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Embargoed Until 3:45 p.m. ET, Sunday, Nov. 8, 2015
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
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.
•
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
• Activity during all doses of study drug (30, 60 and
120 mg).
• Standard HF endpoints
• Six minute walk distance
• KCCQ
• NT-proBNP levels
Baseline Features
Characteristic
Age (years)
Female
White race
BMI (kg/m2)
Hx hypertension
Hx of coronary disease
Diabetes
Hx of atrial fibrillation
Mean values or % shown
Placebo 1st
(n=59)
69
64%
92%
35
92%
61%
36%
34%
ISMN 1st
(N = 51)
68
49%
86%
36
88%
63%
43%
37%
All p > 0.05
Baseline Features
Characteristic
NYHA class II/III
6MWD (m)
KCCQ (higher better)
NT-proBNP (median, pg/ml)
E/e’ - (normal ≤ 8)
LAVI (ml/m2) - (normal < 29)
Mean values or % shown except as noted
Placebo 1st
(n=59)
56% / 41%
321
60
248
15
39
ISMN 1st
(N = 51)
49% / 51%
300
55
210
15
41
*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
321
322
0.91
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
Distance (m)
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
Placebo
N=110
9
6
2
1
0
3
ISMN
N=110
16
14
2
5
1
6
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