SHA24/051002

Disclosures Speaker’s bureau:

Servier International, Bayer, Roche, Iroko Boehringer Ingelheim

Research grant:

Servier International, Boehringer Ingelheim, Novartis, Roche

Advisory Board:

Servier International, Bayer, Roche Boehringer Ingelheim

Optimising treatment of hypertension & coronary disease: evidence fixed combination BY Roberto FERRARI , MD, Ph.D. FESC

Multiple Antihypertensive agents are needed to reach BP goal Trial (Achieved SBP) ASCOT-BPLA (136.9 mmHg) ALLHAT (138 mmHg) IDNT (138 mmHg) RENAAL (141 mmHg) UKPDS (144 mmHg) ABCD (132 mmHg) MDRD (132 mmHg) HOT (138 mmHg) AASK (128 mmHg) LIFE (144 mmHg) Average no. of antihypertensive medications 11

2

3

4

Reproduced from Am J Med 116(5A), Bakris et al. pp. 30S–8. Copyright © 2004, with permission from Elsevier; Dahlöf et al. Lancet 2005;366:895–906

Monotherapy versus combination strategies Mild BP elevation Low/moderate CV risk Conventional BP target

Choose between

Marked BP elevation High/very CV high risk Lower BP target

Two-drug combination at low dose

Single agent at low dose

If goal BP not achieved Previous agent at full dose

Switch to different agent at low dose

Previous combination at full dose

Add a third drug at low dose

If goal BP not achieved Two-to three-drug combination at full dose

Full dose monotherapy

Two-three drug combination at full doses

ESH-ESC Guidelines, J Hypertens 2007

Combination therapy in hypertension rationale

•

Action on various mechanisms of hypertension

•

Neutralization of counter-regulatory mechanisms

• •

Improved efficacy-tolerability ratio Better compliance

Which combination therapy?

2007 ESH−ESC recommendations Diuretics

β-blockers

Angiotensin receptor blockers (ARBs)

α-blockers

Calcium channel blockers (CCBs)

Preferred combinations

Angiotensin-converting enzyme (ACE) inhibitors

Other possible combinations

« 2007 Guidelines for the management of hypertension » J Hypertens 2007;25:1105–8

Reduction in cardiovascular events in hypertensive patients at CV risk Unadjusted Hazard ratio (95% CI)

Selected end-points

Primary Non-fatal MI (incl silent) + fatal CHD

0.90 (0.79-1.02)

Secondary Total coronary end point Total CV event and procedures All-cause mortality Cardiovascular mortality Fatal and non-fatal stroke

0.87 (0.79-0.96) 0.84 (0.78-0.90) 0.89 (0.81-0.99) 0.76 (0.65-0.90) 0.77 (0.66-0.89)

Tertiary New-onset diabetes mellitus New-onset renal impairment

0.70 (0.63-.078) 0.85 (0.75-0.97)

Post hoc Primary end point + revascularization CV death + MI + stroke

0.86 (0.77-0.96) 0.84 (0.76-0.92)

0.50

0.70

1.00

amlodipine Âą perindopril better

1.45

2.00

atenolol Âą thiazide better Dahlof B et al. Lancet 2005; 366: 895-906.

Why?

• Synergy at clinical level • Synergy at experimental level

• Different mechanisms and molecular site of action

ACEi reduce risk of CHD CCBs reduce risk of stroke Coronary artery disease

28 trials > 175.000P

Stroke

Verdecchia P et Al., Hypertension 2005;46:386-392

Two different sites of action ACE inhibition Perindopril ACE inhibition

Ca 2+

eNOs

eNOs

eNOs

Ca 2+

Inositol triphosphate cycle

NO

NO

NO

Increase in cyclic GMP

Induction of relaxation Vasodilatation

Reduction in cytosolic calcium

Prevention of contraction Vasodilatation

VOC

Angiotensin II

VOC

Bradykinin

CCB Amlodipine

RCC

Perindopril

CCB Amlodipine

RCC

ACE inhibition Perindopril

Endothelium – ACEi

Smooth muscle - CCBs

 Weight: 1.5 kg, surface: >800 m2  Produces >250 active substances

Atheroma formation and progression: a struggle between death and regeneration

• Endothelial cells undergo suicide

(apoptosis) and regenerate, every 3 months

• When a mismatch occurs and apoptosis exceed regeneration, the endothelium loses its continuity

Atherosclerosis

ACS

PERTINENT substudy (1175 pts) Isolation of human endothelium

Incubated (72 h) with serum from Healthy subjects

EUROPA pts

ecNOS Apoptosis

To mimic the effects of circulating blood on endothelial function

PERTINENT Apoptosis Analysis in cultured HUVECs

Effects of HUVEC incubation with serum from: Controls

CAD PERTINENT patients baseline

Apoptosis

20

1 year

P<0.01

P<0.05

10

0

Controls n=45

Placebo Treated n=43 n=44

Placebo Treated n=43 n=44

#P=controls vs baseline *P=perindopril vs placebo

Ceconi C et al. Cardiovasc Res. 2006

Endothelial apoptosis and atherosclerosis

Normal rate of apoptosis: 3%

Excess rate of apoptosis

Maintenance of endothelial layer

Endothelium continuity

Protection against atherosclerosis

Onset of atherosclerotic Plaque erosion and rupture

ACEi and apoptosis: a class effect? (after 1 weekâ&#x20AC;&#x2122;s treatment) 12

P<0.001

P<0.001

10

10.7

P<0.001

*

8

**

6 4 2

8.8

9.5

10.0

7.5

4.3 0.8

en al ap ril

ra m ip ril qu in ap ri l tra nd ol ap ril

0

co nt ro LP l S in fu si on pe rin do pr i ll

% Apoptosis

P<0.001

* P<0.001 vs LPS Ceconi C et al. Cardiovasc Drugs Ther. 2007;21:423-429.

How does perindopril reduce endothelial apoptosis?

• By reducing angiotensin-II and TNF-α (pro-apoptotic)

• By enhancing bradykinin (anti-apoptotic)

What about endothelial regeneration ?

Bone marrow produces endothelial progenitor cell (EPC) to be incorporated into vessels

Stable Angina Patients *

4.5

*

EPC cells (u/mm3)

4 3.5 3 2.5 2 1.5 1 0.5 0

baseline

10 days

Perindopril

1 month Time

3 months

Placebo

6 months

ACE inhibition (with perindopril) reduces death and improves life of the endothelium

Protection against ACS

But… endothelium is not all…

• Smooth muscle cells are also important to

– maintain vascular tone – avoid vasoconstriction – avoid remodelling

Contraction %

Amlodipine inhibits the calcium channel from the inside and prevents potassium induced smooth muscle contraction

N A N

Amlodipine

A

Nicardipine

Amlodipine Nifedipine

Nicardipine Nisoldipine

Antihypertensive mode of action of ACE inhibition and calcium channel blockade.

ACE inhibition Perindopril ACE inhibition

Ca 2+

eNOs

eNOs

eNOs

Ca 2+

Inositol triphosphate cycle

NO

NO

NO

Increase in cyclic GMP

Induction of relaxation Vasodilatation

Reduction in cytosolic calcium

Prevention of contraction Vasodilatation

VOC

Angiotensin II

VOC

Bradykinin

CCB Amlodipine

RCC

Perindopril

CCB Amlodipine

RCC

ACE inhibition Perindopril

Evidence of efficacy

• ASCOT • STRONG • EUROPA • Other trials

Blood pressure reduction in ASCOT atenolol Âą thiazide amlodipine Âą perindopril

180 160

164.1 SBP 163.9

Mean difference 2.7

137.7

mm Hg

140

136.1

120 100 80

94.8

DBP

Mean difference 1.9

94.5

79.2 77.4

60 Baseline

0.5

1

1.5

2

2.5

3

Time (years)

3.5

4

4.5

5

5.5

Last visit

ACEi/CCB allows BP control VS. BP decrease

• ASCOT CAFE: optimal central BP control

• Ambulatory BP: optimal control of nocturnal BP

• Optimal control of over expressed BP variability

• Simple and better tolerated regime

STRONG Trial SafeTy & efficacy analysis of coveRsyl amlodipine in uncOntrolled & Newly diaGnosed hypertension

• Out-patient clinic based prospective study • 1250 hypertensive patients • Aged 40 – 70yrs (av = 55yrs) diagnosed or uncontrolled hypertensives • Newly (mono or combo therapy) • Av BP = 167/101 mmHg Bahl VK, Jadhav UM, Thacker HP. Management of hypertension with the fixed combination of perindopril and amlodipine in daily clinical practice: results from the STRONG study. Am J Cardiovasc Drugs.

2009;9:135-142.

0

Blood pressure efficacy in the whole population and in severly hypertensive patients FAST & STRONG BP reductions Whole population 15 days

Mean BP change from baseline (mmHg)

0

30 days

60 days

Severe HT SBP >180 60 days

–10

–11*

–16

–20

–21* –30

–23

–29*

–29

–40

–41*

–50 –60

–63*

–70 1250 whole hypertensive population at baseline: 32.6%: newly diagnosed hypertension 40.5%: hypertension uncontrolled on monotherapy 26.9%: hypertension inadequately managed with another combination therapy. *P<0.0001

SBP

DBP

30

161 severely hypertensive patients with SBP >180 mmHg Newly diagnosed: n=50 Uncontrolled on monotherapy: n=53 Inadequately managed on combination therapy: n=58

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

Reductions from baseline BP in representative clinical trials of ARB/CCB and ACEi/CCB combinations in hypertensive Valsartan/Am Dose, Dose, mg mg0

5/5

5/5

Telmisartan/Am

160/5-10

80/10

Olmesartan/Am

20/5

40/10

Ramipril/Am

2.5-10/2.5-10

Benazepril/Am

2.5-5/5-10

-10

-9

Δ BP, mm Hg

-12 -15

-20

-19 -21

-23 -30

-26

-29

-26

-19

-20

-23

-29

-29

-36

-40

-42 -50

-43 SBP > 180 mm Hg

SBP > 180 mm Hg

-60

-63 -70

Patients, n

1250

161

64

1078

161

162

117

111

1. Poulter N. 2008 ISH-ESH. 2. Bahl VK et al.. Am J Cardiovasc Drugs.

Drugs. 2009;9:135-142. 3. Poldermans D, Glazes R, Kargiannis S, et al. Clin Ther. 2007;29:279-288. 4. Littlejohn TW, Postgrad Med. .

2009;121:5-14.

5.

Chrysant SG, et al.

Clin Ther.

Med Ther. 2008;30:587-604. 6. Dischinger Miranda R. Clin Ther. 2008. 7.Ueng KC. Blood Press Suppl.

Suppl. 2008.11. 8.

Destro et al. J Am Soc Hypertens. 2008;2:294– 2008;2:294–302.

Reduction in total mortality and major cardiac events with perindopril/CCB Primary end point

Total mortality

(CV death, MI, resuscitated cardiac arrest) (%) 6 8 7 6 5 4 3 2 1 0

5

35%

Placebo/CCB

P=0.0147

Perindopril/CCB 0

12

24

36

48

60

Time (months from randomization) Patients at risk Pl/CCB 1100 Per/CCB 1022

1076 1005

1055 992

1029 974

762 746

16 9

Bertrand ME, et al. Am Heart J. 2010;159:795-802.

Incidence

Incidence

(%) 9

4

46%

Placebo/CCB

3

P<0.01

2

Perindopril/CCB

1 0 0

12

24

36

48

60

Time (months from randomization) Patients at risk Pl/CCB 1100 Perl/CCB 1022

1084 1015

1075 1010

1059 1000

801 770

16 8

Perindopril / amlodipine fixed combination with evidence-based data Perindopril + amlo

Valsartan + amlo

Olmesartan + amlo

Indication Hypertension

Yes

Yes

Yes

Indication CAD

Yes

no

no

BP-independent effects

Yes

no

no

CV protection evidence

Yes

no

no

CAFE

no

no

CABP decrease

Meta-analysis of ARBs and ACE inhibitors trials conducted before 2006 ARBs vs comparators (11 trials, n=55,050)

RRR (%)

ACE inhibitors vs comparators (39 trials, n=150,943)

+8%*

RRR (%)

8

0

6

-2

4 2

+1%

+1%

Global death

CV death

-8%

-6

-6%

-8

-2 -4

-10

-6

-12

-8

-14

CV death

MI

-4

0

Global death

Stroke

Stroke

-9% 

-12% 

MI

-14% 

* P=0.03

** P=0.0005; *** P<0.00001

Adapted from Strauss MH, Hall AS. Circulation. 2006;114:838-854.

ACE inhibitors vs ARB Unique Differences

Data from meta-regression analyses

ACE inhibitors

BP-independent effect

Stroke

RRR = -2% (8% to -13%)

HF

RRR = 5% (15% to -5%)

CHD

RRR = 9% (14% to 3%)

Stroke p=0.6 HF p=0.6

ARBs Stroke

RRR = 1% (18% to -20%)

HF

RRR = 17% (38% to -12%)

CHD

RRR = -8% (17% to -39%)

30%

20%

10% 0% 10%

Risk Decrease

20%

CHD p=0.002

30%

Risk Increase J Hypertens. 2007;25:951-958.

NEMJ 2008

ONTARGET – Telmisartan increased MI

Following Followingthe theONTARGET ONTARGETresults results“the “theFDA FDAexperts expertspanel panelvoted votedunanimously unanimouslyagainst against expanding expandingthe thetelmisartan telmisartanindication indicationfor forall allhigh-risk high-riskpatients patientsand andinstead insteadfocused focused on onthose thoseintolerant intolerantto toan anACE ACEinhibitor” inhibitor” Downloaded Downloadedhttp://www.theheart.org/article/1014115.do http://www.theheart.org/article/1014115.do ONTARGET Investigators. New Engl J Med. 2008;358:1547-1559.

Eur Heart J 2012

Main results n=76 615

n=82 383

Van Vark LC, Bertrand M, Akkerhuis KM, et al. Eur Heart J. Online 17 Apr 2012.

Impact of ACE inhibitors on all-cause mortality

Cardiovascular mortality HR (95% CI) (random effects model)

Impact of ACE inhibitors on cardiovascular mortality

Why?

• ARBS have little (or no) effect on bradykinin

• Do not reduce endothelial apoptosis

• Do not improve endothelial regeneration

ANG II

AT1

AT3 6

VASOCONSTRICTION WATER RETENTION PROLIFERATION ANTI APOPTOSIS

AT2 VASODILATATION NO WATER RETENTION ANTI PROLIFERATION PRO APOPTOSIS

SEVERAL OTHER EFFECTS

ANG II ARB’s

AT1

AT3 6

VASOCONSTRICTION WATER RETENTION PROLIFERATION ANTI APOPTOSIS

AT2 VASODILATATION NO WATER RETENTION ANTI PROLIFERATION PRO APOPTOSIS

SEVERAL OTHER EFFECTS

Perindopril decreases rate of the endothelial cell apoptosis in post-AMI patients Normal controls

Perindopril 8 mg

25

Valsartan 80 mg #

Apoptotic nuclei (%)

# 20

*

15 10 5

Baseline Day 30

Baseline Day 30

#p=0.01 vs control *p=0.04 vs baseline

Baseline Day 30

Cangiano E , Ferrari R - Am J Cardiovasc Drugs.

2011 Jun 1;11(3):189-198.

Myocardial Infarction Patients *

7

*

*

*

6

EPC (u/mm3)

5 4 3 2 1 0 baseline

3 days

Perindopril

5 days Time

7 days

ARB

10 days

Conclusion Perindopril is an optimal RAS inhibitor for the combination with amlodipine:

• Synergistic efficacy • Proven efficacy in CV prevention in

hypertension and CAD (ASCOT and EUROPA)

• The only RAS inhibitor/CCB with a

double indication: hypertension and CAD

END THANK YOU