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SENIORS

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

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  1. 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

  2. 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

  3. 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

  4. 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

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

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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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%)

  17. 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%)

  18. 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

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

  20. SENIORS SENIORS Sub studies ECHO Neurohormonal

  21. 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

  22. 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

  23. 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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