Beta-blockers play an important role in the management of cardiovascular diseases by reducing sympathetic nervous system activation, balancing myocardial oxygen supply and demand, increasing the threshold for ventricular fibrillation during ischemia, and reducing myocardial oxygen consumption. They are indicated for hypertension, ischemic heart disease, arrhythmias, congestive heart failure, and other conditions. Studies show beta-blockers reduce mortality and cardiovascular events in heart failure and post-myocardial infarction more than other drug classes.

1. Role of beta-blockers in the management of
cardiovascular diseases

2. The Cardiovascular Continuum in Hypertension and the
Relative Preventive Effect of BP Lowering and Ancillary
Actions of Antihypertensive Agents
BP 
+
Specific
Ancillary
Actions
BP 
+
Specific
Ancillary
Actions
BP 
+
Specific
Ancillary
Actions BP 
+
Specific
Ancillary
Actions
Metabolic Syndrome
Dyslipidemia
LVH
IMT
Microalb.
Mild Renal Disease
Recent Diabetes
Endothelial Dysfunction
MI
Stroke
CHF
ESRD
Angina
TIA
Claudicatio
Proteinuria
Moderate Renal Disease
Established Diabetes
Subclinical
Organ
Damage
Risk
Factors
Clinical
Disease
Cardio-
vascular
Event
Death
Hypertension
Zanchetti J Hypertens 2005;23:1113-20

4. Kaplan’s clinical hypertension

5. Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.21

7. Poldermans D et al. NEJM 1999; 341: 1789-94
Zaugg M. Der Anaesthesist 2000; 49: 570-585
Reduce sympathetic nervous system activation
(heart rate and myocardial contractility); balance
the myocardial oxygen supply/demand ratio
Increase the threshold for ventricular fibrillation in the
presence of ischemia
May increase the stability of coronary atherosclerotic plaques
May reduce myocardial oxygen consumption by suppressing
lipolysis, causing the myocardium to metabolize more glucose
instead of fatty acids
Cardioprotective mechanisms of beta-blockers

8. Indications for ß-Blockade & US FDA-Approved Drugs
Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2
Bisoprolol, atenololPerioperarive ischemia
Propranolol, timolol, metoprolol, carvedilolAMI, follow-up
Atenolol, metoprololAMI, early phase
NoneSilent ischemia
Propranolol, nadolol, atenolol, metoprololAngina pectoris
1. Ischemic Heart Disease
US FDA-Approved DrugsIndications for ß-Blockade

9. Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2
2. Hypertension
Hypertension, systemic Acebutolol, atenolol,
bisoprolol, labetalol,
metoprolol, nadolol,
pindolol, propranolol,
timolol
Hypertension, severe, urgent Labetalol
Hypertension with LVH Prefer angiotensin receptor
blocker
Hypertension, isolated systolic No outcome studies, prefer
diuretic, CCB
Pheochromocytoma( already
receiving ˆ blockade)
Propranolol
Hypertension, severe, perioperative Esmolol
Indications for ß-Blockade US FDA-Approved Drugs
Indications for ß-Blockade & US FDA-Approved Drugs

10. 3. Arrhythmias
Excess urgent sinus tachycardia Esmolol
Tachycardias (sinus, SVT &VT) Propranolol
Supraventricular, perioperative Esmolol
Recurrences Of Afib, Afl Sotalol
Control of ventricular rate in
Afib,Afl
Propranolol
Digitalis-induced
tachyarrhythmias
Propranolol
Anesthetic arrhythmias Propranolol
PVC control Acebutolol,
propranolol
Serious ventricular tachycardia Sotalol
Indications for ß-Blockade US FDA-Approved Drugs
Indications for ß-Blockade & US FDA-Approved Drugs
Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2

11. 4 Congestive Heart Disease Carvedilol, metoprolol
(bisoprolol)
5. Cardiomyopathy
Hypertrophic obstructive
cardiomyopathy
Propranolol
6. Other cardiovascular indications
Neurocardiogenic syncope, aortic
dissection
(Propranolol; ? all)
Marfan’s syndrome, mitral valve
prolapse, congenital QT
prolongation
Tetralogy of Fallot, fetal
tachycardia
7. Central indications
Anxiety (Propranolol)
Opie LH. Drug for the Heart. Elsevier Saunders 2005, 6th ed p.2
Indications for ß-Blockade US FDA-Approved Drugs
Indications for ß-Blockade & US FDA-Approved Drugs

12. - Chobanian AV et al. JNC 7. JAMA 2003 ; 289 : 2560-2572
- ESH Guidelines Committee. J Hypertens 2003 ; 21 : 1011-1053
Compelling indications for beta-blockade
Hypertension /Heart Failure
Hypertension /post MI
Hypertension /high CAD risk
Hypertension /Diabetes Mellitus
Hypertension /arrhythmias
Hypertension /angina pectoris

13. MECHANISMS OF PRIMARY (ESSENTIAL) HYPERTENSION
BRAUNWALD'S HEART DISEASE

14. BRAUNWALD'S HEART DISEASE
renal juxtaglomerular
Renin-Angiotensin Mechanism
ACEI
ARB
Beta-blocker

15. Beta-blocker therapy should be started and continued for
3 years in all patients with normal LV function after MI or
ACS.
Beta-blocker therapy should be used in all patients with
LV systolic dysfunction (EF ≤40%) with heart failure or
prior MI, unless contraindicated. (Use should be limited
to carvedilol, metoprolol succinate, or bisoprolol, which
have been shown to reduce risk of death.)
Beta blockers may be considered as chronic therapy for
all other patients with coronary or other vascular
disease.
I IIa IIb III
I IIa IIb III
I IIa IIb III
Beta-Blocker Therapy

16. Beta Blockers
Beta blockers are indicated for all patients
recovering from UA/NSTEMI unless
contraindicated. (For those at low risk, see
Class IIa on the next slide). Treatment should
begin within a few days of the event, if not
initiated acutely, and should be continued
indefinitely.
Patients recovering from UA/NSTEMI with
moderate or severe LV failure should receive
beta-blocker therapy with a gradual titration
scheme.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

17. Beta Blockers
It is reasonable to prescribe beta blockers to
low-risk patients (i.e., normal LV function,
revascularized, no high-risk features) recovering
from UA/NSTEMI in the absence of absolute
contraindications.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

18. 18
b-Blocker Saves Lives in Heart Failure?
b–blocker is the most important progress in
Heart Failure Rx in the last 5 years

19. Effect of medical therapies that affect the natural history of heart
failure based on the primary site of action. CRT-(D) indicates
cardiac resynchronization therapy plus defibrillator; ACEIs,
angiotensin-converting enzyme inhibitors; and Aldo, aldosterone

21. Volume
Overload
Pressure
Overload
Loss of
Myocardium
Impaired
Contractility
LV Dysfunction
EF < 40%
 Cardiac
Output
Hypoperfusion
 End Systolic Volume
 End Diastolic Volume
Pulmonary Congestion
Left Ventricular Dysfunction

22. 22
Effect of BetaBlockadeonOutcome
inPatientsWithHFandPost-MI LVD
↓23%mortality(p=.031)25BIDpost-MI
LVD
carvedilolCAPRICORN5
↓35%mortality(p=.0014)25BIDseverecarvedilolCOPERNICUS4
↓34%mortality(p=.0062)200QDmild/
moderate
metoprolol
succinate
MERIT-HF3
↓34%mortality(p<.0001)10QDmoderate/
severe
bisoprololCIBIS-II2
↓48%diseaseprogression
(p=.007)
6.25-
25BID
mild/
moderate
carvedilolUSCarvedilol1
Outcome
Target
Dose(mg)
HF
SeverityDrugStudy
1.Colucci WSet al. Circulation1196;94:2800-6.
2. CIBISII Investigators. Lancet 1999;353:9-13.
3. MERIT-HFStudyGroup. Lancet 1999;353:2001-7.
4. Packer Met al. NEngl JMed2001;3441651-8.
5. TheCAPRICORNInvestigators. Lancet 2001;357:1385-90.

24. Placebo-controlled randomised European trial
Objectives:
 Mortality
 Tolerability of beta-blockade
by bisoprolol in heart failure
Lechat Ph et al. Circulation 1994; 90: 1765–1773
C I B I S I
Cardiac Insufficiency Bisoprolol Study

25. • Reduction of mortality with bisoprolol in patients ...
... in total (n = 641) – 20% p = 0.22
... without myocardial infarction – 47% p = 0.01
... with dilated cardiomyopathy – 53% p = 0.01
... with a ventricular rate of over 80 beats/minute – 42% p < 0.05
• Reduction by one NYHA class in patients receiving ...
... bisoprolol 21% p = 0.04
... placebo 15%
• Reduction in heart failure decompensation – 32% p < 0.01
requiring hospitalisation
Lechat Ph at the CIBIS investigators’ meeting at the Journées Européennes
de la Société Française de Cardiologie, Paris, 1994
CIBIS I: Main results

26. • Double-blind, placebo-controlled, randomised trial
• 2,647 patients included (NYHA III + IV)
• Bisoprolol administered on top of standard therapy
(diuretic + ACE inhibitor)
CIBISIIInvestigatorsandCommittees.Lancet1999;353:9–13
CIBIS II
Cardiac Insufficiency Bisoprolol Study

27. • Ambulatory patients with stable CHF of all aetiologies
• NYHA functional class III or IV
• Stable on ACE inhibitor and diuretic
• Aged 18 – 80 years
• Left ventricular ejection fraction ≤ 35%
CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13
CIBIS II
Main inclusion criteria

28. In the bisoprolol-treated group of patients there was a reduction in
• All-cause mortality (independent of aetiology) by 34% (p<0.0001)
• Sudden death by 44% (p<0.0011)
• All-cause hospital admissions by 20% (p<0.0006)
• Hospital admissions due to worsening heart failure by 36% (p<0.0001)
CIBIS II Investigators and Committees. Lancet 1999; 353: 9–13
CIBIS II
Main results at a glance

29. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22: 1527-60
Chronic heart failure:
 Still a major clinical and public health problem
 Current pharmacological therapy:
 ACE-inhibitors
 Beta-blockers
 Diuretics
 Aldosterone antagonists
 Digitalis glycosides
C I B I S III
Cardiac Insufficiency Bisoprolol Study

30. Background
 Guidelines universally recommend that treatment of
patients with chronic heart failure (CHF) should be initiated
with an angiotensin-converting enzyme inhibitor (ACEi) to
which a β-blocker should be added as second step therapy.
 These recommendations are not based on evidence.
 No study has examined the safety and efficacy of initiating
CHF treatment with an ACEi versus a β-blocker.
 Several mechanistic reasons support choosing beta-
blockade as first therapy in CHF.
Willenheimer et al., Circulation 2005; 112: 2426-35

31. Background (conti…)
• Sympathetic nervous system is activated prior to RAAS in CHF.
• In the early course of CHF, sudden death is the most prevalent
mode of death.
• β-blockers in contrast to ACEi are proven highly effective in
reducing sudden death.
• From the pathophysiological point of view it may be appropriate to
start with a β-blocker first.
Willenheimer et al., Circulation 2005; 112: 2426-35

32. PoldermansDetal.NEJM1999;341:1789-94
ZauggM.DerAnaesthesist2000;49:570-585
reduce sympathetic nervous system activation
(heart rate and myocardial contractility); balance
the myocardial oxygen supply/demand ratio
increase the threshold for ventricular fibrillation in the
presence of ischemia
may increase the stability of coronary atherosclerotic plaques
may reduce myocardial oxygen consumption by suppressing
lipolysis, causing the myocardium to metabolize more glucose
instead of fatty acids
Cardioprotective mechanisms of beta-blockers

33. Beta-blockade:
• Renoprotective in patients with CHF,
reduce the risk of worsening renal function which is frequently observed
with ACE-inhibitors
1,2
 pretreatment with beta-blockers protective against the potential
development of renal impairment with ACE-inhibitors
• More effective in reducing sudden cardiac death than ACE-inhibitors
3-7
 up to 40-60% of patients with CHF die from sudden cardiac death
(mainly in early stages of CHF)
4,7,8
1.KnightELetal.AmHeartJ1999;138:849-552.BartBA.AmHeartJ1999;138:801-33.CIBISIIInvestigators
Committees.Lancet1999;353:9-134.MERIT-HFStudyGroup.Lancet1999;353:2001-7
5.PackerMetal.NEnglJMed2001;344:1651-586.GargRetal.JAMA1995;273:1450-56
7.AliotEetal.EurHeartJ2002:4(SupplD);D31-D428.UretskyBFetal.JACC1997;30:1589-97
CIBIS III
Rationale

34. Sudden Death
In Chronic Heart Failure
50-80
30-50
5-30
5-15
20-50
30-70
II
III
IV
Sudden Death(%)Annual Mortality (%)NYHA Functional Class
These data summarize mortality estimates from the published data
Uretsky and Sheahan JACC 1997;30 : 1589-97

35. • ACE-inhibitors:
mortality reduction of about 25%1
• ACE-inhibitors + beta-blockers:
further reduction of 30-35%2-5
1.GargRetal.JAMA1995;273:1450-562.ShibataMCetal.EurJHeartFailure2001;3:351-57
3.CIBISIIInvestigatorsCommittees.Lancet1999;353:9-134.MERIT-HFStudyGroup.Lancet1999;
353:2001-75.PackerMetal.NEnglJMed2001;344:1651-586.ExnerDVetal.JACC1999;33:916-23
 beta-blockers more effective than ACE-inhibitors in CHF?6
CIBIS III
Rationale

36. • Age ≥ 65 years
• Mild to moderate CHF (NYHA class II or III)
• LVEF ≤ 35%
• Stable CHF since ≥ 7 days
(without clinically relevant fluid retention/diuretic adjustment)
Willenheimeretal.,Circulation2005;112:2426-35
Cardiac Insufficiency Bisoprolol Study III
Inclusion criteria

37. Bisoprolol-first (o.d.)
Enalapril-first (b.i.d.)
Bisoprolol o.d.
Enalapril b.i.d.
Bisoprolol o.d.
Enalapril b.i.d
week Study end
1 - 2.5 years
0 2 4 6 8 10 26 28 30 32 34 36week Study end
1 - 2.5 years
First up-titration
First up-titration
Second up-titration
Second up-titrationMaintenance period
Maintenance period
Second maintenance period
22-100 weeks
Second maintenance period
16-94 weeks
1.25
2.5
3.75
5.0
7.5
1.25
2.5
3.75
5.0
7.5
2.5 5.0
2.5 5.0
* * * * * * * * * * * * * * * * ……….……. * * * * *
* = visits
10.0 mg
10.0 mg
10.0 mg
10.0 mg
Bisoprolol o.d.
Enalapril b.i.d
0 2 4 6 8 10 26 28 30 32 34 36
* * * * * * * * * * * * * * * * ……….……. * * * * *
Willenheimeretal.,Circulation2005;112:2426-35
Study design
Cardiac Insufficiency Bisoprolol Study III

38. In terms of combined mortality / hospitalization
Bisoprolol-first was non-inferior to enalapril-first in the ITT sample
Bisoprolol-first was close to non-inferior to enalapril-first
in the PP sample
Willenheimer et al., Circulation 2005; 112: 2426-35
Intention-to-treat (ITT)
Per-protocol (PP)
Cardiac Insufficiency Bisoprolol Study III
Conclusions

39. There was no difference in safety between the two strategies,
showing that a bisoprolol-first strategy does not cause concerns
Willenheimer et al., Circulation 2005; 112: 2426-35
Cardiac Insufficiency Bisoprolol Study III
Conclusions

40. The CIBIS III result supports a free choice
of initial treatment for CHF - enalapril or bisoprolol -
based on the physician’s individual judgment
in each patient
Willenheimer et al., Circulation 2005; 112: 2426-35
Clinical implication

41. MERIT-HF: Metoprolol CR/XL Randomized
Intervention Trial in congestive Heart Failure
Purpose
To determine whether metoprolol controlled/extended release
(CR/XL) once daily, in addition to standard therapy, can lower
mortality in patients with decreased ejection fraction and
symptoms of heart failure
Reference
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic
heart failure: Metoprolol CR/XL Randomised Intervention Trial in
Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001–7.

42. MERIT-HF: Metoprolol CR/XL Randomized
Intervention Trial in congestive Heart Failure
- TRIAL DESIGN -
Design
Randomized, double-blind, placebo-controlled
Patients
3991 patients with left ventricular ejection fraction <0.40 and NYHA
class II-IV heart failure, stabilized by optimum standard therapy (any
combination of diuretics + ACE inhibitor)
Follow up and primary endpoint
Aim 2.4 years follow up. Primary endpoint all-cause mortality
Treatment
Patients assigned metoprolol received 12.5 (NYHA III-IV) or 25 mg
(NYHA II) once daily, increasing over 8 weeks to maximum target
dose 200 mg once daily

43. MERIT-HF: Metoprolol CR/XL Randomized
Intervention Trial in congestive Heart Failure
- RESULTS -
• Study halted at mean follow up of 1 year on recommendation of
independent safety committee because predefined criteria met
and exceeded:
—All-cause mortality significantly lower in metoprolol CR/XL
group (145 vs. 217, 34% risk reduction, P=0.0062)
—Significantly fewer cardiovascular deaths (128 vs. 203),
sudden deaths (79 vs. 132) and death from worsening heart
failure (30 vs. 58)
• Drug well tolerated, as defined by permanent early
discontinuation of treatment (13.9% of metoprolol CR/XL group
versus 15.3% placebo)

44. MERIT-HF: Metoprolol CR/XL Randomized
Intervention Trial in congestive Heart Failure
- RESULTS continued -
MERIT-HF Study Group. Lancet 1999;353:2001–7.
No patients lost to follow up
MERIT-HF trial profile
3991 patients
randomized
2001 patients
placebo
217 patient
deaths
1784 patients alive
1539 patients on treatment
145 patient
deaths
1990 patients
metoprolol CR/XL
1845 patients alive
1614 patients on treatment

45. MERIT-HF: Metoprolol CR/XL Randomized
Intervention Trial in congestive Heart Failure
- RESULTS continued -
Cumulative all-cause mortality
MERIT-HF Study Group. Lancet 1999;353:2001–7.
Follow up (months)
P = 0.0062 (adjusted for
interim analysis)
P = 0.00009 (nominal)
0
0
3 6 9 12 16 18 21
5
10
15
20
Placebo
Metoprolol CR/XL
Cumulative
mortality
(%)

46. MERIT-HF: Metoprolol CR/XL Randomized
Intervention Trial in congestive Heart Failure
- RESULTS continued -
MERIT-HF Study Group. Lancet 1999;353:2001–7.
0 0.5 1.0 1.5
Relative risk for mortality
Relative risk (95% CI)
Mortality Metoprolol CR/XL better
Risk
reduction
(%)
Total mortality
Cardiovascular mortality
Sudden death
Death from worsening
heart failure
34
38
41
49
0.0062
0.00003
0.0002
0.0023
P

47. MERIT-HF: Metoprolol CR/XL Randomized
Intervention Trial in congestive Heart Failure
- SUMMARY -
Metoprololol CR/XL once daily in addition to optimum standard
therapy:
• Was well tolerated and did not increase risk in any of subgroups
analyzed
• Improved survival in clinically stable patients, equating to
prevention of 1 death per 27 patients treated per year

48. Effect of carvedilol, bisoprolol and metoprolol on
mortality in CHF
• 1094 patients with class II–IV CHF randomised to placebo
or carvedilol for up to 15 months
• 65% in all-cause mortality (stopped by DSMB)
US Carvedilol Heart Failure Program
CIBIS II trial
• 2647 patients with class III–IV CHF randomised to placebo
or bisoprolol for up to 3 years
• 34% in all-cause mortality (stopped by DSMB)
MERIT-HF trial
• 3991 patients with class III–IV CHF randomised to placebo
or metoprolol for up to 3 years
• ~34%  in all-cause mortality (stopped by DSMB)
Packer (1996); CIBIS-II (1999); MERIT-HF (1997)

49. Multicentre trials of b-blocker effects on
morbidity and mortality in CHF
Study Effect on Effect on Effect on
pre-specified endpoint mortality morbidity
MDC  Morbidity/mortality  Non-significant  In risk of worsening
by 34% (p=0.058) in mortality heart failure
CIBIS-I  Mortality by Mortality by 20%  Hospitalisations
20% (p=0.22) (especially non-ischaemic) for heart failure by 34%
ANZ Carvedilol  Morbidity/mortality  Mortality by 25–35%  Cardiovascular
by 26% (p=0.02) (ischaemic only) hospitalisations by
25–30%
US Carvedilol  Mortality by Mortality by 65%  Cardiovascular
65% (p=0.001) (ischaemic and hospitalisations by 26%
non-ischaemic)
ANZ, Australia–New Zealand Cooperative Study
CIBIS-I, Cardiac Insufficiency Bisoprolol Study
MDC, Metoprolol in Dilated Cardiomyopathy Study
US Carvedilol, US Carvedilol Heart Failure Program

50. b-adrenergic blocking drugs in heart failure
Principal randomized trials - more than 250 patients,
greater than 6 months follow-up
Annualized mortality rate
Placebo mortality
rate (annualized %)
b-blocker mortality
rate (annualized %)
US Carvedilol 15%* 6%*
CIBIS-II 13.2% 8.8%
MERIT-HF 11.0% 7.2%
*estimated from 7 month data

51. Carvedilol vs placebo in patients with mild, moderate
and severe CHF
The US Study Program protocol
• Patient population
– 1094 patients with chronic CHF
– CHF  3 months
– LVEF 35% despite  2 months treatment with diuretics + ACE-I
• Planned study duration
– 6–12 months (prematurely terminated because of a significant effect of
carvedilol on survival)
• Exclusion criteria
– active ventricular tachycardia
– HR <68 bpm
– systolic BP <85 mmHg or >160 or diastolic BP > 100 mmHg
• Primary outcomes
– death from cardiovascular causes
• Secondary outcomes
– frequency of hospitalisation for cardiovascular reasons Packer (1996)

52. Effect of carvedilol on morbidity
and mortality
The US Study Program
ACE inhibitor
Digitalis
Diuretic
Packer (1996)
Mortality
Hospital days
–52%
–65%
Carvedilol

53. Cause and incidence of death in the US
Carvedilol Heart Failure Program
Cause of death
Progressive heart failure
Sudden death
Myocardial ischaemia
Other cardiovascular causes
Noncardiovascular causes
Placebo Carvedilol
(n=398) (n=696)
No. (%)
13 (3.3) 5 (0.7)
15 (3.8) 12 (1.7)
2 (0.5) 1 (0.1)
1 (0.3) 2 (0.3)
0 2 (0.3)
Packer (1996)

54. US Carvedilol Heart Failure Program
Most frequent adverse reactions leading to
discontinuation of treatment
Adverse event*
Heart failure
Fatigue
Myocardial infarction
Bradycardia
Dyspnoea
Dizziness
Hypotension
Syncope
Nausea
Abnormal liver function
Worsening renal function
Depression
Placebo Carvedilol
(n=398) (n=696)
no. (%)
9(2.3) 11(1.6)
3(0.8) 5(0.7)
4(1.0) 3(0.4)
0 6(0.9)
4(1.0) 2(0.3)
0 3(0.4)
1(0.3) 2(0.3)
1(0.3) 2(0.3)
0 3(0.4)
1(0.3) 2(0.3)
1(0.3) 2(0.3)
1(0.3) 2(0.3)
*Patients may have had more than one reaction
leading to withdrawal of placebo or carvedilol
Packer (1996)

55. Patient subgroup Placebo Carvedilol
(%) (%)
Mild heart failure 3.7 0.9
Moderate heart failure 7.6 4.5
Severe heart failure 5.7 2.9
Age<59 years 5.8 2.0
Age59 years 9.6 4.3
Male 7.2 3.2
Female 9.6 3.1
Ischaemic cause 9.0 3.9
Non-ischaemic cause 6.7 2.5
US Carvedilol Heart Failure Program
% deaths in patient subgroups
Packer (1996)

56. US Carvedilol Heart Failure Program
Effects in patient subgroups
Patient subgroup*
Protocol
Mild heart failure
Moderate heart failure
Dose-ranging
Severe heart failure
Age (yr)
<59
59
Gender
Male
Female
Left ventricular
ejection fraction
<0.23
0.23
Placebo Carvedilol
5/134 2/232
11/145 6/133
13/84 12/261
2/35 2/70
11/190 7/350
20/208 15/346
22/304 17/534
9/94 5/162
20/209 10/334
11/189 12/360
No of deaths/total no
Hazard ratio
(98% Cl)†
0.22 (0.04–1.14)
0.57 (0.21–1.54)
0.27 (0.12–0.60)
0.53 (0.07–3.76)
0.30 (0.11–0.80)
0.38 (0.19–0.77)
0.41 (0.22–0.80)
0.23 (0.07–0.69)
0.25 (0.11–0.56)
0.49 (0.21–1.14)
* For continuous variables, medians were used to define the subgroups. The type of heart
failure was not recorded for one patient in the placebo group and two in the carvedilol group.
The ejection fraction was not recorded for two patients in the carvedilol group.
Packer (1996)
†CI denotes confidence interval

57. * For continuous variables, medians were used to define the subgroups. The type of heart
failure was not recorded for one patient in the placebo group and two in the carvedilol
group. The ejection fraction was not recorded for two patients in the carvedilol group.
Patient subgroup*
6-minute walk (m)
<396
396
Cause of heart failure
Ischaemic
Non-ischaemic
Systolic blood pressure
(mm Hg)
<115
115
Heart rate (bpm)
<82
82
Placebo Carvedilol
20/202 17/345
11/196 5/351
17/189 13/332
14/208 9/362
19/210 13/337
12/188 9/359
10/186 11/354
21/212 11/342
No of deaths/total no
Hazard ratio
(98% Cl)†
0.49 (0.25–0.93)
0.25 (0.09–0.71)
0.35 (0.16–0.73)
0.35 (0.15–0.83)
0.34 (0.17–0.70)
0.38 (0.15–0.95)
0.61 (0.25–1.49)
0.26 (0.12–0.55)
†CI denotes confidence interval
US Carvedilol Heart Failure Program
Effects in patient subgroups
Packer (1996)

58. 58
Study of Effects of Nebivolol Intervention on
Outcomes and Rehospitalisation in Seniors
with Heart Failure
A randomised, double-blind, placebo-controlled
phase III study
SENIORSSENIORS

59. 59
• 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%
Hillingdon study results
baseline characteristics
BackgroundSENIORSSENIORS

60. 60
• To evaluate the effect of nebivolol
compared to placebo on mortality and
morbidity in elderly CHF patients
Study objectiveSENIORSSENIORS

61. 61
• 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 - Outcome measuresSENIORSSENIORS

62. 62
• 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
Inclusion criteriaSENIORSSENIORS

63. 63
• 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
Main exclusion criteriaSENIORSSENIORS

64. 64
2135 randomised
1067 assigned to
nebivolol
1061 assigned to
placebo
Patients not in ITT: 7
6 from excluded centre
1 error in randomisation
2128 evaluable
Patient flowSENIORSSENIORS

65. 65
IV 19 (1.8) 24 (2.3)
Age (mean, yrs)
Male (n, %)
Nebivolol
76.1
657 (61.6)
Placebo
76.1
686 (64.7)
LVEF  35 % (n, %)* 683 (64.3) 686 (64.8)
LVEF (mean, %) 36.0 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 1SENIORSSENIORS

66. 66
Aldosterone Antag. 298 (27.9) 272 (25.6)
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)
Aetiology of Heart Failure (n %)
Ischaemic 812 (76.1) 809 (76.3)
Idiopathic 166 (15.6) 167 (15.7)
Antiarrhythmics 91 (8.3) 119 (11.2)
Baseline characteristics 2SENIORSSENIORS

67. 67
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%)
Maintenance dose achievedSENIORSSENIORS

68. 68
• Nebivolol significantly reduced death or
hospitalisation in elderly heart failure patients
• The effect was similar regardless of ejection
fraction, age or gender
ConclusionsSENIORSSENIORS

69. 69
• 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
Clinical implicationsSENIORSSENIORS