BB in HTN 2007

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In the name of Allah, Most Gracious, Most Merciful

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BETA BLOCKERS-IN HYPERTENSION

- Dr. Mohammed Sadiq Azam

First yr. PG

M - I

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HISTORY

1948: Ahlquist classified adrenergic receptors

into and receptors.

1958: Dichloroisoprenaline (DCI) First BB

1963: Therapeutic breakthrough, Propronololintroduced by J.W.Black

1980: BB become the most popular antiHTNs

after diuretics. Practolol First 1 selective.

2003: BB become the most controversial

antiHTNs!!

2010: ??????

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PHYSIOLOGY OF RECEPTORS

Receptor 1 2 3

Location Heart,

JG cells of kidney

Bronchi, Blood

vessels, Uterus, GIT,

Urinary tract, Eye

Adipose tissue

Selective agonist Dobutamine SalbutamolTerbutaline

BRL37344

Selective antagonist Metoprolol

Atenolol

ISI118551

-methyl propronlol

CGP20712A (+B1)

ICI118551 (+B2)

Potency of NA as

agonist

Strong Weak Strong

Role Cardiac

+ Inotropic

+ Chronotropic

Vasodilatation

Bronchodilatation

Glucagon levels

Lipolysis

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CLASSIFICATION OF BLOCKERS

(Ref: Tripathi KD, antiadrenergic drugs, Essentials of Med. Pharmacology, p124, 5e:2003)

1. Non selective (1 & 2): Without ISA :

Propronolol

Sotalol

Timolol

With ISA:

Pindolol

With additional blocking property:

Labetolol

Carvedilol

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(Ref: Tripathi KD, antiadrenergic drugs, Essentials of Med. Pharmacology, p124, 5e:2003)

2. Cardioselective (1):

Metoprolol

Acebutolol

Esmolol

Atenolol Bisoprolol

Betaxolol

Celiprolol

3. Selective (2): Butoxamine

ICI118551

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(Ref: Braunwald, Systemic Hypertension:Therapy, Heart Disease, p1002:f38-11,7e:2005)

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GENERATION CLASS COMPOUND

First Non selective Propronolol

Second Selective Metoprolol

Third Beta blocker - vasodilator Carvedilol

Bucindolol

Nebivolol

(Ref: Braunwald, Drugs in treatment of Heart Failure, Heart Disease, p590:t23-11,7e:2005)

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PHARMACODYNAMICS

On Heart: HR, Force of contraction, Cardiac Output

systole by conduction ( synergy of fibres)

Cardiac work, O2 consumption:

Total coronary flow:

Restricted to subepicardial region, subendocardial region is not affected.

Overall Effect : O2 supply/demand status & exercise tolerance.

Refractory period & automaticity - rate of DP in ectopic foci

AV conduction : Delayed

doses: membrane stabilisation & direct depressant (Quinidine like) effect.

Blocks cardiac stimulatory action of adrenergic drugs but NOT Digoxin, Ca,

Methyl xanthines, glucagon.

(Prototype: Propronlol)

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PHARMACODYNAMICS

On Blood vessels:

Inhibits VD & BP caused by Isoprenaline

Augments BP caused by Adrenaline

Re-reversal of vasomotor reversal seen after -blockade (Reverse Dale)

No direct effect on blood vessels => little acute change in BP

Prolonged use: BP in hypertensive subjects but NOT in normotensives.


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PHARMACODYNAMICS

Mechanisms of Anti Hypertensive action:

1. Initially: TPR and C.O (15-20%) => little change in BP

Chronic use: resistance vessels adapt TPR , CO => BP

2. NA release from sympathetic terminals due to blockade of-mediated

release.

3. 1 mediated renin release from kidney (upto 60% in BB with ISA - )

4. Central action sympathetic outflow


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PHARMACOKINETICS

Oral absorption: Good

Low Bioavailability (due to FP metabolism in Liver)

Oral:Parental dose ratio = 40:1

Interindividual variation in extent of FPM +

Lipophilic, easily crosses BBB

Liver metabolism depends on HBF ( on chronic use)

BA with meals as food FPM

Metabolism is saturatable. BA with doses

Plasma protein binding > 90%

Excretion in urine as Glucronides


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DRUG INTERACTION

Additive depression of SA node and AV conduction with digitalis and

verapamil .

Delayed recovery from hypoglycemia

Unopposed action - TPR

Indomethacin/NSAIDs- Attenuate anti HTN action

Cimitidine inhibits Ppnl metabolism.

Ppnl metabolism by HBF

Ppnl BA of CPZ by FPM


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ADR & CONTRA INDICATIONS

Fatigue - MC ADR

Myocardial insufficiency C/I in severe HF

Bradycardia - in patients with SSS

variant angina unopposed mediated coronary VC

Impairment of carbohydrate tolerance in pre diabetics.

Altered plasma lipid profile - TGL , LDL - HDL

Sudden withdrawal rebound HTN, angina, sudden death

exercise capacity 2 mediated VD to skeletal muscle

Worsening of PVD


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ADR & CONTRA INDICATIONS

Non selective BBs can precipitate life threatening AE of BA

C/I in partial/ complete heart block can ppt arrest

C/I in pheochromocytoma can ppt a severe HTN crisis.

Sexual dysfunction in males

?? Effect on depression reported r/o suicide compared to

CCB/ACEI

Caution in DM, elderly, pregnancy (esp. non specific BB)


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THE MILLION DOLLAR QUESTION

And now

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TO BE OR NOT TO BE??

The Role of Beta Blockers in Hypertension

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WHAT THE JNC 7 SAYS

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WHAT THE JNC 7 SAYS

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WHAT DOES EVIDENCE POINT AT??

EBM

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THE COCHRANE REVIEW

Evidence no.1

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COCHRANE ON BB in HTN

The review, published online January 24, 2007, bases this conclusion on "the

relatively weak effect of beta blockers to reduce stroke and the absence of an effect

on coronary heart disease when compared with placebo or no treatment"

and"the trend toward worse outcomes in comparison with calcium-channel blockers,

renin-angiotensin-system inhibitors, and thiazide diuretics.

Most of the evidence for these conclusions comes from trials where atenolol was

the beta blocker used, and it is not known at present whether there are differences

between the different subtypes of beta blockers or whether beta blockers have

differential effects on younger and elderly patients.

(Prototype: Atenolol)

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Results showed that the risk of all-cause mortality was not different between first-

line beta blockers and placebo, diuretics, or inhibitors of the renin angiotensin

system but was higher for beta blockers compared with calcium blockers.


Comparative drug RR of all-cause mortality

for beta blockers

95% CI

Placebo 0.99 0.88-1.11

Diuretics 1.04 0.91-1.19

ACE inhibitors/ARBs 1.10 0.98-1.24

Calcium blockers 1.07 1.00-1.14

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The risk of total cardiovascular disease was lower for first-line beta blockers compared

with placebo but was significantly worse for beta blockers compared with calcium

blockers. There was no significant difference in this end point with beta blockers when

compared with either diuretics or ACE inhibitors/ARBs.


Comparative drug RR of total CV disease forbeta blockers

95% CI

Placebo 0.88 0.79-0.97

Diuretics 1.13 0.99-1.13



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The lower risk of total cardiovascular disease

with beta blockers compared with placebo was

primarily a reflection of the significant decrease

in stroke, whereas coronary heart disease (CHD)

risk was not significantly different between beta

blockers and placebo.

Similarly, the increase in total cardiovascular

disease with beta blockers compared with

calcium blockers was due to an increase in

stroke with the beta blockers.

There was also an increase in stroke with beta

blockers as compared with inhibitors of the

renin angiotensin system. CHD was not

significantly different between beta blockers and

diuretics, calcium blockers, or renin-angiotensin-

system inhibitors.


Comparative

drug

RR of stroke

for beta

blockers

95% CI

Placebo 0.80 0.66-0.96

Diuretics 1.17 0.65-2.09

ACE

inhibitors/

ARBs

1.30 1.11-1.53

Calcium

blockers

1.24 1.11-1.40

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The authors conclude that "beta blockers are inferior to various calcium-channel

blockers for all-cause mortality, stroke, and total cardiovascular events and to renin-

angiotensin-system inhibition for stroke."

Is age important?

Noting that a previous meta-analysis (by Khan and McAlister) found beta blockers

to be inferior to all other therapies only in elderly patients, they point out that this

claim relies heavily on the Medical Research Council trial in elderly hypertensivepatients, in which the dropout rate was 25%. They say: "At present, there are

insufficient data to make a valid comparison of beta-blocker effects on younger vs

elderly patients, although this is an important hypothesis."


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Are there differences between beta blockers?

They point out that of the 40,245 participants using beta blockers in this review,

atenolol was used by 30,150 (75%). "Due to the paucity of data using beta blockers

other than atenolol, it is not possible to say whether the effectiveness (or lack

thereof) and (in)tolerability of beta blockers seen here is a property of atenolol or is

a class effect of beta blockers across the board.

The authors note that the information reported in the trials considered in thisreview was insufficient to explore the effect of race or ethnicity, as most trial

participants were white.


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THE ASCOT-BPLA TRIAL

Evidence No.2

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ASCOT-BPLA TRIAL

Anglo-Scandinavian Cardiac Outcomes TrialBlood Pressure Lowering Arm (ASCOT-

BPLA) trial have confirmed preliminary findings showing that an antihypertensive

strategy based on amlodipine, with perindopril added as required, significantly

reduced all-cause mortality and other cardiovascular end points, including stroke,

compared with an atenolol-based strategy, with the

diuretic bendroflumethiazide added as required.

A 10% reduction in nonfatal MI and fatal coronary heart disease (CHD), the primary

end point of the trial, did not reach statistical significance, a finding that the

researchers attribute to the early stop of the trial.

A reduction in all-cause mortality seen with the amlodipine/perindopril strategy

caused the trial to be stopped in November 2004.


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ASCOT-BPLA TRIAL


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ASCOT-BPLA:

PRIMARY AND SECONDARY END POINTS


End point Amlodipine-

based regimen

Atenolol-based

regimen

Unadjusted hazard

ratio (95% CI)

p

Primary end point

(n)

429 474 0.90 (0.79-1.02) 0.1052

Fatal and nonfatal

stroke (n)

327 422 0.77 (0.66-0.89) 0.0003

Total CV events and

procedures (n)

1362 1602 0.84 (0.78-0.90)

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ASCOT-BPLA:



End point Amlodipine-

based regimen

Atenolol-based

regimen

Unadjusted

hazard ratio (95%CI)

p

New-onset

diabetes

567 799 0.70 (0.63-0.78)

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NEW ONSET DIABETES: TRIALS

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ASCOT-BPLA:



Patients with new or prior diabetes were = 3x more likely to have a

CV event than those without diabetes.

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THE CAFE TRIAL

Evidence No.3

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CAFE TRIAL


Conduit Artery Function Evaluation (CAFE), a sub-

study of the ASCOT, which compared the BB atenolol

+/- a diuretic with a regimen based

on amlodipine +/- without the ACEI, perindopril.

CAFE findings showed substantial reductions in

central aortic BP with amlodipine + perindopril overatenolol + diuretic, despite very similar brachial BPs

between the groups.

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CAFE TRIAL


The greater vasodilation seen with amlodipine-based

treatment might translate into a reduction in the strength of

the reflected wave velocity from the periphery, thereby

reducing central arterial pressures.

Williams pointed out that a 3- to 4-mm-Hg difference in BP

seen between groups in central aortic pressures translates

into roughly a 25% difference in stroke risk (similar to the 27%reduction in stroke risk seen in ASCOT in the amlodipine/perindopril arm,

supporting the possibility that this difference in central pressures may

explain the differences seen in outcomes between groups).

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CAFE TRIAL


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CAFE TRIAL


Measure Amlodipine-based

vs Atenolol-based

regimen (mm Hg)

95% CI p

Brachial systolic BP 0.7 -0.4 to 1.7 0.2

Central aortic

systolic BP

4.3 3.3 to 5.4

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THE CACHET TRIAL

Evidence No.4

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CACHET TRIAL


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CACHET TRIAL


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EUROPEAN SOCIETY REACTS

The Impact

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WHAT THE ESC/ESH SAYS

BB vs CCB:

In support ofASCOT-BPLA

INVEST trial: also showed equal incidence of CVevents in patients with CAD in whom treatment was

started with a CCB (verapamil, often + ACE I) or with

a BB (atenolol often + D)

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BB vs ARB: In the LIFE study in more than 9000 hypertensive patients

with electrocardiographic left ventricular hypertrophy mean

blood pressure was reduced to the same degree in the groups

in which treatment was initiated with either losartan or the b-blocker atenolol.

Over the about 5 years of follow-up losartan-treated patients

showed a significant 13% reduction in major cardiovascular

events (the primary end point) with no difference in theincidence of myocardial infarction, but a 25% difference in the

incidence of stroke.

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The LIFE study and the ASCOT study, both of which showedsuperiority of an ARB, and, respectively, a CCB over therapy

initiated by a BB as far as stroke (LIFE) or stroke and mortality

(ASCOT) were concerned.

These two large trials have strongly influenced a recent meta-analysis which concluded that BB initiated therapy is inferior

to others in stroke prevention, but not in prevention of

myocardial infarction and reduction in mortality.

On the basis of a similar meta-analysis, the National Institutefor Health and Clinical Excellence (NICE) in the United

Kingdom has advised the use of b-blockers only as fourth line

antihypertensive agents.

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THE VERDICT

efficacy on CV endpoints (esp. Stroke) 1,3,4

Metabolically unfriendly - r/o New onset DM 1

Least cost effective 2

No significant difference in all cause mortality

compared to A or D but higher than with CCB 3

Risk for CV disease worse with BB compared to CCB 3

Should be used as 4th line drugs in HTN 2

Source: 1 ASCOT-BPLA trial, LIFE study2 NICE guidelines CG34:Hypertension3 Cochrane Review: BB should not be fist line for HTN , Jan 24, 2007

4

CAFE trial: Circulation, Mar 2006; CACHET trial: Stroke 2006

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BUT, IS IT SO???LETS LOOK BACK

The future looks bleak for Beta Blockers..

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Comparative drug RR of all-cause mortality forbeta blockers

95% CI

Placebo 0.99 0.88-1.11

Diuretics 1.04 0.91-1.19



Comparative drug RR of total CV disease for beta

blockers

95% CI

Placebo 0.88 0.79-0.97

Diuretics 1.13 0.99-1.13



Comparative

drug

RR of stroke for

beta blockers

95% CI

Placebo 0.80 0.66-0.96

Diuretics 1.17 0.65-2.09

ACE inhibitors/

ARBs

1.30 1.11-1.53

Calcium

blockers

1.24 1.11-1.40

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ASCOT-BPLA TRIAL

(Prototype: Atenolol)End point Amlodipin

e-based

regimen

Atenolol-

based

regimen

Unadjusted

hazard ratio

(95% CI)

p

Primary end

point (n)

429 474 0.90 (0.79-

1.02)

0.1052

Fatal and

nonfatal

stroke (n)

327 422 0.77 (0.66-

0.89)

0.0003

Total CV

events and

procedures

(n)

1362 1602 0.84 (0.78-

0.90)

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NEW ONSET DIABETES: TRIALS

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CAFE & CACHET TRIALS


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ATENOLOL

Developed in 1976, USFDA approved in 1981.

Short acting beta blocker.

Good BP but doesnt improve outcome.

Bad safety profile in stroke1

CBF2, less reduction in central aortic pressure3

Metabolically unsafe - incidince of new onset DM4

Bad safety profile in elderly5

Must NOT be used in uncomplicated HTN.

Source: 1 ASCOT-BPLA trial2 CACHET trial3 CAFE trial4 LIFE trial, ASCOT-BPLA trial

5

MRC study

BETA BLOCKERS IN HTN

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BETA BLOCKERS IN HTN

WHERE DO THEY STAND??

Atenolol is BAD as a first line drug in uncomplicated HTN.

NOT ALL BETA BLOCKERS ARE.

The outcomes seen in the recent clinical trials seem to be

more of a DRUG EFFECT than a CLASS EFFECT!!

Newer BB, esp. vasodilatory BB like nebivolol hold a

promising future for these drugs.

Lack of clinical data on these drugs has limited their

recommendation by international guidelines.

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THE EVIDENCE IN FAVOUR OF BB

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ESC-ESH 2007 Guidelines state: Also, in the INVEST trial, a treatment strategy based on the initial

administration of a b-blocker followed by the addition, in mostpatients, of a thiazide diuretic was accompanied by an incidence of all

cardiovascular and cause-specific events similar to that of a treatment

initiated with the calcium antagonist verapamil followed by the

addition of the ACE inhibitor trandolapril.

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ESC-ESH 2007 Guidelines state: Finally, a recent meta-analysis shows that, when compared with

placebo, BB based therapy did indeed reduce stroke significantly.

This suggests that at least part of the inferiority of the b-blocker-

thiazide combination reported in ASCOT may be due to a lesser blood

pressure reduction, particularly of central blood pressure, that

occurred in this trial with this therapeutic regimen.

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JNC 7 & ESC-ESH 2007 AGREE

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THE LAST WORD

Newer BBs especially the vasodilatory BB like Nebivolol and

Carvedilol are metabolically neutral they DO NOT increase

the incidence of newer diabetics.

Newer BBs in fact the central aortic pressure thus the risk

of stroke by > 25%.

Newer BBs (nebivolol) can be used in elderly even with a

reduced EF (SENIORS trial, J. Am. Coll. Cardiol. 2009;53;2150-2158).

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THE LAST WORD

Newer BBs can be used in young HTNs/preHTNs to CO and

thus prevent worsening of HTN or development of HTN.

BB though conventionally placed as Category C drugs in

pregnancy, hold promise as newer BBs are being developed

with better safety profiles (Labetolol BB OC in Pregnancy).

Newer BBs like Nebivolol, Carvedilol and Metoprolol can be

safely used in Diabetes as they do not exacerbate

hypoglycaemia unlike conventional BB (Ppnl, Atenolol).

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THE LAST WORD

The sins of one (Atenolol) must not be made an excuse for the

execution of many (BB as a class).

The bad profiles seen in recent trials seems to be more of a

DRUG EFFECT than a CLASS EFFECT.

BB can remain a first line drug in HTN as HTN remains a

leading cause of HF and BB are a DOC in HF as well (? dual

benefit).

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THE LAST WORD

In anyone with any type of cardiac condition BB remain THE

first line drug of choice (JNC7, ESC-ESH 2007 guidelines).

In uncomplicated HTN (if such a term exists!), there are many

other drugs that have carved a niche for themselves, namely

ACEIs, ARBs, CCBs and Diuretics.

Diuretics remain the first line drugs in uncomplicated HTN, a

result largely of their low cost rather than improved outcome.

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QUESTIONS ?

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BB in HTN 2007

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