1. A randomised, double-blind, placebo-controlled phase III study
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

2. BRING UP Reasons for not commencing -blockade
SENIORS
Background
BRING UP Reasons for not commencing -blockade OR
95% CI
P value
Age
0.97
0.0001
NYHA class (III-IV v I-II)
0.62
0.0001
Systolic blood pressure
1.02
0.0001
Heart rate
1.01
0.0001
Ejection fraction (not available vs.
available)
0.46
0.0022
Maggioni A et al. Heart 2003

3. Hillingdon study results baseline characteristics
SENIORS
Background
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%

4. Women Men LV systolic function among elderly
with CHF: The Cardiovascular
Health Study
SENIORS
12%
29%
41%
21%
Women
Men
67%
30%
Kitzman et al, AJC 2001

5. SENIORS
Study objective
To evaluate the effect of nebivolol compared to placebo on mortality and morbidity in elderly CHF patients

6. Recruitment by geographic region
SENIORS
Recruitment by geographic region
CENTRAL
543
EAST
827
WEST
765

7. SENIORS - Outcome measures
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 minute walk test

8. A clinical diagnosis of chronic heart failure (HF) and either of:
SENIORS
Inclusion criteria
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

9. Main exclusion criteria
SENIORS
Main exclusion criteria
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

10. Study design Maintenance SENIORS Screening Observation Period
Final Follow up
Randomisation
EOP Visit
FFU Visit
Up-Titration (mg)
Down-Titration
Maintenance 10 5
2.5
1.25
Up to 16 weeks 3
weeks
1 month
1 to 4
weeks
Up to 40 months

11. Patient flow 2135 randomised 2128 evaluable 1067 assigned to nebivolol
SENIORS
Patient flow
2135 randomised
Patients not in ITT: 7
6 from excluded centre error in randomisation
2128 evaluable
1067 assigned to nebivolol
1061 assigned to placebo

12. A randomised, double-blind, placebo-controlled phase III study
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

13. * 7 patients with missing LVEF at baseline
SENIORS
Baseline characteristics 1 IV
19 (1.8)
24 (2.3)
Age (mean, yrs)
Male (n, %)
Nebivolol
76.1
657 (61.6)
Placebo
686 (64.7)
LVEF  35 % (n, %)*
683 (64.3)
686 (64.8)
LVEF (mean, %)
36.0
NYHA Class (n, %) I
32 (3.0)
29 (2.7) II
603 (56.5)
597 (56.3)
III
413 (38.7)
411 (38.7)
* 7 patients with missing LVEF at baseline

14. Baseline characteristics 2
SENIORS
Baseline characteristics 2
Prior Revascularisation (n, %)
PTCA
Nebivolol
47 (4.4)
Placebo
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)
119 (11.2)
Aetiology of Heart Failure (n %)
Ischaemic
812 (76.1)
809 (76.3)
Idiopathic
166 (15.6)
167 (15.7)

15. Nebivolol Placebo Maintenance dose achieved Mean ± SD > 5 mg
SENIORS
Maintenance dose achieved
Mean ± SD
> 5 mg
Nebivolol
7.7 ± 3.6
815 (76.4%)
Placebo
8.5 ± 3.1
881 (83.0%)
On 10 mg
688 (64.5%)
805 (75.9%)

16. No. of events: Nebivolol 332 (31.1%); Placebo 375 (35.3%)
All cause mortality or CV hospital admission (primary outcome)
SENIORS
Event free
Survival %
Nebivolol
Placebo
Hazard Ratio 0.86 [0.74;0.99] p = 0.039
No. of events: Nebivolol 332 (31.1%); Placebo 375 (35.3%)

17. No. of events: Nebivolol 169 (15.8%); Placebo 192 (18.1%)
All cause mortality
(main secondary outcome)
SENIORS
Event free
Survival %
Nebivolol
Placebo
Hazard Ratio 0.88 [0.71;1.08] p = 0.214
No. of events: Nebivolol 169 (15.8%); Placebo 192 (18.1%)

18. Death or CV hospitalisation by subgroup
SENIORS
Favours
Nebivolol
Favours
Placebo
Nebivolol
Placebo
125 (33.6%)
110 (28.9%)
> 35 %
LVEF
249 (36.3%)
219 (32.1%)
 35 %
0.50
0.60
0.70
0.80
0.90
1.00
1.10
1.20
125 (33.3%)
101 (24.6%)
Female
Sex
250 (36.4%)
231 (35.2%)
Male
199 (37.1%)
184 (34.8%)
> 75 y
Age
176 (33.5%)
148 (27.5%)
70-75 y
375 (35.3%)
332 (31.1%)
Total
Hazard ratio and 95% CI

19. Discontinuation Category
Premature treatment discontinuations (other than death)
SENIORS
Discontinuation
Nebivolol
Placebo
Patient
Request
Other Reason
Developed
Contraindication
Mandatory
Indication
Intolerance
Discontinuation Category

20. SENIORS
Sub studies
ECHO
Neurohormonal

21. Conclusions Nebivolol significantly reduced death or
SENIORS
Conclusions
Nebivolol significantly reduced death or
hospitalisation in elderly heart failure patients
The effect was similar regardless of ejection
fraction, age or gender

22. Clinical implications
SENIORS
Clinical implications
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

23. Acknowledgements SENIORS 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
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