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SENIORS. SENIORS. S tudy of E ffects of N ebivolol I ntervention on O utcomes and R ehospitalisation in S eniors with Heart Failure A randomised, double-blind, placebo-controlled phase III study. SENIORS. SENIORS. Background.

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SENIORS

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

SENIORS

Background

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


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%

SENIORS

SENIORS

Background

Hillingdon study resultsbaseline characteristics


SENIORS

SENIORS

LV systolic function among elderly

with CHF: The Cardiovascular

Health Study

12%

29%

21%

41%

Women

Men

67%

30%

Kitzman et al, AJC 2001


SENIORS

SENIORS

Study objective

  • To evaluate the effect of nebivolol compared to placebo on mortality and morbidity in elderly CHF patients


SENIORS

SENIORS

Recruitment by geographic region

CENTRAL

543

EAST

827

WEST

765


SENIORS

SENIORS

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 6 minute walk test


SENIORS

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


SENIORS

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


SENIORS

SENIORS

Study design

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


SENIORS

SENIORS

Patient flow

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


SENIORS

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

SENIORS

Nebivolol

Placebo

Age (mean, yrs)

76.1

76.1

LVEF  35 % (n, %)*

IV

LVEF (mean, %)

II

I

III

NYHA Class (n, %)

603 (56.5)

683 (64.3)

32 (3.0)

413 (38.7)

36.0

19 (1.8)

411 (38.7)

597 (56.3)

24 (2.3)

36.0

29 (2.7)

686 (64.8)

Male (n, %)

657 (61.6)

686 (64.7)

Baseline characteristics 1

* 7 patients with missing LVEF at baseline


SENIORS

SENIORS

Nebivolol

Placebo

Prior Revascularisation (n, %)

PTCA

47 (4.4)

34 (3.2)

ACE Inhibitors

Aldosterone Antag.

Diuretics

Antiarrhythmics

Ischaemic

Idiopathic

Cardiac Glycosides

812 (76.1)

916 (85.9)

415 (38.9)

298 (27.9)

91 (8.3)

880 (82.5)

166 (15.6)

420 (39.6)

910 (85.8)

809 (76.3)

272 (25.6)

167 (15.7)

884 (83.3)

119 (11.2)

CABG

101 (9.5)

94 (8.9)

Medication for Heart Failure (n, %)

Aetiology of Heart Failure (n %)

Baseline characteristics 2


SENIORS

SENIORS

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%)

Maintenance dose achieved


SENIORS

SENIORS

Nebivolol

Placebo

All cause mortality or CV hospital admission (primary outcome)

Event free

Survival %

Hazard Ratio 0.86 [0.74;0.99] p = 0.039

No. of events: Nebivolol 332 (31.1%); Placebo 375 (35.3%)


SENIORS

SENIORS

Nebivolol

Placebo

All cause mortality

(main secondary outcome)

Event free

Survival %

Hazard Ratio 0.88 [0.71;1.08] p = 0.214

No. of events: Nebivolol 169 (15.8%); Placebo 192 (18.1%)


SENIORS

SENIORS

LVEF

Age

148 (27.5%)

101 (24.6%)

184 (34.8%)

332 (31.1%)

110 (28.9%)

219 (32.1%)

231 (35.2%)

176 (33.5%)

125 (33.3%)

125 (33.6%)

250 (36.4%)

375 (35.3%)

249 (36.3%)

199 (37.1%)

> 75 y

> 35 %

Female

 35 %

Male

70-75 y

Total

Sex

0.60

0.50

0.70

0.80

0.90

1.00

1.10

1.20

Death or CV hospitalisation by subgroup

Favours

Nebivolol

Favours

Placebo

Nebivolol

Placebo

Hazard ratio and 95% CI


SENIORS

SENIORS

Premature treatment discontinuations (other than death)

Discontinuation

Nebivolol

Placebo

Patient

Request

Other Reason

Developed

Contraindication

Mandatory

Indication

Intolerance

Discontinuation Category


SENIORS

SENIORS

Sub studies

ECHO

Neurohormonal


SENIORS

SENIORS

Conclusions

  • Nebivolol significantly reduced death or

  • hospitalisation in elderly heart failure patients

  • The effect was similar regardless of ejection

  • fraction, age or gender


SENIORS

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


SENIORS

SENIORS

Acknowledgements

Steering Committee:

Philip Poole-Wilson (UK), Andrew Coats (AUS) (Co Chairs), Anker S ,Böhm M, Borbola J, Cohen-Solal A, DumitrascuD, 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 atwww.cteu.organdwww.menarini.com


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