369N=3491

N=3314 N=3455

GFR<60≥60

N=3494N=3121

N=3349 N=3075

Ejection Fraction

<40≥40

N=4385N=1186

N=4335 N=1171

CADNoYes

N=3115N=3743

N=3082N=3685

DiabetesNoYes

N=3930N=2930

N=3887 N=2882

24 hours6 hours

Dyspnea at 6 and 24 HoursOdds for Marked-Moderate Improvement

OR <1: Favors Placebo; OR >1: Favors Nesiritide;Odds Ratio of Markedly/Moderately vs. Other

All Subjects N=6860 N=6769

InotropesNoYes

N=6574 N=286

N=6481 N=288

Vasodilators

NoneAny IV VasoNo IV NitroIV Nitro

N=5912 N=943 N=5965 N=894

N=5835 N=929 N=5886 N=882

DiureticsNoYes

N=691 N=6169

N=679 N=6090

Study Medication Bolus

NoYes

N=2612 N=4248

N=2564 N=4205

Time from Hosp to Rand

<15.5≥15.5

N=3428N=3432

N=3369N=3400

24 hours6 hours

Dyspnea at 6 and 24 HoursOdds for Marked-Moderate Improvement

OR <1: Favors Placebo; OR >1: Favors Nesiritide;Odds Ratio of Markedly/Moderately vs. Other

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

Secondary endpoints

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

Renal Safety

Anytime Through Day 30Placebo(n=3509)

Nesiritide(n=3498)

P-value

>25% decrease eGFR 29.5% 31.4% 0.11

End of Treatment Creatinine

Creatinine (mg/dL)

Cu

m D

ist

0 2 4 6 80

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

Creatinine (mg/dL)

Cu

m D

ist

0 2 4 6 80

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

NesiritidePlacebo

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 Hypotension12.4%(436)

21.4%(748)

9.0(7.2 to 10.7)

<.001

Symptomatic Hypotension4.0%(141)

7.1%(250)

3.1(2.1 to 4.2)

<.001

Hypotension

COMBINED 30 day w/out ASCEND 1.28 (0.73, 2.25)

30-day mortality meta-analysis

1 100.1

Odds Ratio (95% CI)

PROACTION (N=237) 6.93 (0.89, 53.91)

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)

ASCEND-HF (N=7007) 0.89 (0.69, 1.14)

COMBINED with ASCEND 1.00 (0.76, 1.30)

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.

Conclusions

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

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;