Beta Blocker on Hypertension Management

Challenging the Controversy

Focus on Bisoprolol
ISFANUDDIN N.KAOY

What is the latest issue

in Hypertension?

JNC 7

Blood Pressure Classification

BP Classification

SBP mmHg

DBP mmHg

Normal

<120

and

<80

Prehypertension

120139

or

8089

Stage 1 Hypertension

140159

or

9099

Stage 2 Hypertension

>160

or

>100

Life Style Modification

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those
with diabetes or chronic kidney disease)
Initial Drug Choices
Without Compelling Indications

With Compelling Indications

Stage 1 Hypertension
(SBP 140 159 or DBP 90
99 mmHg)

Stage 2 Hypertension
(SBP > 160 or DBP > 100
mmHg)

Thiazide-type diuretics for

most. May consider ACE-I,
ARB, BB, CCB, or
combination

2-drug combination for

most (usually thiazide-type
diuretic and ACEI, or ARB,
or B, or CCB).

Drugs for the

compelling indications)
Other antihypertensive
drugs diuretics, ACEI,
ARB, B, CCB) as
needed

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure
is achieved. Consider consultation with hypertension specialist
NIH Publication No. 03-5233, 2003

GLB.IRB.06.10.09

BP Targets

JNC VII

ESH-ESC

WHO-ISH

<140/90
DM

<140/90
lower if tolerated

SBP <140
DM

renal

DM

Renal CVD

<130/80

<130/80

<130/80

Algorithm for Drug Treatment of Hypertension

Initial Drug Choices
Without Specific or Compelling Indications
Stage 1 Hypertension
(SBP 140159 or DBP 9099 mmHg)
Thiazide-type diuretics for most.*
May consider ACEI, ARB, CCB, or
(BB??)---or combination**

Stage 2 Hypertension
(SBP >160 or DBP >100 mmHg)
2-drug combination for most
(usually thiazide-type diuretic and
ACEI, or ARB, CCB or (BB??)

*Diuretic or CCB preferred in patients >60 years of age

**Combination therapy may also be appropriate initial therapy in

patients with diabetes or renal disease

Treatment Guidelines: Similarities and Differences

Between JNC 7 and ESH1,2

Initial drug choice:

ESH makes no specific recommendation on initial drug choice as the
benefit of therapy is due to lowering of blood pressure (BP) per se
JNC 7 suggests diuretic as first-line treatment, alone or in combination,
unless contraindicated

Combination therapy:
ESH and JNC 7 accepted that most patients will need to use two or
more drugs in order to achieve goal BP

Choice of drugs, in both guidelines, is influenced by factors such as:

Cardiovascular risk profile
Presence of target organ damage, clinical cardiovascular disease,
renal disease and diabetes

GLB.IRB.06.10.09

Presence of co-existing disorders

Possibility of interactions with drugs used for other conditions
1. Cifkova Rl, et al. J Hypertens. 2003;21:10111053
2. Chobanian AV, et al. JAMA. 2003;289:25602572

Diuretics
Betablockers

Angiotensinreceptor
blockers

Alphablockers

Calcium
channel
blockers
ACE
inhibitors

Possible combinations of different classes of antihypertensive

agents as suggested in ESC ESH guidelines. The most
rational combinations are represented as red lines

AB/CD Rule for optimisation of

antihypertensive treatment
( AB/CD =ACEi, Beta-blocker Ca++-blocker, Diuretic)
AGE
STEP:

1:

Younger
(<55)

Older
(>55)

Renin

A or B

C or D

C or D

2:
3:

A or B

A or B
+

C or D

Resistant HT / 4: Add / substitute alpha blocker

5: Re-consider 20 causes trial of spironolactone
Intolerance
Dickerson et al. Lancet 353:2008-11;1999

2007 ESH/ESC Guidelines

Diuretics

-blockers

AT1-receptor
blockers

1-blockers

Calcium
antagonists

ACE inhibitors

High blood pressure mechanisms

High renin
(Dry vasocontriction)

Pathophysiologic difference

Low renin
(Wet vasocontriction)

Arterioles
Higher
High
Low
Low
High
High
High
Low
Yes

Peripheral resistance
Aldosterone
Plasma volume
Cardiac output
Haematocrit
Blood urea
Blood viscosity
Tissue perfusion
Postural hypotension

High
Low to High
High
High
Low
Low
Low
High
No

High renin essential hypertension

Renovascular and malignant hypertension

Clinical examples

Low renin essential hypertension

Primary aldosteronism

(+) Stroke
(+) Heart attack
(+) Renal damage
(+) Retinopathy encephalopathy

Vascular sequelae

(-)
(-)
(-)
(-)

(+) Converting enzyme inhibitor

Treatments

(-)
(-)
(+)
(+)
(+)

(+) Beta blocker

(-) Calcium channel blocker
(-) Diuretics
(-) Alpha blockers

Acute neurohormonal effects on blood

pressure homeostasis
Perfusion

RAA

SNS
Heart rate and cardiac output
Sodium and water retention
Blood pressure

The Ascot Study

What We Have Learned

The ASCOT Result :

Should The Hypertension Guidelines
be Rewritten ?
Amlodipin + Perindropil
VS

Atenolol + Thiazide

ASCOT Trial
BP Targets <140/90 m Hg or <130/80 mm Hg in Patients with Diabetes

Unblinded - Probe Design

Amlodipine 5-10 mg

Atenolol 50-100 mg

add

add

Perindopril 4-8 mg
add

Bendroflumethiazide-K
1.25 - 2.5 mg

Doxazosin 4-8 mg
Other medications
More than 50% in each group were on 2 or more medications; 26% crossed
over to other study drugs; 40%
*Lancet 2005;366:895

used Rx not prescribed by investigators

Perindopril makes the difference between ASCOT, INVEST and

ALLHAT
ALLHAT

ASCOT

INVEST

CCB amlodipine + addon vs. thiazide diuretic

(n=8215)

CCB + perindorpil 4 to 8
mg (70%) vs. atenolol +
thiazide
(n = 9639 vs. 9618)

CCB + trandolapril vs.

BB + trandolapril
(n = 9758 vs. 9791)

All cause
mortality

NS

11%
(p=0.0247)

NS

Combined
CHD

NS

13%
(p=0.007)

NS

Combined
CVD

NS

16%
(p=0.0001)

No data available

Stroke

NS

23%
(p=0.003)

NS

16%
(p=0.1257)

No data available

No data available

30%
(p<0.0001)

1.2%
(<p ?)

NS

S (HR 0.85%)

NS

Heart failure
New onset of
diabetes
New onset
renal
impairment

S in favor of
diuretic

ASCOT : Final Conclusion

CCB + perindopril based therapy
confers an advantage over atenolol
+ thiazide based therapy on all major
CV end points, all cause mortality
and new onset diabetes
Irrespective of the reasons for benefit,
the standard regimen of beta blocker
+ thiazide should not be preferred to
the CCB + perindopril regimen for
most patients

CONCLUSION
JNC 7 and other guidelines provides
many guidance to the management of
hypertension
The ASCOT result MAY change the
guidelines
Perindopril makes the difference
between the ASCOT, ALLHAT and
INVEST results

ASCOT Trial*
Primary Objectives
To compare the effect on non-fatal
myocardial infarction (MI) and fatal CHD
of an antihypertensive regimen
based on a B-blocker +/- diuretic with a
regime based on a CCB +/- ACE-I
, Lancet 2005;366:895

ASCOT Trial*

No significant difference in primary outcome

(fatal & non fatal MI) but CCB/ACE-I significantly
reduced secondary endpoints, i.e., total CHD and CV
events including strokes

BP control better with CCB/ACE-I, especially 1st

few months

(differences 5.9/2.1 mm Hg at 3 months)

Mean trial differences: 2.7/1.9 mm Hg between therapies

Did the differences in BP or specific treatments

determine the outcome?

ASCOT INVESTIGATORS
CONCLUSIONS

Contemporary

therapy [CCB/ACE]
is superior to older therapy
[BBL/Diuretic] in the management of
hypertension---

RESULTS ARE GENERALIZABLE-

PROBLEMS with those conclusions.

1The B-blocker used in the ASCOT
trial was inappropriately dosed.
Atenolol is not a once-a-day drug
= weak B-1 selective

2- It is well-known that in the elderly

B-blockers are not as effective in
lowering BP as a CCB or a diuretic

ASCOT Trial*

Report failed to reference or mention

ALLHAT, SHEP or STOP-2 studies
where results were different
Lancet 2005;366:895

Stop-2- No difference in CV
outcome- Beta Blocker/diuretic
compared to ACE/CCB
ALLHAT.- Diuretic based RX
equal to or better than[ in some
subgroups] an ACE or CCB based
treatment group
SHEP-Diuretic based RX-elderly
marked reduction in CV events
compared to placebo

 THERE IS LITTLE DOUBT THAT A

combination of an ACEI and a CCB is
effective and is a reasonable choice
for therapy for many hypertensives. At
present, however, there is no strong
evidence that this is a preferred
combination when compared to a
diuretic/ ACEI or ARB, etc

British Hypertension Society 2006

Based on recent clinical trial
results,[ASCOT TRIAL plus other
data]
B-blockers should no longer be used
as initial antihypertensive therapy

B-blockers may be 1st step treatment

In younger people but probably
should be considered as 3rd or
4th step therapy in other patients.
Strong implication that B-blockers
should be withdrawn from treatment
unless compelling indication for
their use---(angina, heart failure,
etc.)
British Hypertension Society, 2006

NICE recommendations 2006 Vs

ESH ESC guideline 2007
Beta-blockers tidak lagi merupakan pilihan rutin terapi
hypertension => step no 4!
Pembatasan penggunaan!
-blocker + 2nd drug: jangan thiazide diuretic (resiko
timbulnya diabetes) tetapi dengan Ca antagonist

Vs
5 kelas anti hipertensi dapat secara setara sebagai 1stline treatment: initiation and maintenance....termasuk blockers !
(dengan pembatasan spt ;tidak direkomendasikan pada
pasien dengan metabolic syndrome atau resiko tinggi
diabetes).
Kombinasi -blocker + thiazide masih valid sebagai
alternatif terapi

How should we interpret

the hypertension
clinical trial results?

Should conclusions of a clinical trial

be based on results of primary or

secondary outcomes?
How much statistical manipulation
is acceptable to prove a point?

REBUTTAL

Criticisms of the

ALLHAT Conclusions

Conclusions were based solely on analyses of secondary

endpoints.
Messerli, We should remember [as we were told by
the ALLHAT investigators] that secondary endpoints are
soft

data that should not form a basis for main

conclusions or lead to a labeling of a drug class as

preferred ----

WHAT ABOUT ASCOT?

Conflicting Data
1. ALLHAT (favors a diuretic) Blinded
2. STOP-2
(equal outcomes B-BL/D vs CCB or ACE-I)
3. ASCOT
(different outcomes CCB/ACE-I vs B-BL/D)
4.VALUE
(CCB reduces MI events more than an ARB)

Are there explanations for these differences?

CRITICS
ALLHAT
Wrong add-on drugs
Demographics favored diuretics
Should have adhered to primary outcome results
BP differences accounted for difference in outcome
VALUE
Statistical manipulations to explain
results
ASCOT
Wrong comparator medication
Secondary analyses for conclusions?
Are the results generalizable?

CONCLUSIONS

The message is clear

Beta blocker still useful

New Generation B-1 > selective

BISOPROLOL: 1-blocker paling selektif

Bisoprolol
1:75

Metoprolol

increasing
1-selectivity

1:20

no
selectivity

1.8:1
Propranolol

increasing
2-selectivity

300:1
ICI
118.551

Ratio of constants of inhibition

Atenolol

Betaxolol

1:35

1:35

Thank You
For your kind attention