Randall C. Starling, M.D., M.P.H., F.A.C.C.Randall C. Starling, M.D., M.P.H., F.A.C.C.

Section of Heart Failure and Cardiac Transplant MedicineSection of Heart Failure and Cardiac Transplant Medicine

Department of Cardiovascular MedicineDepartment of Cardiovascular Medicine

Kaufman Center for Heart FailureKaufman Center for Heart Failure

Acute Heart FailureAcute Heart Failure

2

A Public Health Epidemic

• Over 1 million annual hospital admissions (increased 90% in past 10 years)

• Most common discharge diagnosis for patients older than 65 years

• 6.5 million hospital days per year• Single largest expense for Medicare

• Greatest portion of expense related to hospital care

Acute decompensated heart failure

11AHA. AHA. 2006 Heart and Stroke Statistical Update2006 Heart and Stroke Statistical Update22Hunt SA et al. ACC/AHA guidelines. 2005. Hunt SA et al. ACC/AHA guidelines. 2005.

3

Continues to Grow• Estimated 10 million in 2037

• Incidence: about 550,000 new cases each year

• Prevalence is 2% in persons aged 40 to 59 years, progressively increasing to 10% for those aged 70 years and older

1991 2001 2037

3.54.8

10.0

0

2

4

6

8

10

Pat

ien

ts i

n U

S (

mil

lio

ns)

Year

Prevalence of heart failure

4

Worsening chronicheart failure (75%)

De novo heartfailure (23%)

Advanced/ end-stageheart failure (2%)

Fonarow GC. Rev Cardiovasc Med. 2003; 4 (Suppl. 7): 21Cleland JG et al. Eur Heart J. 2003; 24: 442

The Major Reason for Heart Failure Hospitalizations

Outcomes in Patients Hospitalized With HF

Fonarow, GC. Rev Cardiovasc Med. 2002;3(suppl 4):S3Jong P et al. Arch Intern Med. 2002;162:1689

0

25

50

75

100

20%

50%

30Days

6Months

Hospital Readmissions

0

25

50

75

100

12%

50%

30Days

12Months

Mortality

33%

5Years

Mean LOS: 6.5 days

Most Common IV MedicationsAll Enrolled Discharges (n=105,388) October 2001-January 2004

0

10

20

30

40

50

60

70

80

90

100

Pat

ien

ts (

%)

IV Diuretic Dobutamine Dopamine Milrinone Nesiritide Nitroglycerin Nitroprusside

IV Vasoactive Meds

88%

6% 6% 10%3% 1%

10%

ADHERE® CART: Predictors of Mortality

SYS >BP 115SYS >BP 115n=24,933n=24,933

SYS >BP 115SYS >BP 115n=24,933n=24,933

SYS >BP 115SYS >BP 115n=7,150n=7,150

SYS >BP 115SYS >BP 115n=7,150n=7,150

6.41%6.41%n=5,102n=5,1026.41%6.41%

n=5,102n=5,10215.28%15.28%N=2,048N=2,04815.28%15.28%N=2,048N=2,048

21.94%21.94%n=620n=620

21.94%21.94%n=620n=620

12.42%12.42%n=1,425n=1,42512.42%12.42%n=1,425n=1,425

5.49%5.49%n=4,099n=4,0995.49%5.49%

n=4,099n=4,0992.14%2.14%

n=20,834n=20,8342.14%2.14%

n=20,834n=20,834

BUN 43BUN 43N=33,324N=33,324

BUN 43BUN 43N=33,324N=33,324

Greater thanLess than

2.68%2.68%n=25,122n=25,122

2.68%2.68%n=25,122n=25,122

8.98%8.98%n=7,202n=7,2028.98%8.98%

n=7,202n=7,202

Cr <2.75Cr <2.752,0452,045

Cr <2.75Cr <2.752,0452,045

Highest to Lowest Risk CohortOR 12.9 (95% CI 10.4-15.9)

Reference: Fonarow GC, et al. Risk stratification for in-hospital mortality in heart failure using classification and regression tree(CART) methodology. JAMA. 2005;293:572-580.

YESYES YESYES

YESYES

Baseline BUN Predictive of 60 day OutcomesACTIV trial

Filappatos GJ Cardiac Fail 2007;13:360e364 Filappatos GJ Cardiac Fail 2007;13:360e364

N=319N=319

Klein L. Circ Heart Fail. 2008;1:25-33.Klein L. Circ Heart Fail. 2008;1:25-33.

N=949N=949

Mullens W et al. Am J Cardiol 2008;101:1297–1302Mullens W et al. Am J Cardiol 2008;101:1297–1302

N=513N=513

Mullens W et al. Am J Cardiol 2008;101:1297–1302Mullens W et al. Am J Cardiol 2008;101:1297–1302

N=513N=513

Copyright ©2008 American College of Cardiology Foundation. Restrictions may apply.

Abraham, W. T. et al. J Am Coll Cardiol 2008;52:347-356

In-Hospital Mortality by SCr and SBPFrom OPTIMIZE HF Registry

In-Hospital Mortality According to Troponin I or Troponin T Quartile

Peacock WF 4th et al. N Engl J Med 2008;358:2117-2126

Mortality According to Type of Treatment and Troponin Status

Peacock WF 4th et al. N Engl J Med 2008;358:2117-2126

16

State of the Art, circa 1974

• Diuretics• Vasodilators• Oxygen• Consider inotropic therapy

Ramirez and Abelmann, NEJM, 1974Ramirez and Abelmann, NEJM, 1974

Acute heart failure therapy

and 2010?and 2010?

What Should be the Goals of Therapy of ADHF?

Make the patient feel better: Make the patient feel better: reduce dyspnea and improve reduce dyspnea and improve QOLQOL

Reduce MortalityReduce Mortality

Reduce RehospitalizationReduce Rehospitalization

Do it safelyDo it safely

18

Dyspnea at 3 Hours

–10

0

10

20

30

40

50

60

70

80

90

100

Nesiritide PlaceboNitroglycerin

Imp

rove

d (

%)

Worsened (%)

P = 0.034

P = 0.191

P values are based on van Elteren test with 7-point ordinal scale

VMAC: Primary End Point

VMAC Investigators. JAMA. 2002;187:1531–1540. VMAC Investigators. JAMA. 2002;187:1531–1540.

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

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 decompensated 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 (recombinant human B-type natriuretic peptide) was approved by the FDA to reduce PCWP and improve dyspnea, based on efficacy at 3 hrs in ADHF.

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

Investigator independence framed by a joint academic executive and steering committee

Large, pragmatic international trial model

• Focused

• Efficient study design

• Streamlined procedures

• Simple follow-up

Permissive enrollment criteria for broad population clinical ADHF

Meaningful outcomes

“Real world” treatment (local standards of care guided by manual constructed by international committee of ADHF experts)

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

Secondary endpoints:

• Overall well-being by self‑assessed Likert scale 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 from randomization through Day 30

• Cardiovascular rehospitalization and cardiovascular mortality from randomization through Day 30

Safety endpoints:

• All cause mortality

• Renal function: 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 /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 dypsnea

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

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

LVEF <40% 79.5 80.8

Baseline characteristics

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

Baseline characteristics

Placebo (n=3511) Nesiritide (n=3496)

Labs/Studies

BNP (pg/mL) 989 (544, 1782)

994 (549, 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

P=0.319.4

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)

%

Regional variation in outcomes

Regional variation in outcomes

All-Cause Death/HF Rehosp Day 30 N=6836

SexFemaleMale

N=1192N=2221

Age≤ 6465-74≥ 75

N=1514N=871N=1028

Race

WhiteBlack or African AmericanAsianOther

N=1913N=512N=834N=154

Region

North AmericaLatin AmericaAsia-PacificCentral EuropeWestern Europe

N=1547N=324N=837N=474N=231

30 day death/HF readmission subgroups

Difference (%) and 95% Confidence Interval

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

All-Cause Death/HF Rehosp Day 30 N=6836

Baseline SBP (mmHg)< 123

≥ 123

N=1646

N=1767

Baseline Ejection Fraction (%)<40

≥ 40

N=2179

N=604

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

<60

≥ 60

N=1704

N=1534

History of CADNo

Yes

N=1525

N=1887

History of Diabetes MellitusNo

Yes

N=1949

N=1464

30 day death/HF readmission subgroups

Difference (%) and 95% Confidence Interval

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

All-Cause Death/HF Rehosp Day 30 N=6836

Inotrope Use at Randomization

No

Yes

N=3272

N=141

Vasodilators

None

Any IV Vasodilators

No IV Nitroglycerin

IV Nitroglycerin

N=2962

N=448

N=2987

N=425

Diuretic Use from Hosp through Rand

No

Yes

N=329

N=3084

Study Drug BolusNo

Yes

N=1310

N=2103

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%

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 20.90.2

(-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

30-day mortality meta-analysis

1 100.1

Odds ratio (95% CI)

Mills (311)

Colluci/Efficacy (325)

Comparative (326)

PRECEDENT (329)

VMAC (339)

PROACTION (341)

ASCEND-HF

COMBINED 30 day w/out ASCEND

COMBINED with ASCEND

Odds Ratio (95% CI)

0.38 (0.05, 2.74)

1.24 (0.23, 6.59)

1.43 (0.50, 4.09)

0.59 (0.18, 2.01)

1.63 (0.77, 3.44)

6.93 (0.89, 53.91)

0.89 (0.69, 1.14)

1.28 (0.73, 2.25)

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 ADHF.

Further analysis of ASCEND-HF may allow a better understanding of patients with ADHF and patient profiles that may potentially benefit from nesiritide.

Our results from this large randomized trial emphasize the challenges of making therapeutic decisions on inadequate evidence and highlight 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 Tan, MD; John R. Teerlink, 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;