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Hypertension: The 21st Century Dajjal
1. 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.
6. 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.
24. Beta Blockers and Endothelial
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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
25. Comparison of Beta Blockers
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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
27. Chemical Structure of Nebivolol
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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
28. Unique Dual Mode of Action of
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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
29. The Cardioselectivity of Nebivolol
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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
30. Reduction in Systemic Vascular
Resistance: Master title style
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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
31. Blood Pressure Lowering Efficacy:
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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
33. Blood Pressure Lowering Efficacy:
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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
34. Sustained Blood Pressure Control:
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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
35. Haemodynamic Effects of
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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.
37. Nebivolol and Exercise Tolerance
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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.
38. Nebivolol and Lipid Metabolism
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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.
39. Nebivolol and Carbohydrate
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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
40. Nebivolol and New Onset of
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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.
41. Nebivolol and Erectile Function
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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.
42. Nebivolol and Sexual Activity
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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
44. Comparison with Carvedilol
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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.
45. Effect on LV end-systolic volume
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(ml)
80 79
7.6% 9.1%
75
73
72
70
66
65
6 months
6 months
Baseline
Baseline
60
55
Carvedilol Nebivolol
Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.
46. Effect on LVEF (%)
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39
38
38
37
37
36 12% 12%
35
34
34
33
33
6 months
6 months
Baseline
Baseline
32
31
30
Carvedilol Nebivolol
Lombardo RMR, et al. Am J Cardiovasc Drugs 2006;6:259-63.
47. The ENECA Trial
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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.
48. The ENECA Trial: Results
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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
Edes I, et al. Eur J Heart Fail 2005;7:631-9.
49. The ENECA Trial: Results
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Survival Rate
82%
81%
81%
81%
Survival rate (%)
80%
80%
79%
79%
78%
78%
78%
77%
77%
Placebo Nebivolol 5mg OD
Edes I, et al. Eur J Heart Fail 2005;7:631-9.
50. The ENECA Trial: Results
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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
Edes I, et al. Eur J Heart Fail 2005;7:631-9.
51. The SENIORS Trial
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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.
52. Epidemiology of CHF
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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.
53. Age and EF of patients in major
placebo controlled trials of BBs in
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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.
54. SENIORS: distribution of EF
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Moen MD, et al. Drugs 2006; 66(10):1389-409.
55. The SENIORS Trial: Results
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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.
56. The SENIORS Trial: Results
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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,
57. The SENIORS Trial: Results
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Sudden cardiac death
25 Placebo
Patients having an event (%)
Nebivolol
20
15
RRR 38%
10
5
0
0 6 12 18 24 30
Months
Moen MD, et al. Drugs 2006; 66(10):1389-409.
58. Achievement of Target Dose in BB
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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%
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.
59. Conclusion
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SENIORS provides the first large
scale data for a potentially beneficial
effect of beta blockade in HF patients:
– With preserved EF
– In elderly
Moen MD, et al. Drugs 2006; 66(10):1389-409.
60. Results of BB Trials in HF
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Results for All Cause Mortality
Trial Beta Blocker %↓
MERIT-HF Metoprolol XL 34
CIBIS-II Bisoprolol 34
COPERNICUS Carvedilol 35
SENIORS Nebivolol 38
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.
61. The SENIORS Trial: Sub Group
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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
62. The SENIORS Trial: Sub Group
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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