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

BRING UP Reasons for not commencing -blockade SENIORS Background BRING UP Reasons for not commencing -blockade OR 95% CI P value Age 0.97 0.96 - 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

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%

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

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

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

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

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

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

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

Patient flow 2135 randomised 2128 evaluable 1067 assigned to nebivolol 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

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

* 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

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)

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%)

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%)

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%)

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

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

SENIORS Sub studies ECHO Neurohormonal

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

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

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 Slides available at www.cteu.org and www.menarini.com