Fixed Combination in Hypertension, any radical change?

2007 ESHESC Recommendations for combining BP-lowering drugs

ASCOT

2007 Guidelines for the management of hypertension J Hypertens 2007;25:110587

2

ACEI-CCB Combination: Synergy for BP Lowering

SNS

Renin

Ang I

X
Activation of a1R (VSMC) CCB

ACEI CCB

Ca++

Ang II

X
VSMC

X
Vasoconstriction Reduced Na+ scrtion

Vasodilatation
Increased secretion of Na+ and water

BP

Blood pressure evidence

The example of Perindopril+Amlodipine

Early & Strong BP Reduction

n= 1 250 > 160mmHg n= 161 > 180mmHg

Perindopril+Amlodipine
Bahl UK. Fixed dose perindopril and amlodipine in moderate-to-severe hypertension. 14th World Congress of Heart Disease 2008, Toronto, Canada.

BP Reduction
Whatever the profile of hypertensive patients

Perindopril+Amlodipine

Bahl VK et al. Am J Cardiovasc Drugs. 2009;9:135-142.

BP Reduction
In patients uncontrolled on monotherapy

Perindopril+Amlodipine

Bahl VK et al. J hypertens. 2010;28():e98

BP Reduction
In patients uncontrolled on combinations

Perindopril+Amlodipine

Bahl VK et al. J hypertens. 2010;28():e98

Comparison with landmark trial

n= 1 250

n= 19 342

SBP
0

DDP
0

SBP

DDP

-10

-10

-20

-20

-23
-30
-30

-27

-40

-40

-42
BP decrease (mmHg)

-50
Amlodipine 5mg + Perindopril 5mg

-50

-44

Amlodipine 5/10mg+Perindopril 5/10mg

Bahl UK. Fixed dose perindopril and amlodipine in moderate-to-severe hypertension. 14th World Congress of Heart Disease 2008, Toronto, Canada. Poulter NR, Chang CL, Dahlof B, Gupta AK, Sever PS, Wedel H, on behalf of the ASCOT investigators. Evaluating the efficacy of the stepped-care anti-hypertensive strategies used in the Anglo-Scandinavian Cardiac Outcomes Trial BP Lowering Arm (ASCOT-BPLA). Hypertension. 2008. OS11/1.

Comparison with other drugs

Mourad JJ, et al. Curr Med Res Opin. 2010;26:2263-2276

10

Blood pressure quality

The example of Perindopril-Amlodipine

11

European Society of Cardiology:

Drugs which exert their antihypertensive effect over 24 hours with a once-a-day administration should be preferred
Perindopril Amlodipine Enalapril Quinilapril Ramipril Lisinopril Captopril Lercanidipine Felodipine Losartan Irbesartan Olmesartan Valsartan Aliskiren 0 20 40
% T/P Ratio
1.Hurst M el al. Drugs. 2001;61(6):867-896. 2. Hernandez RH et al. Blood Press Monit. 2001;6(1):47-57. 3. McClellan KJ et al. Drugs. 2000;60(5):1123-1140. 4. Diamant M et al. J Hum Hypertens. 1999;13(6):405-412. 5. Zannad F et al. Am J Hypertens. 1996;9(7):633-643. 6. Gradman AH, et al. Circulation. 2005;111:1012-1018. 7. Neutel JM et al. J Clin Hypertens. (Greenwich). 2002;4(5):325-331. 8. Hermida RC et al. Hypertens. 2003;42(3):283-290.

100 100 75 63 55 60 38 80 50 78 70 70 69 70
60 80 100

12

BP variability: main cause of CV events.3

Stabilizes blood pressure to avoid excessive BP variability 1,2

/Perindopril

1.Rothwell PM et al. Lancet Neurol. 2010;9(5):469-480 2. Rothwell PM et al. Lancet. 2010;375:938-948. 3. Rothwell PM et al. Lancet. 2010;375:895905.
13

Blood pressure quality

Central Aortic Blood Pressure and Cafe study

14

What is central aortic blood pressure?

BP measured at the aortic level which reflects the pressure at key organ level

Central aortic blood pressure

Brachial blood pressure

15

Normal central aortic BP

Outgoing wave = blood exiting the heart via aorta Reflected wave = back wave of blood returning to the heart. This is dependent on the stiffness of the artery.

Aortic root = The sum of the outgoing and reflected wave

16

Elevated central aortic BP

Outgoing wave remains the same Reflected wave will travel back more quickly due to arterial stiffness. This means that it will arrive back at the heart earlier. Aortic root pressure will be higher & thus the pressure at the key organs too
Figure 1

17

Consequences of high central aortic BP

1. Higher overall pressure = risk of target organ damage eg stroke

LVH

2. Increase LV load = LV hypertrophy

3. in blood volume returning to the heart during diastole = risk of ischaemia

18

Pulse Wave Analysis

Brachial Blood Pressure

140

Transfer function

140

70 Radial

70

Central Aortic

19

Trial Overview
To examine the difference between recommended betablocker/thiazide versus newer Perindopril/Amlodipine BP regimen on central aortic BP

2,070 ASCOT patients

Average BP = 160/92 4yr follow-up

20

Effective in reducing central aortic BP control

Central Aortic BP reduction is linked to a reduction in CV events

Similar brachial BP reductions

A central aortic SBP difference of 4.3 mmHg

Perindopril

21

Unique lifesaving benefits

Cardiovascular protection and mortality reduction stronger than recommended regimen

/Perindopril

/Perindopril

Dahlf B et al. Lancet. 2005:366;895-906.

22

Synergy of ACEI + CCB

The synergistic action of Perindopril-Amlodipine

23

A synergistic mode of action

Perindopril Amlodipine

Ferrari R. Optimizing the treatment of hypertension and stable coronary artery disease: clinical evidence for fixed-combination perindopril/amlodipine. Curr Med Res Opin. 2008;24:3543-3557.
24

A synergy also decreasing side effects

ACE Inhibitor Perindopril CCB Amlodipine

Induction of relaxation = Vasodilation

Prevention of constriction = Vasodilation

Ferrari R. Optimizing the treatment of hypertension and stable coronary artery disease: clinical evidence for fixed-combination perindopril/amlodipine. Curr Med Res Opin. 2008;24:3543-3557.
25

Reduces ankle edema in comparison with CCB

Amlodipine alone

Perindopril-Amlodipine

Precapillary vasodilation => oedema

Venous dilation hence normalising intracapillary pressure

Messerli FH, et al. Am J Cardiol. 2000;86(11):1182-1187 Ferrari, R. Current Med. Research & Opinion, 2008, 24 (12), 3543-3557
26

Reduces ankle oedema

270 250

247

Number of patients

230 210 190 170 150 130 110 90 70 144 116

- 52%

M0

Perindopril-Amlodipine

M1

M3

Hatala et al.. Submitted to ESH 2010

27

Perindopril + Amlodipine decreases oedema

Amlodipine
o ankle edema in 22% of patients

CCB-related ankle edema cannot be relieved by diuretics

o only fluid retention

Amlodipine + perindopril fixed combination in STRONG Study

o ankle edema in 0.7%

28

Perindopril + Amlodipine decreases cough

ACEI inhibit kininase II bradykinin CCB

arachidonic acid
stim. PLAz inhibit

PGEz
stim. pulm. sensory C fibers

Ca++- dep. release of glutamate at solitary tract nucleus

coughing

inhibit

Perindopril in EUROPA study cough in 2.7% Perind + amlo in STRONG Study cough in 1.5%

29

Perindopril + Amlodipine

Provides stronger BP reduction (40-63 mmHg)

o Controls BP over 24 h
o Decreases central BP

Provides stronger life saving benefits

ASCOT

Offers excellent safety

o Oedema 0.7% o Cough 1.5%

30

Perindopril + Amlodipine is

High BP patients > 160mmHg Uncontrolled BP on Amlodipine

31

Thank you

32

33

Radical change in hypertension

34