prof malcom ppt

7/29/2019 Prof Malcom PPT

1/54

The modern role of beta-blockers inthe treatment of cardiovascular

disease; focus on hypertension

JM Cruickshank

Saudi ArabiaNovember 2012


2/54

The Cardiovascular Continuum


3/54

The Effect of Early Intervention with Atenolol in Reducing

Mortality in Acute Myocardial Infarction; ISIS-1

500

400

300

200

100

0

48

73

171

231

261

119

167

208

234

294

266

321

287

341

312

364

330

382

344

403

359

419

368

439

386

458

402

475

420

491

1 2 3 4 5 6 7 8 9 10 1112 13 14

Group allocated

control

Group allocatedatenolol

*** 2p < 0.002

** 2p < 0.04***

**

EarlyI.V. 5 + 5mg End of

oral dose

Days from randomisation

Oral 100mg/day

Numberof

vasculardeaths


4/54

COMMIT Trial AMI cases radomised

to metoprolol or placebo

N = 45,852 AMI cases who received thrombolytics

IV followed by oral metoprolol for 1 month

No reduction in death rate by metop

Re-infarction reduced by 18% (sig) by metop VF reduced by 17% (sig) by metop

Cardiogenic shock increased 30% (sig) by metopmainly 1st day

Give IV BB only when haemodynamics are stable


5/54

Secondary prevention of myocardial infarction with

different types ofb - blockers

b1 - selectivewithout ISA

b1 - selectivewith ISA

non-selective

without ISA

non-selective

with ISA

b- blockerswithout ISA

Reductionofm

ortality

b- blockerswith ISA

-30

-20

-10

-

Yusuf S et al. Progress Cardiovasc. Diseases 1985; 5: 335-371


6/54

b- blockers in MI

Kjekhus (1985)

Reduction in heart rate (min )-1

Reduction

inmortality

(%)

alprenolol

timolol

metoprolol

propranolol

practolol

sotalol

oxprenolol

pindolol

50

40

30

20

10

00 4 8 12 16 20


7/54

DECREASE-IV ; 1,066 medium-risk patients (mean age 64 y) for elective

non-cardiac surgery were randomised to control, bisoprolol (2.5 mg,

titrate to HR-50-70 bpm), fluvastatin or combination, 30 days pre-

surgery and 30 days post. Podermans et al Munich 2008.


8/54

TIBBS Study N=520 CAD Patients

Hard events (death, M.I. Hospitalisation) significantly lower on Bisoprolol than SR

Nifedipine

1.0

0.9

0.8

0.7

0.6

0.5

0 50 100 150

Days

Eventfree

survival

200 250 300 350 400

Bisoprolol

Nifedipine s.r.

p=0.03

von Arnim et al 1996


9/54

High heart-rates are harmful in patients with

stable CAD + DM. Anselmino M et al 2010

HR78

bpm


10/54

Framingham 26 y follow-up: low resting heart

rates protect from sudden death. Kannel 1985


11/54

Figure 30. Beta-blockers and hard end-point

placebo-controlled trials in systolic heart failure;

ISA reduces efficacy (all-cause death).

Xam-

ISA

(ns)% change

Bucind-ISA

10%(ns)

Nebiv-ISA

12% (ns)

Bisop

34%(sig)Metop

35%(sig)

Carv

35%(sig)

HR 13-14 bpmHR 8-9 bpm


12/54

Figure 31. CIBIS III prevention of sudden

death with bisoprolol vs ACEI. 2005

Results of the CIBIS III study: Circulation, 2005; 112:121

10

8

6

4

2

0

0 6 12

Months

%

P = 0.049

46% Riskreduction in

Sudden CardiacDeath

Enalapril - first

Bisoprolol - first


13/54

The Cardiovascular Continuum


14/54

Mortality due to leading global risk

factors. Lopez AD et al Lancet 2006


15/54

Dr. Wilfried Meyer, IMM Paris31 Aug 2011

15

Current UK NICE Committee recommendations

for the treatment of hypertension

BBs = 4th or 5th line !!

Or only among the also-runs!


16/54

Different Predictors of Diastolic Hypertension (DH) ( raised

systolic SDH) and Isolated Systolic Hypertension (ISH)

FRAMINGHAM StudyFranklin et al, Circulat 2005

Predictors of Diastolic Hypertension (

Systolic Hypertension) = DBP 90mmHg

( SBP 140 mmHg)Predictors of Isolated Systolic

Hypertension = SBP 140 mmHg +DBP < 90 mmHg

1. Young age

2. Male sex

3. High BMI at baseline

4. Increased BMI during follow-up

5. Main mechanism of DH and SDH is

raised peripheral resistance

1. Older age

2. Female sex

3. Increased BMI during follow-up (weak)

4. ISH arises more commonly from normaland high normal BP, than burned out

diastolic hypertension

5. Only 18% with newonset ISH had a

previous DBP 95 mmHg6. Main mechanism of ISH is increased

arterial stiffness = aging of arteries


17/54

Table 3. First-line beta-blockers (atenolol) perform poorly in elderly

hypertension (wide pulse-pressure)

Trial Beta-blockerMean-age

(y)

Initial BP

(mm Hg)

Pulse-

Pressure

(mm Hg)

Result

MRC ElderlyAtenolol (vs

placebo vs

diuretic)

70 185/91 94

Only 1st line diuretics differed

from placebo in stroke

prevention; diuretic superior to 1st

line atenolol in reducing coronaryevents

HEPAtenolol (vs non-

treatment)69 196/99 97

Significant reduction in stroke but

no effect on coronary events by

atenolol

LIFE

Atenolol (vs

losartan) 67 174/98 76

Losartan superior to atenolol in

reducing cardiovascular mortality

and non-fatal and fatal stroke

ASCOT

Atenolol

diuretic (vs

amlodipine

perindopril)

63 164/94 70

Amlodipine perindopril was

superior to atenolol diuretic in

reducing all-cause mortality and

all coronary and stroke end-points


18/54

Effect of different antihypertensive agents (v placebo) on

brachial (B) and aortic (A) pulse-pressure in 52 elderly

(mean age 77y) systolic hypertensives (random, DB,

crossover x 1 month). Morgan T et al 2004

0

5

10

15

B A

ACE 1 b Blockers CaB DiurB A B A B A

ACE= perindopril; BB = atenolol (25-50mg); CaB = felodipine; diur = hydrochlorth.

Fall inPulse

Pressure

(mm Hg)

*

*


19/54

Figure 23. The INVEST Study :- n=22,576 hypertensives with CHD, mean age 66y,

randomised to Verapamil / ACE inhibitor or Atenolol / Thiazide based treatment.

Equal effects on primary and secondary end points (but Verap / ACE combination

less effective in subjects with CCF). Pepine CJ et al 2003.

Calcium

Antagonist

Strategy

(CAS)

(n=11,267)

Non-Calcium

Antagonist

Strategy

(NCAS)

(n=11,309)

Rate per 1000Patient-Years

Rate per 1000Patient-Years

RR (95% CI) FavoursCAS

FavoursNCAS

First Event

Death

Non-fatal Myocardial Infarction

Non-fatal Stroke

Cardiovascular-Related Death

Cardiovascular-Related Hospitalization

36

28

5

4

14

24

37

29

5

5

14

23

0.98 (0.90-1.06)

0.98 (0.90-1.07)

0.99 (0.79-1.24)

0.89 (0.70-1.12)

1.00 (0.88-1.14)

1.03 (0.93-1.14)

0.6 0.8 1.0 1.2 1.4

RR (95% CI)


20/54

In 30 lean (L), 20 peripherally obese (PO) and 26 centrally obese

(CO) subjects (mean age 36y), muscle sympathetic nerve activity

(MSNA) was significantly higher in CO than PO and L subjects

70

55

40

25L PO CO

MSNA

***

*

(bs/100 hb)

Grassi et al, J.Hypertens 2004

S mpatho e itation in normal ei ht and obesit


21/54

Sympatho-excitation in normal-weight and obesity-

related hypertension (HT), vs normotensives (NT), in

middle-aged (37-50 y) subjects.

Lambert E et al 2007


22/54

Framingham: Effect of resting heart rate on all-cause death, CHD and

CVD events in untreated male hypertensives, followed-up for 36 years.

Gillman MW et al 1993.

Figure 28a R l ti hi b t ) hi h ( 4 l/L


23/54

Figure 28a. Relationship between a) high (> 4 nmol/L =dotted line) and low (< 4 nmol/L = continuous line) plasma

noradrenaline levels (independent of BP) and survival, and (b)

cardiovascular mortality, in middle-aged hypertensives.

Peng Y-X et al 2006.


24/54

Agonist Activity and the b1 ReceptorFullb1 agonist activity (efficacy)eg. Noradrenaline

Cellwall

Full coupling

Ca++Troponin

cAMP

Phosphorylation

Contraction

(Cardiac = +ve inotropism)

ATP

b1

Highaffinity

G


25/54

Risk

Ratio

Beta-receptor density (Bmax) and cAMP levels (in

lymphocytes) as predictors of MI and stroke in middle-aged

hypertensives followed for 7 years. Peng Y 2006.

1.851.9

1.17 1.18


26/54

Randomised, controlled hypertension ( diabetes) studiesof 1st line BBs in young/middle-aged diastolic hypertensives

Trial BBMean Age

(y)

Initial BP

(mm Hg)

PP

(mm Hg)

IPPPSHOxprenolol

(v diuretic) 52 173 / 108 65

MRC Mild

Hypertension

Propranolol

(v diuretic v

placebo)

51 161 / 98 63

MAPHY Metoprolol(v diuretic) 52 167 / 108 59

UK PDSAtenolol

(v Captopril) 56 159 / 94 65

di b /h i d d i i h


27/54

UKPDS 39 - diabetes/hypertension study end points in the

randomised Tight (1st line atenolol or captopril) and Less Tight BP

control groups (BP diff=10/5); 10 year follow-up(RR plus 95% confidence intervals)

UK Prospective Diabetes Study Group

Any diabetes related end point

Deaths related to diabetes

All cause mortality

Myocardial infarction

Stroke

Peripheral vascular disease

Microvascular disease (eye/kidney)

0.1 1 10

Favours tightcontrol

Favours less tightcontrol

Clinical end point


28/54

UKPDS all primary end-point trends favour atenolol

vs captopril when compared with less-tight BP control

(diff = 10/5 mm Hg) over 10 year follow-up

% decrease

vs less tight

BP-control


29/54

UKPDS Study Effect of BB or ACE inhibitor

on death from any cause after 20 years

follow-up. NEJM 08

Death from any cause

- 23% less on BB(*)


30/54

BB/Smoking interaction (MI)

in young/mid-age hypertensives

% reduct

in MI

IPPPSH

Ox vs D

MRC1

Pr vs P

MRC1

Pr vs D MAPHYMe vs D


31/54

BB/smoking interaction (CV events)

in the elderly hypertensive (MRCe)

% reduct

CV event

vs placebo

Aten 1st

Diu 2nd

Aten 2nd

Diu 1st


32/54

Effect of Smoking ( ) and Sham Smoking

( ) on Plasma Catecholamines

Norepinephine

(pg/ml)

Epinephrine(pg/ml)

350

300

250

150

100

50

200

150

0

-10 0 10

Minutes

20 30

Cryer et al. 1976


33/54

Peri-operative interaction between adrenaline

and beta-blockers. Tarnow J, Muller R 1991

Change in

Mean BP

-mm Hg

39.2

18.1

9.39.0

TIBBS S d N 520 P i i h ild


34/54

TIBBS Study N=520 Patients with mild

hypertension and CAD

1.0

0.9

0.8

0.7

0.6

0.5

0 50 100 150

Days

Eventfree

survival

200 250 300 350 400

Bisoprolol

Nifedipine s.r.

p=0.03

von Arnim et al 1996


35/54

Figure 13. Decrease in coronary atheromatous volume

(mm3) by BBs over 1 year (independent of statins, ACE

inhibitors, other drugs, LDL Conc., HR). Sipahi I et al 2007

-0.4(ns)

-2.4

(p


36/54

Table 1. In 106 patients who had 2 coronary angiograms over6 months, plaque disruption was significantly less frequent with

beta-blocker usage and more common at high heart rates.

Heidland V and Strauer B 2001

A li Mild H i S d di i


37/54

Australian Mild Hypertension Study diuretic vs

placebo in 3427 hypertensives (mean age 50 y).

Lancet 1980

n/ocases


38/54

Change in muscle sympathetic nerve activity after 3 months

diuretic therapy in untreated hypertensives. Menon DV et al

2009

% change

in muscle

symp. n.activity

spironolact chlorthalidone


39/54

Figure 21. Olmesartan vs placebo (randomised) in 4447 DM2,

mean age 57, mean BMI 31, BP 136/81, over 3.2 years.Haller H et al NEJM 2011

0

2

4

6

8

10

12

14

16

CV

death

(all)

CV

death

(CHD

history)

Sudden

death

MI

death

placebo

Olmesartan

n/o

events

p=0.01

P=0.02


40/54

Figure 22. ARBs and sympathetic nerve activity;

double-blind, random, X-over, placebo-controlled study

in young, hypertensive males. Heusser K et al 2003

BP HR

Musc

Symp

Plasma

Noradren

% change


41/54

ABCD Study; in middle-aged hypertensives with

diabetes randomised to enalapril or nisoldipine

there was a significant increase in MI in the CB

group. Estacio RO et al 1998

n/o MI p


42/54

Dihydropyridine CBs and noradrenaline/resting heart-

rate levels after 24 weeks therapy. Fogari R et al 2000.


43/54

80

60

40

20

non-smokers (n = 69) smokers (n = 25)

64%58%

80%

52%

p


44/54

160

150

140

130

120

110

100

90

80

70

60

BP

(mmHg)

and

Heart Rate

In 34 young (28-55yrs) hypertensives, Bisoprolol 5mg was more

effective than Amlodipine 5mg, Doxazosin 104mg, Bendrofluazide

2.5mg, Lisinopril 2.5-10mg (double blind, crossover,

1 month each) incontrolling office and 24 hr BP

Deary; Brown et al J. Hypert. 2002

Anti hypertensive efficacy of bisoprolol(5mg)


45/54

Anti-hypertensive efficacy of bisoprolol(5mg),

losartan, amlodipine and diuretic in 187 middle-aged

men; random, D-B, placebo-controlled x 1 month.

Porthan K et al 2009

Bisoprolol vs losartan: effects (rand/DB) on


46/54

Bisoprolol vs losartan: effects (rand/DB) on

BP/renal function over 1 year in 72

hypertensives (mean age 50 y). Parrinello G et al 2009

% change

DBPCreat

Clear

X (sig)

SBP


47/54

Effect of bisoprolol and enalapril on LVH in 56

randomised hypertensives, mean age 50y, over a 6

month periodGosse et al 1990

10

5

15

5

10

15

5

10

%

reduction

LVM

PWT

Septal T

Bisoprolol Enalapril

7

13

11

4

3

7


48/54

Fogarl et al 1980

Effect of various Beta Blockers on HDL

**

****

**

**

**

**

**

**

** *

+10

0

-10

-20

-30

-40 6 12 18 24 30 36 months

* p < 0.05

** p < 0.01vs. baseline}

%

HDL-

cholesterol

MepindololBisoprolol

PropranololAtenolol


49/54

Bisoprolol: b1-selectivity and glucose metabolism in hypertensives

with type II diabetes mellitus (2 hr after administration)

170 10

9

8

7

6

160

150

140

130

120

110

100

A B C A B C(p >0.05)C-B (p >0.05)C-B

glucose(mg/dl)

HbA(%)

1

A: initial value B:after 2 weeks

of bisoprolol

C:after 2 weeks

of placebon = 20x + SEM

Janka HU et al. J Cardiovasc Pharmacol 1986: 8 (Suppl.11): 961 99

Eff t f Bi l l d At l l Ai R i t


50/54

90

9

8

7

70

50

b1 3 6 12

Placebo Bisoprolol Atenolol

1 3 6 12 1 3 6 122 4 6 24 b 2 4 6 24 b 2 4 6 24

AWR

(cm HO/l/s)2

HR

(beats/min)

Effect of Bisoprolol and Atenolol on Airway Resistance

in patients with Reversal Obstruction Airways Disease

Dorow et al 1986


51/54

Beta-blockers and sexual

dysfunction vs placebo

Beta-blocker Sexual dysfunction

- % increase vs

placebo

Reference

Carvedilol 13.5 Fogari R et al 2001

Propranolol 5.0 MRC-Mild Hypert

1985

Atenolol 3.0 Silvestri A et al

2003

Bisoprolol 0.0 Broekman CP et al

1992


52/54

100

75

50

25

0

ICI 118,551

B1/B2

Selectivity

Ratios

PropranololMetoprolol

AtenololBetaxolol

Bisoprolol

1/25

20 /1

35 /135 /1

75 /1

1/50

1/300

1/300

12/

Wellstein et al Europ Heart J 1987

Beta1 and Beta2 Selectivity Ratios


53/54

Conclusion

Beta-blockers are highly effective across the whole CV spectrum The active ingredient is beta-1 blockade

Thus highly beta-1 selective bisoprolol is the most effective way tolower BP in young/middle-aged, reverse LVH, preserve renal function,reverse/stablise atheroma, avoid metabolic disturbance and the vitalsmoking/adrenaline/hypertension interaction (seen withnon/moderately selective BBs),and avoid impotence (worst with carv)

In the young/middle-aged hypertensive beta-1 blockade is highlyeffective in preventing stroke/MI/CCF vs placebo/diuretics; in theelderly BBs belong second-line to diuretics or CBs (1st line if CAD )

Beta-1 selective bisoprolol is a highly effective anti-ischaemic, anti-

arrhythmic and anti-heart failure agent

Longditudinal observational cohort studies


54/54

Longditudinal, observational cohort studies

draw wrong conclusions on beta-blockers.

Bangalore S et al JAMA 2012

prof malcom ppt

Documents