Download Redfield_NEAT-HFpEF FINAL

Nitrate’s Effect on Activity Tolerance in
Heart Failure with Preserved Ejection
Fraction (NEAT)
A Randomized Clinical Trial
Margaret M Redfield
On behalf of the
NHLBI Heart Failure Clinical Research Network
Heart Failure Clinical Research Network
University of Vermont Medical Center
Mayo Clinic
Tufts Medical Center
Cleveland Clinic
Washington University
Brigham
and Women’s
Hospital
Jefferson Medical
College
DCRI Coordinating Center
University
of Pennsylvania
Emory University School of Medicine
Duke University
School of Medicine
Regional Clinical Centers
Coordinating Center
www.hfnetwork.org
Background
• Exercise intolerance is a cardinal feature of HFpEF
and perpetuates sedentary behavior,
deconditioning and frailty.
• Nitrates are commonly prescribed for symptom
relief in HFpEF.
Background
• The hemodynamic effects of nitrates may
attenuate pulmonary congestion with exertion and
improve exercise capacity in HFpEF.
• HFpEF pts may be at increased risk for nitrate
induced hypotension or other side effects.
• Ventricular and Vascular Stiffening
• Comorbid conditions
• Polypharmacy
Background
• Patient-worn accelerometers provide continuous
assessment of physical activity during daily life.
•
As compared to intermittent coached exercise
tests, daily activity may more accurately reflect
the impact of a therapy on patient’s functional
status.
Hypothesis
• As compared to placebo, isosorbide mononitrate
(ISMN) will improve daily activity in HFpEF
patients as assessed by patient worn
accelerometer devices.
• Average daily accelerometer units
Study population
•
•
•
NYHA class II-IV HF symptoms + EF ≥ 50%
Objective evidence of HF (at least one)
HF hospitalization
Elevated NT-proBNP or BNP
Elevated rest or exercise PAWP at RHC
Echo Doppler Diastolic Dysf (≥ 2 variables)
Identify HF symptoms as the primary factor
limiting ability to be active on screening
questionnaire
Versus neurologic, orthopedic or life-style factors
Study Design: Randomized, double-blind,
placebo-controlled crossover study
* Or maximally tolerated dose
NEAT Primary End-point
• Average daily accelerometer units (AAU) during
the 120 mg (or maximally tolerated) dose
• Two hip-worn, tri-axial, high sensitivity accelerometers
• Worn 24 hours per day (except bathing)
• Throughout the entire study
Secondary End-points
• Additional accelerometer endpoints
• Hours active per day at the 120 mg dose
• Area under the curve for time and daily
accelerometer units during all doses of study drug
(30, 60 and 120 mg).
• Standard HF endpoints
• Six minute walk distance and dyspnea score
• HF specific quality of life (KCCQ)
• NT-proBNP levels
Crossover Analysis
• Intention to treat
• Mixed Model: Treatment Effect (ISMN-Placebo)
• Sequence effect
• Period effect
• Random effect of each patient
•
110 patients powered to detect:
• 43 m difference in 6MWD (>90%)
• 5 pts difference in KCCQ (>80%)
• 2.5% change relative to baseline in AAU (>90%)
Baseline Features
Characteristic
Age (years)
Female
White race
BMI (kg/m2)
HF hsp in past year
Hx hypertension
Hx of coronary disease
Diabetes
Hx of atrial fibrillation
Mean values or % shown
Placebo 1st
(n=59)
69
64%
92%
35
27%
92%
61%
36%
34%
ISMN 1st
(N = 51)
68
49%
86%
36
24%
88%
63%
43%
37%
All p > 0.05
Baseline Features
Characteristic
Systolic BP
NYHA class II/III
6MWD (m)
KCCQ (higher better)
Ejection fraction (%)
NT-proBNP (median, pg/ml)
E/e’ - (normal ≤ 8)
LAVI (ml/m2) - (normal < 29)
Rel Wall Th ≥ 0.42
Mean values or % shown except as noted
Placebo 1st
(n=59)
132
56% / 41%
321
60
65
248
15
39
45%
ISMN 1st
(N = 51)
129
49% / 51%
300
55
62*
210
15
41
50%
*p < 0.05
Agreement Between Accelerometers
A v e r a g e D a ily A c c e le ro m e tr y U n its
D u r in g th e P E P P h a s e o f P e r io d s 1 a n d 2
40000
R ig h t A c c e le r o m e te r
P e rio d 1
P e rio d 2
30000
20000
10000
R = 0 .9 9
0
0
10000
20000
30000
L e ft A c c e le ro m e te r
40000
Primary Endpoint
Is o s o r b id e m o n o n it r a t e
10
9000
9
8000
7000
6000
5000
0
-5 0 0
p = 0 .0 6
-1 0 0 0
10000
8
7
6
5
0 .0
- 0 .5
p = 0 .0 2
9000
8000
7000
6000
5000
0
-5 0 0
p = 0 .0 2
-1 0 0 0
- 1 .0
120 m g D ose
T r e a t m e n t D if f e r e n c e
A c c e le r o m e t e r U n it s / D a y
10000
H o u r s A c t iv e p e r D a y
A v g D a ily A c c e le r o m e t e r U n it s
P la c e b o
120 m g D ose
A ll D o s e s
(3 0 -1 2 0 m g )
Primary and Secondary Endpoints
Is o s o r b id e m o n o n it r a t e
10
9000
9
8000
7000
6000
5000
0
-5 0 0
p = 0 .0 6
-1 0 0 0
10000
8
7
6
5
0 .0
- 0 .5
p = 0 .0 2
9000
8000
7000
6000
5000
0
-5 0 0
p = 0 .0 2
-1 0 0 0
- 1 .0
120 m g D ose
T r e a t m e n t D if f e r e n c e
A c c e le r o m e t e r U n it s / D a y
10000
H o u r s A c t iv e p e r D a y
A v g D a ily A c c e le r o m e t e r U n it s
P la c e b o
120 m g D ose
A ll D o s e s
(3 0 -1 2 0 m g )
P la c e b o - B A S E L IN E
Is o s o r b id e m o n o n itr a te - B A S E L IN E
P la c e b o - D O S E
Is o s o r b id e m o n o n itr a te - D O S E
D O S E - B A S E L IN E T r e a tm e n t D iff e r e n c e
A v e ra g e D a ily A c c e le ro m e te r U n its
12000
10000
8000
6000
400
0
-4 0 0
-8 0 0
-1 2 0 0
p = 0 .3 9
p = 0 .4 2
p = 0 .2 2
p = 0 .0 5
p = 0 .0 3
p < 0 .0 0 1
30 m g
60 m g
120 m g
30 m g
60 m g
120 m g
P la c e b o
Is o s o r b id e m o n o n it r a t e
P la c e b o - B A S E L IN E
Is o s o r b id e m o n o n itr a te - B A S E L IN E
P la c e b o - D O S E
Is o s o r b id e m o n o n itr a te - D O S E
D O S E - B A S E L IN E T r e a tm e n t D iff e r e n c e
A v e ra g e D a ily A c c e le ro m e te r U n its
12000
10000
8000
6000
400
0
-4 0 0
-8 0 0
-1 2 0 0
p = 0 .3 9
p = 0 .4 2
p = 0 .2 2
p = 0 .0 5
p = 0 .0 3
p < 0 .0 0 1
30 m g
60 m g
120 m g
30 m g
60 m g
120 m g
P la c e b o
Is o s o r b id e m o n o n it r a t e
Other Secondary Endpoints
Placebo
N=110
ISMN
N=110
P value
Distance (m)
321
322
0.91
Dyspnea (1-10)
3.97
3.89
0.74
KCCQ (Lower worse)
61.6
59.7
0.16
NT-proBNP (pg/ml)
497
550
0.22
Systolic BP (mmHg)
129
125
0.04
6 Minute Walk
Data are the model derived estimates of the mean treatment value
Safety / Tolerability Endpoints
Characteristic
Discontinued study drug
Any Event of Interest
Arrhythmia
Worsening HF
Stroke
Presyncope/Syncope
SAE - Death
SAE - Other
Placebo
N=110
9
6
2
1
0
3
0
1
ISMN
N=110
16
14
2
5
1
6
0
2
All p > 0.05
Summary
• As compared to placebo, isosorbide
mononitrate decreased daily activity levels and
did not improve submaximal exercise capacity,
quality-of-life scores or NT-proBNP levels in
HFpEF patients.
Conclusions
• These data do not support use of long acting
nitrates for symptom relief in HFpEF.
• Patient worn devices provide unique information
about the impact of therapies on patients daily
functional status