The SENIORS trial: effects of beta-blockers in elderly patients with heart failure

1. The SENIORS trial: effects of beta-blockers in elderly patients with heart failure Dr Marcus Flather Director Clinical Trials and Evaluation Unit, Royal Brompton Hospital and Imperial College, London Heart Failure 2009, Nice, France m.flather@rbht.nhs.uk www.cteu.org

2. Potential conflicts of interest • Member of Steering Committee of the SENIORS trial • Research grants and honoraria for speaker meetings from Menarini

3. Professor Philip Poole-Wilson 1943-2009

4. Incidence of Heart Failure in The Population The Hillingdon Study Cowie, Wood, Coats, Poole-Wilson, Thompson, Suresh, Sutton % • Population of 151,000 in West London • 82 GP’s • Rapid access HF clinic • Survey of all admissions to local hospital • 20 month study • HF diagnosed by a panel of experts Eur Heart J. 1999 Mar;20(6):421-8. Age (years)

5. LV systolic function in elderly patients with HF: The Cardiovascular Health Study: cross sectional population based survey 12% 29% 21% 41% Women Men 67% 30% n= 426, >65 yrs Kitzman et al, Am J Cardiol. 2001 Feb 15;87(4):413-9

6. 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 On behalf of the SENIORS Steering Committee and Investigators Study sponsored by Menarini SpA Flather, Shibata, Coats et al European Heart Journal 2005;26: 215–225

7. SENIORS SENIORS: Study Objective • To evaluate the safety and efficacy of nebivolol, a beta-1 receptor blocker with vasodilating properties, compared to placebo, on mortality and morbidity in elderly CHF patients with a broad range of EF

8. SENIORS Study Outcomes Primary outcome Composite of all-cause mortality or cardiovascular hospital admissions* (time to first event) Main secondary outcome All-cause mortality (time to event) * Admissions for AMI, unstable angina pectoris, worsening of CHF, stroke, TIA, cardiac arrhythmia, cardiac arrest, thromboembolic episode, dissection of aortic aneurysm, invasive/surgical procedure, or other cardiac reasons)

9. 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

10. 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

11. SENIORS Study drug administration 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

12. 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%) SENIORS Maintenance Dose Achieved

13. Nebivolol (1067) Placebo (1061) Age (mean, yrs) 76.1 76.1 LVEF  35 % (n, %) * II I NYHA Class (n, %) LVEF (mean, %) III IV 683 (64.3) 603 (56.5) 413 (38.7) 32 (3.0) 19 (1.8) 36.0 597 (56.3) 411 (38.7) 686 (64.8) 24 (2.3) 36.0 29 (2.7) Male (n, %) 657 (61.6) 686 (64.7) SENIORS Baseline Characteristics 1 * 7 patients with missing LVEF at baseline

14. SENIORS: Distribution of Age 225 75 years 200 175 150 125 Number of patients 100 75 50 25 SENIORS 0 70 75 80 85 90 95 Age (years)

15. SENIORS: Distribution of Ejection Fraction 600 500 400 Number of patients 300 200 100 0 10 - 14 15 - 19 20 - 24 25 - 29 30 - 34 35 - 39 40 - 44 45 - 49 50 - 54 55 - 59 60 - 64 65 - 69 70 - 74 75 - 80 Left ventricular ejection fraction (%) 35%

16. Event free Survival % Hazard Ratio 0.86 [0.74;0.99] p = 0.039 SENIORS No. of events: Nebivolol 332 (31.1%); Placebo 375 (35.3%) ARR 4.2% All Cause Mortality or CV Hospital Admission (Primary Outcome)Average treatment period 21 months n= 2128 European Heart Journal 2005;26: 215–225

17. Event free Survival % Hazard Ratio 0.88 [0.71;1.08] p = 0.214 SENIORS No.of events: Nebivolol 169 (15.8%); Placebo 192 (18.1%) All Cause Mortality(Main Secondary Outcome)Average treatment period 21 months n=2128

18. SENIORS Premature Treatment Discontinuations (other than Death) Discontinuation Other reasons Clinical reasons Patient Request Discontinuation 24.6% Placebo 26.6% Nebivolol Discontinuation Category

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

20. Potential effects of nebivolol on death or CV hospitalisation by dose achieved Placebo Nebivolol 10mg 5mg % events 0mg 1.25-2.5mg Months after randomisation Dobre, Van Veldhuisen et al Am Heart J. 2007 Jul;154(1):109-15

21. 21

22. 22

23. Cost Effectiveness of Nebivolol in Elderly Patients with Heart Failure: SENIORS Cost effectiveness analysis indicates that nebivolol is highly cost-effective treatment for elderly patients with HF compared to standard therapy with Incremental cost of £1,720 Incremental life years were 0.831 Incremental quality adjusted life years (QALYs) were 0.649 The incremental cost effectiveness ratio was: £2,069 (95% CI 1,947 to 2,217)(€ 3,000)per life year £2,670 (95% CI 2,475 to 2,918)(€ 3,871)per QALY Freemantle et al 2007

24. Nebivolol cost-effectiveness for the treatment of CHF in comparison to other selected therapies NICE threshold2 Medical interventions Nebivolol (for CHF) 3 Angiotensin II receptor antagonist (for hypertension)4 Not cost- effective Inhaled corticosteroids (for asthma)5 Combination therapy (2-adr. rec. agonist/ corticosteroid oral inhaler) (for asthma)6 Statin (for hypercholesterolaemia)1,7 Lipase inhibitors (for obesity)8 Potentially cost-effective Cox-II inhibitors (non high risk) (for arthritis)8 Neuraminidase inhibitor (for influenza)8 Cost-effective -interferon (for multiple sclerosis)1,8 Statins Nebivolol Cost-effectiveness of Nebivolol compares favourably with many other medical interventions.

25. 25 SENIORS subgroups which most closely resemble previous studies 250 700 600 200 500 150 400 Number of patients Number of patients 300 100 200 50 100 0 0 75 yrs 35% 70 80 85 90 95 20-24 40-44 50-54 60-64 70-74 '10-14 LVEF (%) Age (years) Flather MD. EHJ 2005;26:215-5

26. 26 Comparing SENIORS with previous BB Trials All cause mortality • CIBIS II Investigators, Lancet 1999; 353:9-13; • MERIT HF Study group, Lancet 1999; 353: 2001-07; • Packer M et al. N Eng J Med 2001;344(22):1651-1658

27. Age and EF of Patients in Major Placebo-Controlled Trials of ß-Blockers in CHF Trial ß-blocker N Mean EF Mean age US Carvedilol Carvedilol 1094 22 58 MERIT-HF Metoprolol XL 3991 28 64 CIBIS-II Bisoprolol 2647 28 61 BEST Bucindolol 2708 23 60 COPERNICUS Carvedilol 2289 20 63 Nebivolol 2128 76 SENIORS 36 Total 14857

28. European Society of Cardiology Heart Failure Guidelines 2008 Dickstein et al EHJ 29:2388-442

29. SENIORS Conclusions • Beta blockers are now standard treatment for heart failure but are still under used • The elderly have a different HF profile to younger patients • All elderly patients with impaired EF or history of HF admission should be considered for beta blockers with careful titration and monitoring • Nebivolol is the only agent with specific evidence in the elderly, and can be applied go a broad range of patients including preserved LF function

30. Acknowledgements • SENIORS Steering Committee and Investigators • SENIORS Co-Chairs: Philip Poole-Wilson and Andrew Coats • Menarini • European Society of Cardiology

31. Discussion