Heart Failure

1
Nebivolol
in
Heart Failure
2
Heart Failure

• Common
• Difficult
• Mortal
• Expensive
• prevalently affecting elderly (mean age74 yrs)

3
HEART FAILURE problem dimension

• In a city with a population of 1 million people
• 10.000 patients with heart failure
• 5.000 hospital admission /year
• 2.000-3.000 new diagnosis / year
• J Cleland JACC 2003 42 1234

4
INCIDENCE OF HEART FAILURE IN AGE GROUPS
(Framingham Heart Study)
35
30
10-15/1.000 in over 70
25
20
n diseases/1000 habitants
F
15
M
10
5
0
55- 64
45-54
65-74
75-84
85-94
Age groups
Kannel W.B. 1994
5
HEART FAILURE MORTALITY
Death frequently occurs in elderly people
92 of general mortality has been observed in
patients over 65 years.
6
HEART FAILURE
HF is a complex clinical syndrome that can
result from any cardiac disorder impairing the
ability of the ventricle to eject blood or to
fill with it Heart is not able to satisfy
metabolic needs of the body, Or it does it with
an increased ventricular filling pressure (That
is with an increased work).
Reduced cardiac output reduced ejection
fraction (EF lt35-40)
Braunwald 2005,
7
Enlarged heart
Healthy heart
8
HEART FAILURE CAUSES
MYOCARDIAL INFARCTION
LEFT VENTRICULAR DILATION
ISCHAEMIC HEART DISEASE
LEFT VENTRICULAR DYSFUNCTION
ANGINA PECTORIS
ARTERIAL HYPERTENSION
HEART FAILURE
Valvular diseases
LEFT VENTRICULAR HYPERTROPHY
DIASTOLIC DYSFUNCTION
9
Types of heart failure
Depending on heart function mainly impaired,
HEART FAILURE can be divided into
Systolic heart failure
Diastolic heart failure
10
EJECTION FRACTION
Echocardiographic parameter expressing the pump
function
EF systolic volume / tele-diastolic volume
x 100
regular EF gt40-60
11
Systolic heart failure

• Stroke volume
• Ejection fraction
• Cardiac output

REDUCTION
12
Diastolic Heart Failure

Difficult filling of the
ventricle EF is normal or mildly
reduced
13
Two types of HF
Most common form of heart failure.
Systolic heart failure
More frequent in women, elderly, hypertensives
Diastolic heart failure
Sometimes they can coexist deficit of the pump
function AND ventricular filling phase impairment
Systo-diastolic heart failure
14
SYSTOLIC H. F.
DIASTOLIC H. F.
Left Ventricle
Bad emptying
Bad filling
Increase ventricle pressure
Pulmonary congestion,

Pulmonary capillary pression increase
15
SYSTOLIC , DIASTOLIC H. FAILURE
symptoms can be superimposable DYSPNOEA
Reduced Tolerance to maximal exercise
16
Heart Failure signs and symptoms

• Dyspnoea

Hepatomegaly
Tachycardia
Hypotension
Asthenia (Severe stage)
Peripheral Oedema
17
New York Heart Association (NYHA) classification
18
Compensatory mechanism (short term)
Vasoconstriction maintain organ perfusion
19
COMPENSATORY MECHANISMS in the long time...
become toxic to the myocardium
20
Compensatory mechanism (long term)

Salt and water retention pulmonary
congestion
Vasoconstriction exacerbates pump dysfunction,
increase afterload and hypoperfusion
Sympathetic activation increase energy
expenditure
21
COMPENSATORY MECHANISMS IN HEART FAILURE
Difficulty of the heart in pumping the blood
Blood peripheral perfusion reduction
Renal hypoperfusion
Baroceptors Activaction (cardiac chambers,
carotid sinus, aortic arch )
Renin release
Aldosterone
Angiotensin II
Sympathetic activation
Peripheral resistance increase
Volemia increase
Tachycardia positive inotropic effect
Pump function restoring
22
COMPENSATORY MECHANISMS IN HEART FAILURE
Difficulty of the heart in pumping the blood
Blood peripheral perfusion reduction
Renal hypoperfusion
Baroceptors Activaction (cardiac chambers,
carotid sinus, aortic arch )
Renin release
Aldosterone
Angiotensin II
Sympathetic activation
Peripheral resistance increase
Volemia increase
Tachycardia positive inotropic effect
Vasoconstriction Hypoperfusion
Oedema
Tachycardia
23
Noradrenaline plasmatic concentration and
prognosis correlation in chronic heart failure
patients
SOLVD study
24
Toxic effects of Angiotensin II
and Aldosterone chronic action
Noradrenaline and Aldosterone chronic release
HEART FAILURE PROGRESSION
25
DIURETICS
Therapy

• Mainly used to reduce water retention symptoms
  (peripheral oedema and pulmonary congestion).
• They rapidly improve dyspnoea and maximal
  exercise tolerance
• No evidence in reducing mortality.

VASODILATORS

• They reduce cardiac work (after-load)
• No evidence in reducing mortality.

26
Drugs used in the treatment of HF
27
HEART FAILURETREATMENT

• Diuretics in patients with water retention
• ACE inhibitors (ARB, if intolerant)
• Beta blockers (if not contraindicated)
• Digitale (if not contraindicated)
• Aldosterone Antagonists(Spironolactone) in
  patients with preserved renal function, normal
  kaliemia and recent symptoms/ NYHA IV class

Hunt SA et al. J Am Coll Cardiol. 2001 38 2101
28
Beta-blockers
exert a protective effect on the heart since
they prevent the damage to myocardial cells
caused by catecholamines reduce the work of
heart and its oxygen consumption decrease the
probability of arrhythmias directly and
indirectly prevent the mechanism leading to left
vetricular remodelling
29
Guidelines for the diagnosis and treatment of
chronic heart failure executive summary (update
2005)
ACE-I are recommended as 1st line therapy in pts
with a reduced LVEF,(lt40-45) with or without
symptoms. BB should be considered for the
treatment of ALL PATIENTS (NYHA II-IV), WITH
MILD/ MODERATE/SEVERE HF from ischemic/Non
ischemic cardiopathy on standard treatment,
unless theres a contraindication
30
Guidelines for the diagnosis and treatment of
chronic heart failure executive summary (update
2005)
Beta Blockers

• Hospitalizations reduction, symptoms and exercise
  capacity improvement, slowing progression of
  heart failure, survival improvement.

• Starting with low dosage
• To reach gradually the maximum dose tolerated.

• To add to the therapy with ACE - I and Diuretics

31
Endothelial dysfunction in CHF predicts mortality
and hospitalisation
1.0
0.8
FMD gt median
Proportion surviving/ without hospitalisation
0.6
P0.013
0.4
FMD lt median
0.2
70
50
30
10
0
Follow-up (months)
Katz SD et al. Circulation. 2005111310-314
32
HEART FAILURE IN ELDERLY
Progressive aging of the population
Currently the greatest percentage of CHF
patients is represented by the ELDERLY.
However, current therapy of CHF is based on
evidence obtained from trials performed in
younger patients
33
Main clinical trials performed with beta
blockers (vs placebo) in patients with heart
failure MEAN AGE

• Trial Molecule N Mean Age
• US Carvedilol Carvedilol 1094
  58
• MERIT-HF Metoprolol CR/XL 3991 64
• CIBIS II Bisoprolol 2647
  61
• BEST Bucindolol 2708 60
• COPERNICUS Carvedilol 2289
  63
• MEAN 61

34
INCIDENCE OF HEART FAILURE IN AGE GROUPS
(Framingham Heart Study)
35
30
10-15/1.000 in over 70
25
20
n diseases/1000 habitants
F
15
M
10
5
0
55- 64
45-54
65-74
75-84
85-94
Age groups
Kannel W.B. 1994
35
Age of Patients in Major ß-Blocker CHF Clinical
Trials
36
Euroheart Failure Distribution of ejection
fraction
11,015 patients in 115 hospitals in 24 countries
Percentage of patients
Women
14
Men
12
10
8
6
4
2
0
lt10
10-
15-
20-
25-
30-
35-
40-
45-
50-
55-
60-
65-
70-
75-
14
19
24
29
34
39
44
49
54
59
64
69
74
80
Left Ventricular Ejection Fraction ()
Cleland et al Euroheart Survey EHJ 2003
37
Ejection Fraction () of Patients in Major
Placebo-Controlled Trials of ß-Blockers in CHF
EF
N
ß-blocker
Trial
22.6
1094
Carvedilol
US Carvedilol
28.0
3991
Metoprolol CR/XL
MERIT-HF
27.5
2647
Bisoprolol
CIBIS-II
23.0
2708
Bucindolol
BEST
19.8
2289
Carvedilol
COPERNICUS
24.9
Mean
38
TEMISTOCLE (hearT failurE epideMIological STudy
FADOI-ANMCO in taLian pEople)
2.127 patients observed in Internal Medicine
69 (1468)
gt70 yrs of these 7.7
(114) discharged with BB
Beta Blockers not prescribed because of (1.354
paz)

• PAOD(arteriopathy). 1.1
• No indications 1.5
• BAV gt2 o HRlt50 bpm 3.0
• Diabetes 3.5
• Hypotension 4.0
• Other 10.4
• NYHA IV 11.4
• COPD 37.2
• Advanced age gt75 yrs 43.8

Di Lenarda et al. Am Heart J. 2003
39
Italian Network on Congestive Heart Failure in CHF
lt 70
gt 70
AGE
Women
21.3
35.3
SBP
127 20
134 21
HR (bpm)
79 15
78 15
Creatinine gt 2.5 mg/dl
2.4
3.6
Ischaemic Etiology
37.8
50.4
EF()
gt40
22.6
32.6
30 - 40
40.6
38.9
lt30
36.8
28.5
40
BRING UP Reasons for Not Commencing ß-Blockade
Maggioni A et al. Heart 2003
41
Cardiovascular hospitalisation by rate of
guidelines adherence
1.0
0.9
0.8
Estimated probability
Low adherence (0-33)
0.7
Middle adherence (50-67)
0.6
High adherence (100)
Log rank test p0.002
0.5
0
20
60
100
120
40
80
140
160
180
days
Komajda M et al. Eur Heart J 2005
42
NEBIVOLOL IN CHF
CLINICAL TRIALS WITH NEBIVOLOL
43
ENECA trial Study protocol
Main Inclusion Criteria

• 260 hospitalised patients aged more than 65
  years
• Chronic heart failure stages (NYHA II - IV)
• Left ventricular ejection fraction (LVEF) ? 35 
• Stable basic medication of heart failure with
  ACE inhibitors or angiotensin-II A1-receptor
  antagonists (A-II A), diuretics and/or digitalis
  for a minimum of 2 weeks prior to inclusion

44
ENECA trial Primary end-point
Change in LVEF in response to 8 months
treatment with Nebivolol
p0.008
LVEF improvement (visit1 vs. visit11)
45
ENECA STUDY
Nebivolol significantly improves LVEF and didnt
change the QoL of elderly CHF patients
LVEF can be considered a reliable surrogate
parameter to evaluate the therapy in CHF.
46
SENIORS


Study of Effects of Nebivolol Intervention on
Outcomes and Rehospitalisation in Seniors with
Heart Failure Randomized, double blind, placebo
controlled, phase III study 2.135 PATIENTS, 200
CENTRES, 11 EUROPEAN C.

Flather MD. EHJ 200526215-25
47
Study objective



To evaluate effects of nebivolol (1,25 - 10
mg/die) or placebo - as add on therapy -
on total mortality and morbility (CV
hospitalizations) in elderly patients (gt 70 yrs)
with heart failure
Flather MD. EHJ 200526215-25
48
Comparison population in CHF vs SENIORS
SENIORS gt 70
IN CHF gt 70 yrs
Women
38.4
35.3
NYHA III - IV
40.5
39.8
SBP
138.6
134 21
HR (bpm)
79.2
78 15
Creatinine gt 2.5 mg/dl
------
3.6
Ischaemic Etiol.
68.9
50.4
EF ()
gt40
35.7
32.6
gt 35
30 - 40
38.9
lt30
64.3
28.5
lt 35
49
Why Nebivolol in CHF?
Highly cardio-selective Physiological
vasodilation (NO mediated) Positive
effect on endothelial function Tzemos,
Circulation 2001104511

50
NEBIVOLOL
Pharmacodynamic properties In hypertensive
patients during acute or chronic treatment with
nebivolol systemic vasal resistances decrease.
Cardiac output with Nebivolol, despite the
Heart Rate reduction, remains preserved at rest
or during maximal exercise thanks to the increase
of the stroke volume
51
Inclusion Criteria

• Age ? 70 years
• clinical CHF diagnosis and one of the following
• - documented EF ? 35 in the previous 6 months
  
• or
• - HF hospitalizations in the previous year

Flather MD. EHJ 200526215-25
52
Basal Characteristics AGE and EF
250
700
600
200
500
150
400
300
100
N patients
N patients
200
50
100
0
0
70
75
80
85
90
95
'10-14
20-24
30-34
40-44
50-54
60-64
70-74
Age (yrs)
LVEF ()
Flather MD. EHJ 200526215-5
53
Study Design
Randomisation
EOP Visit
FFU Visit
Final Follow up
Screening
Observation Period
Down-Titration
Up-Titration (mg)
Maintenance
10
5
2.5
1.25
Up to 16 weeks
1 to 4 weeks
3 weeks
1 month
Up to 30 months
Flather MD. EHJ 200526215-25
54
PRIMARY END POINT


All cause Mortality and all CV
hospitalizations (Combined)
Flather MD. EHJ 200526215-25
55

• All cause mortality
• All cause hospitalizations
• All cause Mortality and hospitalizations
• CV death
• CV hospitalizations
• CV death and CV hospitalizations
• Functional Capacity, evaluated with
• Variation NYHA class
• Walk-Corridor-Test at 6 minutes

SECONDARY END POINTS

Flather MD. EHJ 200526215-25
56
All Cause Mortality or CV Hospital Admission
(Primary Outcome)
Hazard Ratio 0.86 0.740.99 p-value 0.039¹
RRR 14
Mean Follow up 21 months
¹ adjusted by sex, age and baseline LVEF
unadjusted HR 0.85 0.74 0.99 p-value 0.034
No. of events Nebivolol 332 (31.1) Placebo 375
(35.3)
57
CV Mortality or CV Hospitalisation (Secondary
End-Point)
RRR 16
Hazard Ratio 0.84 0.720.98 p-value 0.027¹
Mean Follow up 21 months
¹ adjusted by sex, age and baseline LVEF
No.of events Nebivolol 305 (28.6) Placebo 350
(33.0)
Flather MD. EHJ 200526215-25
58
Other secondary end points(time to event)
Hazard
Nebivolol
Placebo
95 CI
p-value¹
ratio¹
n1067
n1061
Secondary outcomes
All cause mortality
169 (15.8)
192 (18.1)
0.88
0.71 1.08
0.21
CV mortality
123 (11.5)
145 (13.7)
0.84
0.66 1.07
0.17
0.62
0.42 0.91
0.014
Sudden cardiac death²
44 (4.1)
70 (6.6)
Non CV mortality²
26 (2.4)
20 (1.9)
Unknown / not classified²
20 (1.9)
27 (2.5)
CV hospitalisation
256 (24.0)
276 (26.0)
0.90
0.76 1.06
0.20
All cause hospitalisation
359 (33.6)
364 (34.3)
0.96
0.82 1.10
0.47
CV mortality/CV hospit.
305 (28.6)
350 (33.0)
0.84
0.72 0.98
0.027
¹ HR (and p value) calculated on time to event.
Analyses adjusted by sex, age and LVEF, unless
otherwise specified ² Not pre-specified
analyses Each cell in these columns
contains the number of events and the percentage
of events Considered within CV
mortality Unknown/ not classified category
includes not witnessed, not sudden cardiac
death, not classified, vital status information
from patients who prematurely terminated the
study
Flather MD. EHJ 200526215-25
59
Effect of the 10 mg dose on secondary end-points
Endpoint (time to first event) 10 mg dose group 10 mg dose group SENIORS overall SENIORS overall
Endpoint (time to first event) HR CI 95 p-value HR CI 95 P-value
All cause mortality or CV hospital admission 0.73 0.61-0.87 lt 0.001 0.860.66- 0.95 0.039
All cause mortality 0.76 0.59-0.97 0.027 0.88 0.71-1.08 0.214
All cause hospital admission 0.79 0.67-0.94 0.008 0.95 0.82-1.10 0.473
All cause mortality or all cause hospital admission 0.75 0.64-0.88 lt 0.001 0.89 0.78-1.02 0.082
CV mortality 0.71 0.53-0.95 0.020 0.84 0.66-1.07 0.165
CV hospital admission 0.74 0.60-0.90 0.003 0.90 0.76-1.06 0.204
CV mortality or CV hospital admission 0.70 0.58-0.84 lt 0.001 0.84 0.72-0.98 0.027
SENIORS efficacy results relative risk reduction
vs placebo for nebivolol 10 mg dose and nebivolol
all doses (SENIOR overall)
60
Which maintenance dose was reached by the
patients?
61
How many patients reached the target dose
compared to previous BB trials?
Patients reaching target dose

42
CIBIS II (10 mg o.d.)2

MERIT HF
64
(200 mg o.d.)1

COPERNICUS
65
(25 mg bid)3
SENIORS
68
(10 mg o.d.)4
1 . MERIT HF Study group, Lancet 1999 353
2001-07 2 . CIBIS II Investigators.
Committees,Lancet 1999,353 9-13 3. Packer M et
al. N Eng J Med 2001344(22)1651-1658 4. Flather
MD. EHJ 200526215-5
62
Effect of nebivolol on primary endpoint at
maintaining dose
All cause mortality or CV hospitalizations
The greatest beneficial effect on primary
endpoint has been observed in patients reaching
target dose of 10 mg
63
Treatment Compliance
Nebivolol Placebo
anticipated treatm suspension 27 25
pts in therapy in different study phases
Nebivolol Placebo
100
90
80
70
60
50
96
97
83
85
70
70
65
64
40
30
20
10
6 months
12 months
Ended study
End titrat
Flather MD. EHJ 200526215-25
64
Anticipated treatment suspension causes ()
20
Placebo
Nebivolol
15
Other
Incoming of Contraindications
10
7.8
6.3
Adv. Events
Intolerance
4.4
5
2.7
2.2
1.3
1.2
0.8
0
Causes
Flather MD. EHJ 200526215-25
65
Premature Treatment Discontinuations for Reasons
other than Death
Placebo
Nebivolol
Patient Request
Other Reason
11.6
10.3
Developed Contraindication
Mandatory Indication
Intolerance to lowest dose
7.8
6.3
4.4
3.0
2.7
2.2
1.6
0.8
66
What was the Incidence of the AE Bradycardia ?
Flather MD. EHJ 2005
67
Incidence of AE Bradycardia leading to
treatment withdrawal
68
Did Nebivolol affect blood glucose levels?
Change in mean fasting blood glucose (mmol/l)
in diabetic and non-diabetic patients
Flather MD. EHJ 2005
69
Time to all cause mortality or CV hospitalisation
for nebivolol with target dose 10 mg vs. placebo
50
Nebivolol
Placebo
45
40
35
30
plt0.001
HR0.73
Patients experiencing the event ()
25
20
15
10
RRR 27
5
0
0
3
6
9
12
15
18
21
24
27
30
Months
70
Time to CV mortality for nebivolol with target
dose 10 mg vs. placebo
50
Nebivolol
Placebo
45
40
35
30
Patients experiencing the event ()
25
RRR 29
20
p0.020
15
HR0.71
10
5
0
0
3
6
9
12
15
18
21
24
27
30
Months
71
Time to unexpected sudden cardiac death (months)
25
Nebivolol
Placebo
20
15
p0.013
Patients experiencing the event ()
HR0.62
RRR 38
10
5
0
0
3
6
9
12
15
18
21
24
27
30
Months
72
IS IT POSSIBLE...
TO COMPARE THE SENIORS RESULTS WITH OTHER BETA
BLOCKER TRIALS?
NO, BUT...
73
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
70
80
85
90
95
35
20-24
40-44
50-54
60-64
70-74
'10-14
LVEF ()
Age (years)
Flather MD. EHJ 200526215-5
74
Effect of ?-Blockers on All-Cause Mortality or CV
Hospitalization in Elderly Patients
COPERNICUS
65 yrs
CIBIS II
MERIT-HF
gt 69 yrs
SENIORS
70 yrs
1.0
0.8
0.6
0.4
0.2
0.0
1.2
Relative Risk
75
Effect of ?-Blockers on All-Cause Mortality or CV
Hospitalization in Elderly Patients
COPERNICUS
65 yrs
CIBIS II
71 yrs
MERIT-HF
gt 69 yrs
All
SENIORS
70 - 75 yrs
lt 35
1.0
0.8
0.6
0.4
0.2
0.0
1.2
Relative Risk
76
Homogeneous populations Adjusted for age and
for EF
Primary Endpoint RR Mortality and CV
hospitalizations SENIORS (nebivolol) (684
pz) - 27 subgroup lt75,2 yrs and EFlt35
MERIT-HF (metoprolol) - 24
COPERNICUS (carvedilol) - 27
MERIT-HF (metoprolol) - 30 subgroup
gt65 72 yrs and EFlt40
(EHJ 2004251300-9).
Flather MD. EHJ 2005
77
Relative Risk All cause mortality
SENIORS (nebivolol) (684 pts) - 38 subgroup
lt75,2 yrs and EFlt35 MERIT-HF
(metoprolol) - 34 COPERNICUS (carvedilol)
- 35 CIBIS II (bisoprolol) - 34
MERIT-HF (metoprolol) - 37 subgroup gt65
m.72 yrs and EFlt40
(EHJ 2004251300-9).
Flather MD. EHJ 2005
78
Time to all cause mortality or CV hospitalisation

in patients with LVEF lt35 and agelt75.2 yrs
50
Primary end point
Nebivolol
Placebo
45
40
35
30
p0.023
25
HR0.73
Patients experiencing the event ()
20
15
RRR 27
10
5
0
0
3
6
9
12
15
18
21
24
27
30
Months
79
Time to all cause mortality in
patients with LVEF gt35 and agelt75.2 yrs
50
Nebivolol
Placebo
45
40
35
30
RRR 38
Patients experiencing the event ()
25
20
p0.011
15
HR0.62
10
5
0
0
3
6
9
12
15
18
21
24
27
30
Months
80
What is the effect of Nebivolol on
echocardiographic parameters of CHF?
81
Gr.1 Change in LVEF at 12 months
49
4.5
p0.008
Change in LVEF () at 12 months
- 0.1
Mean
Mean0.95 Conf. Interval
Placebo
Nebivolol
Ghio et al. EHJ 2006
82
50
Gr.1 Change in LVESV at 12 months
7.0 ml
Change in LVESV (ml) at 12 months
p0.016
- 19.2 ml
Mean
Mean0.95 Conf. Interval
Placebo
Nebivolol
Ghio et al. EHJ 2006
83
Effects of Beta-blocker therapy on the Relation
Between LV Filling Pressure and Stroke Volume in
Patients with Diastolic Heart Failure
Atenolol
Nebivolol
60
60
55
55
50
50
SVI, ml/m2
45
45
SVI, ml/m2
40
40
35
35
Rest
Peak Exercise
Rest
Peak Exercise
0
0
0
15
20
25
30
0
15
20
25
30
PWP, mm Hg
PWP, mm Hg
Nodari, Metra, Dei Cas. Eur J Heart Fail,
20035621-7.
84
Frequency of comorbidities
60-70
70
60
60
50
40
10-30
25
25
25
30
20
10
0
Lipid disorders
Renal impair.
Hypertension
CAD
Diabetes
COPD
Euro Heart Failure Survey, Lancet 2004
85
Percentage of comorbidities in SENIORS

NEBIVOLOL () PLACEBO ()
Prior history of CAD 69
68 Hypertension 61
62 Hyperlipidemia 46
46 Atrial fibrillation
34
35.5 Diabetes
26 25.3 Creatinine
(µmol/L) 35.1(102.0) 35
(103.5)
86
Haemodynamic control Volume expansion Total
body autoregulation Increased Peripheral
resistance Increased blood pressure
Heart failure
Cardiorenal connection
Renal failure
NO-ROS dysbalance SNS activation RAS activation
CV damage
87
Haemodynamic control Volume expansion Total
body autoregulation Increased Peripheral
resistance Increased blood pressure
Heart failure
Cardiorenal connection
Renal failure
NO-ROS dysbalance SNS activation RAS activation
Nebivolol
CV damage
88
Effect of Nebivolol on the primary end-point by
levels of baseline Creatinine Clearance
66 ml/min
50 - 66 ml/min
lt 50 ml/min
P 0.040
lt 40 ml/min
P 0.015
lt 35 ml/min
1.0
0.9
0.8
0.7
0.6
0.5
1.1
1.2
1.3
RR
Patients with events of the primary outcome (all
cause mortality or CV hospitalization) Hazard
Ratio (p-value) calculated on time to event.
Analyses adjusted by gender, age and LVEF
89
Nebivolol in HF

• elderly patients
• men and women
• moderate low EF
• associate conditions
• (systolic HTN, PAD)

SENIORS type patients
NEBIVOLOL
90
Guidelines for the diagnosis and treatment of
chronic heart failure (update 2005)

• Treatment of congestive heart failure in elderly
  patients - Beta blockers
• With the exclusion of patients with such
  contraindications as sick sinus node, AV- block,
  COPD, beta blockers are well tolerated in elderly
  patient.
• Treatment with beta blockers should not be
  exclusively suspended because of elderly age of
  the patients

91
Guidelines for the diagnosis and treatment of
chronic heart failure (update 2005)

• Beta blockers
• In Heart Failure patients, different molecules
  of beta blockers could bring different clinical
  benefits. Thus, only bisoprolol, carvedilol,
  metoprolol succinate and nebivolol should be
  recommended (Class of recommendation I, level of
  evidence A)

92
Conclusions
Nebivolol significantly reduced death or
hospitalisation in elderly heart failure
patients The effect was statistically independent
of ejection fraction, age or gender The 10 mg
dose was well tolerated and demonstrated larger
beneficial effects In comparing like for like
patients Nebivolol appears to be at least as
effective as metoprolol CR, bisoprolol or
carvedilol
93
Conclusions
Nebivolol was well tolerated, 68 pts received
10 mg daily dose for a mean period of 18
months The safety profile of nebivolol almost
overlapped that of placebo in terms of incidence,
type, severity
94
QUESTIONS
What are the peculiar characteristics of SENIORS?
Which percentage of patients achieved the target
dose?
Which is the primary endpoint in SENIORS and
what is the risk reduction in the primary
endpoint?
Compared to the previous BB trials, how can we
consider the results achieved in SENIORS?
95
QUESTIONS

• What is the first line therapy in HF Why
  diuretics are used?
• According to ESC 2005 on CHF when BB should be
  used ?
• When diuretics are used?

96
QUESTIONS

• .What is the incidence of heart failure in the
  population?
• What is the mean age of patients with heart
  failure in the population?

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QUESTIONS

• What models of heart failure have been used to
  explain the pathophysiology of heart failure?
• What are the most common compensatory mechanisms
  in HF ?
• Why do they become toxic in the long time?