arterial health and hypertension, ACEI vs ARB

1. ARTERIAL HEALTH IN HYPERTENSION:
IMPACT ON OUTCOME
PROF KYAW SOE WIN
DEPARTMENT OF CARDIOVASCULAR MEDICINE
MANDALAY GENERAL HOSPITAL
MYANMAR
30th September 2018
GP Forum
(Malaysia & Myanmar)
Kuala Lumpur 29th-30th September 2018

2. CHANGING HEALTH SCENARIO – MAJOR FACTORS OF MORTALITY
• MALNUTRITION
• INFECTION
• CARDIO-VASCULAR DISEASES
• CEREBRO-VASCULAR DISEASES
• RENAL DISEASES
• COMMON DENOMINATOR HYPERTENSION

3. World Health Organisation. Global atlas on cardiovascular disease prevention and control. 2011. Available at: http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/index.html
0 1000 2000 3000 4000 5000 6000 7000 8000
Attributable deaths due to selected risk factors (in thousands)
Indoor smoke from solid fuels
Childhood underweight
Alcohol use
Unsafe sex
High cholesterol Overweight
and obesity Physical inactivity
High blood glucose
Tobacco
Raised blood pressure
About 14% of global
mortality can be
attributed to
hypertension
HYPERTENSION IS THE NUMBER ONE RISK FACTOR FOR
GLOBAL MORTALITY

4. WHY THIS SHIFT?
• IMPROVING HYGEINE
• INFECTION CONTROL STEPS
• BETTER DRUGS & VACCINES
• BASIC MEDICAL FACILITY AVAILABLE
TO COMMON MAN
• THE URBAN LIFE
• INCREASE STRESS LEVELS
• SMOKING
• ALCOHOLISM
• CHANGING FOOD HABITS
• SEDENTARY JOBS
• NO PHYSICAL EXCERCISE
THE PRICE WE PAY: 10 - 20% PREVALENCE OF HYPERTENSION ALL OVER THE WORLD

5. JACC March 20, 2018 Volume 71, Issue 11

7. J Cardiol Curr Res 2017, 10(1): 00353

8. J Cardiol Curr Res 2017, 10(1): 00353

9. Bjertness et al. BMC Public Health (2016) 16:590
DOI 10.1186/s12889-016-3275-7

10. HISTORICAL LESSONS ON THE RISKS OF HYPERTENSION
AND THE BENEFITS OF TREATMENT
CHDIncidenceRate/
1000PersonYears
CumulativeFatal&
NonfatalEndpoints
The Framingham Study
Ann Intern Med. 1961; 55:33–50.
Hypertension Increases
Morbidity and Mortality
0
20
40
60
80
100
120
140
Men Women
Normotension
Hypertension

11. HISTORICAL LESSONS ON THE RISKS OF HYPERTENSION
AND THE BENEFITS OF TREATMENT
CHDIncidenceRate/
1000PersonYears
CumulativeFatal&
NonfatalEndpoints
The Framingham Study
Ann Intern Med. 1961; 55:33–50.
Hypertension Increases
Morbidity and Mortality
0
20
40
60
80
100
120
140
Men Women
Normotension
Hypertension
0
10
20
30
40
50
Placebo Active Treatment
Treatment Decreases
Morbidity and Mortality
The Vet. Adm. Study II
JAMA. 1970; 213:1143–1152.

13. BENEFIT OF TREATING HIGH BP
• PERSISTANT REDUCTION OF BP ↓ CVD ↓ CORONARY DEATH
• 5mmHg 34% 21%
• 7.5mmHg 46% 29%
• 10mm Hg 56% 37%

14. Treatment goals for managing hypertension
British Hypertension Guideline 2011
“Prime motivation for treatment in hypertension, an asymptomatic
condition, is the prevention of mortality and morbidity.”
ESH-ESC Guideline
“The primary goal of treatment of the hypertensive patient is to achieve the
maximum reduction in the long-term total risk of cardiovascular morbidity
and mortality.”
European Heart Journal 2013, The clinical management of primary hypertension in adults; NCGC May 2011

15. Key
A – ACE inhibitor or low-cost
angiotensin II receptor blocker (ARB)1
C – Calcium-channel blocker (CCB)
D – Thiazide-like diuretic

16. Journal of Hypertension October 2013, 31 : 000-000
ASH/ISH October 2013 Updated Clinical Practice Guidelines
For The Management Of Hypertension

17. JNC 8

20. Despite the direct relationship between
blood pressure increase and CV events,
the mere blood pressure reduction is not sufficient
to normalize relative CV risk

21. Controlling hypertension reduces CV
outcomes
Relationship between BP and CV risk is continuous: lower is better

22. Controlling hypertension reduces CV
outcomes
Relationship between BP and CV risk is continuous: lower is better

23. SEA Countries Prevalence Awareness Treatment Control
BRUNEI 19.3
CAMBODIA 24.4 28.6
INDONESIA 23.3 24 15 9
LAOS 24.1 28 16..8 6
MALAYSIA 22.1 71.5 40 16.4
MYANMAR 23.7 67.3 25.6 6.4
PHILIPPINES 22.1 65 42.4 20
SINGAPORE 14.1 69.2 64.5 24.1
THAILAND 21.3 56.6 48.6 20.9
TIMOR LESTE 35.1
VIETNAM 22.2 48.4 29.6 10.7
Average 22.9 53.8 34.6 14.2
WHO Status Report 2014
Personal communications
Hypertension Prevalence, Awareness, Treatment and Control Rates in SEA

24. AVERAGE 14.2% OF HYPERTENSIVE IN ASEAN HAS GOAL
BP LEVEL
• 3 out of 4 hypertensive patients, their BP was not
controlled over 24 hr
• some antihypertensive medication do not improve
arterial health
• How to improve the current situation?
• Choose drug which has 24 hr BP control and improve
arterial health

25. CONTROLLING HYPERTENSION REDUCES CV OUTCOMES
Use drug to improve arterial health
Patient compliance
key for Success:
Use drug for 24 hr BP control

27. CV EVENTS OCCURS IN EARLY MORNING
Heart attack
Stroke
Heart attack
Stroke

28. • Surprisingly, although the current guidelines give detailed
recommendations on the diagnostic potential and use of ABPM, there
are scant recommendations on the benefits and application of the
technique for the initiation of blood pressure-lowering therapy in
clinical practice and virtually no recommendations on how it might be
used to assess the efficacy of drug treatment.
O'Brien E, Dolan E. Ambulatory Blood Pressure Monitoring for the Effective Management of Antihypertensive Drug Treatment. Clin Ther. 2016;38(10):2142-
2151.

29. 24 Hour Duration

30. Screening Perindopril 10 mg (n=30)
Enalapril 20 mg (n=30)
Losartan 100 mg (n=30)
Telmisartan 80 mg* (n=30)
Wash-out WO W4 W12 W24 (weeks)
NEW ESH 2012: the Nedogoda study
First head-to-head study on full-dose therapy:
superior antihypertensive efficacy of Perindopril 10 mg
Design: Randomized, single-blinded, parallel-group study.
Nedogoda S, et al. 2012; J Hypertens. 30 (e-suppl A) Abstract
PP30.489

31. Perindopril 10 mg: superior 24-hour ambulatory blood pressure
reduction
120
125
130
135
140
145
150
155
160
Coversyl 10 mg Enalapril 20 mg Losartan 100 mg Telmisartan 80 mg
Baseline
24 weeks
ABPM
Mean 24-hour SBP reduction versus baseline (mm Hg)
 24  -12 -24  -12  -15
*
Nedogoda S, et al. 2012; J Hypertens. 30 (e-suppl A) Abstract
PP30.489
Perindopril 10 mg

32. MOST POTENT 24 HOUR BP CONTROL
USFDA approved highest TPR
Physicians Desk Reference. NJ: Medical Economic
Company;2008.
Perindopril 100%

33. The best CV protection may be obtained only by
preventing of reversing the pathophysiological alterations
associated to hypertension

34. Mechanism promoting
atherosclerosis
Structural changes Endothelial dysfunction
Increase in stiffness and vascular
resistances
Micro and macro vascular alterations in humans

35. Weight: 1.5 Kg, surface: > 800 m2
Produces >250 active substances
Undergoes the life and death cycle
ENDOTHELIUM

36. ATHEROMA’S FORMATION AND PROGRESSION:
A STRUGGLE BETWEEN DEATH AND REGENERATION
•Endothelial cells undergo suicide (apoptosis) and
regenerate
•When a mismatch occurs, endothelium loses
continuity
Atherosclerosis Acute Coronary Syndrome

37. Normal rate of apoptosis: 3%
Maintenance of endothelium layer
Excess rate of apoptosis
Onset of atheroscleroticProtection against
atherosclerosis
Endothelial apoptosis and atherosclerosis
endothelium continuity
Plaque erosion and rupture

40. PHYSIOLOGICAL EFFECTS OF BRADYKININ
Vasculoprotective Effects of NO
• Vasodilator (via relaxation of SMCs)
• Growth inhibitor (via actions on SMCs)
• Inhibitor of platelet adherence/aggregation
• Inhibitor of endothelial/leukocyte interactions
• ? Counterbalance effects of superoxide anion

42. WHY ?
• Different tissue affinity
• Different effects on the bradykinine (anti-apoptoic) angiotensin (pro-apoptoic)
• Specific effects on typical apoptoic inducer: TNF-
(ANTI) bradykinine angiotensin
(PRO)

43. Different effects on circulating and local RAS
depending on the drug dose
R A S
circulating
low ACE activity
local
high ACE activity
antihypertensive
effect
tissue protective
effect
LOW DOSE HIGH DOSE

44. ACEIs
Tissue ACE affinity
(Tissue potency DD50)
Bradykinin
/angiotensin ratio
Perindopril +++ 1.44
Quinapril + 1.09
Ramipril ++ 1.16
Enalapril - 1
MOST POTENT TISSUE ACE AFFINITY
Direct arterial protection

45. Differential affinity for tissue ACE
Ferrari R, Exp Rev Cardiovasc Ther 2005
0
2
4
6
Perindopril Quinalapril Ramipril Enalapril Fosinopril Captopril

46. BK, bradykinin; Ang I, angiotensin I
Ceconi C, et al. Eur J Pharmacol. 2007
COMPARATIVE AFFINITY OF ACE INHIBITORS TO
BRADYKININ VS ANGIOTENSIN I BINDING SITES OF ACE
1.00
trandolaprilatquinaprilat enalaprilatramiprilatperindoprilat
1.44
1.16
1.09 1.08
1.00
1.10
1.20
1.30
1.40
1.50
BK/AngIselectivityratio
P<0.01
P<0.001

47. Best documented vascular protection
Perindopril

49. Bradykinin / Angiotensin II
Bradykinin(Pg/mL)
p <0.01
CAD PERTINENT
baseline 1 year
14.8
12.4
12.3
18.0
Controls
18.3
p<0.01
0
10
20
5
15
Bradykinin
AngiotensinII(Pg/mL)
p <0.05
CAD PERTINENT
baseline 1 year
17.1
15.8
14.4
12.5
Controls
10.8
p<0.01
Angiotensin II
# p=controls vs baseline
‡ p=∆perindopril vs ∆placebo
0
10
20
5
15
# ‡# ‡

50. 0
5
10
15
20
25
30
35
40
TNF-a(pg/mL)
ControlsControls
n = 45n = 45
18.0
p<0.01 #
Controls
baseline 1 year
p <0.05 ‡
PlaceboPlacebo
n = 44n = 44
PlaceboPlacebo
n = 44n = 44
PerindoprilPerindopril
n = 43n = 43
PerindoprilPerindopril
n = 43n = 43
27.127.7 28.9 24.6
CAD PERTINENT patients
# p= controls vs baseline
‡ p=  perindopril vs  placebo
TNF -  PERTINENT

51. Tissue ACE and
Bradykinin
18

52. * P<0.001 vs induced apoptosis
Differential effect of ACE inhibitors on the rate of endothelial apoptosis at equi-
hypotensive dosages
10.0
7.5
8.8
9.5
4.3
0
6
12
10
4
Rate of apoptosis (%)
2
8
10.7
0.8
P<0.001
P<0.001
P<0.001
P<0.001
*
Ceconi C et al. Eur J Pharmacol 2007

53. REMODELING (PREAMI)

54. PRIMARY ENDPOINT (PREAMI)
Perindopril Better Placebo better
RRR(%) P

55. Overall study population With hypertension Without hypertension
CV death, MI, cardiac arrest
-15
-10
-5
0
-20
RRR
(%)
-20%
-18%
-20%
Patients with CAD
EUROPA Investigators.
Lancet 2003;362:782-88.
Recurrent stroke
-20
-10
0
-30
RRR
(%)
-32%
-27%-28%
PROGRESS Collaborative Group. Lancet
2001;358:1033-41
Post-stroke patients
Macro and microvascular events
-5
0
-10
RRR
(%)
-9%
-10%
-9%
Diabetic patients
ADVANCE Collaborative Group.
Lancet 2007;370:829-40.
Effects of ACEi in patients
With or without Hypertension

56. Overall study population With diabetes Without diabetes
CV death, MI, cardiac arrest
-15
-10
-5
0
-20
RRR
(%)
-20%
-19% -19%
Patients with CAD
EUROPA Investigators.
Lancet 2003;362:782-88
Recurrent stroke
-30
-20
-10
0
-40
RRR
(%)
-38%
-28%-28%
Post-stroke patients
PROGRESS Collaborative Group. Lancet
2001;358:1033-41
Total CV events and procedures
-15
-10
-5
0
-20
RRR
(%)
-13%
-18%
-16%
Hypertensive patients
Dahlof B. Lancet 2005;
366:895-906.
Effects of ACEi in patients
With or without Diabetes

57. -40
-35
-30
-25
-20
-15
-10
-5
0
Prevention of heart failure
-39%
P=0.002
Stable CAD
-26%
P=0.02
Post-stroke
EUROPA Investigators. Lancet 2003;362:782-88. ; Cleland JGF. Eur Heart J 2006;27:2338-2345.
PROGRESS Collaborative Group. Eur Heart J 2003;24:475-484. ; PREAMI Investigators. Arch Intern Med. 2006;166:659-666
Post-MI
-28%
NS
Diastolic HF
-37%
P=0.033

58. 58EFFECTIVE IN REDUCING CENTRAL AORTIC BP CONTROL…
A central aortic
SBP difference
of 4.3 mmHg
Similar brachial BP
reductions
Central Aortic BP reduction is linked to a reduction in CV events
Perindopril

59. Reduction in mortality with amlodipine/perindopril in ASCOT
Cardiovascular mortality
amlodipine/perindopril
(No. of events 263)
atenolol/thiazide
(No. of events 342)
24%, p=0.001
0.0 1.0 2.0 3.0 4.0 5.0
Years
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
%
All-cause mortality
0.0 1.0 2.0 3.0 4.0 5.0
Years
0.0
2.0
4.0
6.0
8.0
10.0
%
atenolol/thiazide
(No. of events 820)
amlodipine/perindopril
(No. of events 738)
11%, p=0.0247
Dahlof B, et al. Lancet. 2005;366:895-906.

60. Best documented vascular protection
Does the effectiveness on vascular alterations translate into
effectiveness on CV events and mortality?
Are RAS blocker equal? Is it equivalent to use an ACE-I or an ARB?
Main questions

61. Mechanism of RAAS Inhibition
Angiotensin II
Receptor Blockers
Angiotensin Converting Enzyme
Inhibitors
1. Suppression of Angiotensin II
2. Up regulation of Bradykinin
1. Blockade of AT1 receptor
2. Up regulation Of Angiotensin II
3. No impact on Bradykinin
?

62. Differential effects of RAAS inhibitors on coronary events
BPLTTC Regression Meta-analysis
“For ACEI, but not for ARB, there is evidence of blood pressure-independent effects on the risk of major coronary
disease events.”
BP Lowering Treatment Trialists Collaboration. J Hypertens 2007
+9%
-8%
P=0.002
Relative risk reduction beyong blood pressure effect (%)
-10% 0%-5% 5% 10%
ACE
inhibitors
ARBs

63. Adapted from: Strauss MH, Hall AS. Circulation. 2006;114:838-854.
-14
-12
-10
-8
-6
-4
-2
0
Global
death
CV death Stroke MI
RRR, %
-9%
***
-12%
**
-6%
-14%
***
ACE inhibitors vs comparators
(39 trials, n=150 943)
-8
-6
-4
-2
0
2
4
6
8
Global
death
CV death Stroke MI
RRR, %
+8%
*
ARBs vs comparators
(11 trials, n=55 050)
-8%
+1%+1%
* p=0.03
** p=0.0005; *** p < 0.00001
ACE inhibitors or ARBs ?
* p=0.03

64. Mortality reduction with RAAS blockers: identical?
Van Vark et al. European Heart Journal 2012.33:2088-
P=0.032
European Heart Journal 2012

65. All-cause mortality: effect of ACE inhibitors
ASCOT-BPLA
ADVANCE
HYVET
Overall
1.03 (0.90-1.15)
0.90 (0.75-1.09)
0.99 (0.62-1.58)
1.32 (0.61-2.86)
0.89 (0.81-0.99)
0.86 (0.75-0.98)
0.79 (0.65-0.95)
0.90 (0.84-0.97)
ACE inhibitor better Control better
Random effects model HR (95% CI) P value
N= 76 6150.50 0.75 1.33 2.01
HR (log scale)
0.03
0.03
0.02
0.87(0.81-0.93)
0.004
<0.001
ALLHAT (lisinopril)
ANBP-2 (enalapril)
pilot HYVET (lisinopril)
JMIC-B (lisinopril, enalapril)
(perindopril)
Van Vark LC et al. Eur Heart J 2012

66. All-cause mortality: effect of ARBs
RENAAL (losartan)
IDNT (irbesartan)
LIFE (losartan)
SCOPE (candesartan)
VALUE (valsartan)
MOSES (eprosartan)
JIKEI HEART (valsartan)
PRoFESS (telmisartan)
TRANSCEND (telmisartan)
CASE-J (candesartan)
HIJ-CREATE (candesartan)
KYOTO HEART (valsartan)
NAVIGATOR (valsartan)
Overall
HR (log scale) Control betterARB better
0.50 0.75 1.33 2.01
1.03 (0.83-1.29)
0.92 (0.69-1.23)
0.88 (0.77-1.01)
0.96 (0.81-1.14)
1.04 (0.94-1.14)
1.07 (0.73-1.57)
1.09 (0.64-1.85)
1.03 (0.93-1.14)
1.05 (0.91-1.22)
0.85 (0.62-1.16)
1.18 (0.83-1.67)
0.76 (0.40-1.30)
0.90 (0.77-1.05)
0.99 (0.94-1.04)
Random effects model HR (95% CI) P value
N=82 383
0.683
Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.

67. Comparison of RAAS blockers for a same BP effect
Relativeriskreduction(%)
-48%
-20%
-35%
-53%
-25%
NS
STROKECHD HEART FAILURE
For a similar blood pressure reduction
(10/5 mm Hg SBP/DBP reduction):
ACE INHIBITORS
ARBs N=100 959 patients
Mean follow-up: 4 years
Thomopoulos C. J Hypertens. 2015;33:195-211.

68. How does it translate into clinical practice?
Brugts et al. Inter J Cardiol.2015.181:425-429
NNT (number needed to treat)
All-cause death
Myocardial infarction
ACEi ARBs
67
80
335, NS
338, NS

69. CHF
Post-MI
CAD risk
Diabetes mellitus
Renal disease
Recurrent stroke
prevention







BB





ACEI



ARB


CCB


AADiuretic
 
Compelling Indications for Specific
Antihypertensive Agents
Based on Favorable Outcome Data From Clinical Trials
BB, beta blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; AA, aldosterone antagonist; CHF, chronic heart failure; MI, myocardial infarction; CAD,
coronary artery disease; DM, diabetes mellitus Chobanian AV et al. JAMA. 2003;289:2560–2572.

70. Diagnosis Drug Treatment
Primary/secondary prevention ACE inhibitor/ARB, or CCB, or thiazide diuretic, or
combination
CAD and stable angina Beta-blocker and ACE inhibitor/ARB and thiazide
diuretic
ACS -- unstable angina, NSTEMI, STEMI Beta-blocker and ACE inhibitor/ARB
Heart failure of ischemic etiology Beta-blocker and ACE inhibitor/ARB and aldosterone
antagonist and diuretic (thiazide or loop) and
hydralazine/isosorbide dinitrate
Guidelines for the Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease. Circulation, 2007
Hypertension and CAD -- Recommended Antihypertensive
Drug Treatments

72. Cerebral
Infarction
Myocardial
Infarction
Sudden
Death
VASCULO-/CARDIO PROTECTION

73. Perindopril has:
• Highest affinity for tissue ACE
• Preservation of bradykinin/ angiotensin II balance
• Greatest anti-apoptotic effect
• Optimal endothelial protection
• Perindopril exerts a specific well-documented CV protection, in addition to
BP reduction
• These effects are not necessarily shared by, or documented for, other ACE
inhibitors or ARBs

74. Vascular Protection of Perindopril
beyond the blood pressure benefit

75. CONCLUSIONS
Among RAAS inhibitors, only ACE inhibitors have demonstrated a significant 10% mortality
reduction in hypertensive patients (P=0.004).
No significant reduction in all-cause mortality could be demonstrated with ARBs (HR, 0.99 (0.95-
1.04); P=0.683).
The difference in treatment effect between ACE inhibitors and ARBs was statistically significant
(P-value for interaction 0.036).
The largest mortality reductions were observed in ASCOT-BPLA, ADVANCE, and HYVET, which
studied the ACE inhibitor perindopril (pooled HR, 0.87 [0.81-0.93]; P<0.001).
Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result
in an important gain in lives saved.
Van Vark LC, Bertrand M, Fox K, Mourad JJ, Boersma E, et al. Eur Heart J 2012; published online April 17.

76. TAKE HOME MESSAGE
If the patient has
• DM CKD Stroke Clinical coronary artery disease, MI or Heart failure
→ ACEI / ARB is preferred: ACEI has more evidence than ARB
• RAAS is central in vascular aging
• Early RAAS blockade is essential to prevent vascular alterations in hypertensive patients
• Perindopril is the best evidence-based treatment for vascular protection in humans
• Perindopril should be initiated rapidly in hypertensive patients