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ARTERIAL HEALTH IN HYPERTENSION:
IMPACT ON OUTCOME
PROF KYAW SOE WIN
DEPARTMENT OF CARDIOVASCULAR MEDICINE
MANDALAY GENERA...
CHANGING HEALTH SCENARIO – MAJOR FACTORS OF MORTALITY
• MALNUTRITION
• INFECTION
• CARDIO-VASCULAR DISEASES
• CEREBRO-VASC...
World Health Organisation. Global atlas on cardiovascular disease prevention and control. 2011. Available at: http://www.w...
WHY THIS SHIFT?
• IMPROVING HYGEINE
• INFECTION CONTROL STEPS
• BETTER DRUGS & VACCINES
• BASIC MEDICAL FACILITY AVAILABLE...
JACC March 20, 2018 Volume 71, Issue 11
J Cardiol Curr Res 2017, 10(1): 00353
J Cardiol Curr Res 2017, 10(1): 00353
Bjertness et al. BMC Public Health (2016) 16:590
DOI 10.1186/s12889-016-3275-7
HISTORICAL LESSONS ON THE RISKS OF HYPERTENSION
AND THE BENEFITS OF TREATMENT
CHDIncidenceRate/
1000PersonYears
Cumulative...
HISTORICAL LESSONS ON THE RISKS OF HYPERTENSION
AND THE BENEFITS OF TREATMENT
CHDIncidenceRate/
1000PersonYears
Cumulative...
BENEFIT OF TREATING HIGH BP
• PERSISTANT REDUCTION OF BP ↓ CVD ↓ CORONARY DEATH
• 5mmHg 34% 21%
• 7.5mmHg 46% 29%
• 10mm H...
Treatment goals for managing hypertension
British Hypertension Guideline 2011
“Prime motivation for treatment in hypertens...
Key
A – ACE inhibitor or low-cost
angiotensin II receptor blocker (ARB)1
C – Calcium-channel blocker (CCB)
D – Thiazide-li...
Journal of Hypertension October 2013, 31 : 000-000
ASH/ISH October 2013 Updated Clinical Practice Guidelines
For The Manag...
JNC 8
Despite the direct relationship between
blood pressure increase and CV events,
the mere blood pressure reduction is not su...
Controlling hypertension reduces CV
outcomes
Relationship between BP and CV risk is continuous: lower is better
Controlling hypertension reduces CV
outcomes
Relationship between BP and CV risk is continuous: lower is better
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...
AVERAGE 14.2% OF HYPERTENSIVE IN ASEAN HAS GOAL
BP LEVEL
• 3 out of 4 hypertensive patients, their BP was not
controlled o...
CONTROLLING HYPERTENSION REDUCES CV OUTCOMES
Use drug to improve arterial health
Patient compliance
key for Success:
Use d...
CV EVENTS OCCURS IN EARLY MORNING
Heart attack
Stroke
Heart attack
Stroke
• Surprisingly, although the current guidelines give detailed
recommendations on the diagnostic potential and use of ABPM,...
24 Hour Duration
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 ...
Perindopril 10 mg: superior 24-hour ambulatory blood pressure
reduction
120
125
130
135
140
145
150
155
160
Coversyl 10 mg...
MOST POTENT 24 HOUR BP CONTROL
USFDA approved highest TPR
Physicians Desk Reference. NJ: Medical Economic
Company;2008.
Pe...
The best CV protection may be obtained only by
preventing of reversing the pathophysiological alterations
associated to hy...
Mechanism promoting
atherosclerosis
Structural changes Endothelial dysfunction
Increase in stiffness and vascular
resistan...
Weight: 1.5 Kg, surface: > 800 m2
Produces >250 active substances
Undergoes the life and death cycle
ENDOTHELIUM
ATHEROMA’S FORMATION AND PROGRESSION:
A STRUGGLE BETWEEN DEATH AND REGENERATION
•Endothelial cells undergo suicide (apopto...
Normal rate of apoptosis: 3%
Maintenance of endothelium layer
Excess rate of apoptosis
Onset of atheroscleroticProtection ...
PHYSIOLOGICAL EFFECTS OF BRADYKININ
Vasculoprotective Effects of NO
• Vasodilator (via relaxation of SMCs)
• Growth inhibi...
WHY ?
• Different tissue affinity
• Different effects on the bradykinine (anti-apoptoic) angiotensin (pro-apoptoic)
• Spec...
Different effects on circulating and local RAS
depending on the drug dose
R A S
circulating
low ACE activity
local
high AC...
ACEIs
Tissue ACE affinity
(Tissue potency DD50)
Bradykinin
/angiotensin ratio
Perindopril +++ 1.44
Quinapril + 1.09
Ramipr...
Differential affinity for tissue ACE
Ferrari R, Exp Rev Cardiovasc Ther 2005
0
2
4
6
Perindopril Quinalapril Ramipril Enal...
BK, bradykinin; Ang I, angiotensin I
Ceconi C, et al. Eur J Pharmacol. 2007
COMPARATIVE AFFINITY OF ACE INHIBITORS TO
BRAD...
Best documented vascular protection
Perindopril
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....
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 ‡
Place...
Tissue ACE and
Bradykinin
18
* P<0.001 vs induced apoptosis
Differential effect of ACE inhibitors on the rate of endothelial apoptosis at equi-
hypoten...
REMODELING (PREAMI)
PRIMARY ENDPOINT (PREAMI)
Perindopril Better Placebo better
RRR(%) P
Overall study population With hypertension Without hypertension
CV death, MI, cardiac arrest
-15
-10
-5
0
-20
RRR
(%)
-20%...
Overall study population With diabetes Without diabetes
CV death, MI, cardiac arrest
-15
-10
-5
0
-20
RRR
(%)
-20%
-19% -1...
-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 Invest...
58EFFECTIVE IN REDUCING CENTRAL AORTIC BP CONTROL…
A central aortic
SBP difference
of 4.3 mmHg
Similar brachial BP
reducti...
Reduction in mortality with amlodipine/perindopril in ASCOT
Cardiovascular mortality
amlodipine/perindopril
(No. of events...
Best documented vascular protection
Does the effectiveness on vascular alterations translate into
effectiveness on CV even...
Mechanism of RAAS Inhibition
Angiotensin II
Receptor Blockers
Angiotensin Converting Enzyme
Inhibitors
1. Suppression of A...
Differential effects of RAAS inhibitors on coronary events
BPLTTC Regression Meta-analysis
“For ACEI, but not for ARB, the...
Adapted from: Strauss MH, Hall AS. Circulation. 2006;114:838-854.
-14
-12
-10
-8
-6
-4
-2
0
Global
death
CV death Stroke M...
Mortality reduction with RAAS blockers: identical?
Van Vark et al. European Heart Journal 2012.33:2088-
P=0.032
European H...
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 (0.6...
All-cause mortality: effect of ARBs
RENAAL (losartan)
IDNT (irbesartan)
LIFE (losartan)
SCOPE (candesartan)
VALUE (valsart...
Comparison of RAAS blockers for a same BP effect
Relativeriskreduction(%)
-48%
-20%
-35%
-53%
-25%
NS
STROKECHD HEART FAIL...
How does it translate into clinical practice?
Brugts et al. Inter J Cardiol.2015.181:425-429
NNT (number needed to treat)
...
CHF
Post-MI
CAD risk
Diabetes mellitus
Renal disease
Recurrent stroke
prevention







BB





ACEI



ARB...
Diagnosis Drug Treatment
Primary/secondary prevention ACE inhibitor/ARB, or CCB, or thiazide diuretic, or
combination
CAD ...
Cerebral
Infarction
Myocardial
Infarction
Sudden
Death
VASCULO-/CARDIO PROTECTION
Perindopril has:
• Highest affinity for tissue ACE
• Preservation of bradykinin/ angiotensin II balance
• Greatest anti-ap...
Vascular Protection of Perindopril
beyond the blood pressure benefit
CONCLUSIONS
Among RAAS inhibitors, only ACE inhibitors have demonstrated a significant 10% mortality
reduction in hyperte...
TAKE HOME MESSAGE
If the patient has
• DM CKD Stroke Clinical coronary artery disease, MI or Heart failure
→ ACEI / ARB is...
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
 arterial health in hypertension
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arterial health in hypertension

  1. 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. 2. CHANGING HEALTH SCENARIO – MAJOR FACTORS OF MORTALITY • MALNUTRITION • INFECTION • CARDIO-VASCULAR DISEASES • CEREBRO-VASCULAR DISEASES • RENAL DISEASES • COMMON DENOMINATOR HYPERTENSION
  3. 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. 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. 5. JACC March 20, 2018 Volume 71, Issue 11
  6. 6. J Cardiol Curr Res 2017, 10(1): 00353
  7. 7. J Cardiol Curr Res 2017, 10(1): 00353
  8. 8. Bjertness et al. BMC Public Health (2016) 16:590 DOI 10.1186/s12889-016-3275-7
  9. 9. 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
  10. 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 0 10 20 30 40 50 Placebo Active Treatment Treatment Decreases Morbidity and Mortality The Vet. Adm. Study II JAMA. 1970; 213:1143–1152.
  11. 11. BENEFIT OF TREATING HIGH BP • PERSISTANT REDUCTION OF BP ↓ CVD ↓ CORONARY DEATH • 5mmHg 34% 21% • 7.5mmHg 46% 29% • 10mm Hg 56% 37%
  12. 12. 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
  13. 13. Key A – ACE inhibitor or low-cost angiotensin II receptor blocker (ARB)1 C – Calcium-channel blocker (CCB) D – Thiazide-like diuretic
  14. 14. Journal of Hypertension October 2013, 31 : 000-000 ASH/ISH October 2013 Updated Clinical Practice Guidelines For The Management Of Hypertension
  15. 15. JNC 8
  16. 16. Despite the direct relationship between blood pressure increase and CV events, the mere blood pressure reduction is not sufficient to normalize relative CV risk
  17. 17. Controlling hypertension reduces CV outcomes Relationship between BP and CV risk is continuous: lower is better
  18. 18. Controlling hypertension reduces CV outcomes Relationship between BP and CV risk is continuous: lower is better
  19. 19. 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
  20. 20. 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
  21. 21. CONTROLLING HYPERTENSION REDUCES CV OUTCOMES Use drug to improve arterial health Patient compliance key for Success: Use drug for 24 hr BP control
  22. 22. CV EVENTS OCCURS IN EARLY MORNING Heart attack Stroke Heart attack Stroke
  23. 23. • 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.
  24. 24. 24 Hour Duration
  25. 25. 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
  26. 26. 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
  27. 27. MOST POTENT 24 HOUR BP CONTROL USFDA approved highest TPR Physicians Desk Reference. NJ: Medical Economic Company;2008. Perindopril 100%
  28. 28. The best CV protection may be obtained only by preventing of reversing the pathophysiological alterations associated to hypertension
  29. 29. Mechanism promoting atherosclerosis Structural changes Endothelial dysfunction Increase in stiffness and vascular resistances Micro and macro vascular alterations in humans
  30. 30. Weight: 1.5 Kg, surface: > 800 m2 Produces >250 active substances Undergoes the life and death cycle ENDOTHELIUM
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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)
  35. 35. 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
  36. 36. 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
  37. 37. Differential affinity for tissue ACE Ferrari R, Exp Rev Cardiovasc Ther 2005 0 2 4 6 Perindopril Quinalapril Ramipril Enalapril Fosinopril Captopril
  38. 38. 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
  39. 39. Best documented vascular protection Perindopril
  40. 40. 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 # ‡# ‡
  41. 41. 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
  42. 42. Tissue ACE and Bradykinin 18
  43. 43. * 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
  44. 44. REMODELING (PREAMI)
  45. 45. PRIMARY ENDPOINT (PREAMI) Perindopril Better Placebo better RRR(%) P
  46. 46. 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
  47. 47. 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
  48. 48. -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
  49. 49. 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
  50. 50. 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.
  51. 51. 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
  52. 52. 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 ?
  53. 53. 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
  54. 54. 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
  55. 55. Mortality reduction with RAAS blockers: identical? Van Vark et al. European Heart Journal 2012.33:2088- P=0.032 European Heart Journal 2012
  56. 56. 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
  57. 57. 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.
  58. 58. 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.
  59. 59. 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
  60. 60. 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.
  61. 61. 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
  62. 62. Cerebral Infarction Myocardial Infarction Sudden Death VASCULO-/CARDIO PROTECTION
  63. 63. 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
  64. 64. Vascular Protection of Perindopril beyond the blood pressure benefit
  65. 65. 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.
  66. 66. 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

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