Randall C. Starling, M.D., M.P.H., Randall C. Starling, M.D., M.P.H., F.A.C.C. F.A.C.C. Section of Heart Failure and Cardiac Transplant Section of Heart Failure and Cardiac Transplant Medicine Medicine Department of Cardiovascular Medicine Department of Cardiovascular Medicine Kaufman Center for Heart Failure Kaufman Center for Heart Failure Acute Heart Failure Acute Heart Failure
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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
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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.
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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
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10
Pat
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ts i
n U
S (
mil
lio
ns)
Year
Prevalence of heart failure
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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
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Pat
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ts (
%)
IV Diuretic Dobutamine Dopamine Milrinone Nesiritide Nitroglycerin Nitroprusside
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
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)
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;