Upload
trimed-media-group
View
2.714
Download
4
Tags:
Embed Size (px)
Citation preview
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
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
Sponsor
Scios Inc.
Independent DSMBChair: Sidney Goldstein
Salim Yusuf,
David DeMets,
Milton Packer,
John Kjekshus
Study organization
North America
Academic 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
CommitteeChair: 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
“Real world” treatment
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
jects
Placebo Nesiritide
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 Death
0
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=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 CADNo
Yes
N=3092
N=3742
History of Diabetes MellitusNo
Yes
N=3923
N=2913
-10 -5 0 5 10
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
No
Yes
N=6556
N=280
Vasodilators
None
Any IV Vasodilators
No IV Nitroglycerin
IV Nitroglycerin
N=5889
N=942
N=5943
N=892
Diuretic Use from Hospitalization toRand
No
Yes
N=691
N=6145
Study Drug BolusNo
Yes
N=2609
N=4227
Time from Hosp to
Rand (hrs)
<15.5
≥15.5
N=3426
N=3410
-10 -5 0 5 10
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
% S
ub
jects
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
jects
50
60
6 Hours
3444
Placebo
13.4
28.7
34.1
21.7
P=0.030
3416
Nesiritide
15.0
29.5
32.8
20.3 3398
Placebo
27.5
38.6
22.1
9.5
3371
Nesiritide
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=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
CADNo
Yes
N=3115
N=3743
N=3082
N=3685
DiabetesNo
Yes
N=3930
N=2930
N=3887
N=2882
0 1 2 0 1 2
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
InotropesNo
Yes
N=6574
N=286
N=6481
N=288
Vasodilators
None
Any IV Vaso
No IV Nitro
IV Nitro
N=5912
N=943
N=5965
N=894
N=5835
N=929
N=5886
N=882
DiureticsNo
Yes
N=691
N=6169
N=679
N=6090
Study
Medication
Bolus
No
Yes
N=2612
N=4248
N=2564
N=4205
Time from
Hosp to
Rand
<15.5
≥15.5
N=3428
N=3432
N=3369
N=3400
0 1 20 1 2
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 3020.7 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; 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;