Transcript SENIORS

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SENIORS
Study of Effects of Nebivolol Intervention on
Outcomes and Rehospitalisation in Seniors
with Heart Failure
A randomised, double-blind, placebo-controlled
phase III study
SENIORS
Background
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BRING UP
Reasons for not commencing -blockade
OR
95% CI
P value
Age
0.97
0.96 - 0.97
0.0001
NYHA class
(III-IV v I-II)
0.62
0.51 - 0.75
0.0001
Systolic blood pressure
1.02
1.01 - 1.02
0.0001
Heart rate
1.01
1.01 - 1.02
0.0001
Ejection fraction
(not available vs.
available)
0.46
0.28 - 0.76
0.0022
Maggioni A et al. Heart 2003
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Background
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Hillingdon study results
baseline characteristics
• 296 (54%) Male
• Median age 76 years (90% range 55-89)
• 161 (29%) Clinic: 391 (71%) Hospital
• NYHA Class: II - 8%; III - 33%; IV - 59%
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LV systolic function among elderly
with CHF: The Cardiovascular
Health Study
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12%
29%
Men
21%
41%
Women
67%
30%
Normal
Mildly Red
Mod/Sev Red
Kitzman et al, AJC 2001
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Study objective
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• To evaluate the effect of nebivolol
compared to placebo on mortality and
morbidity in elderly CHF patients
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Recruitment by geographic
region
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CENTRAL
543
EAST
827
WEST
765
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SENIORS - Outcome measures
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• Primary Outcome
– Time to composite of all cause mortality or
cardiovascular hospital admissions
• Secondary Outcomes
– Time to all cause mortality
– Time to cardiovascular hospital admissions
– Time to cardiovascular mortality
– Time to all cause hospital admissions
– Time to composite of all cardiovascular mortality or
cardiovascular hospital admissions
– Functional capacity by NYHA class and by
6 minute walk test
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Inclusion criteria
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• Age  70 years
• A clinical diagnosis of chronic heart failure
(HF) and either of:
a) documented LVEF  35% within previous 6
months
or
b) hospital admission within previous 1 year for
congestive HF
• Written consent prior to enrolment into the
study
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Main exclusion criteria
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• New drug therapy for heart failure
• Any change in cardiovascular drug therapy
in the 2 weeks prior to randomisation
• Heart failure due primarily to valvular heart
disease
• Contra-indication or previous intolerance to
beta blockers
• Heart rate < 60 beats per minute
• Systolic blood pressure < 90mmHg
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Study design
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Screening
Observation Period
Randomisation
Final Follow up
EOP Visit
Up-Titration
(mg)
5
Maintenance
FFU Visit
DownTitration
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2.5
1.25
1 to 4
weeks
Up to 16 weeks
Up to 40 months
3
1
weeks month
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Patient flow
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2135 randomised
Patients not in ITT: 7
6 from excluded centre
1 error in randomisation
2128 evaluable
1067 assigned to
nebivolol
1061 assigned to
placebo
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SENIORS
Study of Effects of Nebivolol Intervention on
Outcomes and Rehospitalisation in Seniors
with Heart Failure
A randomised, double-blind, placebo-controlled
phase III study
SENIORS
Baseline characteristics 1
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Nebivolol
Placebo
Age (mean, yrs)
76.1
76.1
Male (n, %)
657 (61.6)
686 (64.7)
LVEF  35 % (n, %)*
683 (64.3)
686 (64.8)
LVEF (mean, %)
36.0
36.0
I
32 (3.0)
29 (2.7)
II
603 (56.5)
597 (56.3)
III
413 (38.7)
411 (38.7)
IV
19 (1.8)
24 (2.3)
NYHA Class (n, %)
* 7 patients with missing LVEF at baseline
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Baseline characteristics 2
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Nebivolol
Placebo
Prior Revascularisation (n, %)
PTCA
47 (4.4)
34 (3.2)
CABG
101 (9.5)
94 (8.9)
Medication for Heart Failure (n, %)
ACE Inhibitors
880 (82.5)
884 (83.3)
Diuretics
916 (85.9)
910 (85.8)
Cardiac Glycosides
415 (38.9)
420 (39.6)
Aldosterone Antag.
298 (27.9)
272 (25.6)
Antiarrhythmics
91 (8.3)
Aetiology of Heart Failure (n %)
119 (11.2)
Ischaemic
812 (76.1)
809 (76.3)
Idiopathic
166 (15.6)
167 (15.7)
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Maintenance dose achieved
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Nebivolol
Placebo
Mean ± SD
7.7 ± 3.6
8.5 ± 3.1
> 5 mg
815 (76.4%)
881 (83.0%)
On 10 mg
688 (64.5%)
805 (75.9%)
All cause mortality or CV hospital
admission (primary outcome)
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Event free
Survival %
Nebivolol
Placebo
100
90
Hazard Ratio 0.86 [0.74;0.99]
80
p = 0.039
70
60
50
0
6
12
18
Time (months)
24
30
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No. of events: Nebivolol 332 (31.1%); Placebo 375 (35.3%)
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All cause mortality
(main secondary outcome)
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Event free
Survival %
Nebivolol
Placebo
100
90
80
70
Hazard Ratio 0.88 [0.71;1.08]
p = 0.214
60
50
0
6
12
18
24
30
36
Time
No. of events: Nebivolol 169 (15.8%); Placebo 192 (18.1%)
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Death or CV hospitalisation by
subgroup
Nebivolol
Favours
Nebivolol
Placebo
LVEF
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Favours
Placebo
 35 % 219 (32.1%) 249 (36.3%)
> 35 % 110 (28.9%) 125 (33.6%)
Sex
Male
231 (35.2%) 250 (36.4%)
Female 101 (24.6%) 125 (33.3%)
Age
70-75 y 148 (27.5%) 176 (33.5%)
> 75 y
184 (34.8%) 199 (37.1%)
Total
332 (31.1%) 375 (35.3%)
0.50
0.60
0.70
0.80
0.90
1.00
Hazard ratio and 95% CI
1.10
1.20
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Premature treatment
discontinuations (other than death)
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Discontinuation
Nebivolol
20%
Placebo
Patient
Request
15%
11.6
10.3
10%
Developed
Contraindication
Mandatory
Indication
5%
3.0
4.4
8.1
6.5
Intolerance
2.7
1.6
Other Reason
2.2
0.8
0%
Discontinuation Category
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Sub studies
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ECHO
Neurohormonal
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Conclusions
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• Nebivolol significantly reduced death or
hospitalisation in elderly heart failure patients
• The effect was similar regardless of ejection
fraction, age or gender
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Clinical implications
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• Advanced age should not be considered a
contra-indication to beta blockade in chronic
heart failure
• The SENIORS study indicates that beta
blockade can be recommended for heart
failure regardless of ejection fraction
• Nebivolol is an effective agent for elderly heart
failure patients
SENIORS
Acknowledgements
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Steering Committee:
Philip Poole-Wilson (UK), Andrew Coats (AUS) (Co Chairs), Anker S ,Böhm M, Borbola J,
Cohen-Solal A, Dumitrascu D, Ferrari R, Flather M, Lechat P,Parkhomenko A, Shibata M,
Soler-Soler J, Spinarova L,Tavazzi L, Toman J †, Van Veldhuisen D,
Clinical Events Committee:
Thygesen K (Chair) Frenneaux M, Tendera M, Sinagra, G
Data and Safety Monitoring Committee:
A Zanchetti (Chair), Lewis B, Nieminen M, Sleight P, Thompson S
Menarini Ricerche (Study Sponsor):
Maggi CA, Capriati A, Koch I, Mordenti G, Schumacher K
Parexel (CRO)
All participating Investigators and all participating patients
Slides available at www.cteu.org and www.menarini.com