Transcript ascend-hf lbct final

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, Corthera
Full listing of disclosures at dcri.org
UNLABELED or UNAPPROVED USE: None
Study organization
Sponsor
Scios Inc.
Executive Committee
Independent DSMB
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
Chair: Sidney Goldstein
Salim Yusuf,
David DeMets,
Milton Packer,
John Kjekshus
International Steering Committee
Clinical Event
Committee
Chair: John McMurray
ROW:
Coordinating center:
Johnson & Johnson
Global Clinical
Operations
DCRI
Adrian Hernandez,
Craig Reist,
Gretchen Heizer
North America
Academic Consortium:
(DCRI, C5, Jefferson,
Henry Ford, Canadian
VIGOUR Centre)
>800 Investigators and Study Coordinators at 398 Sites
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
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”)
Co-Primary objectives
To assess whether nesiritide vs placebo,
in addition to standard care provides:
• Significant improvement
in self-assessed dyspnea
at 6 or 24 hrs
using 7-point Likert scale
60
Markedly Better
Moderately Better
40
% Subjects
• Reduction in rate of
HF rehospitalization
or all-cause mortality
through Day 30
20
0
Minimally Better
No Change
Minimally Worse
Moderately Worse
20
40
Markedly Worse
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
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
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
• 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
 Acute coronary syndrome
 Severe anemia or active bleeding
 Treatment with levosimendan or
milrinone
 Unstable doses of IV vasoactive
medication within 3 hours
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%
Enrollment
7141 patients
30 Countries & 398 Sites
Western Europe = 7%
35 sites
North America = 45%
214 sites
Latin America = 9%
39 sites
Central Europe = 14%
48 sites
Asia-Pacific = 25%
62 sites
>800 Investigators and Study Coordinators
Study population
Randomized (n=7141)
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)
Placebo MITT=3511
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)
Nesiritide MITT=3496
Baseline characteristics
Placebo (n=3511)
Nesiritide (n=3496)
67 (56, 76)
67 (56, 76)
Female (%)
34.9
33.4
Black or African American
15.0
14.7
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)
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
Age (yrs)
Systolic Blood Pressure (mmHg)
Medical History (%)
Continuous variables as median (IQR 25th, 75th); MITT population
Baseline characteristics
Placebo
(n=3511)
Nesiritide (n=3496)
LVEF <40% within 12 mths (%)
79.5
80.8
BNP (pg/mL)
989
Labs/Studies
NT pro-BNP (pg/mL)
Creatinine (mg/dL)
994
(543, 1782)
(544, 1925)
4461
4508
(2123, 9217)
1.2
(2076, 9174)
1.2
(1.0, 1.6)
(1.0, 1.5)
Loop diuretics
95.3
94.9
Inotropes
4.4
4.3
Vasodilators
14.1
15.7
Pre-randomization treatment (%)
Continuous variables as median (IQR 25th, 75th); MITT population
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
4.0
4
6.0
3.6
2
0
30-day Death/HF
Rehospitalization
Risk Diff (95 % CI)
-0.7 (-2.1; 0.7)
30-day Death
-0.4 (-1.3; 0.5)
HF Rehospitalization
-0.1 (-1.2; 1.0)
30 day death/HF readmission subgroups
N=6836
All Subjects
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
No
Yes
N=3923
N=2913
-10
Risk Difference <0: Favors Nesiritide;
Risk Difference >0: Favors Placebo
-5
0
5
Difference (%) and 95% Confidence Interval
10
30 day death/HF readmission subgroups
N=6836
All Subjects
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
No
Yes
N=691
N=6145
Study Drug Bolus
No
Yes
N=2609
N=4227
Time from Hosp to
Rand (hrs)
<15.5
≥15.5
N=3426
N=3410
-10
Risk Difference <0: Favors Nesiritide;
Risk Difference >0: Favors Placebo
-5
0
5
Difference (%) and 95% Confidence Interval
10
Co-Primary Endpoint: 6 and 24 hour dyspnea
6 Hours
24 Hours
70
70
P=0.030
60
42.1%
44.5%
50
13.4
15.0
40
40
% Subjects
60
30
20
10
28.7
29.5
0
34.1
32.8
38.6
37.8
22.1
21.2
9.5
8.6
3398
Placebo
3371
Nesiritide
30
20
10
10
30
21.7
20.3
3444
Placebo
3416
Nesiritide
40
50
60
30.4
20
30
40
27.5
0
10
20
% Subjects
50
66.1% P=0.007 68.2%
Markedly Better
Moderately Better
Minimally Better
Minimally Worse
Moderately Worse
Markedly Worse
No Change
Dyspnea at 6 and 24 Hours
Odds for Marked-Moderate Improvement
6 hours
All Subjects
24 hours
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
No
Yes
N=3930
N=2930
N=3887
N=2882
0
1
20
1
OR <1: Favors Placebo; OR >1: Favors Nesiritide;
Odds Ratio of Markedly/Moderately vs. Other
2
Dyspnea at 6 and 24 Hours
Odds for Marked-Moderate Improvement
6 hours
24 hours
All Subjects
Inotropes
N=6860
N=6769
N=6574
N=286
N=6481
N=288
N=5912
N=943
N=5965
N=894
N=5835
N=929
N=5886
N=882
No
Yes
N=691
N=6169
N=679
N=6090
No
Yes
N=2612
N=4248
N=2564
N=4205
<15.5
≥15.5
N=3428
N=3432
N=3369
N=3400
No
Yes
None
Any IV Vaso
Vasodilators
No IV Nitro
IV Nitro
Diuretics
Study
Medication
Bolus
Time from
Hosp to
Rand
0
1
2
0
OR <1: Favors Placebo; OR >1: Favors Nesiritide;
Odds Ratio of Markedly/Moderately vs. Other
1
2
Secondary endpoints
Placebo
(n=3511)
Nesiritide
(n=3496)
Difference
(95% CI)
Pvalue
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
11.8%
(402)
10.9%
(372)
-0.9
(-2.4 to 0.6)
0.24
CV death or CV rehosp
through Day 30
Well Being at 6 hours*
Well Being at 24 hours*
Placebo
(n=3511)
Nesiritide
(n=3496)
P-value
40.3%
41.4%
0.32
63.7%
65.7%
0.02
*Combined response for moderately/markedly better
Renal Safety
Anytime Through Day 30
>25% decrease eGFR
Placebo
(n=3509)
Nesiritide
(n=3498)
P-value
29.5%
31.4%
0.11
1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.5
0.4
0.6
0.5
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0
0
2
4
6
Creatinine (mg/dL)
Nesiritide
Discharge or 10 day Creatinine
Cum Dist
Cum Dist
End of Treatment Creatinine
Placebo
8
0
0
2
4
6
Creatinine (mg/dL)
8
Hypotension
Risk
Difference
(95% CI)
Placebo
(n=3509)
Nesiritide
(n=3498)
Any hypotension
(Through Day 10/discharge)
15.3%
(538)
26.6%
(930)
(9.4 to 13.1)
Asymptomatic Hypotension
12.4%
(436)
21.4%
(748)
9.0
(7.2 to 10.7)
<.001
Symptomatic Hypotension
4.0%
(141)
7.1%
(250)
3.1
(2.1 to 4.2)
<.001
11.3
Pvalue
<.001
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
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 prespecified 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.
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;