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