GLOBAL STRATEGY FOR

THE TREATMENT
OF HYPERTENSION :
FOCUS ON FIX
LOW-DOSE COMBINATION
Trends in awareness, treatment, and control of
high blood pressure in adults ages 18 - 74
NATIONAL HEALTH AND NUTRITION EXAMINATION
SURVEY, Weighted
II
(1976-1980)
III (Phase 1
1988-1991)
III (Phase 2
1991-1994)
1999-2000
Awareness 51 73 68 70
Treatment 31 55 54 59
Control | 10 29 27 34
High blood pressure is systolic blood pressure (SBP) K mmHg or diastolic blood
pressure (DBP) K 9 mmHg or taking antihypertensive medication.
| SBP < mmHg and DBP < 9 mmHg
140 / 90 mmHg 160 / 95 mmHg
USA Canada Finland Spain Australia
England France Germany Scotland India
~ 65 yr only
27 22 20,5 20 19
6 24 22,5 17,5 9
European heart journal suppl B vol 2 ,March 2000
Patients (%) with BP Controlled Worldwide Patients (%) with BP Controlled Worldwide
!oor compliance
Under aggressiveness oI physician in HT
treatment
Wrong medication; not proper combination;
medication interIering risk with B! control
White Coat HT
!seudo HT
Secondary HT
Barriers to achieve B! goals
Thiazides 50-55
Beta bIockers 45-50
ACE - inhibitors 50-60
CaIcium channeI bIockers 40-60
AIpha bIockers (prazosin) 35-40
CentraI agonists 30-35
DRUG RESPONDERS (%)
Data derived from Am J cardiol 987;59():8F-52F

Estimated Efficacy of Mono therapy

with old criteria
1 2 3 4
Number of anti hypertensive agent
TRIAL Target-mmHg
UK!DS DB! 85
ABCD DB! 75
HOT DB! 80
AASK MA! 92
Bakris G et aII
Am Kidney JournaI 2000
Average number of antihypertensive agents needed
Per patient to achieve target BP
Average number of antihypertensive agents needed
Per patient to achieve target BP
Algorithm Ior Treatment oI Hypertension
Not at GoaI BIood Pressure (<140/90 mmHg)
(<130/80 mmHg for those with diabetes or chronic kidney disease)
InitiaI Drug Choices
Drug(s) for the compeIIing
indications
ther antihypertensive drugs
(diuretics ACE ARB BB CCB)
as needed.
ith CompeIIing
Indications
LifestyIe Modifications
Stage 2 Hypertension
(SBP > or DBP > mmHg)
2-drug combination for most (usually
thiazide-type diuretic and
ACE or ARB or BB or CCB)
Stage 1 Hypertension
(SBP 59 or DBP 999 mmHg)
Thiazide-type diuretics for most.
May consider ACE ARB BB CCB
or combination.
ithout CompeIIing
Indications
Not at GoaI
BIood Pressure
ptimize dosages or add additional drugs
until goal blood pressure is achieved.
Consider consultation with hypertension specialist.
NC 7 , ama May 21,2003
Therapeutic strategies oI hypertension
ESH-ESC guidelines 2003
Add a
third drug
at low dose
hoose between
Single agent
at low dose
2 drug combination
at low dose
!revious agent
at Iull dose
Switch to diIIerent
Agent at low dose
!revious
combination
at Iull dose
2-3 drug combination
2-3 drug combination
II goal B! not achieved
II goal B! not achieved
hypertension 2003 ,21, 1011 - 1053
Dose titration
Low-dose combination
Very-Iow-dose
combination
Burden
from
treatment

Cardio-
vascuIar
risk

ith most antihypertensive drugs, the burden from treatment increase when
the dosage is increased in order to decrease bIood pressure (BP) further and
reduce cardiovascuIer risk. Low-dose combination aIIow enhancement of
antihypertensive efficacy, but generaIIy not at the expense of an increased
burden. This is even more true with very-Iow-dose combination.
BP during antihypertensive treatment
Diuretics
.-bIockers AT
1
receptor
bIockers
Ca Antagonist
o-bIockers
ACE Inhibitors
2003 GuideIines for Management of Hypertension, J of Hypertension 2003
C.I. : VerapamiI + BIocker
LD contains bisoprolol and hydrochlorothiazide
in smaller than usual doses:
- Lodoz 2.5 : Bisoprolol 2.5 mg + HCT .25 mg
- Lodoz 5 : Bisoprolol 5 mg + HCT .25 mg
Advantages: excellent efficacy
low dose-related adverse events
FDA approved as first-line antihypertensive
and side effects comparable to placebo
Fit very well to JNC-7 and ESH/ESC 2 guidelines
New concept - no traditionaI combination
18/11/2011 19:34 Bisoprolol-Dias 13
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BisoproIoI and HCTZ fit very weII
24-Hour Efficacy of Lodoz
In miId to moderate hypertension
Lewin AJ Lueg MC Fargum S Cardenas P A Clinical Trial
Evaluating the Clin Cardiol. 72-7 (99)
iastolic Reduction after 18 weeks iastolic Reduction after 18 weeks
-19
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CVR&R November 1996
Sistolic Reduction after 18 weeks Sistolic Reduction after 18 weeks
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CVR&R November 1996
Response Rate Response Rate
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2000
3000
4000
5000
6000
7000
8000
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Joel M. Neutel, MD;' Clyde N. Rolfi MD;2 Suzanne N. Et all
CVR&R November 1996
8%
Response rates under up to 84 %
Response defined as a sitting diastolic blood pressure of > 9 mm Hg and/or
a decrease from baseline of < mm Hg measured 2 hours after dosing.
Response rates (from several trials)
() FRSHMAN et al. Arch ntern Med. 99; 5:-8
() NEUTEL et al. Cardiovas. Rev Rep. 99; 7:-5
(5) PAPADEMETRU et al. Cardiovasc Rev Rep. Dec. 998
(2) FRSHMAN et al. J Clin Pharmacol. 995; 5:82-88
() PRSANT et al. Am Heart J. 995; :59-
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(2) () () () (5) () () (trial no.)
Diarrhea
Bradycardia
Dizziness
Asthenia
Edema
Headache
LD Placebo
%
5%
%
25%
2%
5%
%
5%
%
TotaI rate
of patients
with at
Ieast one
adverse
event
TotaI rate
of patients
with at
Ieast one
adverse
event
Rash
Cough
Diarrhea
Dyspepsia
Nausea
Dizziness
Asthenia
Edema
Headache
29%
27%
Joel M. Neutel, MD;' Clyde N. Rolfi MD;2 Suzanne N. Et all
CVR&R November 1996
Incidence of adverse events Incidence of adverse events
eneral Well-Being
ndex
ung Self-Rating
Depression Scale
Vital Sign
Quality of Life
Baseline
mprovement
Decline
LD Amlodipine Enalapril
*
*
Change in mean scores of quality-of-life measures (WER 99)
WER et al. Amer J Hyperten. 99; 9:85-859
"&ALITY of LIFE "&ALITY of LIFE
No change of potassium levels during long-term treatment:
results of Bisoprolol 5 mg + HTZ 12.5 mg
No change of potassium levels during long-term treatment:
results of Bisoprolol 5 mg + HTZ 12.5 mg
Pender J et al: Long term follow-up treatment with bisoprolol plus HCT (5 + 2.5
mg) in mild to moderate hypertension. n: Bisoprolol in Combination Therapy of
Hypertension Wells Medical Ltd. 99 27
Lodoz shows no significant adverse effects on potassium levels,
lipid levels (mean total cholesterol), and glucose tolerance.
Under Lodoz significantly less hypokalemia (0.7 ) occurs
than under high dosed HCTZ (2S mg, 6.S )
!nfluence on
laboratory
values
Total
cholesterol
mg/dl
LDL
chol.
mg/dl
HDL
chol.
mg/dl
Triglycer.
mg/dl
Clucose
mg/dl
Pot.
mval/l
Ca
mg/dl
Creatinine
mg/dl
Uric acid
mg/dl
Baseline 20S.1 113.2 S1.8 143.0 104.3 4.26 3.10 1.03 S.8S
Final 206.3 113.3 S0.2 1S1.0 110.8 4.2S 3.20 1.11 6.43
acc. PR!SANT et al., Am Heart ]. 133S, 130: 3S3366
Laboratory values at baseline and after at least 8 weeks
treatment with Lodoz
Laboratory values at baseline and after at least 8 weeks
treatment with Lodoz
Bisoprolol + .25 HCT
st line
USA , France,South AIrica,Indonesia,Argentina,Brazil,Chile,Colombia,Costa Rica,Dominian Rep,Mexico
El Salvador,Guatemala,Honduras,Nicaragua,!anama,!eru,Venezuela,Hongkong,!hilippines,Singapore,
Thailand
orld of Lodoz in 1an 2004
Launched in 22 countries
orld of Lodoz in 1an 2004
Launched in 22 countries