Treatment of Hypertension,

Focus on ACE-Inhibitor
Conseptual definition of hypertension

Still debate the level of BP

that is considered abnormal

Sir George Pickering (1972)

“There is no dividing line.
The relationship between arterial pressure
and mortality is quantitative; the higher
the pressure, the worse the prognosis”
HYPERTENSION ?
 Definition and classification of hypertension
WHO/ISH 2003
Hypertension is defined as blood pressure ≥140/90 mmHg
Category Systolic Diastolic
(mmHg) (mmHg)

Optimal <120 <80

Normal <130 <85
High-normal 130-139 85-89
Grade 1 hypertension (mild) 140-159 or 90-99
Subgroup: borderline 140-149 90-94

Grade 2 hypertension 160-179 or 100-109

(moderate)
Grade 3 hypertension (severe) ≥180 or ≥110
Isolated systolic hypertension ≥140 <90
Subgroup: borderline 140-149 <90

2003 WHO/ISH Statement on Hypertension.

When a patient’s systolic and diastolic blood pressures fall J Hypertens 2003;21:1983-1992; 1999 WHO/ISH Guidelines for the
into different categories, the higher category should apply Management of Hypertension. J Hypertens 1999;17:151-183
Definition and classification of hypertension: ESH/ESC
2013
Hypertension is defined as blood pressure ≥140/90 mmHg

Category Systolic Diastolic

(mmHg) (mmHg)
Optimal <120 <80

Normal 120-129 80-84

High normal 130-139 85-89

Grade 1 hypertension (mild) 140-159 90-99

Grade 2 hypertension 160-179 100-109

(moderate)
Grade 3 hypertension (severe) ≥180 ≥110

Isolated systolic hypertension ≥140 <90

2013 ESH/ESC Guidelines for the management of arterial hypertension

www.jhypertension.com
 JNC VI : Classification of hypertension

Systolic Diastolic

Optimal < 120 <80

Normal < 130 < 85

High Normal 130 - 139 85 – 89

Hypertension
Stage 1 140 – 149 90 – 99
Stage 2 150 – 179 100 – 109
Stage 3 > 180 > 110
JNC VII : Classification of hypertension
Systolic Diastolic

Normal < 120 <80

Pre-hipertensi 120-129 80-89

Stage 1 140-159 90 - 99
Hypertension
Stage 2
Hypertension
> 160 > 100
 “High Normal”/ “Prehypertension” BP
is Not Benign
Cumulative incidence of CV events* (%)

14 High 14
Men normal Women
12 12
1.6-fold High
Normal 10 2.5-fold normal
10 greater risk†
greater risk†
8 8

6 Optimal 6
Normal
4 4

2 2
Optimal
0 0
0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14
Time (yr) Time (yr)

*CV death, MI, stroke, CHF. †Age-adjusted risk comparison of High normal versus normal.
Optimal: <120/<80 mm Hg. Normal: 120-129/80-84 mm Hg. High normal: 130-139/85-89 mm Hg.

Vasan RS et al. N Engl J Med 2001;345:1291-1297.

Hypertension is a prevalent disease affecting 1 billion
people today

60 55
49
50 47
42
Prevalence* of HTN (%)

40 38 38

30 27 28

20

10

0
a ly en in y
a d SA Ita d a nd a an
d
an
U l p l
an e g S n m
C Sw En Fi er
G

*Among persons aged 35–64 years old; age and sex adjusted Wolf-Maier et al. JAMA 2003;289:2363–9
HTN = BP 140/90 mmHg or on treatment
Most people denied of having HTN measured by digital BP
Hypertension

HTN
4%

HTN
35%

Normal
65%
normal
96%
N=853.252 N=853.252
 Cardiovascular mortality risk doubles with each
20/10 mmHg increment*

CV mortality risk
8
8x
6

4
4x
2
2x
1x
0
115/75 135/85 155/95 175/105
SBP/DBP (mmHg)

*Individuals aged 40–69 years Lewington et al. Lancet 2002;360:1903–13

 ABPM

- Information about BP during daily activities and sleep

- Evaluation “white coat” hypertension
- Asses apparent drug resistance, episodic hypertension
Average BP > 135/85 awake
Average BP > 125/75 sleep
-
BP decrease 10-20 mmHg (night)
Risk CV
-

-
 Target Organ Damage

 Heart
• Left ventricular hypertrophy
• Angina or prior myocardial infarction
• Prior coronary revascularization
• Heart failure
 Brain
• Stroke or transient ischemic attack
 Chronic kidney disease
 Peripheral arterial disease
 Retinopathy
 This left ventricle is very thickened (slightly over 2 cm in
thickness), but the rest of the heart is not greatly enlarged.
This is typical for hypertensive heart disease. The
hypertension creates a greater pressure load on the heart to
induce the hypertrophy.

Department of General
Kieran McGlade NovPractice
2001 QUB
 The left ventricle is markedly thickened in this patient
with severe hypertension that was untreated for many
years. The myocardial fibers have undergone
hypertrophy.

Kieran McGlade
Department of General
Nov 2001
Practice QUB
Search for asymptomatic organ damage, cardiovascular
disease, and chronic kidney disease

2013 ESH/ESC Guidelines for the management of arterial hypertension

 Syst-Eur*: reduction in cardiovascular (CV)
risk end points

Stroke MI HF All CV end points

Reduction with active treatment (%)

-5%

-15%

-25%
P<0.001

-30% -29%
-35%
-31%
P=0.003

-45% -42%
Subjects are elderly persons with ISH.
 12 to 13 mm Hg drop in systolic BP reduces
4-year risk of CAD, stroke, mortality

CHD Stroke CVD mortality All-cause mortality

0%
Reduction in risk (%)

-10%
P=0.005

-13%
-20% P<0.0001

-21% P<0.001

-30% -25%

P<0.001
-40%
-37%

Meta-analysis of 10 randomized trials.

He and Whelton, J Hypertens, 1999.
 JNC VII: Management of Hypertension

Initial Drug Therapy

Lifestyle Without Compelling With Compelling
BP Classification Modification Indication Indication

Normal Encourage
<120/80 mm Hg

Prehypertension Yes No drug indicated Drug(s) for the compelling

120-139/80-89 mm Hg indications

Stage 1 hypertension Yes Thiazide-type diuretics Drug(s) for the compelling

140-159/90-99 mm Hg for most; may consider
ACE-I, ARB, BB, CCB, or
combination
Stage 2 hypertension Yes 2-drug combination for most
≥160/100 mm Hg (usually thiazide-type diuretic
and ACE-I, ARB, BB, or
CCB)
ACE-I = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor
blocker; BB = beta blocker; CCB, = calcium channel blocker.
Chobanian AV et al. JAMA. 2003;289:2560-2572.
indications; other
antihypertensive drugs
(diuretics, ACE-I, ARB, BB,
CCB) as needed
Drug(s) for the compelling
indications; other
antihypertensive drugs
(diuretics, ACE-I, ARB,
BB, CCB) as needed
LIFESTYLE
Blood pressure goals in hypertensive patients

21
Drugs to be preferred in specific conditions
Updated UK NICE Guidelines for the Treatment of
Newly Diagnosed Hypertension
55 years or
<55 years
black at any age
ACEI (or ARB*) CCB or thiazide-
Step 1
or Beta-Blocker type diuretic

ACEI (or ARB*) or Beta-Blockers + CCB or

Step 2
ACEI (or ARB*) + thiazide diuretic

ACEI (or ARB*) + Beta-Blockers + CCB +

Step 3
diuretic

Add further diuretic therapy, α-blocker, .

Step 4
Consider seeking specialist advice

*If ACE inhibitor (ACEI) not tolerated

NICE guideline 2005
NICE clinical guideline 127, 2011
 ANGIOTENSIN II

Altered Altered Altered

Peripheral Renal Cardiovascular
Resistance Function Structure

I. Direct vasoconstriction I. Increased Na + I. Stimulation of cell growth

reabsorption
II. Enhancement of by proximal tubule II. Hemodynamic changes
peripheral noradrenergic
neurotransmission II. Increased aldosterone A. Increased cardiac
release afterload + preload
III. Increased sympathetic
discharge (CNS) III. Altered renal B. Increased vascular
hemodynamics wall tension
IV. Catecholamine release (vasoconstriction)
from adrenal medulla

Vascular + Cardiac
Rapid Pressor Response Slow Pressor Response
Hypertrophy + Remodeling
 Angiotensinogen
Inactive peptides Renin
Angiotensin I
ACE-i
ACE
Bradykinin Angiotensin II
Endothelial dysfunction Proliferation fibrosis
Impaired NO synthase TGF-β
Inflammation Adhesion
IL-6, MCP-1, PDGF VCAM, ICAM
Thrombosis Lipid oxidation
PAI-1, TF LOX-1

Protection
ATHER against
O S C Lthe
E Reffects
O S I Sof P
angiotensin
R O C E S SII on
atherosclerosis process
Ferrari R, et al. Expert Rev CardiovascTher . 2005;3(1):15-29
Probstfield JL., et al. Am J Cardiol.2010;105:10A-20A
 Recommended Drugs
Diuretic -blocker ACEI ARB CCB Aldo ANT Clinical trial basis
ACC/AHA Heart Failure Guideline,
MERIT-HF, COPERNICUS, CIBIS,
Heart failure SOLVD, AIRE, TRACE, ValHEFT,
RALES, CHARM

Post myocardial ACC/AHA Post-MI Guideline,

BHAT, SAVE, Capricorn,
infarction
EPHESUS

High coronary disease ALLHAT, HOPE, ANBP2, LIFE,

risk CONVINCE, EUROPA, INVEST

Diabetes NKF-ADA Guideline, UKPDS,

ALLHAT

Chronic kidney disease NKF Guideline, Captopril Trial,

RENAAL, IDNT, REIN, AASK,

Recurrent stroke prevention PROGRESS

JNC-7 Guideline. Hypertension 2003.

 Setting/indication Class Level
To control blood pressure I A
Patients with heart failure, systolic left ventricular I A
dysfunction, diabetics, previous MI or stroke, high
coronary disease risk

Class I: Evidence and/or general agreement that a given procedure/treatment is

benefical, useful and effective
Level of Evidence A: Data derived from multiple randomised clinical trials or meta-
analyzes

Wood D, et al. Eur Heart J. 1998;19:1434-503

Chobanian AV, et al. JAMA 2003;289:2560-72
Enzyme binding differences
among ACE inhibitors

Dell’Italia LJ, Rocic P, Lucchesi PA. Curr Probl Cardiol 2002;27:6-34

Effects of an Angiotensin-Converting
Enzyme Inhibitor, Ramipril, on Death
from Cardiovascular Causes,
Myocardial Infarction, and Stroke in
High-Risk Patients
The Heart Outcomes Prevention Evaluation
(HOPE) Study Investigators

N Engl J Med, January 20, 2000

 HOPE - Background

• ACEIs improve the outcome in patients with

LV dysfunction, whether or not they have
symptomatic heart failure.
• This study assessed the role of an ACEI,
ramipril, in patients who were at high risk for
cardiovascular events but who did not have
LV dysfunction or heart failure.

N Engl J Med, January 20, 2000

 HOPE - Design
• A total of 9,297 high-risk patients, > 55 years old,
who had evidence of vascular disease or diabetes
plus one other cardiovascular risk factor and who
were not known to have a low EF or heart failure
were randomly assigned to receive ramipril (10 mg
per day) or matching placebo for a mean of 5 years.
• The primary outcome was a composite of MI, stroke
or death from cardiovascular causes. Each of these
endpoints were also analyzed separately.
• Secondary endpoints were death from any cause, the
need for revascularization, hospitalization for
unstable angina or heart failure, and complications
related to diabetes.
N Engl J Med, January 20, 2000
 HOPE - Kaplan-Meier Estimates of the
Composite Endpoint of CV Death, MI or Stroke
in the Ramipril and Placebo Groups
0,2
Ramipril
0,15 Placebo
% of Patients

P<0.001
0,1

0,05

0
0 500 1000 15000
Days of Follow-up
N Engl J Med, January 20, 2000
 HOPE - Primary Endpoint Results
25
22% Risk Reduction Ramipril
p<0.001
20 Placebo
17,7 16% Risk
20% Risk Reduction Reduction
% with an event

15 14,1 p=<0.001 p=0.006

25% Risk Reduction 12,2 12,2

p<0.001 9,9 10,4
10 8,1 31% Risk Reduction
0% Risk Reduction
p=<0.001
6,1 p=0.78
4,9 4,3 4,1
5 3,4

0
MI/Stroke/ CV Death MI Stroke Non CV Death Total
CV Death Mortality
N Engl J Med, January 20, 2000
 HOPE - Secondary and Other Endpoint
Results
25
16% Risk Reduction
p<0.001 Ramipril
20 18,6 Placebo
16 23% Risk Reduction
% with an event

p<0.001
15
16% Risk Reduction 11,7
p=0.03 9,2 32% Risk Reduction
10
7,4 13% Risk Reduction p=0.002
6,2 p=0.19
5,3
5 3,3 3,8 3,7

0
Revascularization DM HF Heart Failure New diagnosis of
Complications Hospitalization Diabetes Mellitus
N Engl J Med, January 20, 2000
 HOPE - Results in Patients with Diabetes
25 34% Risk Reduction
p=0.0007 Ramipril
19,6
20 Placebo

15,3
% with an event

15
38% Risk Reduction

9,6
10
6
5

0
MI/Stroke/CV Death CV Death

G. Dagenais, ESC 1999

 HOPE - BP Effects

Outcome Baseline Change at 1 Change at 2 Change at

(mmHg) month (mmHg) months (mmHg) (mmHg)

Ramipril SBP 139 -6.0 -3.0 -2.0

Placebo SBP 139 -2.0 0.00 0.00
Ramipril DBP 79 -3.0 -3.0 -3.00
Placebo DBP 79 -1.0 -1.0 -2.00

N Engl J Med, January 20, 2000

 HOPE - Summary of Results
• Patients randomized to ramipril had risk
reductions of:
– MI, stroke, CV death -22%
– CV death -25%
– MI -20%
– Stroke -31%
– Revascularization procedures* -16%
– New onset of diabetes -32%
*Revascularization procedures included PTCA, CABG or peripheral angioplasty
N Engl J Med, January 20, 2000
 HOPE - Summary of Results (continued)

• The beneficial effect of treatment with ramipril on the

composite outcome was consistently observed
among the following predefined subgroups:
– patients with and without diabetes
– men and women
– those with and without evidence of cardiovascular
disease
– those < 65 years of age and those > 65 year of
age
– those with and without hypertension at baseline*
– those with and without microalbuminuria
*A reduction of 2 mm Hg in diastolic blood pressure (as seen in this trial) might at best
account for about 40% of the reduction in the rate of stroke and about 25% of the reduction of MI.
N Engl J Med, January 20, 2000
 HOPE - Summary of Results (continued)

There was a clear benefit of ramipril among patients:

with and without evidence of coronary artery disease at
baseline
with and without a history of myocardial infarction
with a documented EF > 40% (27% risk reduction,
p<0.001)
Benefits were also observed whether or not patients
were also taking (at randomization):
ASA or other antiplatelet agents
beta-blockers
lipid-lowering agents
antihypertensive agents

N Engl J Med, January 20, 2000

 HOPE - Conclusions

• “Ramipril significantly reduces the rates of

death, myocardial infarction, and stroke in a
broad range of high-risk patients who are not
known to have a low ejection fraction or heart
failure”

N Engl J Med, January 20, 2000

HOPE for Patients with Diabetes
MICRO-HOPE
Substudy of HOPE focusing on
microalbuminuria, cardiovascular, and renal
outcomes in patients 55 or older with diabetes
Study objective: To assess whether the addition
of ramipril to the current medical regimens of
high-risk patients with diabetes can reduce the
risk of CV events
97% of the patients in MICRO-HOPE had T2DM

Data from: HOPE Study Investigators. Lancet. 2000;355:253-259.

MICRO-HOPE*: Primary Outcome
Reductions in Stroke, MI, and
CV Death
0.20
25%
Reduction Placebo
Proportion of Patients
Reaching End Points

0.15 in Events
P = 0.0004*
Ramipril
0.10
16%
0.05 Reduction
in Events
at 1 Year
0
0 500 1,000 1,500
Days of Follow-Up
*Trial halted early because of the highly significant risk reductions seen with ramipril.
Data from: HOPE Study Investigators. Lancet 2000; 355: 253-259.
MICRO-HOPE: Ramipril Significantly
Reduces Cardiovascular Morbidity
Ramipril Effects Beyond Baseline Therapy
• Aspirin • Diuretics
• Other Antiplatelet Agents • Beta-Blockers
• Lipid-Lowering Agents • Calcium-Channel Blockers
Nonfatal CV Total
Stroke MI Death Mortality
0
Risk Reduction (%)

-5
-10
-15
-20
-25 22%
*P = 0.0074
†
-30 24% †P = 0.01
§
-35 ‡P = 0.0001
33%
§P = 0.0004
-40 * 37%
‡
Data from: HOPE Study Investigators. Lancet 2000; 355: 253–259.
 Effects of Ramipril:
HOPE vs. MICRO-HOPE
HOPE MICRO-HOPE
40 37
35 32 33
30 26
24
25 22
20
20 16
15
10
5
0
Stroke Nonfatal CV Death Total
MI Mortality
Data from: HOPE Study Investigators. Lancet. 2000;355:253-259.
HOPE Study Investigators. N Engl J Med 2000; 342: 145-153.
 MICRO-HOPE
Only study to show improved
outcomes in diabetics with A II
Blockade.
RAMIPRIL EFFICACY IN NEPHROPATHY STUDY - REIN
The GISEN group*

The REIN study was designed to formally address the

hypothesis that glomerular protein traffic, and its
modification by an ACE inhibitor, influenced renal
disease progression in non-diabetic chronic
nephropathies

Comparison was made with conventional

antihypertensive treatment at comparable level of
systemic blood pressure control

* GISEN: Gruppo Italiano di Studi Epidemiologici in Nefrologia

49
REIN CORE: Interim analyses
Rate of GFR decline according to base-line proteinuria
- Interim analysis on 177 patients

p=0.001

0.89±0.11
1.0
Rate of GFR decline

Rate of GFR decline

(ml/min/month)

(ml/min/month)
p=0.0001
1.0 0.39±0.10
0.67±0.08 0.5

0.5
0.25±0.08
0
Conventional Ramipril

0
STRATUM - 1 STRATUM - 2
U. Prot. 1-3 g/24 h U. Prot. ≥ 3 g/24 h

Kidney survival: Conventional 54 % Ramipril 77 %

GISEN Group, Lancet, 1997
50
REIN CORE: Stratum 2
Renoprotection is associated with reduction of proteinuria

Systolic Blood Pressure Reduction in Proteinuria

on follow-up vs baseline
150 40
P < 0.002
140 20
mm Hg

130 0

%
120 -20

110 -40

100 -60
Placebo Ramipril Placebo Ramipril

GISEN group, Lancet, 1997

51
REIN CORE: Stratum 1

100
% of patients with ESRD

80

Conventional (18 events)

60

40 P = 0.01

20
Ramipril (9 events)
0
0 12 24 36 48 60 72
Follow up (months)

Ruggenenti et al., Lancet, 1999

52
REIN CORE - Stratum 1:
Follow Up BP and proteinuria

Systolic Blood Pressure Change in Proteinuria

on follow-up vs baseline
P = 0.003
150 40

140 20
mm Hg

130 0

%
120 -20

110 -40

100 -60
Placebo Ramipril Placebo Ramipril

GISEN group, Lancet, 1997

53
PROTEINURIA REDUCTION IS RENOPROTECTIVE
PER SE - I

All published trials with data were segregated in different subgroups

according to the response to different treatments:
- ACE inhibitor therapy
- BP reduction
- low-protein diet

The considered efficacy parameters were:

- reduction in proteinuria
- improved renal outcome - slower D GFR
- less doubling s. creat
- less ESRD

Ruggenenti et al., Lancet, 2004

54
 Reduction of Cardiovascular Risk by
Regression of Electrocardiographic
Markers of Left Ventricular Hypertrophy by
the Angiotensin-Converting Enzyme
Inhibitor Ramipril
Mathew J, et al. Circulation 2004;104;1618.
Change in Status of ECG Markers of LVH in
the Ramipril Group Compared With the
Placebo Group
 Use of ramipril in preventing
stroke: double blind randomised
trial
Bosch, et al. BMJ 2002;321:1-5.
 KaplanMeier estimates of the development of stroke by
treatment group. The relative risk of developing stroke in the
ramipril group compared with the placebo group was 0.68 (95%
confidence interval 0.56 to 0.84; P=0.0002)
Impact of ramipril on stroke based
on baseline blood pressure
 SUMMARY

RAMIPRIL :
 An ACEi
 Unique combination of several properties (a high tissue
ACE affinity and long duration of action)
 Has a wide range of effects:
 vasodilatory,  antiischemic,
 hemodynamic,  antiatherogenic, &
 cardiovascular remodeling  antithrombotic actions