The modern role of beta-blockers in the treatment of cardiovascular disease; focus on hypertension

JM Cruickshank Saudi Arabia November 2012

The Cardiovascular Continuum

The Effect of Early Intervention with Atenolol in Reducing Mortality in Acute Myocardial Infarction; ISIS-1
500
458 439 475 419 420 386 330 344 359 368 402 491

400

Group allocated control

341 321 294 261 231 266 287

403 382 364

Number 300 of vascular deaths

200
171

**
312

Group allocated atenolol

234
208 167

***

*** 2p < 0.002 ** 2p < 0.04

100

119 73 48

Early I.V. 5 + 5mg

Oral 100mg/day

End of oral dose

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Days from randomisation

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 metop mainly 1st day Give IV BB only when haemodynamics are stable

Secondary prevention of myocardial infarction with different types of b - blockers

-30 R e duc tion of morta lity

b1 - selective
without ISA non-selective without ISA

-20

b1 - selective
with ISA non-selective with ISA

-10

b - blockers without ISA

b - blockers with ISA

-

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

b - blockers in MI
50
alprenolol

40 Reduction in mortality (%) 30 20 10 0 0 4 8 12 16 20 Reduction in heart rate (min-1)

timolol metoprolol propranolol practolol sotalol oxprenolol pindolol

Kjekhus (1985)

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

TIBBS Study N=520 CAD Patients

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

1.0 0.9

Event 0.8 free survival 0.7

0.6 0.5 0 50 100 150 200 250

Bisoprolol
p=0.03

Nifedipine s.r.

300

350

400

Days
von Arnim et al 1996

High heart-rates are harmful in patients with stable CAD + DM. Anselmino M et al 2010

HR<62 bpm

HR>78 bpm

Framingham 26 y follow-up: low resting heart rates protect from sudden death. Kannel 1985

Figure 30. Beta-blockers and hard end-point placebo-controlled trials in systolic heart failure; ISA reduces efficacy (all-cause death).
% change
XamISA (ns)

HR 8-9 bpm

HR 13-14 bpm

Bucind- NebivISA ISA 10%(ns) 12% (ns) Bisop Metop 34%(sig) 35%(sig) Carv 35%(sig)

Figure 31. CIBIS III prevention of sudden death with bisoprolol vs ACEI. 2005
10 Enalapril - first 8 6
46% Risk reduction in Sudden Cardiac Death

Bisoprolol - first

%
4 2
P = 0.049

0 0

12

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

The Cardiovascular Continuum

Mortality due to leading global risk factors. Lopez AD et al Lancet 2006

Current UK NICE Committee recommendations for the treatment of hypertension

BBs = 4th or 5th line !! Or only among the also-runs!

Dr. Wilfried Meyer, IMM Paris 31 Aug 2011 15

Different Predictors of Diastolic Hypertension (DH) ( raised systolic SDH) and Isolated Systolic Hypertension (ISH) FRAMINGHAM Study
Franklin et al, Circulat 2005

Predictors of Diastolic Hypertension ( Systolic Hypertension) = DBP 90 mmHg ( SBP 140 mmHg)
1. 2. 3. 4. 5. Young age Male sex High BMI at baseline Increased BMI during follow-up Main mechanism of DH and SDH is raised peripheral resistance 6. 5. 1. 2. 3. 4.

Predictors of Isolated Systolic Hypertension = SBP 140 mmHg + DBP < 90 mmHg
Older age Female sex Increased BMI during follow-up (weak) ISH arises more commonly from normal and high normal BP, than burned out diastolic hypertension Only 18% with new onset ISH had a previous DBP 95 mmHg Main mechanism of ISH is increased arterial stiffness = aging of arteries

Table 3. First-line beta-blockers (atenolol) perform poorly in elderly hypertension (wide pulse-pressure)

Trial

Beta-blocker

Mean-age (y)

Initial BP (mm Hg)

PulsePressure (mm Hg)

Result
Only 1st line diuretics differed from placebo in stroke prevention; diuretic superior to 1st line atenolol in reducing coronary events Significant reduction in stroke but no effect on coronary events by atenolol Losartan superior to atenolol in reducing cardiovascular mortality and non-fatal and fatal stroke Amlodipine perindopril was superior to atenolol diuretic in reducing all-cause mortality and all coronary and stroke end-points

MRC Elderly

Atenolol (vs placebo vs diuretic)

70

185/91

94

HEP

Atenolol (vs nontreatment) Atenolol (vs losartan)

69

196/99

97

LIFE

67

174/98

76

ASCOT

Atenolol diuretic (vs amlodipine perindopril)

63

164/94

70

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
15

Fall in Pulse 10 Pressure (mm Hg) 5

* *

ACE 1

b Blockers

CaB

Diur

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

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) Rate per 1000 Patient-Years

First Event Death Non-fatal Myocardial Infarction Non-fatal Stroke Cardiovascular-Related Death Cardiovascular-Related Hospitalization 36 28 5 4 14 24

Non-Calcium Antagonist Strategy (NCAS) (n=11,309) Rate per 1000 Patient-Years

37 29 5 5 14 23

RR (95% CI)
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)

Favours CAS

Favours NCAS

0.6

0.8

1.0

1.2

1.4

RR (95% CI)

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
MSNA

70
(bs/100 hb) 55

**

40

25

PO

CO
Grassi et al, J.Hypertens 2004

Sympatho-excitation in normal-weight and obesityrelated hypertension (HT), vs normotensives (NT), in middle-aged (37-50 y) subjects. Lambert E et al 2007

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.

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.

Figure 28a.

Agonist Activity and the b1 Receptor

Full b1 agonist activity (efficacy) eg. Noradrenaline
High affinity Cell wall

b1
ATP

Full coupling
G

Ca++ Troponin cAMP Phosphorylation

Contraction (Cardiac = +ve inotropism)

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.
Risk Ratio 1.85
1.9

1.17

1.18

Randomised, controlled hypertension ( diabetes) studies of 1st line BBs in young/middle-aged diastolic hypertensives
Trial BB Oxprenolol (v diuretic) Propranolol (v diuretic v placebo) Metoprolol (v diuretic) Atenolol (v Captopril) Mean Age (y) 52 Initial BP (mm Hg) 173 / 108 PP (mm Hg) 65

IPPPSH MRC Mild Hypertension MAPHY

51

161 / 98

63

52

167 / 108

59

UK PDS

56

159 / 94

65

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)

Clinical end point

Any diabetes related end point Deaths related to diabetes All cause mortality Myocardial infarction Stroke Peripheral vascular disease Microvascular disease (eye/kidney)
0.1
Favours tight control
UK Prospective Diabetes Study Group

1
Favours less tight control

10

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

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(*)

BB/Smoking interaction (MI) in young/mid-age hypertensives

% reduct in MI IPPPSH Ox vs D MRC1 Pr vs P MRC1 Pr vs D

MAPHY Me vs D

BB/smoking interaction (CV events) in the elderly hypertensive (MRCe)

Aten 1st Diu 2nd

% reduct CV event vs placebo

Aten 2nd Diu 1st

Effect of Smoking ( ) and Sham Smoking ( ) on Plasma Catecholamines

350 300

Norepinephine (pg/ml)

250 200

150 150

Epinephrine (pg/ml)

100 50 0 -10 0 10 20 30

Cryer et al. 1976

Minutes

Peri-operative interaction between adrenaline and beta-blockers. Tarnow J, Muller R 1991

39.2

Change in Mean BP -mm Hg 9.0 9.3

18.1

TIBBS Study N=520 Patients with mild hypertension and CAD

1.0 0.9

Event 0.8 free survival 0.7

0.6 0.5 0 50 100 150 200 250

Bisoprolol
p=0.03

Nifedipine s.r.

300

350

400

Days
von Arnim et al 1996

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
Atheroma volume (mm3) over 1 year 0
-0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -2.4 (p<0.0001) -3.5 (sig) -0.4 (ns)
not on BB (n=361) on BB (n=1154) likely charge with dose atorvastin (vs pravas.)

Table 1.

In 106 patients who had 2 coronary angiograms over 6 months, plaque disruption was significantly less frequent with beta-blocker usage and more common at high heart rates. Heidland V and Strauer B 2001

Australian Mild Hypertension Study diuretic vs placebo in 3427 hypertensives (mean age 50 y). Lancet 1980

n/o cases

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

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

16 n/o events 14 12 10 8 6
4

p=0.01 P=0.02

placebo Olmesartan

2 0 CV death (all) CV Sudden death death (CHD history) MI death

Figure 22. ARBs and sympathetic nerve activity; double-blind, random, X-over, placebo-controlled study in young, hypertensive males. Heusser K et al 2003

% change

BP

HR

Musc Symp

Plasma Noradren

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<0.001

Dihydropyridine CBs and noradrenaline/resting heartrate levels after 24 weeks therapy. Fogari R et al 2000.

Bisoprolol: Treatment of hypertension in smokers in comparison to atenolol

Success rates in smokers after 8 weeks treatment

%
80
80% 64% 58%

p <0.05

< 96 mm Hg

60
40 20

52%

non-smokers (n = 69)
Bisoprolol 10 - 20 mg Atenolol 50 - 100 mg

smokers (n = 25)

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
160 150 140

BP (mmHg) and Heart Rate

130
120 110 100 90 80 70 60

Deary; Brown et al J. Hypert. 2002

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 BP/renal function over 1 year in 72 hypertensives (mean age 50 y). Parrinello G et al 2009
SBP DBP Creat Clear

% change

X (sig)

Effect of bisoprolol and enalapril on LVH in 56 randomised hypertensives, mean age 50y, over a 6 month period Gosse et al 1990
% reduction LVM
15 10 5 7 13 11

15

PWT

10
5 10 3

Septal T
5

7 4

Bisoprolol

Enalapril

Effect of various Beta Blockers on HDL

+10 % HDL0 cholesterol -10 -20 -30 -40 6

Mepindolol Bisoprolol

** **

** **
12

** **
18

** **
24

** **
30

Propranolol * Atenolol

36 months

* p < 0.05 ** p < 0.01

vs. baseline

Fogarl et al 1980

Bisoprolol: b1-selectivity and glucose metabolism in hypertensives with type II diabetes mellitus (2 hr after administration)
glucose (mg/dl)
170 160 10 9 8 7 6

HbA (%)

150
140 130 120 110 100

A
n = 20 x + SEM

B C (p C-B >0.05) B:after 2 weeks of bisoprolol

B C (p C-B>0.05)

A: initial value

C:after 2 weeks of placebo

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

Effect of Bisoprolol and Atenolol on Airway Resistance in patients with Reversal Obstruction Airways Disease
9 AWR (cm HO/l/s) 2 8 7

90
HR 70 (beats/min) 50
b 1 2 3 4 24 6 12 6 b 1 2 3 4 6 24 6 12 b 1 2 3 4 6 24 6 12

Placebo

Bisoprolol

Atenolol

Dorow et al 1986

Beta-blockers and sexual dysfunction vs placebo

Beta-blocker Sexual dysfunction - % increase vs placebo 13.5 5.0 3.0 0.0 Reference

Carvedilol Propranolol Atenolol Bisoprolol

Fogari R et al 2001 MRC-Mild Hypert 1985 Silvestri A et al 2003 Broekman CP et al 1992

Beta1 and Beta2 Selectivity Ratios

100

75 / 1
75 50 25 0 1/ 25 1/ 50 1/ 300 1/ 300
ICI 118,551

B1/B2 Selectivity Ratios

35 / 1 20 / 1

35 / 1

1/ 2
Propranolol Metoprolol Atenolol Betaxolol Bisoprolol

Wellstein et al Europ Heart J 1987

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 to lower BP in young/middle-aged, reverse LVH, preserve renal function, reverse/stablise atheroma, avoid metabolic disturbance and the vital smoking/adrenaline/hypertension interaction (seen with non/moderately selective BBs),and avoid impotence (worst with carv) In the young/middle-aged hypertensive beta-1 blockade is highly effective in preventing stroke/MI/CCF vs placebo/diuretics; in the elderly BBs belong second-line to diuretics or CBs (1st line if CAD ) Beta-1 selective bisoprolol is a highly effective anti-ischaemic, antiarrhythmic and anti-heart failure agent

Longditudinal, observational cohort studies draw wrong conclusions on beta-blockers. Bangalore S et al JAMA 2012