Nebil

HYPERTENSION ST
THE DAJAL OF 21 CENTURY

Presented by

DR. ABDUL RAB SHAIKH
MD CARDIOLOGY ( UK)
DIPLOMA IN CARDIOLOGY (UK)
C O N S U LTA N T I N T E R V E N T I O N A L C A R D I O L O G I S T
R E D C R E S C E N T I N S T I T U T E O F C A R D I O L O G Y.

Cardiovascular Mortality Risk with
20/10 mmHg Increments in SBP/DBP*

8
Cardiovascular mortality risk

8X
risk
6

4
4X
risk
2

2X
0 1X risk risk

115/75 135/85 155/95 175/105
SBP/DBP (mmHg)

Individuals aged 40–69 years
SBP = systolic blood pressure
DBP = diastolic blood pressure Lewington et al. Lancet 2002;360:1903–13

2 MM HG BP REDUCTIONS CAN SIGNIFICANTLY
REDUCE THE RISK OF CV EVENTS

Meta-analysis of 61 prospective, observational studies
1 million adults

2 mm Hg
decrease in
mean SBP
7%

10%
Lewington S et al. Lancet 2002;360:1903-1913.

Aprovel Vs. Other Antihypertensive

How to get rid of this Dajjal.
• Phase 1 – dietary protocols.
• Phase 2 - medical therapy.

JNC 7: Treatment Algorithm for Hypertension
Lifestyle modifications

Not at goal blood pressure (<140/90 mm Hg)
(<130/80 mm Hg for those with diabetes or chronic kidney disease)

Initial drug choices

Without compelling indications With compelling indications

Stage 1 hypertension Stage 2 hypertension Drugs for compelling indications
(SBP 140–159 or DBP 90–99 mm Hg) (SBP 160 or DBP 100 mm Hg) Other antihypertensive drugs
Thiazide-type diuretic for most. Two-drug combination for most (diuretic, ACEI, ARB, BB, CCB) as
May consider ACEI, ARB, BB, CCB, (usually thiazide-type diuretic and needed.
or combination. ACEI or ARB or BB or CCB).

Not at goal blood pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.
Consider consultation with hypertension specialist.

SBP=systolic blood pressure; DBP=diastolic blood pressure; ACEI=angiotensin- ®
converting enzyme inhibitor; ARB=angiotensin receptor blocker; BB= -blocker;
CCB=calcium channel blocker
© 2003 Thomson Professional Postgraduate Services®
JNC 7. May 2003. NIH publication 03-5233. www.lipidhealth.org

• Phase 2 – Medical therapy.

Management of Endothelial
Dysfunction

Role of Beta Blockers

Beta Blockers and Endothelial
Click to edit Master title style
Dysfunction

• Beta blockers classically do not affect
endothelial dysfunction.

• Only Nebivolol, a beta blocker with
NO donor properties, has been shown
to improve endothelial function.

Journal of Human Hypertension (2005) 19, S21-S25

Comparison of Beta Blockers
Properties Atenolol Metoprolol Bisoprolol Carvedilol Nebivolol

Generation 2nd 2nd 2nd 3rd 3rd

Cost per day 6 6.2 4.5 11 11.5
100 mg OD
Initial but
recommended 50mg OD preferably in 5 mg OD 6.25 mg BD 5 mg OD
dose divided
doses

Vasodilatory Y (alpha-1 Y (NO
N N N
action antagonism) mediated)

Half life Up to 7 hrs Up to 7 hrs Up to 12 hrs Up to 10 hrs Up to 30 hrs

Bioavailability 50% 80% Up to 35% Up to 96%
Sleep
Y Y Y N N
disturbance
Vascular Health and Risk Management 2007:3 (5) 647-654

Nebivolol

Highly selective β1 antagonist
&
NO mediated vasodilator

Chemical Structure of Nebivolol
F

RSSS
(levo-nebivolol) F
(R 67 145)
O
O O
O
N

N

O O
O O

SRRR F
(dextro-nebivolol)
F (R 67 138)

Mangrella et al, Pharmacol Res 1998, 38(6); 419-31

Unique Dual Mode of Action of
Nebivolol
Nebivolol

d-Nebivolol l-Nebivolol
Highly selective Endothelial NO
β1 antagonist mediated vasodilator

↓ heart rate Sustained vasodilation
↑ stroke volume ↓ PVR
Cardiovasc 2008; 26:115
Am J Cardio 2003; 92: 344-348
Cardiovasc Ther 2008; 26 (3): 189-202

The Cardioselectivity of Nebivolol
45
40.7
40
35
30
1-selectivity

25
20
15.6
15
10
4.2
5
0.7
0
Carvedilol Metoprolol Bisoprolol Nebivolol

Brixius K, et al. Br J Pharmacol 2001; 133:1330-8

Reduction in Systemic Vascular
Resistance: Master title style
Click to edit
Comparison with Bisoprolol
Systemic Vascular Resistance Index

2900
2848 2854
2850
2787
(dyn.sec.cm-5.m2)

2800
2750
2700
2646
2650
2600
2550
2500
Bisoprolol Nebivolol

Clin Drug Invest 2002; 22: 355-9

Blood Pressure Lowering Efficacy:
Comparison with Atenolol
Systolic Diastolic
Blood Pressure Blood Pressure
0

-5

-10

-15
-14.6 -14.8

-20 -18.2
-19.2
Atenolol 100mg
-25 OD

n = 205 hypertensives
Duration = 12 weeks
Gracie et al. Blood pressure suppl 2003; 2:35

Blood Pressure Lowering
Efficacy:
Nebivolol, Bisoprolol Multicenter Study
(NEBIS)
DBP Response AE
Lowering Rate Rate
Bisoprolol Nebivolol
93% 10%
0 92% 8.9%
92% 9%
-2 92% 8%
-4 91% 7%
5.8%
-6 6%
91%
-8 89.6 5%
mmHg

90%
% 4%
-10 90% 3%
-12 89% 2%
-14 89% 1%
-16 88% 0%
-16 -16
-18 Bisoprolol Nebivolol Bisoprolol Nebivolol

n = 273
Duration = 16 weeks
Cardiovasc Drugs Ther 2003; 17:257-63

Blood Pressure Lowering Efficacy:
Comparison with Metoprolol

Complete Normalization of BP

80% 79%

75%

70%
66%
65%

60%

55%
Metoprolol Nebivolol
n = 155
Duration = 12 weeks
Drug Invest 1991; 3:107-10

Sustained Blood Pressure Control:
Comparison with Bisoprolol & Carvedilol

Effect on HR During Exercise and Trough to Peak Ratios

Bisoprolol Carvedilol Nebivolol
First Morn 10mg 50mg 10mg
1 week 5mg OD 25mg BD 5mg OD
0%
% change in Heart Rate

-5%

-10%

-15%
-15%
-20% -17%

-25% -24% 85% 91%

-30% Column 1: 3 hrs following first dose
Column 2: 24 hrs following first dose
58% Column 3: 24 hrs following last dose of 7 days treatment

Cardiology 2006; 106:199-206

Haemodynamic Effects of
Nebivolol
Nebivolol 5mg OD for 14 days
30 Atenolol 100mg OD for 14 days
25
20
15
10
Variation (%)

5
0
-5
-10
-15
-20
EDV ESV SV HR CO LVEF PVR
-25

De Crée J et al. Drug Invest 1991; 3:40-50.

Metabolic Profile

Nebivolol

Nebivolol and Exercise Tolerance
70
64
59
60
50
Endurance time (min)

50

40

30
8% 22%
20

10

0
Placebo Nebivolol 5mg OD Atenolol 100mg OD

Van Bortel LMAB. Cardiovasc Drugs Ther 1992;6:239-47.

Nebivolol and Lipid Metabolism
20 n = 27
Duration = 12 weeks 16.3
Nebivolol 5mg OD
15
Atenolol 50mg OD
Changes in the lipid profile

10 8.7

5

0

-2.4 -2.7 -2
-5
-4.6

-10
-10.1
-11.5
-15
TC LDL-C LDL-C/HDL-C TG
Pesant Y et al. Am J Ther 1999; 8:283-8.

Nebivolol and Carbohydrate
Metabolism
Insulin resistance
Insulin resistance (HOMA index)

3 2.79 2.83
2.67
2.5 2.29

2

1.5 18% 6%
1
6 months

6 months
Baseline

Baseline
0.5

0
n = 72 Nebivolol 5mg OD Metoprolol 100mg OD
Duration = 12 weeks
Celik T, et al. J Hypertens 2006;24:591-6

Nebivolol and New Onset of
Diabetes
New onset diabetes
2.15
2.1
2.1
2.05 14%
Event rate % per year

2
1.95
1.9
1.85
1.8
1.8
1.75
1.7
1.65
Placebo Nebivolol

Agabiti-Rosei E, et al. Drugs 2007; 67:1097-107.

Nebivolol and Erectile Function
Before Nebivolol After Nebivolol
Severity of ED
Severe
Moderate 34 18% 5%
27%
Mild
None
% 59
30%
18% % 9%

Patients treated previously with beta-blockers switched to nebivolol

Doumas M, et al. Asaian J Androl 2006; 8:177-82.

Nebivolol and Sexual Activity
10
8.8
49% 5%
9
8
Sexual intercourse/month

8 7.6
7
6
5 4.5
4
12 weeks

12 weeks
Baseline

Baseline
3
2
1
0
Atenolol 50mg OD Nebivolol 5mg OD

n = 121
Boydak B, et al. Clin Drug Invest 2005;25:409-16

Role of Nebivolol in HF

Landmark Trials

Comparison with Carvedilol
CHF patients with LV dysfunction

A multicentre, double-blind, head to head clinical trial

Study protocol

• CHF patients with left ventricular dysfunction
• Treatment duration: 6 months
• Dosage: Nebivolol 1.25 mg to 5mg OD
Carvedilol 3.125 mg to 25 mg BID

Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.

Effect on LV end-systolic volume
(ml)
80 79
7.6% 9.1%
75
73
72

70
66
65

6 months
6 months

Baseline
Baseline

60

55
Carvedilol Nebivolol


Effect on LVEF (%)
39
38
38
37
37
36 12% 12%
35
34
34
33
33

6 months
6 months

Baseline
Baseline

32
31
30
Carvedilol Nebivolol


The ENECA Trial
Efficacy of Nebivolol in the Treatment of Elderly Patients with Chronic
cardiac failure NYHA Class II-IV as an Add-on therapy to ACE-inhibitors or A-II
antagonists, diuretics and/or digitalis

A multicentre, double-blind, placebo-controlled clinical trial

ENECA trial: study protocol
• Main inclusion criteria: Hospitalised and out-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
• Number of subjects =260
• Dosage: Nebivolol 1.25 mg OD, increasing over 8 weeks to maximum target dose of 10 mg
OD or placebo for 8 months
• Primary end point: Change on LVEF from baseline after 8 months of treatment

Edes I, et al. Eur J Heart Fail 2005;7:631-9.

The ENECA Trial: Results
Relative improvement of LVEF
40%
36%
35%
LVEF % improvment

30%
(visit 1 vs visit 11)

80%
25%
20%
20%
15%
10%
5%
0%
Placebo Nebivolol 5mg OD


Survival Rate
82%
81%
81%
81%
Survival rate (%)

80%
80%
79%
79%
78%
78%
78%
77%
77%
Placebo Nebivolol 5mg OD


Adverse Events
90%
78% 81%
80%
Placebo
Incidence of Aes (%)

70%
60%
50%
40%
30%
20% 15% 12.1%
10%
0%
Adverse events Severe adverse events


The SENIORS Trial
Study of Effects of Nebivolol Intervention on Outcomes and
Rehospitalisation in Seniors with Heart Failure

Double-blind, centrally randomized, placebo controlled, multicentre, international trial

SENIORS trial: study protocol
• Main inclusion criteria: Age ≥ 70 years (70-96 years), clinical diagnosis of chronic heart
failure (CHF) and either of:
a) documented LVEF ≤ 35% within previous 6 months or
b) hospital admission within previous 1 year for CHF
• n = 2128 in from european countries
• Dosage: Nebivolol 1.25 mg OD, increasing over 16 weeks to maximum target dose of 10 mg
OD or placebo
• Primary end point: To evaluate Nebivolol on top of standard therapy on total mortality and
morbidity in elderly heart failure patients
Flather MD, et al. Eur Heart J 2005;26:215-25.

Epidemiology of CHF
12
10.9
9.8
10 Men
Percent of population

Women
8
6.2
5.8
6
4.1
4
2.3
1.8 1.5
2
0.3 0.3 0.5 0.4
0
20-34 35-44 45-54 55-64 65-74 75+

Ages

Source: CDC/NCHS and NHLBI.

Age and EF of patients in major
placebo controlled trials of BBs in
CHF
Beta Mean Mean
Trial n
Blocker Age EF
US Carvedilol Carvedilol 1094 58 22
Metoprolol
MERIT-HF 3991 64 28
XL
CIBIS-II Bisoprolol 2647 61 28
COPERNICU
Carvedilol 2289 63 20
S
25
Overall -- -- 63 (> 40
SENIORS Nebivolol 2128 75 35
excluded)

CIBIS II Investigators & Committees. Lancet 1999; 353:9-13; MERIT HF Study group.
Lancet 1999; 353:2001-7; Packer M, et al. N Eng J Med 2001; 344(22):1651-8;
Flather MD. EHJ 2005; 26:215-5.

SENIORS: distribution of EF

Moen MD, et al. Drugs 2006; 66(10):1389-409.

The SENIORS Trial: Results
Left ventricular remodeling
5 10
4.5 7
5

Change in LVESV (ml)
4
Change in LVEF (%)

0
3
Placebo Nebivolol
-5
2
-10
1
-15
-0.1
0 -20
-19
Placebo Nebivolol
-1 -25

Modified from Ghio S, et al. Eur Heart J 2006;27:562-8.

All-cause mortality or cardiovascular hospital admission
Placebo
50
Nebivolol
Patients having an event (%)

40

30
RRR 14%
20

10

0
0 6 12 18 24 30

Months
N. of events:
nebivolol 332 (31.1%); placebo 375 (35.3%) et al. Eur Heart J 2005;26:215-25.
Flather MD,

Sudden cardiac death
25 Placebo
Patients having an event (%)

Nebivolol
20

15
RRR 38%
10

5

0
0 6 12 18 24 30

Months


Achievement of Target Dose in BB
Trials

Patients reaching
target dose

CIBIS II (bisoprolol 10 mg o.d.) 42%
MERIT-HF (metoprolol 200 mg o.d.) 64%
COPERNICUS (carvedilol 25 mg b.i.d.) 65%

SENIORS (nebivolol 10 mg o.d.) 68%

Flather MD. EHJ 2005; 26:215-5.

Conclusion
SENIORS provides the first large
scale data for a potentially beneficial
effect of beta blockade in HF patients:

– With preserved EF

– In elderly


Results of BB Trials in HF
Results for All Cause Mortality

Trial Beta Blocker %↓

MERIT-HF Metoprolol XL 34

CIBIS-II Bisoprolol 34

COPERNICUS Carvedilol 35

SENIORS Nebivolol 38

Flather MD. EHJ 2005; 26:215-5.

The SENIORS Trial: Sub Group
Analysis
Heart Failure and Renal Impairment
• Renal impairment is a common finding in
patients with HF and is independently
associated with an increased risk of death.

• No study has previously assessed the
interaction between beta blocker response
and renal function in elderly HF patients.

European Journal of Heart Failure (2009) 11, 872-880

The SENIORS Trial: Sub Group
Analysis
• The efficacy of Nebivolol is not reduced in
elderly HF patients with mild or moderate
renal impairment.

• In addition, Nebivolol was safe for use in
those with renal dysfunction.

European Journal of Heart Failure (2009) 11, 872-880

• Thanks for listening. But the best medicine
available is still free to use,…..wait and
watch

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